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Thromb Haemost 2022; 122(06): 1061-1070
DOI: 10.1055/a-1646-2244
Trial Protocol Design Paper

Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in Patients with Provoked Venous Thromboembolism and Enduring Risk Factors: Rationale and Design of the HI-PRO Trial

Behnood Bikdeli
1   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
3   Center for Outcomes Research and Evaluation, Yale School of Medicine, New Haven, Connecticut, United States
4   Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, United States
,
Heather Hogan
1   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Ruth B. Morrison
1   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
John Fanikos
1   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
5   Department of Pharmacy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Umberto Campia
1   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Briana M. Barns
1   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Mariana B. Pfeferman
1   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Julia E. Snyder
1   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Candrika D. Khairani
1   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Samuel Z. Goldhaber
1   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Gregory Piazza
1   Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
2   Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
› Author Affiliations Funding The study has been supported by a research grant by Bristol Myers Squibb/Pfizer Alliance. The funders participated in reviewing the study protocol and provided suggestions. Final decisions were left to the discretion of the study principal investigator (G.P.). The funders had no role in the decision to submit the current manuscript.
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Abstract

Patients with acute venous thromboembolism (VTE) in the setting of transient provoking factors are typically treated with short-term anticoagulation. However, the risk of recurrence may be increased in the presence of enduring risk factors. In such patients, the optimal duration of treatment remains uncertain. HI-PRO is a single-center, double-blind randomized trial. Patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) following a major provoking factor, including major surgery or major trauma, who completed at least 3 months of standard-dose therapeutic anticoagulation and have at least one enduring risk factor (such as obesity or heart failure) will be considered for inclusion. Patients will be randomized to apixaban 2.5 mg twice daily or placebo for 12 months. The primary efficacy outcome will be symptomatic recurrent VTE—a composite of DVT and/or PE at 12 months after randomization. Secondary efficacy outcomes include a composite of death due to cardiovascular causes, nonfatal myocardial infarction, stroke or systemic embolism, major adverse limb events, or coronary or peripheral ischemia requiring revascularization at 12 months, and individual components of these outcomes. The primary safety outcome is major bleeding according to the International Society on Thrombosis and Haemostasis definition. The study plans to enroll 600 patients (300 per arm) to have 80% power for detecting a 75% relative risk reduction in the primary outcome. Active recruitment began in March 2021. HI-PRO will provide clinically meaningful data on whether patients with provoked VTE and enduring risk factors have fewer adverse clinical outcomes if prescribed low-intensity extended-duration anticoagulation.

Keywords

venous thromboembolism - anticoagulation - apixaban - provoked


Publication History

Received: 09 August 2021

Accepted: 14 September 2021

Accepted Manuscript online:
16 September 2021

Article published online:
31 October 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res 2016; 118 (09) 1340-1347
    CrossrefPubMedGoogle Scholar
  • 2 Virani SS, Alonso A, Benjamin EJ. et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation 2020; 141 (09) e139-e596
    CrossrefPubMedGoogle Scholar
  • 3 Fanikos J, Rao A, Seger AC, Carter D, Piazza G, Goldhaber SZ. Hospital costs of acute pulmonary embolism. Am J Med 2013; 126 (02) 127-132
    CrossrefPubMedGoogle Scholar
  • 4 Boon GJAM, Huisman MV, Klok FA. Determinants and management of the post-pulmonary embolism syndrome. Semin Respir Crit Care Med 2021; 42 (02) 299-307
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Klok FA, van der Hulle T, den Exter PL, Lankeit M, Huisman MV, Konstantinides S. The post-PE syndrome: a new concept for chronic complications of pulmonary embolism. Blood Rev 2014; 28 (06) 221-226
    CrossrefPubMedGoogle Scholar
  • 6 Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008; 28 (03) 370-372
    CrossrefPubMedGoogle Scholar
  • 7 Heit JA, Cohen AT, Anderson FJ. Estimated annual number of incident and recurrent, non-fatal and fatal venous thromboembolism (VTE) events in the US. Blood 2005; 106: 1
    PubMedGoogle Scholar
  • 8 Bikdeli B, Bikdeli B. Updates on advanced therapies for acute pulmonary embolism. Int J Cardiovasc Pract 2016; 1: 47-50
    CrossrefPubMedGoogle Scholar
  • 9 Minges KE, Bikdeli B, Wang Y. et al. National trends in pulmonary embolism hospitalization rates and outcomes for adults aged ≥65 years in the United States (1999 to 2010). Am J Cardiol 2015; 116 (09) 1436-1442
    CrossrefPubMedGoogle Scholar
  • 10 Jiménez D, de Miguel-Díez J, Guijarro R. et al; RIETE Investigators. Trends in the management and outcomes of acute pulmonary embolism: analysis from the RIETE registry. J Am Coll Cardiol 2016; 67 (02) 162-170
    CrossrefPubMedGoogle Scholar
  • 11 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 (03) 277-287
    CrossrefPubMedGoogle Scholar
  • 12 Cohen AT, Agnelli G, Anderson FA. et al; VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98 (04) 756-764
    PubMedGoogle Scholar
  • 13 Kahn SR, Comerota AJ, Cushman M. et al; 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 (18) 1636-1661
    CrossrefPubMedGoogle Scholar
  • 14 Pengo V, Lensing AW, Prins MH. et al; Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350 (22) 2257-2264
    CrossrefPubMedGoogle Scholar
  • 15 Galanaud JP, Monreal M, Kahn SR. Epidemiology of the post-thrombotic syndrome. Thromb Res 2018; 164: 100-109
    CrossrefPubMedGoogle Scholar
  • 16 Agnelli G, Buller HR, Cohen A. et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (08) 699-708
    CrossrefPubMedGoogle Scholar
  • 17 Weitz JI, Lensing AWA, Prins MH. et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 (13) 1211-1222
    CrossrefPubMedGoogle Scholar
  • 18 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
    CrossrefPubMedGoogle Scholar
  • 19 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
    CrossrefPubMedGoogle Scholar
  • 20 Kearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing GJ, Kyrle PA. Subcommittees on Control of Anticoagulation, and Predictive and Diagnostic Variables in Thrombotic Disease. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016; 14 (07) 1480-1483
    CrossrefPubMedGoogle Scholar
  • 21 Schindewolf M, Weitz JI. Broadening the categories of patients eligible for extended venous thromboembolism treatment. Thromb Haemost 2020; 120 (01) 14-26
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Prandoni P, Barbar S, Milan M. et al. Optimal duration of anticoagulation. Provoked versus unprovoked VTE and role of adjunctive thrombophilia and imaging tests. Thromb Haemost 2015; 113 (06) 1210-1215
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 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 (02) 199-205
    CrossrefPubMedGoogle Scholar
  • 24 Kakkos SK, Gohel M, Baekgaard N. et al; Esvs Guidelines Committee. Editor's Choice - European Society for Vascular Surgery (ESVS) 2021 clinical practice guidelines on the management of venous thrombosis. Eur J Vasc Endovasc Surg 2021; 61 (01) 9-82
    CrossrefPubMedGoogle Scholar
  • 25 Albertsen IE, Piazza G, Goldhaber SZ. Let's stop dichotomizing venous thromboembolism as provoked or unprovoked. Circulation 2018; 138 (23) 2591-2593
    CrossrefPubMedGoogle Scholar
  • 26 Weitz JI, Bauersachs R, Beyer-Westendorf J. et al; EINSTEIN CHOICE Investigators. Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study. Thromb Haemost 2015; 114 (03) 645-650
    PubMedGoogle Scholar
  • 27 Prins MH, Lensing AWA, Prandoni P. et al. Risk of recurrent venous thromboembolism according to baseline risk factor profiles. Blood Adv 2018; 2 (07) 788-796
    CrossrefPubMedGoogle Scholar
  • 28 Sobieraj DM, Coleman CI, Pasupuleti V, Deshpande A, Kaw R, Hernandez AV. Comparative efficacy and safety of anticoagulants and aspirin for extended treatment of venous thromboembolism: a network meta-analysis. Thromb Res 2015; 135 (05) 888-896
    CrossrefPubMedGoogle Scholar
  • 29 Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. 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 surgical patients. J Thromb Haemost 2010; 8 (01) 202-204
    CrossrefPubMedGoogle Scholar
  • 30 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 (04) 692-694
    CrossrefPubMedGoogle Scholar
  • 31 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126
    CrossrefPubMedGoogle Scholar
  • 32 Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42 (02) 377-381
    CrossrefPubMedGoogle Scholar
  • 33 Simes J, Becattini C, Agnelli G. et al; INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism). Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation 2014; 130 (13) 1062-1071
    CrossrefPubMedGoogle Scholar
  • 34 Austin PC, Lee DS, Fine JP. Introduction to the analysis of survival data in the presence of competing risks. Circulation 2016; 133 (06) 601-609
    CrossrefPubMedGoogle Scholar
  • 35 European Medicines Agency. Guideline on adjustment for baseline covariates in clinical trials. Accessed January 7, 2021 at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-adjustment-baseline-covariates-clinical-trials_en.pdf
    PubMedGoogle Scholar
  • 36 Bikdeli B, Krumholz HM, Hines Jr HH. Minimizing recurrent venous thromboembolism. BMJ 2019; 366: l4686
    CrossrefPubMedGoogle Scholar
  • 37 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 (05) 496-520
    CrossrefPubMedGoogle Scholar
  • 38 Farge D, Frere C, Connors JM. et al; International Initiative on Thrombosis and Cancer (ITAC) advisory panel. 2019 International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2019; 20 (10) e566-e581
    CrossrefPubMedGoogle Scholar
  • 39 Middeldorp S, Prins MH, Hutten BA. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism. Cochrane Database Syst Rev 2014; 2014 (08) CD001367
    PubMedGoogle Scholar
  • 40 Nieto JA, Vicente JA, Prieto LM. et al; RIETE Investigators. Thirty-day outcomes in patients with acute pulmonary embolism who discontinued anticoagulant therapy before 90 days. Am Heart J 2018; 206: 1-10
    CrossrefPubMedGoogle Scholar
  • 41 Smilowitz NR, Mega JL, Berger JS. Duration of anticoagulation for venous thromboembolic events. Circulation 2014; 130 (25) 2343-2348
    CrossrefPubMedGoogle Scholar
  • 42 Prandoni P, Bilora F, Marchiori A. et al. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003; 348 (15) 1435-1441
    CrossrefPubMedGoogle Scholar
  • 43 Sørensen HT, Horvath-Puho E, Pedersen L, Baron JA, Prandoni P. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study. Lancet 2007; 370 (9601): 1773-1779
    CrossrefPubMedGoogle Scholar
  • 44 Gregson J, Kaptoge S, Bolton T. et al; Emerging Risk Factors Collaboration. Cardiovascular risk factors associated with venous thromboembolism. JAMA Cardiol 2019; 4 (02) 163-173
    CrossrefPubMedGoogle Scholar
  • 45 Piazza G, Goldhaber SZ. Venous thromboembolism and atherothrombosis: an integrated approach. Circulation 2010; 121 (19) 2146-2150
    CrossrefPubMedGoogle Scholar
  • 46 Vardi M, Piazza G, Pencina MJ. et al. Risk assessment to predict arterial and venous events in patients undergoing percutaneous coronary intervention. Clin Appl Thromb Hemost 2014; 20 (05) 478-483
    CrossrefPubMedGoogle Scholar
  • 47 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
    CrossrefPubMedGoogle Scholar
  • 48 Schulman S, Kearon C, Kakkar AK. et al; RE-MEDY Trial Investigators, RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368 (08) 709-718
    CrossrefPubMedGoogle Scholar
  • 49 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
    CrossrefPubMedGoogle Scholar
  • 50 Ridker PM, Goldhaber SZ, Danielson E. et al; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348 (15) 1425-1434
    CrossrefPubMedGoogle Scholar
  • 51 Agnelli G, Prandoni P, Santamaria MG. et al; Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001; 345 (03) 165-169
    CrossrefPubMedGoogle Scholar
  • 52 Couturaud F, Sanchez O, Pernod G. et al; PADIS-PE Investigators. Six months vs extended oral anticoagulation after a first episode of pulmonary embolism: the PADIS-PE randomized clinical trial. JAMA 2015; 314 (01) 31-40
    CrossrefPubMedGoogle Scholar