Clinical Surveillance vs. Anticoagulation For low-risk patiEnts with isolated SubSegmental Pulmonary Embolism: protocol for a multicentre randomised placebo-controlled non-inferiority trial (SAFE-SSPE)

Christine Baumgartner, Frederikus A Klok, Marc Carrier, Andreas Limacher, Jeanne Moor, Marc Righini, Jürg-Hans Beer, Martina Peluso, Damiana Rakovic, Menno V Huisman, Drahomir Aujesky, Christine Baumgartner, Frederikus A Klok, Marc Carrier, Andreas Limacher, Jeanne Moor, Marc Righini, Jürg-Hans Beer, Martina Peluso, Damiana Rakovic, Menno V Huisman, Drahomir Aujesky

Abstract

Introduction: The clinical significance of subsegmental pulmonary embolism (SSPE) is currently unclear. Although growing evidence from observational studies suggests that withholding anticoagulant treatment may be a safe option in selected patients with isolated SSPE, most patients with this condition receive anticoagulant treatment, which is associated with a 90-day risk of recurrent venous thromboembolism (VTE) of 0.8% and major bleeding of up to 5%. Given the ongoing controversy concerning the risk-benefit ratio of anticoagulation for isolated SSPE and the lack of evidence from randomised-controlled studies, the aim of this clinical trial is to evaluate the efficacy and safety of clinical surveillance without anticoagulation in low-risk patients with isolated SSPE.

Methods and analysis: SAFE-SSPE (Surveillance vs. Anticoagulation For low-risk patiEnts with isolated SubSegmental Pulmonary Embolism, a multicentre randomised placebo-controlled non-inferiority trial) is an international, multicentre, placebo-controlled, double-blind, parallel-group non-inferiority trial conducted in Switzerland, the Netherlands and Canada. Low-risk patients with isolated SSPE are randomised to receive clinical surveillance with either placebo (no anticoagulation) or anticoagulant treatment with rivaroxaban. All patients undergo bilateral whole-leg compression ultrasonography to exclude concomitant deep vein thrombosis before enrolment. Patients are followed for 90 days. The primary outcome is symptomatic recurrent VTE (efficacy). The secondary outcomes include clinically significant bleeding and all-cause mortality (safety). The ancillary outcomes are health-related quality of life, functional status and medical resource utilisation.

Ethics and dissemination: The local ethics committees in Switzerland have approved this protocol. Submission to the Ethical Committees in the Netherlands and Canada is underway. The results of this trial will be published in a peer-reviewed journal.

Trial registration number: NCT04263038.

Keywords: anticoagulation; randomised clinical trialx; subsegmental pulmonary embolism.

Conflict of interest statement

Competing interests: MC reports grants from Leo Pharma, BMS, Pfizer, personal fees from Bayer, BMS, Pfizer, Sanofi, Leo Pharma, Servier, outside the submitted work. All other authors declare that they have no competing interest with regard to the intellectual concern and proprietary of affairs. The funding source had no role in the design of this study and does not have any role in the conduct, the collection, management, analysis and interpretation of the data, the writing of the manuscript or the decision to submit the results for publication.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Overview of the study design. SAFE-SSPE is a randomised, placebo-controlled, parallel-group non-inferiority trial. Low-risk patients with isolated SSPE without concomitant DVT are randomly assigned in a 1:1 ratio to receive placebo (‘clinical surveillance group’) or anticoagulant treatment with rivaroxaban (‘anticoagulation group’). The primary study outcomes are symptomatic recurrent VTE within 90 days of randomisation. Secondary outcomes include clinically significant bleeding and all-cause mortality, and ancillary outcomes will be health-related quality of life, functional status and medical resource utilisation. DVT, deep vein thrombosis; PE, pulmonary embolism; SSPE, subsegmental pulmonary embolism; VTE, venous thromboembolism.

References

    1. Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. Lancet 2016;388:3060–73. 10.1016/S0140-6736(16)30514-1
    1. Huisman MV, Barco S, Cannegieter SC, et al. . Pulmonary embolism. Nat Rev Dis Primers 2018;4:18028. 10.1038/nrdp.2018.28
    1. Castellucci LA, Cameron C, Le Gal G, et al. . Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA 2014;312:1122–35. 10.1001/jama.2014.10538
    1. Kearon C, Akl EA, Ornelas J, et al. . Antithrombotic therapy for VTe disease: chest guideline and expert panel report. Chest 2016;149:315–52. 10.1016/j.chest.2015.11.026
    1. Büller HR, Prins MH, Jacobson F, et al. . Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–97. 10.1056/NEJMoa1113572
    1. Jun M, Lix LM, Durand M, et al. . Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study. BMJ 2017;359:4323. 10.1136/bmj.j4323
    1. Linkins L-A, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003;139:893–900. 10.7326/0003-4819-139-11-200312020-00007
    1. Scherz N, Méan M, Limacher A, et al. . Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboembolism. J Thromb Haemost 2013;11:435–43. 10.1111/jth.12111
    1. Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med 2011;171:831–7. 10.1001/archinternmed.2011.178
    1. Auer RC, Schulman AR, Tuorto S, et al. . Use of helical CT is associated with an increased incidence of postoperative pulmonary emboli in cancer patients with no change in the number of fatal pulmonary emboli. J Am Coll Surg 2009;208:871–8. 10.1016/j.jamcollsurg.2008.12.030
    1. Ikesaka R, Carrier M. Clinical significance and management of subsegmental pulmonary embolism. J Thromb Thrombolysis 2015;39:311–4. 10.1007/s11239-015-1169-7
    1. Carrier M, Righini M, Wells PS, et al. . Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies. J Thromb Haemost 2010;8:1716–22. 10.1111/j.1538-7836.2010.03938.x
    1. Carrier M, Righini M, Le Gal G. Symptomatic subsegmental pulmonary embolism: what is the next step? J Thromb Haemost 2012;10:1486–90. 10.1111/j.1538-7836.2012.04804.x
    1. Stein PD, Goodman LR, Hull RD, et al. . Diagnosis and management of isolated subsegmental pulmonary embolism: review and assessment of the options. Clin Appl Thromb Hemost 2012;18:20–6. 10.1177/1076029611422363
    1. van der Pol LM, Bistervels IM, van Mens TE, et al. . Lower prevalence of subsegmental pulmonary embolism after application of the years diagnostic algorithm. Br J Haematol 2018;183:629–35. 10.1111/bjh.15556
    1. Barco S, Mahmoudpour SH, Valerio L, et al. . Trends in mortality related to pulmonary embolism in the European region, 2000-15: analysis of vital registration data from the who mortality database. Lancet Respir Med 2020;8:277–87. 10.1016/S2213-2600(19)30354-6
    1. Stein PD, Fowler SE, Goodman LR, et al. . Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006;354:2317–27. 10.1056/NEJMoa052367
    1. Ghanima W, Nielssen BE, Holmen LO, et al. . Multidetector computed tomography (MDCT) in the diagnosis of pulmonary embolism: interobserver agreement among radiologists with varied levels of experience. Acta Radiol 2007;48:165–70. 10.1080/02841850601100859
    1. Gurney JW. No fooling around: direct visualization of pulmonary embolism. Radiology 1993;188:618–9. 10.1148/radiology.188.3.8351321
    1. Schoepf UJ, Costello P. CT angiography for diagnosis of pulmonary embolism: state of the art. Radiology 2004;230:329–37. 10.1148/radiol.2302021489
    1. Carrier M, Klok FA. Symptomatic subsegmental pulmonary embolism: to treat or not to treat? Hematology Am Soc Hematol Educ Program 2017;2017:237–41. 10.1182/asheducation-2017.1.237
    1. Cha S-I, Shin K-M, Lee J-W, et al. . Clinical characteristics of patients with peripheral pulmonary embolism. Respiration 2010;80:500–8. 10.1159/000277929
    1. Donato AA, Khoche S, Santora J, et al. . Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography. Thromb Res 2010;126:e266–70. 10.1016/j.thromres.2010.07.001
    1. Le Gal G, Righini M, Parent F, et al. . Diagnosis and management of subsegmental pulmonary embolism. J Thromb Haemost 2006;4:724–31. 10.1111/j.1538-7836.2006.01819.x
    1. Mehta D, Barnett M, Zhou L, et al. . Management and outcomes of single subsegmental pulmonary embolus: a retrospective audit at North Shore Hospital, New Zealand. Intern Med J 2014;44:872–6. 10.1111/imj.12507
    1. Bariteau A, Stewart LK, Emmett TW, et al. . Systematic review and meta-analysis of outcomes of patients with subsegmental pulmonary embolism with and without anticoagulation treatment. Acad Emerg Med 2018;25:828–35. 10.1111/acem.13399
    1. Eyer BA, Goodman LR, Washington L. Clinicians' response to radiologists' reports of isolated subsegmental pulmonary embolism or Inconclusive interpretation of pulmonary embolism using MDCT. AJR Am J Roentgenol 2005;184:623–8. 10.2214/ajr.184.2.01840623
    1. Douketis JD, Foster GA, Crowther MA, et al. . Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 2000;160:3431–6. 10.1001/archinte.160.22.3431
    1. Pesavento R, de Conti G, Minotto I, et al. . The value of 64-detector row computed tomography for the exclusion of pulmonary embolism. Thromb Haemost 2011;105:901–7. 10.1160/TH10-10-0638
    1. Raslan IA, Chong J, Gallix B, et al. . Rates of overtreatment and treatment-related adverse effects among patients with subsegmental pulmonary embolism. JAMA Intern Med 2018;178:1272–4. 10.1001/jamainternmed.2018.2971
    1. Yoo HH, Queluz TH, El Dib R. Anticoagulant treatment for subsegmental pulmonary embolism. Cochrane Database Syst Rev 2016;1:CD010222.
    1. Chan A-W, Tetzlaff JM, Altman DG, et al. . Spirit 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200–7. 10.7326/0003-4819-158-3-201302050-00583
    1. Peiman S, Abbasi M, Allameh SF, et al. . Subsegmental pulmonary embolism: a narrative review. Thromb Res 2016;138:55–60. 10.1016/j.thromres.2015.12.003
    1. Schoellnast H, Deutschmann HA, Fritz GA, et al. . Mdct angiography of the pulmonary arteries: influence of iodine flow concentration on vessel attenuation and visualization. AJR Am J Roentgenol 2005;184:1935–9. 10.2214/ajr.184.6.01841935
    1. Klok FA, Huisman MV. Management of incidental pulmonary embolism. Eur Respir J 2017;49:1700275. 10.1183/13993003.00275-2017
    1. van der Hulle T, den Exter PL, Planquette B, et al. . Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients. J Thromb Haemost 2016;14:105–13. 10.1111/jth.13172
    1. 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. 10.1111/jth.13336
    1. Prandoni P, Noventa F, Ghirarduzzi A, et al. . 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 1,626 patients. Haematologica 2007;92:199–205. 10.3324/haematol.10516
    1. Iorio A, Kearon C, Filippucci E, et al. . Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med 2010;170:1710–6. 10.1001/archinternmed.2010.367
    1. van der Hulle T, Tan M, den Exter PL, et al. . Recurrence risk after anticoagulant treatment of limited duration for late, second venous thromboembolism. Haematologica 2015;100:188–93. 10.3324/haematol.2014.112896
    1. Moores LK. Are we overtreating isolated subsegmental pulmonary embolism?: first do no harm. JAMA Intern Med 2018;178:1274–5. 10.1001/jamainternmed.2018.2970
    1. 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. 10.1056/NEJMoa1302507
    1. Giugliano RP, Ruff CT, Braunwald E, et al. . Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. 10.1056/NEJMoa1310907
    1. Aujesky D, Roy P-M, Verschuren F, et al. . Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. The Lancet 2011;378:41–8. 10.1016/S0140-6736(11)60824-6
    1. Kearon C. Natural history of venous thromboembolism. Circulation 2003;107:22I–30. 10.1161/01.CIR.0000078464.82671.78
    1. Jiménez D, Aujesky D, Díaz G, et al. . Prognostic significance of deep vein thrombosis in patients presenting with acute symptomatic pulmonary embolism. Am J Respir Crit Care Med 2010;181:983–91. 10.1164/rccm.200908-1204OC
    1. Righini M, Le Gal G, Aujesky D, et al. . Complete venous ultrasound in outpatients with suspected pulmonary embolism. J Thromb Haemost 2009;7:406–12. 10.1111/j.1538-7836.2008.03264.x
    1. Mimier MK, Janczak DT, McBane RD, et al. . Thrombosis of atypical location: how to treat patients in the era of direct oral anticoagulants? Pol Arch Intern Med 2018;128:604–8. 10.20452/pamw.4333
    1. Johnson SA, Stevens SM, Woller SC, et al. . Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and meta-analysis. JAMA 2010;303:438–45. 10.1001/jama.2010.43
    1. Buller HR, Cohen AT, Michael G, et al. . Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007;357:1094–104. 10.1056/NEJMoa064247
    1. Lim W, Le Gal G, Bates SM, et al. . American Society of hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism. Blood Adv 2018;2:3226–56. 10.1182/bloodadvances.2018024828
    1. Méan M, Righini M, Jaeger K, et al. . The Swiss cohort of elderly patients with venous thromboembolism (SWITCO65+): rationale and methodology. J Thromb Thrombolysis 2013;36:475–83. 10.1007/s11239-013-0875-2
    1. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis . Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692–4. 10.1111/j.1538-7836.2005.01204.x
    1. Raskob GE, Spyropoulos AC, Zrubek J, et al. . The mariner trial of rivaroxaban after hospital discharge for medical patients at high risk of VTe. Design, rationale, and clinical implications. Thromb Haemost 2016;115:1240–8. 10.1160/TH15-09-0756
    1. Tritschler T, Kraaijpoel N, Girard P, et al. . Definition of pulmonary embolism-related death and classification of the cause of death in venous thromboembolism studies: communication from the SSC of the ISTH. J Thromb Haemost 2020;18:1495–500. 10.1111/jth.14769
    1. Cohn DM, Nelis EA, Busweiler LA, et al. . Quality of life after pulmonary embolism: the development of the PEmb-QoL questionnaire. J Thromb Haemost 2009;7:1044–6. 10.1111/j.1538-7836.2009.03341.x
    1. Klok FA, Cohn DM, Middeldorp S, et al. . Quality of life after pulmonary embolism: validation of the PEmb-QoL questionnaire. J Thromb Haemost 2010;8:523–32. 10.1111/j.1538-7836.2009.03726.x
    1. Klok FA, Barco S, Siegerink B. Measuring functional limitations after venous thromboembolism: a call to action. Thromb Res 2019;178:59–62. 10.1016/j.thromres.2019.04.003
    1. Boon GJAM, Barco S, Bertoletti L, et al. . Measuring functional limitations after venous thromboembolism: optimization of the Post-VTE functional status (PVFS) scale. Thromb Res 2020;190:45–51. 10.1016/j.thromres.2020.03.020
    1. Yealy DM, Auble TE, Stone RA, et al. . Effect of increasing the intensity of implementing pneumonia guidelines: a randomized, controlled trial. Ann Intern Med 2005;143:881–94. 10.7326/0003-4819-143-12-200512200-00006
    1. Carrier M, Kimpton M, LE Gal G, et al. . The management of a sub-segmental pulmonary embolism: a cross-sectional survey of Canadian thrombosis physicians. J Thromb Haemost 2011;9:1412–5. 10.1111/j.1538-7836.2011.04306.x
    1. Mauri L, D'Agostino RB. Challenges in the design and interpretation of Noninferiority trials. N Engl J Med 2017;377:1357–67. 10.1056/NEJMra1510063
    1. Levine M, Gent M, Hirsh J, et al. . A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334:677–81. 10.1056/NEJM199603143341101
    1. Koopman MM, Prandoni P, Piovella F, et al. . Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996;334:682–7. 10.1056/NEJM199603143341102
    1. Büller HR, Gent M, Gallus AS, et al. . Low-Molecular-Weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997;337:657–62. 10.1056/NEJM199709043371001
    1. Büller HR, Davidson BL, Decousus H, et al. . Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004;140:867–73. 10.7326/0003-4819-140-11-200406010-00007
    1. Büller HR, Davidson BL, Decousus H, et al. . Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003;349:1695–702. 10.1056/NEJMoa035451
    1. Agresti A, Caffo B. Simple and effective confidence intervals for proportions and differences of proportions result from adding two successes and two failures. The American Statistician 2000;54:280–8.
    1. Piaggio G, Elbourne DR, Pocock SJ, et al. . Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA 2012;308:2594–604. 10.1001/jama.2012.87802
    1. Fine JP, Gray RJ. A proportional hazards model for the Subdistribution of a competing risk. J Am Stat Assoc 1999;94:496–509. 10.1080/01621459.1999.10474144

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa