Skip to main content
Top
Published in: Heart and Vessels 4/2024

Open Access 21-02-2024 | Direct Oral Anticoagulant | Original Article

The effect of off-label use of reduced-dose direct oral anticoagulants therapy in the treatment of pulmonary embolism comparable to standard-dose therapy

Authors: Shinji Yamazoe, Hajime Imai, Yasuhiro Ogawa, Naoaki Kano, Yosuke Murase, Keita Mamiya, Tomoyo Ikeda, Kei Hiramatsu, Jun Torii, Katsuhiro Kawaguchi

Published in: Heart and Vessels | Issue 4/2024

Login to get access

Abstract

Direct oral anticoagulants (DOACs) have been shown to be effective and safe in preventing pulmonary embolism recurrence. In this single-center retrospective observational study, we aimed to evaluate the efficacy and safety of reduced-dose DOACs in 86 consecutive patients with acute pulmonary embolism. Patients were divided into standard-dose and reduced-dose DOACs groups. Initial clot volume did not significantly differ between the two groups (standard-dose DOACs vs. reduced-dose DOACs, 18.8 [Q1–Q3 7.3–30.8] mL vs. 10.0 [Q1–Q3 3.2–27.9] mL, p = 0.1). Follow-up computed tomography (CT) within 30 days showed a higher rate of clot volume reduction or disappearance in the standard-dose group compared to the reduced-dose group (standard-dose DOACs vs. reduced-dose DOACs, 81.6% vs. 53.9%, p = 0.02). However, at the final follow-up CT, there was no significant difference in clot volume change between the two groups (standard-dose DOACs vs. reduced-dose DOACs, 91.5% vs. 82.0%, p = 0.19). Major bleeding occurred in two patients in the standard-dose group (4.3%) and three patients in the reduced-dose DOACs group (7.7%) (p = 0.5). In conclusion, while standard-dose DOACs demonstrated superior efficacy in early clot reduction, reduced doses of apixaban and edoxaban showed comparable efficacy and safety profiles in long-term treatment of acute pulmonary embolism in certain patients.
Appendix
Available only for authorised users
Literature
1.
go back to reference Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361(24):2342–2352CrossRefPubMed Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361(24):2342–2352CrossRefPubMed
2.
go back to reference Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz S, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Shellong S, Segers A (2012) Oral rivaroxaban for the treatment of symptomatic Pulmonary Embolism. N Engl J Med 366(14):1287–1297CrossRefPubMed Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz S, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Shellong S, Segers A (2012) Oral rivaroxaban for the treatment of symptomatic Pulmonary Embolism. N Engl J Med 366(14):1287–1297CrossRefPubMed
3.
go back to reference Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI (2013) Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369(9):799–808CrossRefPubMed Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI (2013) Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369(9):799–808CrossRefPubMed
4.
go back to reference Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369(15):1406–1415CrossRefPubMed Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369(15):1406–1415CrossRefPubMed
5.
go back to reference Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, HuismanMV, Humbert M, Jennings CS, Jiméne D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Áinle FN, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL (2019) 2019 ESC guidelines for the diagnosis and management of acute Pulmonary Embolism developed in collaboration with the European Respiratory Society (ERS): the Task Force for the diagnosis and management of acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Respir J 54(3) Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, HuismanMV, Humbert M, Jennings CS, Jiméne D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Áinle FN, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL (2019) 2019 ESC guidelines for the diagnosis and management of acute Pulmonary Embolism developed in collaboration with the European Respiratory Society (ERS): the Task Force for the diagnosis and management of acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Respir J 54(3)
6.
go back to reference Kohsaka S, Katada J, Saito K, Jenkins A, Li B, Mardekian J, Terayama Y (2020) Safety and effectiveness of non-vitamin K oral anticoagulants versus warfarin in real-world patients with non-valvular atrial fibrillation: a retrospective analysis of contemporary Japanese administrative claims data. Open Heart 7(1):e001232CrossRefPubMedCentralPubMed Kohsaka S, Katada J, Saito K, Jenkins A, Li B, Mardekian J, Terayama Y (2020) Safety and effectiveness of non-vitamin K oral anticoagulants versus warfarin in real-world patients with non-valvular atrial fibrillation: a retrospective analysis of contemporary Japanese administrative claims data. Open Heart 7(1):e001232CrossRefPubMedCentralPubMed
7.
go back to reference Shen NN, Zhang C, Wang N, Wang JL, Gu ZC, Han H (2021) Effectiveness and safety of under or over-dosing of direct oral anticoagulants in Atrial Fibrillation: a systematic review and Meta-analysis of 148909 patients from 10 real-World studies. Front Pharmacol 12:645479CrossRefPubMedCentralPubMed Shen NN, Zhang C, Wang N, Wang JL, Gu ZC, Han H (2021) Effectiveness and safety of under or over-dosing of direct oral anticoagulants in Atrial Fibrillation: a systematic review and Meta-analysis of 148909 patients from 10 real-World studies. Front Pharmacol 12:645479CrossRefPubMedCentralPubMed
8.
go back to reference Murata N, Okumura Y, Yokoyama K, Matsumoto N, Tachibana E, Kuronuma K, Oiwa K, Matsumoto M, Kojima T, Hanada S, Nomoto K, Arima K, Takahashi F, Kotani T, Ikeya Y, Fukushima S, Itoh S, Kondo K, Chiku M, Ohno Y, Onikura M, Hirayama A (2019) Clinical outcomes of off-label dosing of direct oral anticoagulant therapy among Japanese patients with Atrial Fibrillation identified from the SAKURA AF Registry. Circ J 83(4):727–735CrossRefPubMed Murata N, Okumura Y, Yokoyama K, Matsumoto N, Tachibana E, Kuronuma K, Oiwa K, Matsumoto M, Kojima T, Hanada S, Nomoto K, Arima K, Takahashi F, Kotani T, Ikeya Y, Fukushima S, Itoh S, Kondo K, Chiku M, Ohno Y, Onikura M, Hirayama A (2019) Clinical outcomes of off-label dosing of direct oral anticoagulant therapy among Japanese patients with Atrial Fibrillation identified from the SAKURA AF Registry. Circ J 83(4):727–735CrossRefPubMed
9.
go back to reference Vasanthamohan L, Boonyawat K, Chai-Adisaksopha C, Crowther M (2018) Reduced-dose direct oral anticoagulants in the extended treatment of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 16(7):1288–1295CrossRefPubMed Vasanthamohan L, Boonyawat K, Chai-Adisaksopha C, Crowther M (2018) Reduced-dose direct oral anticoagulants in the extended treatment of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 16(7):1288–1295CrossRefPubMed
10.
go back to reference Aghayev A, Furlan A, Patil A, Gumus S, Jeon KN, Park B, Bae KT (2013) The rate of resolution of clot burden measured by pulmonary CT angiography in patients with acute Pulmonary Embolism. AJR Am J Roentgenol 200(4):791–797CrossRefPubMedCentralPubMed Aghayev A, Furlan A, Patil A, Gumus S, Jeon KN, Park B, Bae KT (2013) The rate of resolution of clot burden measured by pulmonary CT angiography in patients with acute Pulmonary Embolism. AJR Am J Roentgenol 200(4):791–797CrossRefPubMedCentralPubMed
11.
go back to reference Schulman S, Kearon C (2005) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 3(4):692–694CrossRefPubMed Schulman S, Kearon C (2005) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 3(4):692–694CrossRefPubMed
12.
go back to reference Furlan A, Aghayev A, Chang CC, Patil A, Jeon KN, Park B, Fetzer DT, Saul M, Roberts MS, Bae KT (2012) Short-term mortality in acute Pulmonary Embolism: clot burden and signs of right heart dysfunction at CT pulmonary angiography. Radiology 265(1):283–293CrossRefPubMedCentralPubMed Furlan A, Aghayev A, Chang CC, Patil A, Jeon KN, Park B, Fetzer DT, Saul M, Roberts MS, Bae KT (2012) Short-term mortality in acute Pulmonary Embolism: clot burden and signs of right heart dysfunction at CT pulmonary angiography. Radiology 265(1):283–293CrossRefPubMedCentralPubMed
13.
go back to reference Becattini C, Giustozzi M, Cerdà P, Cimini LA, Riera-Mestre A, Agnelli G (2019) Risk of recurrent venous thromboembolism after acute Pulmonary Embolism: role of residual pulmonary obstruction and persistent right ventricular dysfunction. A meta-analysis. J Thromb Haemost 17(8):1217–1228CrossRefPubMed Becattini C, Giustozzi M, Cerdà P, Cimini LA, Riera-Mestre A, Agnelli G (2019) Risk of recurrent venous thromboembolism after acute Pulmonary Embolism: role of residual pulmonary obstruction and persistent right ventricular dysfunction. A meta-analysis. J Thromb Haemost 17(8):1217–1228CrossRefPubMed
14.
go back to reference Qanadli SD, El Hajjam M, Vieillard-Baron A, Joseph T, Mesurolle B, Oliva VL, Barré O, Bruckert F, Dubourg O, Lacombe P (2001) New CT index to quantify arterial obstruction in Pulmonary Embolism: comparison with angiographic index and echocardiography. AJR Am J Roentgenol 176(6):1415–1420CrossRefPubMed Qanadli SD, El Hajjam M, Vieillard-Baron A, Joseph T, Mesurolle B, Oliva VL, Barré O, Bruckert F, Dubourg O, Lacombe P (2001) New CT index to quantify arterial obstruction in Pulmonary Embolism: comparison with angiographic index and echocardiography. AJR Am J Roentgenol 176(6):1415–1420CrossRefPubMed
15.
go back to reference Mastora I, Remy-Jardin M, Masson P, Galland E, Delannoy V, Bauchart JJ, Remy J (2003) Severity of acute Pulmonary Embolism: evaluation of a new spiral CT angiographic score in correlation with echocardiographic data. Eur Radiol 13(1):29–35CrossRefPubMed Mastora I, Remy-Jardin M, Masson P, Galland E, Delannoy V, Bauchart JJ, Remy J (2003) Severity of acute Pulmonary Embolism: evaluation of a new spiral CT angiographic score in correlation with echocardiographic data. Eur Radiol 13(1):29–35CrossRefPubMed
16.
go back to reference Venkatesh SK, Wang SC (2010) Central clot score at computed tomography as a predictor of 30-day mortality after acute Pulmonary Embolism. Ann Acad Med Singap 39(6):442–447CrossRefPubMed Venkatesh SK, Wang SC (2010) Central clot score at computed tomography as a predictor of 30-day mortality after acute Pulmonary Embolism. Ann Acad Med Singap 39(6):442–447CrossRefPubMed
17.
go back to reference Nijkeuter M, Hovens MM, Davidson BL, Huisman MV (2006) Resolution of thromboemboli in patients with acute Pulmonary Embolism: a systematic review. Chest 129(1):192–197CrossRefPubMed Nijkeuter M, Hovens MM, Davidson BL, Huisman MV (2006) Resolution of thromboemboli in patients with acute Pulmonary Embolism: a systematic review. Chest 129(1):192–197CrossRefPubMed
18.
go back to reference Stein PD, Yaekoub AY, Matta F, Janjua M, Patel RM, Goodman LR, Gross ML, Denier JE (2010) Resolution of Pulmonary Embolism on CT pulmonary angiography. AJR Am J Roentgenol 194(5):1263–1268CrossRefPubMed Stein PD, Yaekoub AY, Matta F, Janjua M, Patel RM, Goodman LR, Gross ML, Denier JE (2010) Resolution of Pulmonary Embolism on CT pulmonary angiography. AJR Am J Roentgenol 194(5):1263–1268CrossRefPubMed
19.
go back to reference López-Beret P, Pinto JM, Romero A, Orgaz A, Fontcuberta J, Oblas M (2001) Systematic study of occult pulmonary thromboembolism in patients with deep venous Thrombosis. J Vasc Surg 33(3):515–521CrossRefPubMed López-Beret P, Pinto JM, Romero A, Orgaz A, Fontcuberta J, Oblas M (2001) Systematic study of occult pulmonary thromboembolism in patients with deep venous Thrombosis. J Vasc Surg 33(3):515–521CrossRefPubMed
20.
go back to reference Steffel J, Ruff CT, Yin O, Braunwald E, Park JG, Murphy SA, Connolly S, Antman EM, Giugliano RP (2021) Randomized, double-blind comparison of half-dose Versus full-dose Edoxaban in 14,014 patients with Atrial Fibrillation. J Am Coll Cardiol 77(9):1197–1207CrossRefPubMed Steffel J, Ruff CT, Yin O, Braunwald E, Park JG, Murphy SA, Connolly S, Antman EM, Giugliano RP (2021) Randomized, double-blind comparison of half-dose Versus full-dose Edoxaban in 14,014 patients with Atrial Fibrillation. J Am Coll Cardiol 77(9):1197–1207CrossRefPubMed
21.
go back to reference Yin OQP, Antman EM, Braunwald E, Mercuri MF, Miller R, Morrow D, Ruff CT, Truitt K, Weitz JI, Giugliano RP (2018) Linking endogenous factor xa activity, a biologically relevant pharmacodynamic marker, to Edoxaban plasma concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 Trial. Circulation 138(18):1963–1973CrossRefPubMed Yin OQP, Antman EM, Braunwald E, Mercuri MF, Miller R, Morrow D, Ruff CT, Truitt K, Weitz JI, Giugliano RP (2018) Linking endogenous factor xa activity, a biologically relevant pharmacodynamic marker, to Edoxaban plasma concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 Trial. Circulation 138(18):1963–1973CrossRefPubMed
22.
go back to reference Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369(22):2093–2104CrossRefPubMed Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369(22):2093–2104CrossRefPubMed
23.
go back to reference Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI (2013) Apixaban for extended treatment of venous thromboembolism. N Engl J Med 368(8):699–708CrossRefPubMed Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI (2013) Apixaban for extended treatment of venous thromboembolism. N Engl J Med 368(8):699–708CrossRefPubMed
24.
go back to reference Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363(26):2499–2510CrossRefPubMed Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363(26):2499–2510CrossRefPubMed
25.
go back to reference Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P (2017) Rivaroxaban or Aspirin for Extended treatment of venous thromboembolism. N Engl J Med 376(13):1211–1222CrossRefPubMed Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P (2017) Rivaroxaban or Aspirin for Extended treatment of venous thromboembolism. N Engl J Med 376(13):1211–1222CrossRefPubMed
26.
go back to reference Barra ME, Fanikos J, Connors JM, Sylvester KW, Piazza G, Goldhaber SZ (2016) Evaluation of dose-reduced direct oral anticoagulant therapy. Am J Med 129(11):1198–1204CrossRefPubMed Barra ME, Fanikos J, Connors JM, Sylvester KW, Piazza G, Goldhaber SZ (2016) Evaluation of dose-reduced direct oral anticoagulant therapy. Am J Med 129(11):1198–1204CrossRefPubMed
27.
go back to reference Takase T, Ikesue H, Nakagawa H, Kinoshita M, Muroi N, Kitai T, Furukawa Y, Hashida T (2020) Effect of the number of dose adjustment factors on bleeding risk in patients receiving 30 mg/day edoxaban. J Clin Pharm Ther 45(2):298–302CrossRefPubMed Takase T, Ikesue H, Nakagawa H, Kinoshita M, Muroi N, Kitai T, Furukawa Y, Hashida T (2020) Effect of the number of dose adjustment factors on bleeding risk in patients receiving 30 mg/day edoxaban. J Clin Pharm Ther 45(2):298–302CrossRefPubMed
28.
go back to reference van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV (2014) Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 12(3):320–328CrossRefPubMed van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV (2014) Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 12(3):320–328CrossRefPubMed
29.
go back to reference Nakada K, Okada T, Osada H, Honda N (2010) Relation between pulmonary embolus volume quantified by multidetector computed tomography and clinical status and outcome for patients with acute Pulmonary Embolism. Jpn J Radiol 28(1):34–42CrossRefPubMed Nakada K, Okada T, Osada H, Honda N (2010) Relation between pulmonary embolus volume quantified by multidetector computed tomography and clinical status and outcome for patients with acute Pulmonary Embolism. Jpn J Radiol 28(1):34–42CrossRefPubMed
30.
go back to reference Furlan A, Patil A, Park B, Chang CC, Roberts MS, Bae KT (2011) Accuracy and reproducibility of blood clot burden quantification with pulmonary CT angiography. AJR Am J Roentgenol 196(3):516–523CrossRefPubMed Furlan A, Patil A, Park B, Chang CC, Roberts MS, Bae KT (2011) Accuracy and reproducibility of blood clot burden quantification with pulmonary CT angiography. AJR Am J Roentgenol 196(3):516–523CrossRefPubMed
31.
go back to reference Choi KJ, Cha SI, Shin KM, Lim JK, Yoo SS, Lee J, Lee SY, Kim CH, Park JY, Lee WK (2014) Central Emboli rather than saddle emboli predict adverse outcomes in patients with acute Pulmonary Embolism. Thromb Res 134(5):991–996CrossRefPubMed Choi KJ, Cha SI, Shin KM, Lim JK, Yoo SS, Lee J, Lee SY, Kim CH, Park JY, Lee WK (2014) Central Emboli rather than saddle emboli predict adverse outcomes in patients with acute Pulmonary Embolism. Thromb Res 134(5):991–996CrossRefPubMed
Metadata
Title
The effect of off-label use of reduced-dose direct oral anticoagulants therapy in the treatment of pulmonary embolism comparable to standard-dose therapy
Authors
Shinji Yamazoe
Hajime Imai
Yasuhiro Ogawa
Naoaki Kano
Yosuke Murase
Keita Mamiya
Tomoyo Ikeda
Kei Hiramatsu
Jun Torii
Katsuhiro Kawaguchi
Publication date
21-02-2024
Publisher
Springer Japan
Published in
Heart and Vessels / Issue 4/2024
Print ISSN: 0910-8327
Electronic ISSN: 1615-2573
DOI
https://doi.org/10.1007/s00380-023-02339-5

Other articles of this Issue 4/2024

Heart and Vessels 4/2024 Go to the issue