Pulmonary embolism (PE) is a common medical condition affecting over 250,000 patients in the United States each year.¹ For those patients diagnosed with PE in whom therapeutic anticoagulation is deemed appropriate, current guidelines recommend an initial treatment period of 3 months.² However, extending the duration of anticoagulation beyond this initial period requires careful consideration of multiple factors.

Identifying Provoked vs. Unprovoked PE

Identifying patients who may benefit from extended anticoagulation requires a careful history that permits clinicians to classify a PE as either provoked or unprovoked. Provoking conditions can be then classified into transient and persistent risk factors (Table 1).³ This classification is vital because it is the key driver in determining risk of recurrence. Of note, history of long-distance travel is a question commonly asked of those patients presenting with PE; however, only flights with a duration greater than 12 hours have been associated with increased incidence of venous thromboembolism (VTE).⁴

Table 1: Provoked and Unprovoked Conditions Related to VTE

Provoked Conditions

Major surgery with general anesthesia >30 minutes

Pregnancy, particularly with cesarean delivery

Lower limb plaster cast

Short-term immobilization for >3 days

Prolonged air travel for >12 hours

Hormonal contraception

Hormone replacement therapy

Acute infectious disease

Direct trauma to the leg

Unprovoked or Persistent Risk Factors

Collagen vascular diseases

Antiphospholipid syndrome

Active cancer

Myeloproliferative disorders

Thrombophilia

Current guidelines recommend patients with provoked PE or those with transient risk factors, such as major surgery or immobilization, be treated for a duration of 3 months. This is driven by the fact that the risk for recurrent VTE in these patients is 1% in the first year after stopping anticoagulation and 0.5% per year after.² As long as patients with provoked PE return to their pre-PE baseline, anticoagulation can be stopped after this initial 3-month treatment. Conversely, indefinite anticoagulation is recommended in those patients with unprovoked PE or persistent risk factors. In those with unprovoked PE who elect to stop indefinite anticoagulation, the risk for recurrent VTE is 10% in the first year after stopping anticoagulation and 5% per year after.² Although indefinite treatment is recommended in these patients, it is important to reassess the risks and benefits of ongoing anticoagulation at regular intervals.

Special Patient Populations

Consistent with therapeutic anticoagulation for other disease processes, the benefit of treatment must be weighed against the risk of bleeding. As discussed above, the benefit of anticoagulation is directly related to the risk of recurrence of PE, and patients with unprovoked VTE are at high risk for recurrence if anticoagulation is stopped. Though not necessary for most patients, several tools including the HERDOO2 rule, DASH prediction score, and Vienna Prediction Model have been proposed to better quantify the risk of recurrent VTE after stopping anticoagulation in those patients with unprovoked VTE (Table 2). Male sex and an elevated D-dimer either during or just after discontinuing therapeutic anticoagulation is associated with a higher risk of recurrent VTE (>5% per year) and merit ongoing treatment.^5-10

Table 2: Risk Assessment Tools for VTE Recurrence

Risk Assessment Tool	Factors	Points	Total Score	Annual Risk of Recurrence
HERDOO25,6	Post-thrombotic signs (hyperpigmentation, edema or redness of either leg)	1	0–4	Men: 8.4-13.7%
	D-dimer level >250 µg/L (during anticoagulation)	1		Women with score <2: 1.6-3.0%
	Body mass index ≥30 kg/m2	1		Women with score 2: 7.4-14.1%
	Age ≥65 years	1
DASH7,8	D-dimer level abnormal 1 month after stopping anticoagulation	2	-2 to 4	Score 1: 0.5-5.3%
	Age ≤50 years	1		Score 2: 6.4-6.7%
	Male	1		Score 3: 6.8-12.3%
	Hormone use at VTE onset (female only)	-2
Vienna Prediction Model9,10	Sex	NA	0-350	2-15%, depending on nomogram-based score
	Location of VTE	NA
	D-dimer level elevated  3 weeks after stopping anticoagulation	NA

The risk for bleeding complications while on anticoagulation should be considered in all patients who are recommended indefinite anticoagulation. There are several validated tools that can be used to assess bleeding risk; however, many were developed by analyzing patients with atrial fibrillation on warfarin. Thus, these tools may not accurately reflect bleeding risk in patients with VTE or in whom a direct oral anticoagulant is used.¹¹ For those patients deemed to have a high bleeding risk (Table 3) and unprovoked PE or persistent risk factors, current guidelines recommend against extended therapy.² However, the decision to continue anticoagulation in patients with unprovoked PE and moderate or low risk of bleeding requires further analysis and discussion of the patient's values.

Table 3: Risk Factors for Bleeding With Anticoagulation and Estimated Risk of Bleeding²

Risk Factors
Age >65 years
Age >75 years
Previous bleeding
Cancer
Metastatic cancer
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
Categorized Risk of Bleeding
	Estimated Risk of Bleeding
	Low Risk (0 Risk Factors)	Moderate Risk (1 Risk Factor)	High Risk (≥2 Risk Factors)
Anticoagulation 0-3 months
Baseline risk (%)	0.6	1.2	4.8
Increased risk (%)	1	2	8
Total risk (%)	1.6	3.2	12.8
Anticoagulation after first 3 months
Baseline risk per year (%)	0.3	0.6	≥2.5
Increased risk per year (%)	0.5	1	≥4.0
Total risk per year (%)	0.8	1.6	≥6.5

Given its role as a persistent risk factor, patients with active cancer are also recommended to continue indefinite anticoagulation.^3,12 Current data favor low-molecular-weight heparin over vitamin K antagonists;¹³ however, ongoing studies are analyzing the safety and efficacy of direct oral anticoagulants in this patient population.

Finally, patients presenting with persistent unexplained dyspnea or exercise intolerance 6 months after a PE merit ongoing anticoagulation while additional workup is undertaken. Although these symptoms can be related to underlying comorbidities, patients should be assessed for the presence of new onset pulmonary vascular disease and chronic thromboembolic pulmonary hypertension because these disease processes not only increase the risk for recurrent VTE but can also be more effectively managed if identified early on.¹⁴

Alternate Treatment Strategies

Current guidelines indicate that the choice of anticoagulant in the early phase of treatment can be continued for extended therapy. However, there are alternate medication and dosing options available to patients who require indefinite anticoagulation. In appropriate patient populations, such as those without active cancer or renal insufficiency, direct-acting oral anticoagulants can be considered for extended therapy given the relative reduction in bleeding risk over vitamin K antagonists.² Additionally, the AMPLIFY-EXT (Apixaban After the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis With First-Line Therapy–Extended Treatment) trial and EINSTEIN-CHOICE (Reduced-Dosed Rivaroxaban in the Long-Term Prevention of Recurrent Symptomatic Venous Thromboembolism) trial showed comparable rates of VTE recurrence between higher and lower doses of apixaban (5 mg vs. 2.5 mg) and rivaroxaban (20 mg vs. 10 mg), respectively, suggesting lower-dose options can also be considered.^15,16 If patients with unprovoked PE elect to discontinue anticoagulant treatment entirely, the use of aspirin 81 mg daily may be benefical in reducing major vascular events by about one-third compared with placebo, but aspirin does not reduce the recurrence of PE.¹⁷ Thus, it is important to counsel patients that the use of oral anticoagulants versus aspirin alone reduces the risk of recurrent VTE by approximately 81-92%.^18,19

Follow-Up After Discontinuation of Anticoagulation

For many patients, the decision to stop anticoagulation after the initial treatment course is dictated by concerns regarding anticoagulation and its interference in their daily lives. If a patient with an unprovoked PE and thus higher risk for recurrence elects to discontinue anticoagulation, routine follow-up and serial D-dimer testing at 2-3 weeks and then again at 1-2 months after stopping treatment are recommended. Those patients with elevated D-dimer on follow-up testing should be advised of the ongoing risk of VTE recurrence off anticoagulation. Among patients with elevated D-dimer levels after initial anticoagulation, those who discontinue anticoagulation have an increased hazard ratio for VTE recurrence of 2.27 (95% confidence interval, 1.15-4.46; p = 0.02) compared with those who continued anticoagulation.¹⁹ Additionally, although the presence of a hypercoagulable disorder such as antiphospholipid antibody syndrome, protein C deficiency, or protein S deficiency does not significantly increase the already high risk of recurrence in patients with unprovoked VTE, it is reasonable to test for these disorders during the period after discontinuing anticoagulation so as to best inform the patient's decision.²¹

Key Points

1. Patients diagnosed with PE who are deemed appropriate candidates for therapeutic anticoagulation should be treated for an initial period of 3 months.
2. In general, those patients with unprovoked PE or those with persistent risk factors should be considered for indefinite anticoagulation with routine follow-up to assess ongoing benefit.
3. Validated tools exist to quantify risk of recurrent VTE and may be helpful in patients with unprovoked PE who have an intermediate bleeding risk or in those who choose to discontinue anticoagulation.
4. Serial D-dimer testing is a useful tool to detect recurrence and inform the decision to restart anticoagulation after the initial 3-month period in patients with unprovoked PE.
5. Patients with unexplained persistent dyspnea or exercise intolerance merit ongoing anticoagulation while undergoing workup for new onset pulmonary vascular disease such as chronic thromboembolic pulmonary hypertension.

References

1. Heit JA. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost 2005;3:1611-7.
2. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-52.
3. Kearon C, Ageno W, Cannegieter SC, et al. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016;14:1480-3.
4. Kuipers S, Cannegieter SC, Middeldorp S, Robyn L, Büller HR, Rosendaal FR. The absolute risk of venous thrombosis after air travel: a cohort study of 8,755 employees of international organisations. PLoS Med 2007;4:e290.
5. Rodger MA, Le Gal G, Anderson DR, et al. Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. BMJ 2017;356:j1065.
6. Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008;179:417-26.
7. Tosetto A, Iorio A, Marcucci M, et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012;10:1019-25.
8. Tosetto A, Testa S, Martinelli I, et al. External validation of the DASH prediction rule: a retrospective cohort study. J Thromb Haemost 2017;15:1963-70.
9. Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 2010;121:1630-6.
10. Tritschler T, Méan M, Limacher A, Rodondi N, Aujesky D. Predicting recurrence after unprovoked venous thromboembolism: prospective validation of the updated Vienna Prediction Model. Blood 2015;126:1949-51.
11. Barnes GD, Kanthi Y, Froehlich JB. Venous thromboembolism: Predicting recurrence and the need for extended anticoagulation. Vasc Med 2015;20:143-52.
12. Kearon C, Spencer FA, O'Keeffe D, et al. D-dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy: a cohort study. Ann Intern Med 2015;162:27-34.
13. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-53.
14. Wan T, Rodger M, Zeng W, et al. Residual pulmonary embolism as a predictor for recurrence after a first unprovoked episode: Results from the REVERSE cohort study. Thrombosis Res 2018;162:104-9.
15. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708.
16. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med 2017;376:1211-22.
17. Brighton TA, Eikelboom JW, Mann K, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012;367:1979-87.
18. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709-18.
19. Winters JP, Morris CS, Holmes CE, et al. A multidisciplinary quality improvement program increases the inferior vena cava filter retrieval rate. Vasc Med 2017;22:51-6.
20. Palareti G, Cosmi B, Legnani C, et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006;355:1780-9.
21. Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010;149:209-20.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Pulmonary Hypertension, Hypertension

Keywords: Warfarin, Anticoagulants, Venous Thromboembolism, Risk Factors, Heparin, Low-Molecular-Weight, Aspirin, Protein C Deficiency, Protein S Deficiency, Atrial Fibrillation, Antiphospholipid Syndrome, Vitamin K 2, Follow-Up Studies, Pyridones, Pyrazoles, Pulmonary Embolism, Venous Thrombosis, Risk Assessment, Renal Insufficiency, Hypertension, Pulmonary, Comorbidity, Dyspnea, Neoplasms

< Back to Listings