Pulmonary embolism (PE), can be life-threatening without rapid appropriate therapy and often leads to chronic disease and disability. The ambiguity of symptoms makes PE difficult to diagnose, and available imaging strategies have their limitations. Treatment options for acute PE include fibrinolytics, surgical embolectomy, catheter-directed treatment, or vena cava filter placement as well as traditional parenteral anticoagulants, used alone or as a bridge to a vitamin K antagonist (VKA). The direct oral anticoagulants (DOACs) rivaroxaban and apixaban allow for single drug therapy, eliminating the need for initial parenteral anticoagulation, while dabigatran and edoxaban are initiated after a short course of parenteral therapy. The DOACs serve as a viable alternative to warfarin for chronic management for PE. Pulmonary embolism provoked from transient risk factors often requires a short-term course of anticoagulation (3 months). Unprovoked events, and those that occur in the presence of continuing risk factors such as cancer, or clinical markers such as residual vein thrombosis and elevated d-dimers can predict a higher risk of recurrent events and warrant extended anticoagulation. This review evaluates current recommendations for the treatment of PE, including dosing strategies, duration of therapy, and special populations such as renal impairment, malignancy, and obesity.
KahnSRComerotaAJCushmanM. on behalf of the American Heart Association Council on Peripheral Vascular Disease, Council on Clinical Cardiology, and Council on Cardiovascular and Stroke Nursing. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2014;130:1636–1661.
2.
Deep Vein Thrombosis/Pulmonary Embolism Data and Statistics. Division of Blood Disorders National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. http://www.cdc.gov/ncbddd/dvt/data.html. Published June 22, 2015. Accessed November 5, 2015.
3.
GouldMKGarciaDAWrenSM. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e227S–e277S.
4.
KahnSRLimWDunnAS. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e195S–e226S.
5.
Falck-YtterYFrancisCWJohansonNA. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e278S–e325S.
6.
PrandoniPNoventaFGhirarduzziA. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1626 patients. Haematologica. 2007;91(2):199–205.
7.
KonstantinidesSVTorbickiAAgnelliG. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) Endorsed by the European Respiratory Society (ERS). Eur Heart J. 2014;35(43):3033–3069, 3069a–3069k.
8.
JaffMRMcMurtrySArcherSL. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension. A scientific statement from the American Heart Association. Circulation. 2011;23:1788–1830.
9.
MartiCJohnGKonstantinidesSV. Systematic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2015;36(10):605–614.
10.
MeyerGVicautEDanaysT. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402–1411.
11.
KucherNBoekstegersPMullerOJ. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129(4):479–486.
12.
PiazzaG. A prospective, single-arm, multicenter trial of ultrasound-facilitated, low-dose fibrinolysis for acute massive and submassive pulmonary embolism. http://www.clinicaltrials.gov. NCT01513759. Published June 11, 2013. Accessed November 5, 2015.
13.
SteinPDMattaFKeyesDC. Impact of vena cava filters on in-hospital case fatality rate from pulmonary embolism. Am J Med. 2012;125(5):478–484.
14.
MurielAJimenezDAujeskyD. Survival effects of inferior vena cava filter in patients with acute symptomatic pulmonary embolism and a significant bleeding risk. J Am Coll Cardiol. 2014;63(16):1675–1683.
15.
DecoususHLeizoroviczAParentF. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7):409–415.
16.
PREPIC study group. Eight year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC randomized study. Circulation. 2005;112(3):416–422.
17.
KearonCAklEAComerotaAJ. American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e419S–e94 S.
18.
AgenoWGallusASWittkowskyA. American College of Chest Physicians. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e44S–e88S.
19.
HullRDGershMH. The current landscape of treatment options for venous thromboembolism: a focus on novel oral anticoagulants. Curr Med Res Opin. 2015;31(2):197–210.
20.
HolbrookASchulmanSWittDM. Evidence-based management of anticoagulant therapy. Chest. 2012;141(2 suppl):e152S–e184S.
21.
GarciaDABaglinTPWeitzJI. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e24S–e43S.
22.
QuinlanDJMcQuillanAEikelboomJW. Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2004;140(3):175–183.
MerliGSpiroTEOlssonCG. for the Enoxaparin Clinical Trial Group. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001;134(3):191–202.
25.
The Matisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349(18):1695–1702.
26.
SchulmanSKakkarAKGoldhaberSZ; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764–772.
27.
BüllerHRPrinsMHLensinAW; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287–1297.
28.
PrinsMHLensingAWBauersachsR. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11(1):21.
29.
AgnelliGBullerHRCohenA; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808.
30.
BüllerHRDécoususHGrossoMA; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;9(15):1406–1415.
31.
PrinsMHBamberLCanoSJ. Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of pulmonary embolism; results from the EINSTEIN PE trial. Thromb Res. 2015;135(2):281–288.
32.
CastellucciLACameronCLe GalG. Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA. 2014;312(11):1122.
33.
KimmelSEFrenchBKasnerSE. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013;369(24):2283–2293.
34.
PirmohamedMBurnsideGErikssonN. A randomized trial of genotype- guided dosing of warfarin. N Engl J Med. 2013;369(24):2294–2303.
35.
MurinSRomanoPSWhiteRH. Comparison of outcomes after hospitalization for deep venous thrombosis or pulmonary embolism. Thromb Haemost. 2002;88(3):407–414.
36.
DouketisJDGuCSSchulmanS. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med. 2007;147(11):766–774.
37.
AgnelliGPrandoniPBecattiniC. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med. 2003;139(1):19–25.
38.
CastellucciLACameronCLe GalG. Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis. BMJ. 2013;347:f5133.
39.
BecattiniCAgnelliGSchenoneA. WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959–1967.
40.
HeitJAMohrDNSilversteinMD. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med. 2000;160(6):761–768.
41.
McRaeSTranHSchulmanS. Effect of patient’s sex on risk of recurrent venous thromboembolism: a metaanalysis. Lancet. 2006;368(9533):371–378.
42.
StreiffMB. Predicting the risk of recurrent venous thromboembolism (VTE). J Thromb Thrombolysis. 2015;39(3):353–366.
43.
PiovellaCDalla ValleFTrujillo-SantosJ; And the RIETE Investigators. Comparison of four scores to predict major bleeding in patients receiving anticoagulation for venous thromboembolism: findings from the RIETE registry. Intern Emerg Med. 2014;9(8):847–852.
44.
NietoJASolanoRTrapero IglesiasN; RIETE Investigators. Validation of a score for predicting fatal bleeding in patients receiving anticoagulation for venous thromboembolism. Thromb Res. 2013;132(2):175–179.
45.
SherzNMeanMLimacherA. Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboembolism. J Thromb Haemost. 2013;11(3):435–443.
46.
KhoranaAAFrancisCWCulakovaE. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5(3):632–634.
47.
LymanGHKhoranaAAKudererNM. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(17):2189.
48.
DebourdeauPFargeDBeckersM. International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer. J Thromb Haemost. 2013;11(1):71–80.
49.
FargeDDebourdeauPBeckersM. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost. 2013;11(1):56–70.
50.
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Cancer-Associated Venous Thromboembolic Disease. Version 2. 2014. http://www.nccn.org. Published August 11, 2015. Accessed November 5, 2015.
51.
LeeAYYLevineNMBakerRI. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. CLOT Trial. N Engl J Med. 2003;349(2):146–153.
52.
WuCLeeAYY. Novel or non-vitamin k antagonist oral anticoagulants and the treatment of cancer-associated thrombosis. Semin Thromb Hemost. 2015;41(2):237–243.
53.
VedovatiMCGerminiFAgnelliG. Direct oral anticoagulants in patients with venous thromboembolism and cancer: a systematic review and meta-analysis. Chest. 2015;147(2):475–483.
54.
select-d: Anticoagulation therapy in SELECT-D cancer patients at risk of recurrence of venous thromboembolism. DOI 10.1186/ISRCTN86712308. http://www.isrctn.com/ISRCTN86712308. Published April 25, 2013. Accessed November 5, 2015.
55.
KubitzaDBeckaMZuehlsdorfM. Body weight has limited influence on the safety, tolerability, pharmacokinetics or pharmacodynamics of rivaroxaban (bay 59-7939) in healthy subjects. J Clin Pharmacol. 2007;47(2):218–226.
56.
UpretiVVWangJBarrettYC. Effect of extreme body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol. 2013;76(6):908–916.
57.
LisenfeldKHLehrTDansirikulC. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost. 2011;11:2168–2175.
58.
EINSTEINEXTBauersachsRBerkowitzSDBrennerB; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–2510.
59.
FoxKAAAntmanEMMontalescotG. The Impact of Renal Dysfunction on Outcomes in the ExTRACT-TIMI 25 Trial. J Am Coll Cardiol. 2007;49(23):2249–2255.
60.
HammerstinglCOmranHTrippC. How useful is determination of anti-factor Xa activity to guide bridging therapy with enoxaparin? A pilot study. Thromb Haemost. 2009;101(2):325–332.
61.
HoffmannPKellerF. Increased major bleeding risk in patients with kidney dysfunction receiving enoxaparin: a meta-analysis. Eur J Clin Pharmacol. 2012;68(5):757–765.
62.
MahéIAghassarianMDrouetL. Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost. 2007;97(4):581–586.
63.
PonTKDagerWERobertsAJ. Subcutaneous enoxaparin for therapeutic anticoagulation in hemodialysis patients. Thromb Res. 2014;133(6):1023–1028.
64.
SardarPChatterjeeSHerzogE. Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized trials. Can J Cardiol. 2014;30(8):888–897.
