Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH

Abstract

Whether an episode of venous thromboembolism (VTE) was unprovoked or provoked by an environmental (or acquired) risk factor and, if it was provoked, whether the provoking factor was transient or persistent, has important prognostic and treatment implications 1.Iorio A. Kearon C. Filippucci E. Marcucci M. Macura A. Pengo V. Siragusa S. Palareti G. 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: 1710-1716Crossref PubMed Scopus (2) Google Scholar, 2.Kearon C. Akl E.A. Comerota A.J. Prandoni P. Bounameaux H. Goldhaber S.Z. Nelson M.E. Wells P.S. Gould M.K. Dentali F. Crowther M. Kahn S.R. 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: e419S-e494SAbstract Full Text Full Text PDF PubMed Scopus (2934) Google Scholar. If thrombosis was provoked by a major transient risk factor, such as recent surgery, there is a very low risk of recurrence after stopping therapy 1.Iorio A. Kearon C. Filippucci E. Marcucci M. Macura A. Pengo V. Siragusa S. Palareti G. 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: 1710-1716Crossref PubMed Scopus (2) Google Scholar. At the other extreme, if thrombosis was provoked by a persistent and progressive risk factor, such as metastatic cancer, there is a high risk of recurrence after stopping therapy 3.Prandoni P. Lensing A.W. Piccioli A. Bernardi E. Simioni P. Girolami B. Marchiori A. Sabbion P. Prins M.H. Noventa F. Girolami A. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis.Blood. 2002; 100: 3484-3488Crossref PubMed Scopus (1483) Google Scholar, 4.Heit J.A. Mohr D.N. Silverstein M.D. Petterson T.M. O'Fallon W.M. Melton III, L.J. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population‐based cohort study.Arch Intern Med. 2000; 160: 761-768Crossref PubMed Scopus (773) Google Scholar. Patients with neither an important transient nor persistent provoking risk factor for thrombosis, who are often referred to as having ‘unprovoked’ VTE, have an intermediate risk of recurrence after stopping therapy 1.Iorio A. Kearon C. Filippucci E. Marcucci M. Macura A. Pengo V. Siragusa S. Palareti G. 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: 1710-1716Crossref PubMed Scopus (2) Google Scholar, 2.Kearon C. Akl E.A. Comerota A.J. Prandoni P. Bounameaux H. Goldhaber S.Z. Nelson M.E. Wells P.S. Gould M.K. Dentali F. Crowther M. Kahn S.R. 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: e419S-e494SAbstract Full Text Full Text PDF PubMed Scopus (2934) Google Scholar. Because of the implications for risk of recurrence and how long patients should be treated, it is often important to be able to categorize episodes of VTE as being provoked or unprovoked. This SSC statement discusses issues that are relevant to this categorization and proposes criteria (Table 1) that can be used in clinical practice and for clinical research to categorize episodes of VTE as provoked by a transient risk factor, provoked by a persistent risk factor or unprovoked. Our goal is to standardize what is meant by these terms, identify the strengths and limitations of this terminology, and improve the consistency with which patients are categorized into one of these three groups. Greater consistency in the use of this categorization is expected to benefit clinical practice and investigation.Table 1Definitions for ‘VTE provoked by a transient risk factor’, ‘VTE provoked by a persistent risk factor’ and ‘unprovoked VTE’VTE provoked by a transient risk factor*The length of time it takes for a risk factor to resolve may be unpredictable; therefore, resolution of the risk factor should be confirmed before stopping anticoagulant therapy on this basis.Major transient risk factor during the 3 months before diagnosis of VTEA risk factor is considered ‘major’ if it has been shown to be associated with:1.half the risk of recurrent VTE after stopping anticoagulant therapy (compared with if there was no transient risk factor), when the risk factor occurred up to 3 months before the VTE†Of the two criteria, this is considered to be the most directly relevant and important. Venous thromboembolism (VTE) that has occurred up to 3 months after a major risk factor is expected to have a low risk of recurrence, whereas VTE would need to have occured within 2 months of a minor risk factor for the recurrence risk to be low.; or2.a greater than10‐fold increase in the risk of having a first VTE.Examples:•Surgery with general anesthesia for greater than 30 min.•Confined to bed in hospital (only ‘bathroom privileges’) for at least 3 days with an acute illness.•Cesarean section.Minor (yet important) transient risk factor during the 2 months before diagnosis of VTEA risk factor is considered ‘minor’ if it has been shown to be associated with:1.half the risk of recurrent VTE after stopping anticoagulant therapy (compared with if there was no transient risk factor), when the risk factor occurred up to 2 months before the VTE†Of the two criteria, this is considered to be the most directly relevant and important. Venous thromboembolism (VTE) that has occurred up to 3 months after a major risk factor is expected to have a low risk of recurrence, whereas VTE would need to have occured within 2 months of a minor risk factor for the recurrence risk to be low.; or2.a 3 to 10‐fold increase in the risk of having a first VTE.Examples:•Surgery with general anesthesia for less than 30 min.•Admission to hospital for less than 3 days with an acute illness.•Estrogen therapy.•Pregnancy or puerperium.•Confined to bed out of hospital for at least 3 days with an acute illness.•Leg injury associated with reduced mobility for at least 3 days.VTE provoked by a persistent risk factorActive cancerCancer is considered active if any of the following apply:1.has not received potentially curative treatment; or2.there is evidence that treatment has not been curative (e.g. recurrent or progressive disease)‡The decision as to whether a treated cancer is cured should be made by an experienced clinician, with the decision often requiring that there has been a disease‐free interval of follow‐up. A patient who is categorized as having ‘cancer that may be active’ when VTE occurred may in hindsight be recategorized as having had unprovoked VTE because he or she has had additional cancer‐free follow‐up.; or3.treatment is ongoing.On‐going non‐malignant condition associated with at least a 2‐fold risk of recurrent VTE after stopping anticoagulant therapyExample:Inflammatory bowel disease.Unprovoked VTENo provoking risk factor (transient or persistent)We suggest that, in this context, patients are considered to have unprovoked VTE if they do not meet the criteria for VTE that was provoked by a transient or a persistent risk factor that are outlined above§The presence of non‐environmental (or intrinsic) risk factors, such as hereditary thrombophilias, male sex or older age, does not influence whether an episode of VTE is considered unprovoked or provoked. Also, as in the text, the risk of recurrence in individual patients with unprovoked VTE can be further stratified using other assessments.* The length of time it takes for a risk factor to resolve may be unpredictable; therefore, resolution of the risk factor should be confirmed before stopping anticoagulant therapy on this basis.† Of the two criteria, this is considered to be the most directly relevant and important. Venous thromboembolism (VTE) that has occurred up to 3 months after a major risk factor is expected to have a low risk of recurrence, whereas VTE would need to have occured within 2 months of a minor risk factor for the recurrence risk to be low.‡ The decision as to whether a treated cancer is cured should be made by an experienced clinician, with the decision often requiring that there has been a disease‐free interval of follow‐up. A patient who is categorized as having ‘cancer that may be active’ when VTE occurred may in hindsight be recategorized as having had unprovoked VTE because he or she has had additional cancer‐free follow‐up.§ The presence of non‐environmental (or intrinsic) risk factors, such as hereditary thrombophilias, male sex or older age, does not influence whether an episode of VTE is considered unprovoked or provoked. Also, as in the text, the risk of recurrence in individual patients with unprovoked VTE can be further stratified using other assessments. Open table in a new tab In relationship to assessment of the risk of recurrence, we prefer the term ‘unprovoked’ over ‘idiopathic’ to describe patients with VTE that is not associated with an environmental risk factor (either transient or persistent). The word ‘unprovoked’ focuses attention on whether there is an important environmental provoking factor for the VTE, which is the single variable that most influences the risk of recurrent VTE after anticoagulants are stopped 2.Kearon C. Akl E.A. Comerota A.J. Prandoni P. Bounameaux H. Goldhaber S.Z. Nelson M.E. Wells P.S. Gould M.K. Dentali F. Crowther M. Kahn S.R. 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: e419S-e494SAbstract Full Text Full Text PDF PubMed Scopus (2934) Google Scholar, 5.Kyrle P.A. Rosendaal F.R. Eichinger S. Risk assessment for recurrent venous thrombosis.Lancet. 2010; 376: 2032-2039Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar. The word ‘idiopathic’ suggests that there is no reason for thrombosis. However, whether or not there was an environmental provoking factor, patients may have non‐environmental risk factors for thrombosis, such as a hereditary thrombophilia, older age or male sex, which do not qualify the event as provoked but may influence the risk of recurrence 6.Anderson Jr, F.A. Spencer F.A. Risk factors for venous thromboembolism.Circulation. 2003; 107: I‐9-I‐16Crossref Scopus (1284) Google Scholar, 7.Cannegieter S.C. van Hylckama V.A. Venous thrombosis: understanding the paradoxes of recurrence.J Thromb Haemost. 2013; 11: 161-169Crossref PubMed Scopus (19) Google Scholar. Many episodes of VTE can readily be categorized as having been provoked by a transient risk factor (e.g. recent major surgery) or, alternatively, as being unprovoked (no environmental risk factor). However, when VTE occurs in a patient with a weak transient risk factor for thrombosis (e.g. minor soft tissue injury of the leg) or occurs many months after a major risk factor, it can be difficult to decide if the risk factor is prognostically important enough to justify categorizing the VTE as having been provoked. The degree to which risk factors are associated with thrombosis varies from very weak to very strong, and the point along this continuum that is used to categorize an episode of VTE as provoked (or unprovoked) is somewhat arbitrary (Fig. 1). Among patients with VTE provoked by a transient risk factor, the risk of recurrence after stopping anticoagulant therapy also varies according to the magnitude and reversibility of the provoking factor, in addition to other types of predictors of recurrence 1.Iorio A. Kearon C. Filippucci E. Marcucci M. Macura A. Pengo V. Siragusa S. Palareti G. 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: 1710-1716Crossref PubMed Scopus (2) Google Scholar. Transient risk factors are those that resolve after they have provoked VTE, such as recent surgery or estrogen therapy that is then stopped. However, the decline in risk of VTE with a provoking factor may be incomplete (e.g. after a stroke) or may fluctuate (e.g. inflammatory bowel disease). In these situations it may be difficult to decide if the provoking factor is transient, persistent or a combination of both. Furthermore, VTE may be provoked by a transient risk factor (such as surgery) in patients who have persistent risk factors (such as metastatic cancer). These patients do not fit into either of the categories of provoked VTE that are described in this statement and are expected to have a risk of recurrent VTE that is higher than in those with only a transient risk factor and lower than those with only a persistent risk factor. Some patients with an unprovoked VTE have serious co‐morbid conditions, whereas others do not. If a patient has a persistent condition that is an important risk factor for recurrent VTE, the VTE is considered to be associated with a persistent provoking factor. Cancer is the most important persistent provoking factor for VTE because of its high incidence and strong association with recurrent thrombosis 8.Heit J.A. Silverstein M.D. Mohr D.N. Petterson T.M. O'Fallon W.M. Melton III, L.J. Risk factors for deep vein thrombosis and pulmonary embolism: a population‐based case‐control study.Arch Intern Med. 2000; 160: 809-815Crossref PubMed Scopus (1838) Google Scholar, 9.Timp J.F. Braekkan S.K. Versteeg H.H. Cannegieter S.C. Epidemiology of cancer‐associated venous thrombosis.Blood. 2013; 122: 1712-1723Crossref PubMed Scopus (727) Google Scholar. There is accumulating evidence that chronic inflammatory conditions, such as inflammatory bowel disease, autoimmune disease and chronic infections, can also serve as persistent provoking factors 10.Nguyen G.C. Bernstein C.N. Bitton A. Chan A.K. Griffiths A.M. Leontiadis G.I. Geerts W. Bressler B. Butzner J.D. Carrier M. Chande N. Marshall J.K. Williams C. Kearon C. Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology.Gastroenterology. 2014; 146: 835-848Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 11.Novacek G. Weltermann A. Sobala A. Tilg H. Petritsch W. Reinisch W. Mayer A. Haas T. Kaser A. Feichtenschlager T. Fuchssteiner H. Knoflach P. Vogelsang H. Miehsler W. Platzer R. Tillinger W. Jaritz B. Schmid A. Blaha B. Dejaco C. et al.Inflammatory bowel disease is a risk factor for recurrent venous thromboembolism.Gastroenterology. 2010; 139: 787Google Scholar, 12.Grainge M.J. West J. Card T.R. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study.Lancet. 2010; 375: 657-663Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar, 13.Tichelaar Y.I. Kluin‐Nelemans H.J. Meijer K. Infections and inflammatory diseases as risk factors for venous thrombosis. A systematic review.Thromb Haemost. 2012; 107: 827-837Crossref PubMed Scopus (83) Google Scholar, 14.Holmqvist M.E. Neovius M. Eriksson J. Mantel A. Wallberg‐Jonsson S. Jacobsson L.T. Askling J. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization.JAMA. 2012; 308: 1350-1356Crossref PubMed Scopus (104) Google Scholar, 15.Yusuf H.R. Hooper W.C. Grosse S.D. Parker C.S. Boulet S.L. Ortel T.L. Risk of venous thromboembolism occurrence among adults with selected autoimmune diseases: a study among a U.S. cohort of commercial insurance enrollees.Thromb Res. 2015; 135: 50-57Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 16.Zoller B. Li X. Sundquist J. Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow‐up study from Sweden.Lancet. 2012; 379: 244-249Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar. The presence of co‐morbid conditions that are not important risk factors for VTE does not influence whether thrombosis is considered provoked or unprovoked. However, it can be difficult to know if a patient's co‐morbid condition (e.g. rheumatoid arthritis) is sufficiently associated with recurrent VTE for the patient to be categorized as having had VTE provoked by a persistent provoking factor rather than having had an unprovoked VTE. Active cancer is an important risk factor for VTE, and cancer that has not been cured is considered to be active. After what is anticipated to be curative treatment, there is often uncertainty about whether cure was achieved until the patient has had a prolonged disease‐free interval. However, there is no standardized disease‐free interval that establishes that a cancer is cured; to be confident of cure, the required length of this interval will differ according to the type of treatment (e.g. surgical vs. non‐surgical treatment) and the type and stage of the cancer. Recommendations for definitions of ‘VTE provoked by a transient risk factor’, ‘VTE provoked by a persistent risk factor’ and ‘unprovoked VTE’ are given in Table 1. We propose definitions for provoked and unprovoked VTE to facilitate comparability of patient populations across studies, and to help with decisions about duration of anticoagulant therapy in individual patients. There may, however, be good reasons for investigators to use criteria different to those we have proposed to identify patients as having ‘VTE provoked by a transient risk factor’, ‘unprovoked VTE’ or VTE provoked by a persistent risk factor. We do not discourage this, but encourage investigators to explain why they have chosen other criteria for this categorization. We also encourage investigators to always describe the categorization criteria they have used. In relationship to unprovoked VTE, this description should note (i) if there was extensive screening to detect and exclude patients with occult malignancy and (ii) if patients with thrombophilia, detected either by routine or discretionary testing, were excluded. They should also report if patients who are categorized as having unprovoked VTE have either transient or persistent risk factors for VTE that do not satisfy criteria for a provoked VTE, and report outcomes in these subgroups of patients. We suggest that reporting of recurrent VTE outcomes in subgroups of patients with unprovoked VTE (i.e. presence of minor reversible or persistent risk factors) is more important for interpretation of absolute rates (applicable to cohort studies and randomized trials) than for interpretation of relative treatment effects (applicable to randomized trials). We acknowledge that, despite using standardized criteria (including those that we propose), some patients with VTE will be difficult to categorize as having either provoked or unprovoked VTE. Given that the strength of association between various factors and VTE, and whether or not risk factors were resolved, occur as continua, this is inevitable. There will also be a need to revise the criteria that we have proposed as new information becomes available; for example, it is currently uncertain if weight loss in obese patients lowers the risk of recurrent VTE. Lastly, we are not suggesting that, within each of the three categories that we have described, all patients will have the same risk of recurrence. Other factors influence the risk of recurrence, such as patient sex, post‐treatment D‐dimer level, the number of previous VTEs, and whether deep vein thrombosis was proximal or distal 2.Kearon C. Akl E.A. Comerota A.J. Prandoni P. Bounameaux H. Goldhaber S.Z. Nelson M.E. Wells P.S. Gould M.K. Dentali F. Crowther M. Kahn S.R. 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: e419S-e494SAbstract Full Text Full Text PDF PubMed Scopus (2934) Google Scholar, 5.Kyrle P.A. Rosendaal F.R. Eichinger S. Risk assessment for recurrent venous thrombosis.Lancet. 2010; 376: 2032-2039Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 17.Kearon C. Akl E.A. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism.Blood. 2014; 123: 1794-1801Crossref PubMed Scopus (182) Google Scholar. C. Kearon drafted the document. W. Ageno, S. C. Cannegieter, B. Cosmi, G.‐J. Geersing, P.A. Kyrle and C. Kearon critically reviewed and revised the document before providing final approval. The authors state that they have no conflict of interest.