Community Practice Connections™: Optimizing Outcomes in VTE Management: Collaborating Across the Continuum
December 23, 2020
December 23, 2021
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This activity is provided by Physicians’ Education Resource®, LLC.
This activity is supported by educational grants from Bristol Myers Squibb-Pfizer Alliance.
- Physicians — maximum of 1.50 AMA PRA Category 1 Credit(s)™
All other health care professionals completing this course will be issued a statement of participation.
This educational program is directed toward cardiologists and cardiology subspecialists. Nurse practitioners, physician assistants, nurses, and other health care professionals involved in the treatment and management of patients with VTE are also invited to participate.
This online educational activity features 2 physicians from different disciplines, both renowned experts in the management of venous thromboembolism (VTE). They discuss keys to prompt recognition and accurate diagnosis of VTE, with the goal of establishing early therapeutic intervention and prevention of recurrence. It is important for community physicians to recognize VTE in its early stages and to effectively employ anticoagulant therapies to prevent serious complications. Establishment of prophylactic care plans is essential for preventing recurrent VTE episodes.
Upon completion of this activity, participants should be better able to:
- Demonstrate appropriate, guideline-based decision-making related to the selection, initiation, and duration of pharmacotherapy for patients with VTE
- Analyze the clinical efficacy and safety findings that support pharmacotherapy recommendations in VTE treatment guidelines
- Apply best practices for transitions of care (ToC) across health care settings for patients with DVT, incorporating interdisciplinary collaboration and use of tools and resources
- Discuss key educational and counseling messages with patients and their caregivers to optimize treatment adherence and patient safety
Charles Vega, MD, FAAFP
Health Sciences Clinical Professor
Department of Family Medicine
Assistant Dean for Culture and Community Education
UC Irvine School of Medicine
Director, UC Irvine Program in Medical Education for the Latino Community
University of California, Irvine
Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC
Executive Director of Interventional Cardiovascular Programs
Brigham and Women’s Hospital Heart & Vascular Center
Professor of Medicine
Harvard Medical School
Physicians’ Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Physicians’ Education Resource®, LLC designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Disclosures of Conflicts of Interest
In accordance with ACCME guidelines, PER® has identified and resolved all conflicts of interest for faculty, staff, and planners prior to the start of this activity by using a multistep process.
Charles Vega, MD, FAAFP
- No relevant financial relationships with commercial interests to disclose.
Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC
- Grant Research Support/Research Funding: Amarin, Amgen, AstraZeneca, Bristol Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood Pharmaceuticals, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi-Aventis, The Medicines Company
The staff of Physicians’ Education Resource®, LLC (PER®), have no relevant financial relationships with commercial interests to disclose.
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This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this accredited activity is for continuing education purposes only and is not meant to substitute for the independent clinical judgment of a healthcare professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any company that provided commercial support for this activity.
Module 1: Overview of Anticoagulation Therapy for VTE
Venous thromboembolism (VTE) most commonly manifests in the large veins of the legs or pelvis and presents as deep vein thrombosis (DVT). The term VTE also encompasses pulmonary embolism (PE), which occurs when thrombi dislodge from clots in vein walls and travel through the heart to pulmonary arteries. VTE events affect as many as 900,000 Americans and cause approximately 100,000 premature deaths.1 Approximately 50% of VTE events are related to hospitalizations and surgery, and most of them manifest post-hospital discharge.2 As many as 70% of cases of recurrent VTE could be prevented with anticoagulant therapy, but less than half of hospitalized people receive VTE prophylaxis.3
What are the key presenting symptoms of VTE that physician’s need to be aware of?
Virchow’s triad describes three physiological characteristics that may increase the risk of VTE: hypercoagulability, stasis, and endothelial injury. Hypercoagulability can occur because of pregnancy, oral contraceptives, estrogen replacement therapy, cancer, chemotherapy, and inherited thrombophilias (eg, protein C and protein S deficiencies, antithrombin deficiency, and antiphospholipid syndrome).4 Venous stasis can result from atrial fibrillation, valvular heart disease, prolonged immobility, surgery, and trauma.5,6 Endothelial wall injury due to smoking, chronically elevated blood pressure, and atherosclerotic disease affects blood flow, which can lead to VTE.6
What are the obvious and not so obvious risk factors for VTE?
A systematic review of 7 randomized controlled trials that included 1922 patients assessed the safety and effectiveness of managing people with DVT or PE at home vs in the hospital. It found that low-risk patients who present with an acute uncomplicated DVT can be treated and monitored effectively as outpatients. There is uncertainty, however, about outcomes for home vs hospital treatment for those with PE.4
When do you decide to admit someone for acute VTE as opposed to discharging them home for outpatient care of VTE?
Several anticoagulant therapies are approved for the treatment of VTE in the acute setting, as well as for long-term and short-term prophylaxis (Table).
Table. Anticoagulant Therapy For Treatment and Prevention of VTE
Initial treatment of acute VTE traditionally utilizes unfractionated heparin (UFH), LMWH, or fondaparinux. Heparin inactivates thrombin and activated factor X (factor Xa). By inactivating thrombin, it prevents both fibrin formation and thrombin-induced activation of platelets and factors V and VII. UFH can be administered as a continuous intravenous (IV) infusion or subcutaneous injection and has a faster onset of anticoagulant action than LMWH.7 LMWH is a small fragment of heparin that is administered subcutaneously. It activates antithrombin III which, in turn, inhibits factor Xa and prevents activation of the final common pathway—the conversion of fibrinogen to fibrin.8 Fondaparinux is a synthetic pentasaccharide that targets antithrombin III to selectively inhibit factor Xa and disrupt the coagulation cascade. It is administered subcutaneously and has the advantage of a lower risk of heparin-induced thrombocytopenia (HIT) compared with UFH or LMWH.9
Until direct oral anticoagulants (DOACs) arrived in 2010, warfarin was the only oral anticoagulant available for the outpatient treatment of VTE and other clotting disorders for almost 60 years. Warfarin is a vitamin K antagonist (VKA) that targets the vitamin K epoxide reductase complex 1 (VKORC1). Through inhibition of VKORC1, warfarin reduces the synthesis of active coagulation factors including II, VII, IX, and X.10
Compared with warfarin, DOACs inhibit one clotting factor, either thrombin or factor Xa, in the coagulation cascade.11 The benefits of DOAC therapy compared with warfarin include a fixed dosing schedule that reduces the need for laboratory monitoring and fewer drug-food interactions. Both classes of anticoagulants carry a risk of bleeding; unlike warfarin, most DOACs do not have a reversal agent.
Can you talk about the advantages and disadvantages of outpatient anticoagulation prophylaxis?
Clinical trials of DOAC therapy have shown similar or superior efficacy compared with other VTE treatments and a decreased risk of bleeding. Betrixaban is the most recent DOAC to be approved and is the only oral anticoagulant approved for VTE prophylaxis in acutely ill hospitalized patients. The approval is based on results of the APEX trial, which compared extended-duration betrixaban to short-duration enoxaparin (a LMWH) for prevention of VTE in acutely ill hospitalized patients at risk for VTE. The primary outcome of this trial was analyzed in a hierarchical fashion: first in those with elevated D-dimer level (cohort 1), those with an elevated D-dimer level or an age of at least 75 years (cohort 2), and the overall patient cohort of the entire study population. There was no significant difference between extended duration betrixaban and a standard regimen of enoxaparin in the primary outcome of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism in patients with elevated D-dimer levels, but evidence suggested a benefit for betrixaban in the larger cohorts.12
The RE-COVER and RE-COVER II trials compared 6 months of dabigatran at a fixed dose of 150 mg twice daily with dose-adjusted warfarin therapy for acute VTE treatment after prior therapy with LMWH or UFH. Recurrent VTE or death during 6 months of treatment was similar between groups, but the occurrence of bleeding was lower for dabigatran (HR, 0.70; 95% CI, 0.61-0.79).13 The net clinical benefit from these two trials, in addition to results of the RE-MEDY (active-controlled) and RE-SONATE (placebo-controlled) trials, showed superiority of dabigatran with regards to major bleeding events and bleeding outcomes compared with warfarin (RE-COVER/RE-COVER II: HR, 0.80; 95% CI, 0.68-0.95; RE-MEDY: HR, 0.73; 95% CI, 0.59-0.91).14 Dabigatran is approved for the treatment of VTE in those who have received 5 to 10 days of prior parenteral anticoagulation to reduce recurrence.
The EINSTEIN trial of rivaroxaban and standard therapy of enoxaparin followed by VKA, reported noninferior efficacy of rivaroxaban in terms of recurrent VTE (36 events [2.1%] versus 51 events with enoxaparin-VKA [3.0%]; HR, 0.68; 95% CI, 0.44-1.04; P < .001), major bleeding, or clinically relevant nonmajor bleeding events.15 The EINSTEIN-PE trial of acute symptomatic PE with or without DVT also showed noninferior efficacy of rivaroxaban (HR, 1.12; 95% CI, 0.75-1.68), but fewer major bleeding events occurred compared with the standard therapy group.16 When rivaroxaban was administered for an extended period in patients hospitalized for acute medical illness, it was noninferior to enoxaparin, reduced the risk of thromboembolisms, and was associated with an increased risk of bleeding.17 Rivaroxaban is approved for preventing VTE in hospitalized acutely ill patients at risk for VTE complications and with low risk of bleeding.
The AMPLIFY trial evaluated apixaban versus enoxaparin followed by warfarin in acute VTE and recurrent VTE or death (relative risk [RR], 0.84; 95% CI, 0.60-1.18, P < .001), risk of major bleeding, and nonmajor bleeding events were all lower in the apixaban group.18 Apixaban is approved for prevention of VTE in the setting of hip or knee replacement surgery, treatment of VTE, and reducing risk of recurrent VTE following initial therapy. The potential of apixaban for prevention of VTE in hospitalized patients and an extended course post-hospital discharge was investigated in the ADOPT clinical trial and was not superior to a shorter course of enoxaparin and had more major bleeding events.19
The Hokusai-VTE trial compared edoxaban with warfarin for VTE treatment over 3 to 12 months. Edoxaban was reported to be noninferior to warfarin in terms of efficacy (HR, 0.89; 95% CI, 0.70-1.13; P = .004), and fewer bleeding events occurred in the edoxaban group.20 Edoxaban is approved for VTE treatment in those initially treated with parenteral anticoagulation for 5 to 10 days.
The benefits of anticoagulation for prevention of recurrent VTE should be carefully weighed against the risk of bleeding and other risks to determine the best choice and duration for each individual patient.
How does cost and socio-economic factors weigh into choice of therapy?
- Venous thromboembolism (blood clots). Centers for Disease Control and Prevention. Updated January 7, 2020. Accessed December 15, 2020. https://www.cdc.gov/ncbddd/dvt/ha-vte-data.html
- Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med. 2007;167(14):1471-1475. doi:10.1001/archinte.167.14.1471
- Lau BD, Haut ER. Practices to prevent venous thromboembolism: a brief review. BMJ Qual Saf. 2014;23(3):187-195. doi:10.1136/bmjqs-2012-001782
- Monie DD, DeLoughery EP. Pathogenesis of thrombosis: cellular and pharmacogenetic contributions. Cardiovasc Diagn Ther. 2017;7(suppl 3):S291-S298. doi:10.21037/cdt.2017.09.11
- Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet. 2009;373(9658):155-166. doi:10.1016/S0140-6736(09)60040-4
- Chung I, Lip GY. Virchow’s triad revisited: blood constituents. Pathophysiol Haemost Thromb. 2003;33(5-6):449-454. doi:10.1159/000083844
- Hirsh J, Anand SS, Halperin JL, Fuster V. Mechanism of action and pharmacology of unfractionated heparin. Arterioscler Thromb Vasc Biol. 2001;21(7):1094-1096. doi:10.1161/hq0701.093686
- Mulloy B, Hogwood J, Gray E, Lever R, Page CP. Pharmacology of heparin and related drugs. Pharmacol Rev. 2016;68(1):76-141. doi:10.1124/pr.115.011247
- Paolucci F, Claviés MC, Donat F, Necciari J. Fondaparinux sodium mechanism of action: identification of specific binding to purified and human plasma-derived proteins. Clin Pharmacokinet. 2002;41(suppl 2):11-18. doi:10.2165/00003088-200241002-00002
- Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation. 2003;107(12):1692-1711. doi:10.1161/01.CIR.0000063575.17904.4E
- Riley P, Maan A, Korr KS. Direct oral anticoagulants (DOACs): current status among distinct patient subgroups. R I Med J (2013). 2017;100(5):18-22.
- Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016;375(6):534-544. doi:10.1056/NEMoa1601747
- Schulman S, Kakkar AK, Goldhaber SZ, et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-772. doi:10.1161/CIRCULATIONANAHA.113.0044450
- Feuring M, Schulman S, Eriksson H, et al. Net clinical benefit of dabigatran vs. warfarin in venous thromboembolism: analyses from RE-COVER, RE-COVER II, and RE-MEDY. J Thromb Thrombolysis. 2017;43(4):484-489. doi:10.1007/s11239-017-1479-z
- Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. doi:10.1056/NEJMoa1007903
- Büller HR, Prins MH, Lensin AWA, et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297. doi:10.1056/NEJMoa1113572
- Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368(6):513-523. doi:10.1056/NEJMoa1111096
- Agnelli G, Buller HR, Cohen A et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808. doi: 10.1056/NEJMoa1302507
- Goldhaber SZ, Leizorovicz A, Kakkar AK et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011;365:2167-2177. doi: 10.1056/NEJMoa1110899
- Büller HR, Décousus H, Grosso MA, et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-1415. doi:10.1056/NEJMoa1306638
Module 2: Guidelines for VTE Treatment and Prevention
To help in clinical decision making, several guidelines provide recommendations on the management of VTE, including those from the American College of Chest Physicians (ACCP), American Society of Clinical Oncology (ASCO), and American Society of Hematology (ASH).
Updates to the 2016 ACCP guidelines include recommendations for VTE in the oncology setting and highlight preference for long-term anticoagulant therapy with LMWH over VKA and DOAC therapies. For people without cancer, DOAC therapy is recommended over VKA therapy and VKA is preferred over LMWH. Other updates include statements regarding mechanical prophylaxis, monitoring, and therapy for recurrent VTE.5
ASCO has also updated recommendations for preventing and treating VTE in people with cancer and now states that prophylaxis with apixaban, rivaroxaban, or LMWH can be used for high-risk outpatients in this setting but is still not recommended for routine use in all patients with cancer. Other changes include addressing brain metastases in the VTE treatment section and expanding long-term postoperative LMWH.6
ASH developed several recommendations for initial management of VTE, primary treatment, secondary prevention, and treatment of recurrent VTE events. The Society strongly recommends anticoagulant therapy for individuals with PE and hemodynamic compromise; an internal normalized ratio (INR) range of 2.0 to 3.0 for those taking VKA for secondary prevention; and lifelong anticoagulation for recurrent or unprovoked VTE. Conditional recommendations include home treatment versus hospitalization for patients with uncomplicated DVT and PE at low-risk for complications, and DOACs over VKA for primary treatment.7
While there are differences in recommendations across guidelines, all have the goal of preventing recurrent VTE and reducing hospital readmissions. In the following videos, Dr Vega explains practical considerations of anticoagulant therapy choice in clinical practice.
How does choice of anticoagulation differ in the acute versus chronic settings?
How does choice of therapy differ for frail patients versus fit patients?
Does gender influence choice of therapy?
- Amin AN, Varker H, Princic N, Lin J, Thompson S, Johnston S. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med. 2012;7(3):231-238. doi:10.1002/jhm.1002
- Hull RD, Schellong SM, Tapson VF, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010;153(1):8-18. doi:10.7326/0003-4819-153-1-201007060-00004
- Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368(6):513-523. doi:10.1056/NEJMoa1111096
- Khatib R, Ross S, Kennedy SA, et al. Home vs hospital treatment of low-risk venous thromboembolism: a systematic review and meta-analysis. Blood Adv. 2020;4(3):500-513. doi:10.1182/bloodadvances.2019001223
- Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease CHEST guideline and expert panel report. Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026
- Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020;38(5):496-520. doi:10.1200/JCO.19.01461
- Ortel TL, Neumann I, Ageno W et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738. doi:10.1182/bloodadvances.2020001830
Module 3: Best Practices for Transitions of Care
It is critically important to optimize the transition of care from inpatient to outpatient settings for people who will be taking extended anticoagulation for VTE prophylaxis. Several barriers to successful transition of care have been highlighted at the system, clinical, and patient levels of the process1:
- System level
- Lack of standardized transition process outside of the hospital settings
- Suboptimal capture and communication of key anticoagulation information
- Clinical level
- Inadequate knowledge of risks and benefits of anticoagulation therapy
- Lack of familiarity with practical management of anticoagulation therapy
- Patient level
- Low health literacy
- Socioeconomic status
- Lack of confidence or comprehension
Core tenets of transition of care models for patients receiving VTE prophylaxis:
- Upstream identification and resolution of barriers to care
- Standardized, multidisciplinary processes that use evidence-based practices
- Patient empowerment/education and confirmation of comprehension
- Timely follow-up
- Consistent, accurate medication reconciliation
- Capture and consolidation of key anticoagulation information
- Timely handoff communication
What are important considerations and steps to follow when transitioning care to an outpatient clinician?
What would you say are the keys to success when transitioning care at your center?
Regarding the communication aspect of optimizing transition of care, a recent panel reached consensus on a list of 12 requisite data elements (RDEs) for anticoagulation communication at discharge2:
- Anticoagulant(s) currently used
- Indication(s) for anticoagulation therapy
- Whether the patient is new to anticoagulation or is a previous user
- Start date of anticoagulation (if a patient is a new user)
- Whether treatment for each indication is intended to be acute (short-term) or chronic (long-term)
- Intended duration of therapy
- Date, time, route, dose, and strength of the last 2 doses of anticoagulant given
- Date, time, and magnitude of next dose due
- Most recent assessment of renal function within past 30 days, with date and results
- Documentation of the provision of patient education materials about the anticoagulant
- Assessment of patient/caregiver understanding of their anticoagulation regimen
- If transitioning to a noninstitutionalized setting, expectations for who is responsible for ongoing anticoagulation management
What do you tell your patients about living with VTE and what signs and symptoms should prompt them to seek medical care?
Improved outcomes have been reported when patients take responsibility, understand, and adhere to an anticoagulation plan of care. Elements of education include information about their medication (eg, how it works, how it should be taken); common side effects, signs and symptoms of bleeding and thrombosis; how to access care; monitoring details; diet and lifestyle recommendations; and importance of medication adherence.3
Shared decision-making is another important element for improving treatment adherence and can be accomplished by introducing choice, describing options, and helping patients explore their options and make decisions based on their preferences and lifestyle needs.4
How do you promote medication adherence, and can you give an example from your clinical experience?
Do you recommend PE/DVT support groups for patient outcomes?
- Burnett AE, Mahan CE, Vazquez SR, Oertel LB, Garcia DA, Ansell J. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016;41(1):206-232. doi:10.1007/s11239-015-1310-7
- Triller D, Myrka A, Gassler J, et al. Defining minimum necessary anticoagulation-related communication at discharge: consensus of the care transitions task force of the New York state anticoagulation coalition. Jt Comm J Qual Patient Saf. 2018;44(11):630-640. doi:10.1016/j.jcjq.2018.04.015
- Nutescu EA, Wittkowsky AK, Burnett A, Merli GJ, Ansell JE, Garcia DA. Delivery of optimized inpatient anticoagulation therapy: consensus statement from the anticoagulation forum. Ann Pharmacother. 2013;47(5):714-724. doi:10.1345/aph.1R634
- Elwyn G, Frosch D, Thomson R, et al. Shared decision making: a model for clinical practice. J Gen Intern Med. 2012;27(10):1361-1367. doi:10.1007/s11606-012-2077-6
Module 4: Impact of COVID-19 Pandemic on VTE Management
The coronavirus disease of 2019 (COVID-19) has impacted healthcare in a myriad of ways.
What has been the impact of the pandemic on your clinical practice?
How do you think the pandemic will influence the future of your practice?