Managing venous thromboembolism in Asia: Winds of change in the era of new oral anticoagulants

Thrombosis Research 130 (2012) 291–301

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Review Article

Managing venous thromboembolism in Asia: Winds of change in the era of new oral anticoagulants Alexander Cohen a,⁎, Kuan Ming Chiu b, Kihyuk Park c, Sinnadurai Jeyaindran d, Karmel L. Tambunan e, Christopher Ward f, Raymond Wong g, Sung-Soo Yoon h a

Vascular Medicine, King's College Hospital, London, United Kingdom Cardiovascular Center, Far Eastern Memorial Hospital, Oriental Institute of Technology, New Taipei City, Taiwan Division of Vascular Surgery, Daegu-Catholic University Hospital, South Korea d Department of Medicine, Hospital Kuala Lumpur, Malaysia e Division of Hematology-Medical Oncology, Department of Internal Medicine, School of Medicine, University of Indonesia, Jakarta, Indonesia f Department of Haematology and Transfusion Medicine, Royal North Shore Hospital: Northern Blood Research Centre, Kolling Institute, University of Sydney, New South Wales, Australia g Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, N.T. Hong Kong, China h Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea b c

a r t i c l e

i n f o

Article history: Received 20 February 2012 Received in revised form 24 May 2012 Accepted 24 May 2012 Available online 4 July 2012 Keywords: Anticoagulant Asia Oral Treatment Venous Thromboembolism VTE

a b s t r a c t Despite advances in the management of venous thromboembolism (VTE), treatment of many patients worldwide, especially in Asia, remains inadequate and/or discordant with prevailing guidelines. Although epidemiological studies consistently report lower incidences of VTE in Asians than Caucasians, VTE rates in Asia have probably been gravely underestimated, partly due to comparatively lesser ascertainment. It is becoming evident that Asians are at much higher risk of VTE than was hitherto supposed. Nevertheless, VTE riskassessment is not routine in Asia and thromboprophylaxis rates are much lower than in Western nations. It is important to base decisions about anticoagulation on individual circumstances and weigh the potential benefits and risks. The conventional VTE management paradigm is not ideal. New oral anticoagulants offer advantages over current modalities that may help to streamline patient care and reduce healthcare costs. Initially, they will be mainly used in uncomplicated cases and, in the absence of clear differences in efficacy or safety, convenience, tolerability/adherence and cost will determine treatment choice. There is clear scope to improve VTE prevention and treatment in Asia. Key priorities are raising awareness of best practice and properly implementing guidelines. Uncertainty about the burden of VTE and concern about bleeding are barriers. High-quality Asian epidemiological data are needed to guide healthcare policy and evidence-based practice. More data on the occurrence and management of bleeding complications in Asian patients are also required. Meanwhile, physicians should remain vigilant and strive to act early, decisively and appropriately to diagnose and treat VTE, particularly in patients at high risk. © 2012 Elsevier Ltd. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk Factors, Epidemiology and Burden of VTE in Asia . . . . . . . . Changing Paradigms in VTE Management . . . . . . . . . . . . . . VTE Management Guidelines and Practice in Asia-Pacific . . . . . VTE Treatment . . . . . . . . . . . . . . . . . . . . . . . . Practicalities of VTE Management in the Era of New Oral Anticoagulants Which Anticoagulation Strategy to Pursue? . . . . . . . . . . . Inpatient Vs. Outpatient Treatment . . . . . . . . . . . . . . . Treatment Duration . . . . . . . . . . . . . . . . . . . . . . Treatment Interruption . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: King's College Hospital, London, SE5 9RS, United Kingdom. Tel.: + 44 20 3299 3015; fax: + 44 20 3299 3927. E-mail address: [email protected] (A. Cohen). 0049-3848/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2012.05.025

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Bleeding and Overdose . . . . . . . . Managing Bleeding . . . . . . Monitoring . . . . . . . . . . . . . Managing VTE in Special Circumstances Renal Impairment . . . . . . . Multi-drug Therapy . . . . . . Bodyweight . . . . . . . . . . Conclusions and Recommendations . . . . Guidelines Implementation . . . . . . Changing the Anticoagulation Paradigm Conflict of Interest Statement . . . . . . . Acknowledgements . . . . . . . . . . . . References . . . . . . . . . . . . . . . .

A. Cohen et al. / Thrombosis Research 130 (2012) 291–301

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Introduction Deep vein thrombosis (DVT) and pulmonary embolism (PE) – collectively termed venous thromboembolism (VTE) –are the principal cause of unexpected and preventable hospital patient deaths, accounting for 10% of such fatalities [1,2]. Besides the acute death toll, VTE has a high recurrence rate [3] and serious longer-term complications, notably chronic pulmonary hypertension [4] and post-thrombotic syndrome [5], which affect significant proportions of VTE patients and incur substantial additional treatment costs [6]. Fifty years of advances in preventing and treating VTE have enabled progress in reducing VTE-related mortality and morbidity and the associated healthcare costs [7–17]; yet despite the wealth of compelling evidence from clinical trials and comprehensive best-practice recommendations by expert bodies [2,18–23], many patients worldwide who are at risk of VTE still receive treatment that is inadequate and/or discordant with current guidelines [24–27]. This glaring disparity between evidence and action is a lamentable public health crisis [1,28,29]. Asian physicians appear particularly disinclined to prescribe thromboprophylaxis routinely; reported rates in at-risk surgical and/or medical patients are 20% or lower in China [30], India and Pakistan, and below 1% in Thailand and Bangladesh [27]. This nonchalance probably reflects a lingering perception that VTE is rare in Asians, which stems from limited but influential historical observations [31,32]. Subsequent studies have yielded contradictory findings [33] and because the true burden of VTE in Asia is hard to ascertain, there has been controversy concerning the need for routine thromboprophylaxis [34–37]. Notwithstanding unresolved uncertainties about the incidence of VTE in non-Caucasian populations, it has become increasingly evident that Asians are at significantly greater risk of post-operative VTE than was hitherto supposed, and therefore that routine thromboprophylaxis in Asian at-risk patients is urgently warranted [33,35,37]. Current practice in the Asia-Pacific region differs in some respects from prevailing guidelines and is evolving rapidly, particularly in countries where the medical fraternity has only recently acknowledged VTE as an important issue. Furthermore, newly available options for pharmacological thromboprophylaxis and treatment are changing the current paradigm. It is therefore crucial to raise awareness of VTE among physicians in the region and to disseminate information about the latest evidence in VTE management. To this end, experts from Australia, Hong Kong, Indonesia, Malaysia, South Korea, Taiwan and the United Kingdom, convened to discuss contemporary issues concerning VTE management in the Asia-Pacific region and to make consensus recommendations for everyday practice. Our objectives were: 1) to collate available epidemiological data and address confusion about the burden of VTE in Asian populations; 2) to review current VTE management practices in Asia; 3) to advise on VTE management in different patient groups and special issues that might affect practice; 4) to provide guidance on newly available

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pharmacotherapeutic options and approaches. In so doing, we do not intend to emulate the scope of formal clinical practice guidelines, but rather to provide useful information and practical advice that will help fellow physicians to implement effective interventions that will improve outcomes and quality of life for their patients. This review summarises our key findings and recommendations, which we believe are both timely and pertinent to managing VTE in Asia. Risk Factors, Epidemiology and Burden of VTE in Asia Major orthopaedic surgery (MOS), such as for hip fractures or total hip or knee replacements, carries particularly high risk of VTE [2]. The demonstration that post-operative thromboprophylaxis greatly improves outcomes in Caucasians [8], prompted similar investigations in Asians, which showed that thromboprophylaxis likewise reduces VTE risk in Asian MOS patients, without significantly increased risk of clinically-relevant bleeding complications [33]. VTE rates reported in, mostly small, Asian MOS cohorts vary widely, from some lower than in Caucasians [38–46] to others of similar magnitude [47–57]; these marked differences probably reflect considerable heterogeneity in study designs, patient populations and numbers, procedures performed, and diagnostic methods and criteria used [33]. Nevertheless, a mounting body of evidence indicates that VTE is far from uncommon in Asians, with rates of DVT and PE following MOS approaching those observed in Caucasians [35,37,58,59]. High VTE rates in Asian general surgical and medical cohorts have also been reported [60–63]; however there is a general paucity of data from hospitalised medical or cancer patients in Asia. Studies in Asian populations show consistently that besides major surgery, Asians share the same major non-genetic VTE risk factors as Caucasians, principally, malignancy, immobilisation, trauma, medical illness, and advanced age [64–76]. Most population-based data on VTE epidemiology are from predominantly Caucasian populations. Again, rates vary widely (Table 1) [77–82]; differences between study populations, methodology and size, enrolment criteria, definitions of VTE and management practices, mean that VTE incidence may be underestimated or overestimated and complicate cross-study comparisons [6,80]. The average age-adjusted incidence of VTE is approximately 100–110 per 100,000 person-years, with PE accounting for around one-third of cases [83,84], but may well be higher because VTE is often clinically ‘silent’ [6]. Higher rates of PE diagnosed at autopsy in some studies than others probably account in part for differences between estimated VTE rates [6,83]; for example, autopsy rates in Western Australia are low [77], whereas rates in Olmsted County, Minnesota, USA, exceed the national average [80]. Perplexingly, studies conducted in Asia, mostly in predominantly ethnically Chinese populations, consistently report lower incidences of VTE than in Caucasians (Table 1) [35,75,85–89], with rates on average four-fold or more lower (Fig. 1). However, comparisons between Asian and Western data should be interpreted very cautiously, and it remains unknown to what extent such disparities are genuine, or

A. Cohen et al. / Thrombosis Research 130 (2012) 291–301

293

Table 1 Estimated incidence of venous thromboembolic events from studies in either predominantly Caucasian or Asian populations. Country/region

Population cohort (number)

Metric

Number of VTE events

Australia

Perth community (151,923)

140

France

Brest community and hospital (342,000)

Norway

Nord-Trøndelag County, hospital in- and out-patients age ≥ 20 years (93,769) Olmsted County, Minnesota, community with incident DVT or PE Worcester County, Massachusetts, hospital discharge and outpatients (478,000) UK General Practice community age 20–79 years (1,814,699) Central public healthcare database Retrospective observational National hospital survey National Healthcare Group hospitals admissions (98,121) Korean National Insurance database, hospital and out-patients Taiwan National Health Insurance database, hospital and out-patients Taiwan National Health Insurance database, hospital and outpatients

First event (WHO standard population) First + recurrent First event First event (Segi standard population) First event (age adjusted)

United States of America

United Kingdom Hong Kong Japan Singapore South Korea Taiwan

NR 740 2218 1897

Incidence (100,000 personyears)

Data source [reference]

VTE

DVT

PE

62 (57) 183 136 143 (94) 117

38 (35) 124 NR 93 (61) 48

24 (21) 60 NR 50 (33) 69

116 95 40

40 34 34

Spencer (2008) [81]

Ho (2008) [77] Oger (2000) [78] Naess (2007) [79] Silverstein (1998) [80]

First + recurrent (age adjusted) First event (age adjusted) First event

6,550

138 114 75

Overall incidence First event Overall incidence Overall incidence(Chinese, Indian, Malay)

NR 376 1006 860

21 17 NR 57

17 NR 12 NR

4 NR 6 15

Cheuk (2004) [35] Liu (2002) [85] Sakuma (2009) [86] Molina (2009) [87]

Overall incidence (age adjusted)

NR

14

5

7

Jang (2010) [75]

Crude incidence

5347

16

NR

NR

Lee (2010) [88]

Crude incidence (symptomatic VTE)

2774

17

NR

5

Lee (2011) [89]

Huerta (2007) [82]

VTE: venous thromboembolism. DVT: deep vein thrombosis. PE: pulmonary embolism. NR: not reported.

reflect differences in study methodologies, patient demographics and clinical approaches. There are currently too few Asian epidemiology data to draw firm conclusions, particularly regarding symptomatic events [33], and the incidence of VTE in Asian populations remains uncertain. Indeed, there are good reasons to believe that, similar to post-operative VTE, the overall burden of VTE in Asia has been considerably underestimated. Firstly, not only are Asians subject to the

same non-genetic risk factors as Caucasians, but VTE rates in patients with known non-surgical provoking factors are comparable to those seen in Western studies [90]. Although the ethnic balance of genetic predispositions to VTE differs, with factor V Leiden and prothrombin G20210A common in Caucasians but rare in Asians, higher frequency of proteins C and S and antithrombin deficiency in Asian VTE patients is roughly equivalent to factor V Leiden in Caucasians [90]. While

Fig. 1. Estimated incidences of VTE, DVT and PE from studies in Caucasian and Asian populations.Estimated incidence of venous thromboembolism (VTE), deep vein thrombosis (DVT) and pulmonary embolism (PE) from population/community-based studies in either predominantly Caucasian, or Asian cohorts (see also Table 1). Rate estimates for Caucasian populations are mostly first event and age-adjusted, whereas most Asian studies estimate overall or crude incidence and, except for Korea, are not age-adjusted.

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known interethnic differences in genetics, age profiles, diet, and other factors contribute to a certain proportion of overall VTE risk, these do not fully account for the reported incidence differential between Asians and Caucasians [91]. Secondly, the incidence of VTE across Asia is rising fast, at annual rates of approximately 25%–60% (Table 2) [63,75,86,92–94], and is probably greater than previously reported estimates. This trend is due to a combination of factors including rapid population ageing, increased awareness of VTE and likelihood to pursue a diagnosis [63,75], and also increasing numbers of cancer patients and older and sicker patients undergoing major surgery [2,95]. Thirdly, much of the apparent difference in the incidence of symptomatic VTE between Caucasian and Asian populations probably arises from large variations in ascertainment and access to healthcare [91]. Asian physicians have historically had a low index of suspicion for a problem they believed was rare [95], and were therefore less vigilant than they might otherwise have been [91]. For example, ultrasound scans are commonplace in Western countries, even for minor clots, but far fewer are carried out in often resource-limited Asian countries, resulting in underdiagnosis. Similarly, venography is seldom used in Asia or Australia, unless specified in clinical trials [Tambunan and Ward 2012 personal communications], but has often been used to assess asymptomatic events in MOS studies conducted in most Western countries, which may alter the disease course and conversely lead the frequency of VTE to be overestimated [33]. Comparatively low autopsy rates in Asia, because of cultural practices and/or religious observances [31,95], also make it likely that many PE deaths are undiagnosed. Routine autopsies may reveal higher rates of non-symptomatic thrombosis; for example, autopsy data from Hong Kong, India, Japan and Singapore suggest a similar incidence of PE in Asians and Caucasians [67,96–99]; of 1,000 autopsies reviewed in India, at least 12% of deaths were due to PE, many of which occurred in younger patients with infectious disease [98]. For these reasons, we speculate that the incidence of VTE in Asians may not be markedly dissimilar to Caucasians. We strongly believe that the underestimated burden of VTE in Asia represents an enormous opportunity to improve management practice and patient outcomes in the region.

Table 2 Venous thromboembolism incidence trends in Asia. Country/ region

Metric

Years VTE compared

China

Hospitalised adults (%)

1997 2005

Hong Kong

Cases (per year)

1975 1985

Japan

New PE cases (per year)

1996 2006

Singapore Acute DVT (per 10,000 admissions) South Incidence Korea (100,000 person-years) South New or Korea recurrent DVT cases( per 100,000 population)

1990 2009

DVT PE

0.03 0.14 173 430

58

25

3492 23 7864 7.9 45.3

2004 2008

8.8 3.9 13.8 5.3

2003 2007

35 51

VTE: venous thromboembolism. DVT: deep vein thrombosis. PE: pulmonary embolism.

Annual Data increase source [reference] (%)

64

3.7 7.0

Yang (2011) [93] Woo (1988) [92] Sakuma (2009) [86] Ng (2009) [63]

39(VTE) Jang (2010) [75] 36 Jeon (2010) [94]

Changing Paradigms in VTE Management Successive advances since the landmark introduction of unfractionated heparin (UFH) [7] and the replacement of UFH by low molecular weight heparins (LMWHs) as the standard of care [12], have substantially improved the acute and long-term management of VTE. Other important changes were the transitions from immobilisation to early mobilisation [13] and trends towards out-patient treatment [14] and from short-term to long-term treatment to prevent VTE recurrence and post-thrombotic syndrome [17]. These developments paralleled the rise of evidence-based medicine and are reflected in prevailing clinical practice guidelines for VTE prophylaxis and treatment [2,18–23], which advocate a risk-based management approach and influence much current practice. VTE Management Guidelines and Practice in Asia-Pacific There are good data to support thromboprophylaxis in Asia and some countries, but by no means all, have national guidelines for preventing and/or treating VTE [100–104]; these generally follow guidelines published in 2008 by the American College of Chest Physicians (ACCP) [2,18] and similarly adopt a risk-stratified approach, with MOS or prolonged surgeries, advanced age and the presence of other risk factors placing patients in the highest risk categories. It is important that national guidelines are based on evidence of local risk factors [33], and in this regard Asian guidelines differ somewhat in their risk stratification schemes (Table 3). Unlike ACCP 2008 [2] and 2012 [23] guidelines for prevention of VTE, Chinese and Malaysian guidelines have a very high risk category. Korean guidelines follow Japanese risk stratification, in which prophylaxis is recommended at one level above ACCP, because the Japanese, who are ethnically similar to Koreans, are believed to be less susceptible to VTE than Caucasians [102]. Indian guidelines use a risk assessment score card, in which items represent from one to five risk factors that contribute to a total score [101]. However, VTE risk-assessment is not routine in Asia, even in countries with guidelines; many hospitals lack VTE management protocols, and many patients still do not receive thromboprophylaxis appropriate to their level of risk [27,105–110]. Commonly cited reasons for under-thromboprophylaxis in Asia, particularly among surgeons, include fear of excessive bleeding, confusion about risk assessment and uncertainty about prescribing anticoagulants [90,105–108]. There is a clear unmet need for better implementation of existing guidelines and/or national or regional guidance on how best to manage VTE. In setting standards for best practice, it is important to acknowledge that financial constraints may limit what is feasible, as well as to make evidence-based recommendations that are also practical, userfriendly, and can be implemented in resource-limited settings and at all levels of care [33]. Such guidance should address issues of particular relevance in Asia, such as the use of alternative medicines, and dietary and cultural factors that may predispose patients to bleeding. VTE Treatment Current VTE treatment in Asia-Pacific generally follows ACCP 2008 guidelines. Depending on individual circumstances, initial VTE treatment (≤5 days) is typically subcutaneous LMWH, less often intravenous or subcutaneous UFH, followed by initiation and maintenance of anticoagulation with oral vitamin K antagonists (VKA), which are titrated to attain an international normalised ratio (INR) of 2–3. Fondaparinux is used very little outside the setting of thromboprophylaxis, but it is an option in cases of heparin-induced thrombocytopenia (HIT) [Ward 2011 personal communication]. In our experience, HIT is rarely encountered; however, this may be because HIT is also underrecognised in Asia [Cohen 2012 personal communication]. Occasionally, thrombolysis/thrombectomy, an inferior vena

Table 3 Risk stratification of surgical and medical patients in North American and Asian VTE management guidelines. Guideline [reference] USA ACCP 2008 [2]

China [100]

Malaysia [103]

South Korea [102]

Low

• Minor surgery in mobile patients • Medical patients who are fully mobile

• Operating time b30 minutes, no other risk factors, b 40 years old

• Surgery b 30 minutes in patients b 40 years old with no additional risk factors • Minor medical illness

Moderate

• Most general, open gynaecologic or urologic surgery patients • Medical patients, bed-rest or sick

High

• Hip or knee arthroplasty, hip fracture surgery • Major trauma, spinal cord injury

• Surgery b30 minutes, no other risk factors, 40–60 years old or • Surgery b30 minutes, and one or more risk factors or • Surgery >30 minutes, no risk factors, b 40 years old • Surgery b30 minutes, and one or more risk factors, > 60 years old or • Surgery > 30 minutes, and one or more risk factors, 40–60 years old

• Surgery b 30 minutes in patients with additional risk factors • Surgery b 30 minutes in patients aged 40–60 years with no additional risk factors • Surgery > 30 minutes in patients b40 years with no additional risk factor • Immobilised patients with acute medical illness • Surgery b 30 minutes in patients >60 years old or with additional risk factors • Surgery > 30 minutes in patients >40 years old or with additional risk factors • Fractures, or undergoing major orthopaedic surgery of the pelvis, hip, or lower limb

• Minor surgery in mobile patients • Medical patients who are fully mobile • Major surgery in age b 40 years Minor surgery in age b 60 years • Major surgery in age > 40 years or with risk factor • Non-major surgery in age >60 years or with risk factor • General open gynaecologic or urologic surgery • Medical patients on bed-rest or sick

• Major orthopaedic surgery • Severe trauma • Spinal cord injuries or • Surgery >30 minutes, and some risk factors, > 40 years old

• Surgery > 30 minutes in patients >40 years old plus prior VTE, cancer, or molecular hypercoagulable state • Patients with lower limb paralysis

Very high

• Total hip or knee replacement, hip fracture surgery • Major trauma • Spinal cord injury • Major cancer surgery with additional risk factor • Major surgery in patients with previous VTE or thrombophilia

A. Cohen et al. / Thrombosis Research 130 (2012) 291–301

Risk stratum

USA = United States of America. ACCP = American College of Chest Physicians.

295

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cava (IVC) filter, or other surgical strategies may be indicated. Longterm treatments (≥3–12 months) are principally VKAs, primarily warfarin, or LMWH, for example in patients who are intolerant to warfarin or unlikely to take it as prescribed, or who have cancer or VTE recurrence while on warfarin therapy. Some patients may require extended or indefinite VKA treatment, with periodic assessment of individual risk/benefit [18]. The ACCP 2012 guidelines recommend: 3 months of anticoagulant therapy in patients with a first proximal VTE provoked by surgery or secondary to a non-surgical transient risk factor, or who have unprovoked or recurrent VTE and high bleeding risk; extended therapy for unprovoked first proximal VTE or recurrent VTE with low or moderate bleeding risk. Extended therapy for at least 3 months is also recommended for cancer-associated thrombosis, with LMWH favoured over vitamin K antagonists [19]. Practice in the Asia-Pacific region differs in certain respects from ACCP 2012 guidelines, especially in areas where clinical experience holds sway over evidence-based medicine. For example, most physicians do not consider extended treatment until after two or more recurrences. The use of whole-leg ultrasound to diagnose distal DVTs is widespread in Australia, but not elsewhere [Ward 2011 personal communication]. The risk of gastrointestinal bleeding is an important influence on practice, whereas ACCP guidelines on bleeding history tend to be vague. An analysis of treatment patterns in a Korean hospital showed that surgeons were more likely to use thrombolysis or insert an IVC filter before pharmacological anticoagulation, whereas haematologists and internal medicine specialists use operative measures very conservatively in patients who are haemodynamically stable and without respiratory compromise [111]. Asia-Pacific countries are very heterogeneous in terms of affluence, and healthcare insurance and reimbursement systems vary widely; for example, a certain drug may be government reimbursed or subsidised in some countries, but patient-paid in others. There may also be limitations on the use of anticoagulant drugs. For example, parenteral LMWH is limited to 3 weeks in Korea, and in Australia, the Pharmaceutical Benefits Scheme only subsidises enoxaparin at individual doses lower than 120 mg. Although conventional pharmacotherapeutic modalities have proven efficacy and safety and are very familiar to physicians, they have some drawbacks that make the prevailing treatment paradigm less than ideal, both for patients and physicians [112]. In particular, the need to inject heparin, often twice-daily, not only causes discomfort and aversion among patients, but is also inconvenient, whether administered in hospital or outpatient settings, and incurs a considerable burden of healthcare professionals’ time and lost productivity by families or caregivers. Regular warfarin monitoring and dose recalibration are also very time-consuming for doctors, patients and caregivers. These unmet needs have driven the quest for improved anticoagulants that may cost-effectively circumvent limitations associated with conventional agents, in particular the many shortcomings of warfarin (Table 4) [112,113]. There is currently great interest in new oral agents that inhibit specific blood-clotting factors. Dabigatran etixilate, a direct thrombin inhibitor, and the direct factor Xa inhibitor rivaroxaban, are already approved in the European Union, Canada and several Asian countries for VTE thromboprophylaxis following MOS [114,115]. In clinical trials, both agents proved non-inferior to the current standard of care for treating acute VTE, with a similar safety profile (Table 5) [116,117]. The rivaroxaban clinical development programme included patients from China, Indonesia, Malaysia, Philippines, Singapore, Taiwan and Thailand, and efficacy and safety findings in Chinese orthopaedic patients were consistent with those from the whole study population [118]. However, very few safety data on thromboprophylaxis with new oral anticoagulants in Asian patients have been published. Further regulatory filings for approval in therapeutic indications are either underway, or anticipated. These new oral anticoagulants offer the first alternative to warfarin for 65 years and may facilitate streamlined patient care that reduces

Table 4 Characteristics of an ideal pharmacologic anticoagulant. • Oral administration • Fixed dosing • Rapid onset and offset of action, and rapid action when reinstituted • Predictable pharmacokinetics/pharmacodynamics • No routine coagulation monitoring (but can be monitored if necessary) • Multiple elimination routes • Reversible or has an antidote • No significant food or drug interactions • No risk of thrombocytopenia or other significant side effects

direct and indirect healthcare costs associated with LMWH and warfarin [112]. Dabigatran preceded by LMWH or rivaroxaban monotherapy both enable a simplified regimen, which might be expected to result in greater therapy adherence and cost savings; however, Asian pharmacoeconomic data to support such a conjecture are lacking and more studies are needed. Much work also remains to determine the eventual role of new oral anticoagulants in VTE management, and there are currently no formal guidelines for their use. We have therefore considered several important practical issues pertaining to VTE management in the era of new oral anticoagulants. Practicalities of VTE Management in the Era of New Oral Anticoagulants Which Anticoagulation Strategy to Pursue? The principal rationales underlying trials of new oral anticoagulants were to replace warfarin or both heparin and warfarin. The RE-COVER trial evaluated dabigatran versus warfarin in a dual-drug scheme, with at least 5 days LMWH to provide early intensive anticoagulation prior to commencing dabigatran or to cover the lagtime to reach an effective drug level with VKA [116]. The rivaroxaban EINSTEIN DVT study differed in adopting an all-oral single agent Table 5 Efficacy and safety results in trials of VTE treatment with dabigatran and rivaroxaban. Study name

RE-COVER [116]

EINSTEIN DVT [117]

Agent vs. comparator

Dabigatran vs. warfarin Recurrent VTE or related death 1,274 1,265 30 (2.4) 27 (2.1) 1.10 (0.65–1.84) b 0.001 Major bleeding 1,274 1,265 20 (1.6) 24 (1.9) 0.82 (0.45–1.48) 0.38 Major or clinicallyrelevant non-major bleeding

Rivaroxaban vs. LMWH/VKA First symptomatic recurrent VTE 1,731 1,718 36 (2.1) 51 (3.0) 0.68 (0.44–1.04) b 0.001 Major bleeding 1,718 1,711 14 (0.8) 20 (1.2) 0.65 (0.33–1.30) 0.21 First major or clinically-relevant nonmajor bleeding during treatment 1,718 1,711 139 (8.1) 138 (8.1) 0.97 (0.76–1.22) 0.77

Primary efficacy endpoint Number of patients Number of events (%) Hazard ratio (95% CI) p-value (non-inferiority) Safety endpoint Number of patients Number of events (%) Hazard ratio (95% CI) p-value Safety endpoint

Number of patients Number of events (%) Hazard ratio (95% CI) p-value

1,274 1,265 71 (5.6) 111 (8.8) 0.63 (0.47–0.64) 0.002

RE-COVER: randomised, double-blind, double-dummy, parallel-group study comparing the efficacy and safety of oral dabigatran etexilate to warfarin for six months of treatment of acute symptomatic VTE, following initial treatment with a parenteral anticoagulant approved for this indication. EINSTEIN DVT: randomised, open-label, active-controlled, parallel-group, studies comparing the efficacy and safety of oral rivaroxaban versus standard therapy in the initial treatment of symptomatic deep vein thrombosis and long-term prevention of recurrent venous thromboembolism. CI: confidence interval; LMWH: low-molecular-weight heparin; VKA: vitamin K antagonist; VTE: venous thromboembolism.

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approach from the outset, with rivaroxaban 15 mg twice-daily for 3 weeks to provide intensive initial treatment to reduce the thrombus burden, then 20 mg once-daily thereafter, versus standard-of-care with acute LMWH/UFH injections followed by VKA [117]. The hazard ratio (HR) of dabigatran versus warfarin for recurrent VTE or related death in the RE-COVER study was 1.10 (95% confidence interval [CI] 0.65–1.84) [116]. The HR of rivaroxaban versus warfarin for first symptomatic recurrent VTE or related death in the EINSTEIN DVT study was 0.68 (95% CI 0.44–1.04) (Table 5) [117]. In the absence of head-to-head data, more time and wider experience outside clinical trials are needed to determine whether either of these anticoagulants has advantages in terms of greater efficacy or reduced bleeding risk. Without clear evidence of differences in efficacy between LMWH/VKA and newer oral anticoagulants, treatment choice will be influenced by ease of use, consistency and quality of anticoagulation, monitoring needs, tolerability/side-effects profiles, patient preference and adherence, and cost. For most patients already managed well on VKA, it will probably not be necessary to switch to a new oral anticoagulant. However, some patients currently on VKA may benefit from changing to a new oral anticoagulant, these include patients: unable to comply with INR monitoring; who have unstable or sub-therapeutic INR, for example, those on chronic antibiotic therapy; with adverse drug interactions; or who refuse warfarin. In cases of newly-diagnosed VTE, oral anticoagulant selection will depend on discussions between the physician and patient about ease of use, monitoring versus lack of monitoring requirement, and relative cost of available different drug options. The prospect of replacing longterm LMWH for many patients is potentially appealing; however, there are no data, Asian or otherwise, and LMWH will remain the standard of care in cancer patients with VTE until trials of the new oral anticoagulants in cancer-associated thrombosis are performed and the results known. Inpatient Vs. Outpatient Treatment Provided with adequate support, the majority of proximal DVT cases can be treated as outpatients. In King's College Hospital, London, UK, 60% are never admitted [Cohen 2011 personal communication]; however, admission for 12–24 hours may sometimes be necessary to let severe swelling and pain subside before a patient is fitted with compression stockings and mobilised. Being more convenient and patient-friendly to administer than injected anticoagulants and not requiring routine monitoring like warfarin, the new oral anticoagulants have attributes that might be anticipated to facilitate outpatient management. Data on rivaroxaban support treatment of all DVT patients, except those undergoing thrombolysis or with severe renal failure (creatinine clearance [CrCl] b15 mL/min), without pre-screening to exclude patients with hypercoagulable states or proteins C or S deficiency. However, until more supporting evidence and experience for such practice accrues, some physicians may remain more conservative, particularly with high-risk patients, and prefer to admit the patient, initiate anticoagulation and observe them until the risk of bleeding subsides. Treatment Duration Data on extended therapy with new oral anticoagulants are limited and available evidence does not support prescription for longer than the conventional duration. Current ACCP guidelines recommend anticoagulation for at least 3 months from index VTE, followed by a variable period of further treatment for up to 6 months to reduce the risk of VTE recurrence; treatment beyond 6 to 12 months is only recommended for patients with unprovoked VTE and a clear efficacy and/or safety advantage or those with recurrent VTE. In EINSTEIN EXT, a placebo-controlled extension study of patients treated for a first VTE episode whose risks

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versus benefits of extending anticoagulation were in equipoise, rivaroxaban given for up to 12 months reduced recurrent symptomatic VTE by 82%. [117]. However, there are no data on patients with a clear indication for prolonged prophylaxis such as recurrent DVT, because these were excluded from the extension cohort. Extended dabigatran therapy beyond 6 months also significantly reduced VTE recurrence, with a relative risk reduction of 92% versus placebo [119]. There are trends towards treating post-operative VTE for shorter periods (3 months) than unprovoked VTE, and PE for longer than DVT [Cohen 2011 personal communication]. Treatment Interruption In general, anticoagulation should stop 24 hours before surgery and not recommence at a full dose until 12–24 hours postoperatively. However, decisions about interrupting anticoagulation must be based on individual circumstances including the indication, type of surgery and the patient's thrombotic status, bleeding risk and renal function. For example, a longer time should be allowed for drug clearance in patients with renal impairment, whereas cautious anticoagulation could begin earlier after complex or orthopaedic surgeries; if there is no ongoing bleeding problem, rivaroxaban could start as early as 6–10 hours post-surgery, or within 12 hours if bleeding is well-controlled. Bleeding and Overdose Patient safety is of paramount importance, and in this regard there are too few published Asian data, particularly regarding management of potential bleeding complications associated with the new oral anticoagulants. Encouraging unpublished data from EINSTEIN DVT, in which 20% of study subjects were Asian, show a trend to less recurrence and bleeding in Asian DVT patients who were treated with rivaroxaban than with LMWH/warfarin, with no major bleeding in more than 140 PE patients [Cohen 2012, personal communication]. EINSTEIN PE also showed reduced major bleeding, and EINSTEIN DVT and PE collectively showed a significant halving of major bleeding, with lower rates of intracerebral haemorrhage [120]. The risk of major bleeding in EINSTEIN EXT was 0.7%, with no fatal haemorrhage [117]. Nevertheless, bleeding with new oral anticoagulants will undeniably occur, especially if prescribers fail to appreciate the potential risks and take appropriate precautions; older, frail and less healthy patient groups than were enrolled in clinical trials may be at particular risk. In an audit in New Zealand, a high proportion of bleeding incidents among frail elderly patients occurred either because dabigatran was initiated before the INR had fallen below 2 (25%), or because patients had poor renal function (58%) [121]. Managing Bleeding Irrespective of which anticoagulant drug(s) are used to manage VTE, it is important to balance the risk of bleeding against the benefit of treatment. Should bleeding occur, clinicians must weigh the risk of the bleed, including severity and location, versus the risk of thrombosis if they withdraw anticoagulation. Thrombotic risk is a product of the patient's risk factors and the time elapsed since the index VTE event. The International Society of Thrombosis and Hemostasis defines major bleeding based on three criteria: 1) Fatal or in a critical area; 2) Causing a drop in haemoglobin greater than 2 mg/dL; 3) Requiring transfusion of at least two units of blood/packed red blood cells [122]. If major bleeding occurs, the consensus is that anticoagulation should be stopped until haemostasis is secured through either surgical or conservative means [123]. Anticoagulation does not need to discontinue for minor bleeding. The risk of thromboembolic complications does increase upon cessation of anticoagulation, reaching 40% within 1 month of stopping anticoagulation in acute VTE patients, then dropping to 10% during the second and third months [124]. At present, too little experience has been gained to

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gauge the extent to which current recommendations are helpful in managing bleeding complications of the new oral anticoagulants and there is a need for better understanding and clear guidance about what to do when bleeding episodes occur. Checking haemostasis in cases of overdose or bleeding is of relatively little use for monitoring the new oral anticoagulants and should not be used to guide clinical decisions, because the meaning of the results is unknown. New anticoagulants will prolong prothrombin time (PT) and increase activated partial thromboplastin time (aPTT) in standard tests, so physicians and surgeons should be aware that PT and aPTT results may be abnormal in patients on rivaroxaban or dabigatran. If a patient has taken more than the prescribed dose, whether deliberately or accidentally, a new anticoagulant should be stopped and best supportive care given [125,126]. Activated charcoal may reduce absorption in case of overdose [126,127], and dabigatran can also be dialysed [125]. Asymptomatic patients who are not bleeding should be hospitalised under observation for a few days. Symptomatic patients should be treated as for bleeding. Supportive care in an emergency situation may include fresh frozen plasma, recombinant Factor VIIa or clotting factor concentrates at the physicians’ discretion; however, there is little supporting evidence for such practice [128]. Another common concern among doctors is the ability to reverse anticoagulation in patients who have bleeding events when treated with new oral anticoagulants, compared to warfarin. The anticoagulant effect of rivaroxaban abates in about 24 hours following withdrawal, which is approximately the same time as oral vitamin K reverses warfarin [128]. There is some experience with the use of prothrombin complex concentrate (PCC) to reverse warfarin on an emergent basis. A small cross-over study on the effect of PCC in healthy volunteers taking dabigatran or rivaroxaban, showed that PCC reverses the biochemical effects of rivaroxaban on PT and endogenous thrombin potential, but has no effect on prolongation of aPTT, thrombin time and ecarin clotting time caused by dabigatran [129]. Monitoring As with LMWH, monitoring may be desirable in some circumstances, for example acute bleeding or emergency surgery; however, the role of monitoring for new oral anticoagulants is currently unclear, because there is no consensus on the optimal test parameters or drug levels to use. Until the correct therapeutic range is known, it will not be informative to measure drug levels in thrombosis. In contrast to warfarin, and similar to LMWH, the results of new tests will depend critically on the timing of administration, because blood levels peak and fall rapidly, and it will be some time until standardised assays with clinical correlates are available. In practice, the future of monitoring lies in new assays including HEMOCLOT® dilute thrombin time (dabigatran) [127] and specific anti-Factor Xa assays (rivaroxaban). The most likely use of a calibrated anti-factor Xa assay would be to check trough levels in cases where the time of administration is known, for example to confirm plasma concentration below a safe threshold to proceed with surgery or invasive procedures. Managing VTE in Special Circumstances Renal Impairment Kidney disease, which is particularly common in Asians [130], increases the risk of thrombosis and bleeding, making it important to know how to manage patients with renal impairment. Although warfarin is cleared by the liver, warfarin-induced bleeding is more likely in patients with impaired renal function [131]. Dabigatran is primarily excreted via the kidneys [125] whereas approximately two-thirds of rivaroxaban is metabolised by the liver; the remaining one-third of

the administered dose is excreted unchanged in the urine, mainly via active secretion [126]. Data on use of the new oral anticoagulants in the setting of renal impairment derive from studies that compared the effects of prophylactic doses in volunteers with and without renal insufficiency. In considering these findings, it is important to bear in mind that a greater impact on renal function would be expected at the higher doses used in treatment. Dabigatran exposure, as measured by area under the curve (AUC), was 2.7-fold higher in volunteers with CrCl of 30–50 mL/min and six times higher in those with (CrCl 15–29 mL/min), with double the half life. Dabigatran should therefore be used with caution in patients with moderate renal impairment (CrCl 30–50 mL/min) and is contraindicated in patients with CrCl below 30 mL/min [125]. Rivaroxaban exposure (AUC) increased by 1.4-, 1.5- and 1.6-fold respectively, in patients with CrCl of 50–80, 30–49 and 15–29 mL/min. No dose adjustment is necessary for patients with mild renal impairment (CrCL 50–80 mL/min); however caution should be exercised in using rivaroxaban to treat patients with moderate (CrCl 30–49 mL/min) or severe (CrCl 15–29 mL/min) renal impairment. In such patients, rivaroxaban should be given at therapeutic doses of 15 mg twice-daily for the first 3 weeks followed by a lower dose of 15 mg once-daily thereafter [126]. Multi-drug Therapy It is likely that VTE patients may already be taking anticoagulant or blood-thinning agents such as warfarin, or newer anti-platelet agents and/or aspirin. Warfarin, in particular, has an extensive and growing list of food and drug interactions [113,132], and in cases where there is concern about undesirable interactions in patients on multiple drugs, the new oral anticoagulants offer the potential advantage of having far fewer interactions; few clinically-significant drug or dietary interactions of dabigatran and rivaroxaban have been reported in the setting of VTE prophylaxis following MOS [113]. However, until greater experience of new oral anticoagulants in real-life, long-term therapeutic settings has been gained, clinicians initiating such agents should remain vigilant for potential interactions that may curb or potentiate their action [113]. They should be particularly wary during the crossover period from warfarin to new anticoagulants, when there is a high risk of bleeding, especially before the INR has been brought below 2.0 [121]. When considering initiating anticoagulation in patients on dual anti-platelet therapy, clinicians should weigh the risk/benefit tradeoff. No clinically-significant pharmacokinetic or pharmacodynamic changes have been observed when rivaroxaban is co-administered with non-steroidal anti-inflammatory drugs (NSAIDs), for example, naproxen or aspirin [126]. Concomitant aspirin and dabigatran may increase the risk of bleeding and, although short-term perioperative NSAIDs do not appear to increase bleeding risk in patients on dabigatran, chronic administration increased the risk of bleeding by 50% in patients on both dabigatran and warfarin [125]. Clopidogrel does not significantly affect the pharmacokinetics of either dabigatran or rivaroxaban [125,126]. In general, caution is advisable for patients treated concomitantly with NSAIDs or platelet inhibitors, because these agents typically increase the bleeding risk when used together [126]. Bodyweight The effect of bodyweight on fixed-dose oral anticoagulants is an important consideration in Asians, who tend to have lower bodyweight and BMI than Caucasians that could theoretically increase their risk of bleeding. There is very limited clinical experience of dabigatran at the recommended posology in patients weighing below 50 or more than 110 kg; however, no adjustment is deemed necessary based on available clinical and kinetic data [125]. In the rivaroxaban clinical development programme, extremes of bodyweight (b50 kg or >120 kg) had only a small influence on plasma concentrations and little effect on efficacy. No bodyweight-based dose adjustment of rivaroxaban is required

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[126]. Additional pharmacokinetic studies have shown that bodyweight does not affect AUC at a single 10 mg rivaroxaban dose in patients who weigh less than 50 kg, 70–80 kg, or more than 120 kg [133]. Increasing the start dose of rivaroxaban above 15 mg twice-daily during the first 3 weeks is unlikely to confer greater efficacy due to a dose–response ceiling. Conclusions and Recommendations We have identified key issues and challenges concerning the current and future management of VTE in Asia. Most importantly, prevention is clearly the most cost-effective strategy for managing VTE and there is great scope to improve the practice and discipline of VTE management in Asia. Guidelines Implementation Because the burden of VTE in Asia has been seriously underestimated, risk assessment and thromboprophylaxis are not yet routine, even in countries with VTE guidelines. Furthermore, thromboprophylaxis rates for at-risk patients languish far below those in Europe and the USA. There are urgent needs to properly implement and audit existing guidelines and for regularly updated national and/or regional guidance on how best to manage VTE. Continued uncertainty about the burden of VTE in Asia is a barrier to affording greater priority to this serious public health problem, and high-quality epidemiology data from large welldesigned population-based studies are needed to guide policy in this area. Changing the Anticoagulation Paradigm Conventional pharmacotherapeutic modalities for preventing and treating VTE are less than ideal. Direct oral clotting factor inhibitors are a new class of anticoagulants with some advantages over existing options that may help to streamline patient care and reduce healthcare costs, and will play in increasing role in the future. Asia lags behind in the trend towards greater outpatient treatment of VTE and there are good reasons to follow suit. Management of uncomplicated VTE cases as outpatients would help to control healthcare costs, free hospital beds and reduce inconvenience to patients and their caregivers. An all-oral anticoagulation regime such as rivaroxaban may help to facilitate this change in practice. In the short-term, LMWH and warfarin are likely to remain mainstays of treatment for most patients, particularly in resource-limited settings, and use of the new oral anticoagulants will be limited to uncomplicated cases until more evidence and experience are gained. In particular, more data on the new oral anticoagulants are required in the settings of renal impairment and cancer. Further studies on the occurrence and management of bleeding complications, particularly among Asian patients, during anticoagulant prophylaxis or treatment, are also needed to inform evidence-based best practice. As evidence and experience accrue, the shifting sands of VTE management will continue to offer opportunities to refine clinical practice and improve patient outcomes; however, these will be impossible to realise without a cohesive, integrated and multidisciplinary effort that involves key stakeholders and policy-makers. Meanwhile, physicians should remain vigilant and strive to act early, decisively and appropriately to diagnose and treat VTE, particularly in patients at high risk. Conflict of Interest Statement The authors are all members of the Bayer HealthCare Asia-Pacific Action on Venous Thromboembolism Treatment Advisory Board, and have received honorarium payments for their service in this capacity.

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AC is a medical consultant, and has received consultancy and clinical trial funding from many pharmaceutical companies, including Astellas, AstraZeneca, Bayer, Boheringer-Ingelheim, BMS, Daiichi, GSK, Johnson and Johnson, Mitsubishi Pharma, Pfizer, Portola, sanofi-aventis, Schering Plough, and Takeda. He is an advisor to the United Kingdom Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the National Health Service, on the prevention of VTE. He is also an advisor to Lifeblood: The Thrombosis Charity and is the founder of the European educational charity – The Coalition to Prevent Venous Thromboembolism. CW has been a member of Advisory boards for Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Celgene, Glaxo Smith-Kline, Instrumentation Laboratories and sanofi-aventis, received research support from Pharmion and travel expenses from Janssen, Novartis and Pharmacia. Acknowledgements The Asia-Pacific Action on Venous Thromboembolism Treatment Advisory Board was supported by an educational grant from Bayer HealthCare Pharmaceuticals. Dr David Neil, UBM Medica Asia Pte. Ltd., provided writing assistance and editorial support, which was funded by Bayer HealthCare Pharmaceuticals. References [1] Baglin T. Venous thromboembolism in hospitalised patients: a public health crisis? Br J Haematol 2008;141:764–70. [2] Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(Suppl. 6):S381–453. [3] Samuel Z, Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386–9. [4] Pengo V, Lensing AWA, Prins MH, Marchiori A, Davidson BL, Tiozzo F, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257–64. [5] Kahn SR. The post-thrombotic syndrome: the forgotten morbidity of deep venous thrombosis. J Thromb Thrombolysis 2006;21:41–8. [6] Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, 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;98:756–64. [7] Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960;1:1309–12. [8] Prevention of fatal postoperative pulmonary embolism by low doses of heparin. An international multicentre trial. Lancet 1975;2:45–51. [9] Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988;318:1162–73. [10] Brandjes DP, Heijboer H, Buller HR, de Rijk M, Jagt H, ten Cate JW. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992;327:1485–9. [11] Hommes DW, Bura A, Mazzolai L, Büller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. A meta-analysis. Ann Intern Med 1992;116:279–84. [12] Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med 1999;130:800–9. [13] Partsch H. Bed rest versus ambulation in the initial treatment of patients with proximal deep vein thrombosis. Curr Opin Pulm Med 2002;8:389–93. [14] Koopman MM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van der Meer J, 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. [15] Rodger M, Bredeson C, Wells PS, Beck J, Kearns B, Huebsch LB. Cost-effectiveness of low-molecularweight heparin and unfractionated heparin in treatment of deep vein thrombosis. CMAJ 1998;159:931–8. [16] Brandjes DP, Büller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349:759–62. [17] Prandoni P, Lensing AW, Prins MH, Frulla M, Marchiori A, Bernardi E, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004;141:249–56.

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