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• W2048539513 abstract "SummaryThis review on the treatment of patients with venous thromboembolic disease consists of three sections. The first section describes the epidemiology, natural history and reasons for treatment of venous thromboembolism (VTE), as well as a short overview on the evaluation of the use of antithrombotic agents and the spectrum of treatment options. In the second section, the evidence from clinical studies available to us in 2005 with the various treatment modalities is summarized. This section describes the current recommendations about how to treat patients with VTE initially and long term. Finally, in the third section the challenges for the treatment of patients beyond 2005 are discussed. This review on the treatment of patients with venous thromboembolic disease consists of three sections. The first section describes the epidemiology, natural history and reasons for treatment of venous thromboembolism (VTE), as well as a short overview on the evaluation of the use of antithrombotic agents and the spectrum of treatment options. In the second section, the evidence from clinical studies available to us in 2005 with the various treatment modalities is summarized. This section describes the current recommendations about how to treat patients with VTE initially and long term. Finally, in the third section the challenges for the treatment of patients beyond 2005 are discussed. Venous thromboembolism (VTE), manifested as deep venous thrombosis (DVT), pulmonary embolism (PE) or both is a frequent clinical problem. It may occur spontaneously or as a complication of other diseases or (surgical) interventions. The annual incidence of objectively confirmed episodes of VTE is 2–3 per 1000 inhabitants [1Kearon C. Salzman E.W. Hirsh J. Epidemiology, pathogenesis, and natural history of venous thrombosis.Hemostasis and Thrombosis: basic principles and clinical practice. 2001; : 1153-78Google Scholar] and this rate appears to be similar in different parts of the world. Traditionally, DVT and PE were considered separate diseases, but increasing evidence indicates that there is much overlap in their etiology, occurrence, prognosis and treatment [2Turkstra F. Koopman M.M. Buller H.R. The treatment of deep vein thrombosis and pulmonary embolism.Thromb Haemost. 1997; 78: 489-96Crossref PubMed Scopus (39) Google Scholar]. To underline the fact that these two diseases are indeed a single clinical entity, the term venous thromboembolism was introduced. Clearly there are small differences in for example the incidence of thrombophilic abnormalities or the case‐fatality rate, but that does not invalidate the concept. It has repeatedly been demonstrated that in patients presenting with symptomatic DVT, 50%–80% have evidence of asymptomatic, sometimes major PE. Conversely, in those presenting with symptomatic PE, asymptomatic DVT can be demonstrated in approximately 80% of the cases. Despite the fact that DVT and PE form a single disease entity and that the treatment strategies are largely identical, the clinical (and regulatory) tradition has been to perform separate trials in the two populations. Most studies performed in the treatment of VTE have focused on the short‐term complications, i.e. in the first 3–6 months. These include: local extension of the disease, particularly in DVT, (further) embolization which in the worst case may lead to death, and recurrence of the disease in the weeks to months after the initial episode. Much less studied, but not therefore less important, long‐term complications are the post‐thrombotic syndrome (PTS), pulmonary hypertension, and the late risk of recurrent VTE. The natural history of untreated symptomatic DVT is not well known, but the landmark randomized study by Barritt and Jordan in patients with clinically diagnosed PE clearly showed that if patients do not receive anticoagulant therapy, approximately 25% will have a fatal recurrence, whereas another quarter of the patients will experience recurrent disease that is not fatal [3Barritt D.W. Jordan S.C. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial.Lancet. 1960; 1: 1309-12Abstract PubMed Scopus (1104) Google Scholar]. This trial together with some earlier uncontrolled studies on the use of heparin with or without vitamin K antagonists (VKA) was the basis for accepting anticoagulant therapy in the treatment of patients with VTE. Historically, three phases can be distinguished in the evaluation of antithrombotic therapies (Fig. 1). These three phases coincide to a large extent with the three steps in the evolution of the outcome assessment of treatment success or failure in the respective clinical studies. The first phase, starting in 1938 and lasting until the early 1960s, is characterized by the introduction of heparin, either alone or in combination with VKA and focused on survival as the major outcome. In these early days VTE was mainly diagnosed clinically in the surgical wards and Murray and Best were the first to report the use of heparin in 28 cases of DVT and seven patients with PE [4Murray G. Best C. Heparin and thrombosis: the present situation.JAMA. 1938; 110: 118-22Crossref Scopus (16) Google Scholar]. All patients showed rapid clinical improvement and no further episodes of VTE were observed. In this study as well as in later and larger cohort studies the study outcome was total mortality. From studies with historic controls it was well known that the mortality rate was high and several authors noted that with the introduction of heparin the ‘results are spectacular’ with a very low case fatality rate [5Dalen J.E. Pulmonary embolism: what have we learned since Virchow?: treatment and prevention.Chest. 2002; 122: 1801-17Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. This period is concluded by the above‐mentioned and only randomized trial of Barritt and Jordan in 1960 [3Barritt D.W. Jordan S.C. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial.Lancet. 1960; 1: 1309-12Abstract PubMed Scopus (1104) Google Scholar]. It was felt appropriate and ethically justified at that time to randomize patients to either no treatment or the combination of heparin (repeated i.v. injections of 10 000 IU every 6 h with a total of six doses) and the oral VKA nicoumalone for 14 days. The study was prematurely stopped after 35 patients had been randomized. No deaths or recurrences occurred in the 16 treated patients, whereas of the patients receiving no treatment five died of recurrent PE and another five patients had a non‐fatal recurrence. The treated group was extended to a total of 54 patients and only one non‐fatal recurrence of PE was observed. The second phase commences in the 1970s and lasts until the early 1990s. This period is characterized by the focus on the documentation of objectively confirmed recurrent episodes of symptomatic VTE during 3–6 months of follow up as the major efficacy outcome and major bleeding as the principal safety measure. During this period several important clinical studies were performed, which had a major impact on the way patients with VTE were treated. These included the definition of the most appropriate range for monitoring of heparin with the APTT [6Basu D. Gallus A. Hirsh J. Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time.N Engl J Med. 1972; 287: 324-7Crossref PubMed Scopus (533) Google Scholar], establishing an INR of 2.0–3.0 as the optimal range for VKA treatment [7Hull R. Delmore T. Carter C. Hirsh J. Genton E. Gent M. Turpie G. McLaughlin D. Adjusted subcutaneous heparin versus warfarin sodium in the long‐term treatment of venous thrombosis.N Engl J Med. 1982; 306: 189-94Crossref PubMed Scopus (379) Google Scholar, 8Hull R. Hirsh J. Jay R. Carter C. England C. Gent M. Turpie A.G. McLoughlin D. Dodd P. Thomas M. Raskob G. Ockelford P. Different intensities of oral anticoagulant therapy in the treatment of proximal‐vein thrombosis.N Engl J Med. 1982; 307: 1676-81Crossref PubMed Scopus (624) Google Scholar] and the demonstration that a 5‐day course of heparin was as effective as the standard 10 days [9Hull R.D. Raskob G.E. Rosenbloom D. Panju A.A. Brill‐Edwards P. Ginsberg J.S. Hirsh J. Martin G.J. Green D. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis.N Engl J Med. 1990; 322: 1260-4Crossref PubMed Scopus (484) Google Scholar, 10Gallus A. Jackaman J. Tillett J. Mills W. Wycherley A. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism.Lancet. 1986; 2: 1293-6Abstract PubMed Scopus (278) Google Scholar]. With the introduction of low molecular weight heparins (LMWH) in the early 1990s the third phase in the evolution of antithrombotic therapies in patients with VTE commenced. In the assessment of efficacy the rate of recurrent disease remained the main outcome, but in addition convenience to the patient and ease of administration, as well as the lack of laboratory monitoring developed as a focus of attention. The incidence of recurrent VTE while on treatment with initial LMWH followed by VKA has gradually decreased over time and the observed rates in the clinical studies in the 1990s varied between 2% and 5% in the first 3 months after the initial event. Therefore, given this very effective therapy, reducing the risk of recurrence has become less a focus than further improving patient care. The success of fixed doses of s.c. LMWH (only adjusted to body weight and given once or twice a day) is not so much due to their better efficacy, but mainly the ease of use and the possibility of treating patients out of hospital [11Levine M. Gent M. Hirsh J. Leclerc J. Anderson D. Weitz J. Ginsberg J. Turpie A.G. Demers C. Kovacs M. 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: 677-81Crossref PubMed Scopus (1250) Google Scholar, 12Koopman M.M. Prandoni P. Piovella F. Ockelford P.A. Brandjes D.P. van der Meer J. Gallus A.S. Simonneau G. Chesterman C.H. Prins M.H. 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: 682-7Crossref PubMed Scopus (1210) Google Scholar]. Both for patients with DVT or with PE, this therapy has revolutionized in the past decade the way patients are treated. However, this third phase has only just started. After LMWH, new oral antithrombotic agents, as well as long acting pentasaccharides that can be given s.c. once a week, have been developed. These compounds will further focus our attention on the ease of use. They can be given in fixed doses and will make the distinction between initial and long‐term treatment obsolete. Furthermore, this third phase is characterized by more attention to the safety aspect of antithrombotic therapy. Previously only major bleeding was accounted for, but researchers increasingly assess the frequency of other bleeding relevant for the patient, but not meeting the criteria for a major bleeding event. These so‐called clinically relevant non‐major bleeds may occur with a frequency of 5%–10% during 3 months of treatment with VKA and the newer agents will be tested for their ability to reduce this frequency. With VKA and the novel compounds the incidence of major bleeding is low (1%–2%) and it is difficult to demonstrate a reduction in this rate. The last part of this first section concerns the spectrum of treatment options for patients with VTE. Regardless of the three development phases described above there has always been this spectrum. At one end is the VTE episode that is massive, either with serious compromise of lung perfusion or with impending gangrene of the leg. In these circumstances aggressive treatment with either thrombolysis or even surgical intervention may be indicated. At the other end of the spectrum there is minimal disease, without the tendency to extend or reoccur, that may resolve without antithrombotic therapy. However, the middle part of the spectrum concerns the vast majority of VTE episodes that require the use of anticoagulants, classically LMWH and VKA. In this second section the available evidence from clinical studies on how to treat patients with VTE is briefly summarized. The very recently published seventh ACCP Conference document on antithrombotic therapy for venous thromboembolic disease is the backbone for this section [13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar]. For initial therapy of both DVT and PE s.c. LMWH is recommended over unfractionated heparin (either i.v. or s.c.). LMWH is given once or twice daily in a dose adjusted to body weight only, without the need for laboratory monitoring. This recommendation is based on at least 14 randomized trials in DVT and 12 randomized comparisons in PE. The data from the meta‐analyses of these two sets of trials is summarized in Table 1 [14Van den Belt A.G. Prins M.H. Lensing A.W. Castro A.A. Clark O.A. Atallah A.N. Burihan E. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.Cochrane Database Syst Rev. 2000; : CD001100Google Scholar, 15Quinlan D.J. McQuillan A. Eikelboom J.W. 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: 175-83Crossref PubMed Scopus (345) Google Scholar]. Although unfractionated heparin is an adequate alternative to LMWH, particularly in patients with severe renal failure, LMWH is preferred because of the similar efficacy, the superior safety, the lower overall mortality, particularly in patients with concomitant cancer, the lower risk of heparin‐induced thrombocytopenia and the possibility for treating patients either entirely or partly at home. The latter applies to both patients with DVT or PE, although the clinical experience is larger in DVT patients. VKA treatment should be initiated together with LMWH on the first treatment day and discontinuation of LMWH is recommended when the INR is stable and above 2.0 [13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar]. Furthermore LMWH (and also unfractionated heparin) should be given for at least 5 days, as no trial has ever demonstrated that a shorter duration is effective.Table 1Recurrent symptomatic venous thromboembolism (VTE), major bleeding and mortality at 3 months – summary of two meta‐analyses in deep vein thrombosis and pulmonary embolismLow molecular weight heparin (%)Unfractionated heparin (%)OR (95% CI)Deep vein thrombosis Recurrent VTE86/1998 (4.3)113/2021 (5.6)0.75 (0.55–1.01) Major bleeding30/2353 (1.3)51/2401 (2.1)0.60 (0.39–0.93) Mortality135/2108 (6.4)172/2137 (8.0)0.78 (0.62–0.99)Pulmonary embolism Recurrent VTE30/988 (3.0)39/895 (4.4)0.68 (0.42–1.09) Major bleeding14/1023 (1.4)21/928 (2.3)0.67 (0.36–1.27) Mortality46/988 (4.7)55/895 (6.1)0.77 (0.52–1.15) Open table in a new tab Recently, the synthetic pentasaccharide fondaparinux has been evaluated for the initial treatment of patients with DVT or PE [16Buller H.R. Davidson B.L. Decousus H. Gallus A. Gent M. Piovella F. et al.Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial.Ann Intern Med. 2004; 140: 867-73Crossref PubMed Google Scholar, 17Buller H.R. Davidson B.L. Decousus H. Gallus A. Gent M. Piovella F. Prins M.H. Raskob G. Segers A.E. Cariou R. Leeuwenkamp O. Lensing A.W. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism.N Engl J Med. 2003; 349: 1695-702Crossref PubMed Scopus (41) Google Scholar]. In the DVT study which included a total of 2205 patients, once daily s.c. fondaparinux in a fixed dose according to body weight category (below 50 kg, between 50 and 100 kg and above 100 kg) was compared to s.c. LMWH, whereas in the PE study with 2213 patients the same fondaparinux regimen was evaluated against i.v. unfractionated heparin. All patients received VKA for 3 months. The two studies convincingly showed that fondaparinux is at least as effective and equally safe as unfractionated heparin for the initial treatment of PE and as LMWH for the initial treatment of DVT. Fondaparinux can therefore be considered a good alternative for initial treatment in patients with VTE. The role of thrombolytic therapy in the initial treatment of patients with DVT is controversial and the current recommendation is to refrain from its use with the only exception of patients with massive ileofemoral DVT at risk of limb gangrene [13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar]. For patients with PE a recent meta‐analysis has brought some light to the existing confusion about whether patients with PE should receive thrombolysis [18Wan S. Quinlan D.J. Agnelli G. Eikelboom J.W. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta‐analysis of the randomized controlled trials.Circulation. 2004; 110: 744-9Crossref PubMed Scopus (528) Google Scholar]. In this analysis Wan and colleagues summarized the data from 11 comparative studies with a total of 748 patients. The first study was performed in 1973 while the last was published in 2002. Various regimens and types of thrombolytics were used; in recent trials mostly 100 mg of recombinant tPA infused over 2 h. Overall, the rate of recurrent PE or death was not different between thrombolysis and heparin (OR 0.67; 95% CI 0.40–1.12). However, when the trials were divided in those that included patients with major PE (defined as hemodynamically unstable at presentation) and those that excluded these patients an interesting difference was observed [18Wan S. Quinlan D.J. Agnelli G. Eikelboom J.W. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta‐analysis of the randomized controlled trials.Circulation. 2004; 110: 744-9Crossref PubMed Scopus (528) Google Scholar]. The results are presented in Table 2. Although the total number of patients with major PE was moderate (n = 254) the rate of recurrent PE or death was significantly lower in those receiving thrombolysis (9.4% vs. 19.0%, OR 0.45; 95% CI 0.22–0.92; Table 2), whereas the risk of major bleeding was doubled. For patients, who were hemodynamically stable there was no benefit from thrombolytic therapy. Hence, it appears appropriate to recommend thrombolytic therapy in the small subgroup of patients (1%–5%) who present with hemodynamic instability (although this was not clearly defined, most studies used the criterion of systolic blood pressure below 90–100 mmHg), provided that there are no contraindications. In all other patients the use of thrombolytics is not indicated. Recently a new controversy has emerged about whether thrombolysis is indicated in patients with echocardiographically detected right ventricular dysfunction [19ten Wolde M. Sohne M. Quak E. Mac Gillavry M.R. Buller H.R. Prognostic value of echocardiographically assessed right ventricular dysfunction in patients with pulmonary embolism.Arch Intern Med. 2004; 164: 1685-9Crossref PubMed Scopus (253) Google Scholar]. At present there is inadequate clinical evidence from randomized trials to recommend the use of thrombolytics in these patients.Table 2Subgroup analysis of trials that included major (hemodynamically unstable) pulmonary embolism compared with those that excluded patients with major pulmonary embolismOutcomeTrials that included patients with major PETrials that excluded patients with major PELysis, n/N (%)Heparin, n/N (%)OR (95% CI)Lysis, n/N (%)Heparin, n/N (%)OR (95% CI)Recurrent PE or death12/128 (9.4)24/126 (19.0)0.45 (0.22–0.92)13/246 (5.3)12/248 (4.8)1.07 (0.50–2.30)Recurrent PE5/128 (3.9)9/126 (7.1)0.61 (0.23–1.62)5/246 (2.0)7/248 (2.8)0.76 (0.28–2.08)Death8/128 (6.2)16/126 (12.7)0.47 (0.20–1.10)8/246 (3.3)6/248 (2.4)1.16 (0.44–3.05)Major bleeding28/128 (21.9)15/126 (11.9)1.98 (1.00–3.92)6/246 (2.4)8/248 (3.2)0.67 (0.24–1.86)Source: Ref. (18). Open table in a new tab Source: Ref. (18). Vena caval interruption, usually with caval filters, for the initial treatment is not recommended for VTE patients who receive anticoagulants. The single landmark randomized study by Decousus et al. [20Decousus H. Leizorovicz A. Parent F. Page Y. Tardy B. Girard P. Laporte S. Faivre R. Charbonnier B. Barral F.G. Huet Y. Simonneau G. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep‐vein thrombosis. Prevention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group.N Engl J Med. 1998; 338: 409-15Crossref PubMed Scopus (1542) Google Scholar] clearly demonstrated that there is no long‐term benefit of a permanent filter. Although initially there was some reduction in (a)symptomatic PE, there was a higher risk of recurrent DVT during long‐term follow‐up, with similar mortality rates. A filter, preferably removable, should therefore be considered only for patients with a contraindication for or a serious complication of anticoagulant therapy, as well as in those with recurrent VTE despite adequate anticoagulation [13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar]. Finally, during the initial phase of VTE treatment ambulation as tolerated is recommended [13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar]. Two elegant studies, but with a limited sample size, provided good evidence that bed rest as an additional measure to anticoagulation does not reduce the incidence of scintigraphically detected PE [21Aschwanden M. Labs K.H. Engel H. Schwob A. Jeanneret C. Mueller‐Brand J. Jaeger K.A. Acute deep vein thrombosis: early mobilization does not increase the frequency of pulmonary embolism.Thromb Haemost. 2001; 85: 42-6Crossref PubMed Scopus (124) Google Scholar, 22Schellong S.M. Schwarz T. Kropp J. Prescher Y. Beuthien‐Baumann B. Daniel W.G. Bed rest in deep vein thrombosis and the incidence of scintigraphic pulmonary embolism.Thromb Haemost. 1999; 82: 127-9Crossref PubMed Scopus (97) Google Scholar]. At present the preferred approach for the long‐term treatment of both DVT and PE is VKA except for those patients with cancer. The dose of VKA should be adjusted to maintain a target INR of 2.5 (range 2.0–3.0) for all treatment durations [13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar]. Although somewhat controversial, the ACCP conference document recommended against high‐intensity VKA therapy (INR 3.1–4.0) as well as against low‐intensity VKA therapy (INR 1.5–1.9) [13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar]. The controversy focuses on whether there may be some patients with a very high risk of recurrence (i.e. those with persistent positive antiphospholipid antibodies) who may benefit from a high‐intensity VKA regimen. The only randomized trial that studied this patient group did not confirm a superiority of high intensity over standard intensity therapy (INR 2.0–3.0) in terms of thrombotic protection [23Crowther M.A. Ginsberg J.S. Julian J. Denburg J. Hirsh J. Douketis J. Laskin C. Fortin P. Anderson D. Kearon C. Clarke A. Geerts W. Forgie M. Green D. Costantini L. Yacura W. Wilson S. Gent M. Kovacs M.J. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome.N Engl J Med. 2003; 349: 1133-8Crossref PubMed Scopus (804) Google Scholar]. Two randomized trials in VTE patients compared the intensity of VKA treatment [24Ridker P.M. Goldhaber S.Z. Danielson E. Rosenberg Y. Eby C.S. Deitcher S.R. Cushman M. Moll S. Kessler C.M. Elliott C.G. Paulson R. Wong T. Bauer K.A. Schwartz B.A. Miletich J.P. Bounameaux H. Glynn R.J. Long‐term, low‐intensity warfarin therapy for the prevention of recurrent venous thromboembolism.N Engl J Med. 2003; 348: 1425-34Crossref PubMed Scopus (810) Google Scholar, 25Kearon C. Ginsberg J.S. Kovacs M.J. Anderson D.R. Wells P. Julian J.A. MacKinnon B. Weitz J.I. Crowther M.A. Dolan S. Turpie A.G. Geerts W. Solymoss S. van Nguyen P. Demers C. Kahn S.R. Kassis J. Rodger M. Hambleton J. Gent M. Comparison of low‐intensity warfarin therapy with conventional‐intensity warfarin therapy for long‐term prevention of recurrent venous thromboembolism.N Engl J Med. 2003; 349: 631-9Crossref PubMed Scopus (762) Google Scholar]. The results taken together indicate that although low‐intensity VKA therapy is more effective than placebo it is less effective than standard‐intensity VKA therapy (INR 2.0–3.0), and does not reduce the incidence of bleeding complications. The recommendations about the duration and type of long‐term treatment in patients with a first episode of VTE are summarized in Table 3 [13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar]. Although VKA is mostly used for long‐term treatment, LMWH is preferred in patients with cancer. A randomized trial performed by Lee et al. [26Lee A.Y. Levine M.N. Baker R.I. Bowden C. Kakkar A.K. Prins M. Rickles F.R. Julian J.A. Haley S. Kovacs M.J. Gent M. Low‐molecular‐weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.N Engl J Med. 2003; 349: 146-53Crossref PubMed Scopus (2300) Google Scholar] clearly demonstrated that 3–6 months of LMWH is more effective than standard intensity VKA (recurrence rate 15.7% vs. 8.0%). The risk of bleeding was similar. These findings are supported by an a priori specified subgroup analysis from two randomized trials [27Hull R. Pineo G.F. Mah A. A randomized trial evaluating long‐term low‐molecular‐weight heparin therapy for three months versus intravenous heparin followed by warfarin sodium in patients with current cancer.Thromb Haemost. 2003; Google Scholar]. As all trials only had a follow‐up period of maximally 6 months it is unclear what should be recommended afterwards. Biological reasoning would suggest that if feasible, the LMWH can be continued for a longer period as is often indicated in patients with active cancer.Table 3Long‐term treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)*Patient categoriesDrugDuration (months)CommentsFirst episode of DVT or PE secondary to a transient (reversible) risk factorVKA3Recommendation applies to both proximal and calf vein thrombosisFirst episode of idiopathic DVT or PEVKA6–12Continuation of anticoagulant therapy after 6–12 months may be consideredFirst episode of DVT or PE and cancerLMWH3–6Continuation of LMWH is recommended indefinitely or until the cancer is resolvedFirst episode of DVT or PE with a documented thrombophilic abnormalityVKA6–12Continuation of anticoagulant therapy after 6–12 months may be consideredFirst episode of DVT or PE with documented antiphospholipid antibodies or two or more thrombophilic abnormalitiesVKA12Continuation of anticoagulant therapy after 12 months may be consideredVKA, vitamin K antagonist; LMWH, low molecular weight heparin.*Based on the Seventh ACCP Conference document (13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar). Open table in a new tab VKA, vitamin K antagonist; LMWH, low molecular weight heparin. *Based on the Seventh ACCP Conference document (13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar). For patients with either a first episode of idiopathic VTE or those with a first episode of VTE and a documented thrombophilic abnormality (such as a deficiency of antithrombin, protein C or protein S, factor V Leiden, prothrombin 20210 gene mutation or high factor VIII levels) the current trial evidence indicates that the duration should be 6–12 months. The benefit of continuation of VKA therapy beyond this time point is uncertain and therefore should be decided on an individual basis. The elements which need to be taken into account in the decision to prolong VKA therapy are the risk of bleeding, the risk of recurrence and the patient's preference (13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar). For those who receive prolonged anticoagulant treatment, the risk‐benefit of continuing should be reassessed in the individual patient at periodic intervals. For patients with a first episode of VTE who have documented antiphospholipid antibodies or two or more thrombophilic conditions, the recommendation is to give VKA for 12 months with the suggestion to continue longer. Also for patients with two or more episodes of confirmed VTE prolonged therapy beyond 12 months is suggested, with the same advice about periodic assessments [13Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar]. Two randomized studies have addressed the efficacy of compression stockings, fitted in the first weeks after the initial thrombosis, for the prevention of the PTS [28Brandjes D.P. Buller H.R. Heijboer H. Huisman M.V. de Rijk M. Jagt H. Ten Cate J.W. Randomised trial of effect of compression stockings in patients with symptomatic proximal‐vein thrombosis.Lancet. 1997; 349: 759-62Abstract Full Text Full Text PDF PubMed Scopus (850) Google Scholar, 29Prandoni P. Lensing A.W. Prins M.H. Frulla M. Marchiori A. Bernardi E. Tormene D. Mosena L. Pagnan A. Girolami A. Below‐knee elastic compression stockings to prevent the post‐thrombotic syndrome: a randomized, controlled trial.Ann Intern Med. 2004; 141: 249-56Crossref PubMed Scopus (598) Google Scholar]. Both compared graduated elastic compression stockings with an ankle pressure of 30–40 mmHg during 2 years vs. no intervention. The total number of patients with a first episode of DVT studied was 374. Taken together the findings indicate that both the incidence of total and severe PTS was reduced by approximately 50%–60%. Interestingly, nearly all diagnoses of PTS were made in the first 2 years of observation. This third section of the review briefly describes the development of new anticoagulant agents and the way they may affect the treatment of patients with VTE. Furthermore, it lists the unresolved issues, which should be studied by proper investigations so that by approximately 2010 the third phase of the evaluation of antithrombotic therapies can be successfully concluded. As a result of the better understanding, down to the molecular level, of how the coagulation system functions, several new compounds have been developed (Fig. 2). As suggested by Weitz et al. [30Weitz J.I. Hirsh J. Samama M.M. New anticoagulant drugs: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 265S-86SAbstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar], these new anticoagulants can be subcategorized into those interfering with the initiation of coagulation (i.e. the tissue factor/factor VIIa complex), those inhibiting propagation of coagulation (i.e. factor Xa, but also the cofactors for Xa generation) and those inhibiting thrombin activity. Another way of categorizing all these new compounds is into direct inhibitors (such as several thrombin and factor Xa inhibitors) and indirect inhibitors (mainly the synthetic pentasaccharides which require the natural anticoagulant antithrombin to work). The major difference however is that the pentasaccharides (fondaparinux and idraparinux) need to be given by s.c. injection, whereas all direct inhibitors are administered orally once or twice daily. They share the characteristic that no dose monitoring is required. The use of fondaparinux in the initial treatment of VTE has been discussed above. Idraparinux, another slightly modified synthetic pentasaccharide has the unique feature that it can be given once weekly by the subcutaneous route. Thus far only a dose finding has been published [31Persist InvestigatorsA novel long‐acting synthetic factor Xa inhibitor (SanOrg34006) to replace warfarin for secondary prevention in deep vein thrombosis. A Phase II evaluation.J Thromb Haemost. 2004; 2: 47-53Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar] and large phase III studies in DVT and PE are underway. The other oral direct factor Xa inhibitors are currently undergoing investigation in phase II studies. Of the oral thrombin inhibitors, Ximelagatran has been the most widely tested both in the treatment and prevention of venous and arterial thrombotic diseases. The efficacy and safety of Ximelagatran in comparison with LMWH combined with VKA has been evaluated in acute VTE in the Thrive treatment study [32Fiessinger J.N. Huisman M.V. Davidson B.L. Bounameaux H. Francis C.W. Eriksson H. Lundstrom T. Berkowitz S.D. Nystrom P. Thorsen M. Ginsberg J.S. THRIVE Treatment Study InvestigatorsXimelagatran vs low‐molecular‐weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial.JAMA. 2005; 293: 681-9Crossref PubMed Scopus (328) Google Scholar] and in comparison with placebo for the long‐term treatment of VTE in patients who had received anticoagulation for 6 months [33Schulman S. Wahlander K. Lundstrom T. Clason S.B. Eriksson H. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.N Engl J Med. 2003; 349: 1713-21Crossref PubMed Scopus (492) Google Scholar]. The first study in 2473 patients with DVT alone or in combination with PE revealed a similar efficacy with respect to recurrent VTE and a trend toward a better safety as assessed by the incidence of major bleeding [32Fiessinger J.N. Huisman M.V. Davidson B.L. Bounameaux H. Francis C.W. Eriksson H. Lundstrom T. Berkowitz S.D. Nystrom P. Thorsen M. Ginsberg J.S. THRIVE Treatment Study InvestigatorsXimelagatran vs low‐molecular‐weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial.JAMA. 2005; 293: 681-9Crossref PubMed Scopus (328) Google Scholar]. In the Thrive III study a total of 1223 patients were included and Ximelagatran was clearly superior in reducing the risk of new episodes of VTE (2.8% vs. 12.6%) during 18 months of follow up with a similar bleeding profile as compared with placebo. The use of Ximelagatran, however, is associated with unexplained elevation of liver enzymes which may occur in 6%–12% of patients. This has thus far hampered the registration of this compound for the treatment of VTE. There is no doubt that the compounds already evaluated in phase III as well as those currently under study will significantly change the treatment of VTE in the next 5 years. It is already becoming clear that the distinction between initial and long‐term treatment is going to disappear. These new compounds are given right from the time of diagnosis and continued for 6–12 months, or even longer if indicated. Furthermore, no laboratory monitoring is required, thereby further stimulating out of hospital treatment and making these drugs easy to use. Despite these advances there are several areas which require further study as at present the available clinical evidence does not allow for solid recommendations and therefore clinicians are often uncertain about the proper treatment strategy. First, probably the most confusing area is the duration of long‐term treatment. Although the ACCP conference document gives some guidance, who will benefit from prolonged treatment remains a matter for individual judgment. Hopefully a better knowledge of the individual risks of recurrence and bleeding, together with the development of reliable instruments to assess the patients’ preference may make this decision easier. Also the role of the measurement of residual thrombosis and the presence of certain thrombophilic profiles need to be further studied, in particular whether these may be indicators for prolonged treatment. Secondly, another unsolved topic is the importance of right ventricular dysfunction as assessed by ultrasound, CT scan or biomarkers in patients with PE and a normal blood pressure. Whether they may benefit from more aggressive therapy (thrombolysis or catheter removal of the thrombus) remains uncertain. Thirdly, with the better non‐invasive techniques to detect isolated DVT in the calf veins or muscular veins an old unresolved problem has been reintroduced. Do these patients need a full course of anticoagulant therapy or can surveillance with ultrasound safely detect those thrombi that will extend? Finally, what is going to be the role of caval filters? In particular the new development of filters that can be removed well beyond 5–10 days makes this area confusing. It appeared clear that previous filters were only indicated in those patients that could not be treated with anticoagulants. For these new filters it is necessary to evaluate whether they are useful in certain patient categories at high risk of developing PE. With answers to these remaining questions and the evaluation of new anticoagulants there is no doubt that in the near future the treatment of patients with VTE will become more patient friendly, effective, safe and evidence based." @default.
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