Introduction

Aims

The aim of this document is to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage venous thromboembolism (VTE) and to to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage VTE.

Methodology

This is the fifth revision of this document which was last published in 2006. A literature search performed from 2005 through June 2011 was made available to the faculty that met in July 2011. This was repeated again through August 2012. Both literature searches were performed by an independent agency (Pharmaceutical Strategic Initiatives, North Carolina) by searching Medline and PubMed using standard key terms such as venous thrombosis, upper extremity deep vein thrombosis, VTE, pulmonary embolism (PE), and thrombosis with limits for humans, clinical trial, randomized controlled trial (RCT), meta-analysis. and practice guidelines. Additional key terms were added that were specific to the subject of each chapter. Similar terms were used to search the Cochrane library. The RCTs and meta-analyses were the main sources used to determine efficacy and harm from different prophylactic and therapeutic methods. Observational studies or results from registries were used only when RCT were not available. Only fully published articles in peer-reviewed journals were used. Studies in which the diagnosis of deep venous thrombosis (DVT) or PE was only clinical without confirmation by an objective test were excluded. Abstracts that have not been subsequently published as full articles were also excluded.

For each section of the document, members of the faculty were provided with the references and documentation as well as the opportunity to provide additional data to update it. The updated section was presented to the whole faculty for discussion and comment. Most changes were made on the spot with the agreement of the whole faculty. Parts that required major changes or additions were rewritten by a group and were presented again to the faculty for unanimous acceptance or suggestions for further changes. This process was iterative until the point when the entire faculty was in agreement.

The final draft produced by the faculty was subsequently sent to the corresponding faculty for comments and additional input. Any further changes or corrections were made with the agreement of the whole faculty.

Levels of Evidence

Discrepancies regarding the significance or level of evidence were resolved by discussion involving all members of the faculty. The following method for determination of levels of evidence was consistently used.

High level of evidence was considered to be provided by RCTs with consistent results or systematic reviews that were directly applicable to the target population. In the past, single RCT has not been accepted as adequate for high level of evidence even when they were of a high quality and methodologically sound, and these were considered to provide moderate evidence.^1–3 However, recent single randomized trials that have been rigorously performed are methodologically reliable and are sufficiently large to give clear results that are applicable to most patients, in most circumstances that have been accepted as high level evidence.

Historically, RCT of thromboprophylaxis was an active agent against placebo or no prophylaxis. Following acceptance of routine thromboprophylaxis in moderate- and high-risk patients, recent trials have compared new agents with established prophylactic measures (eg, enoxaparin in patients undergoing hip or knee surgery). Likewise, recent trials have compared new anticoagulants with established treatments for VTE, for example heparins followed by vitamin K antagonists (VKAs). If such trials give clear results for superiority, noninferiority, or inferiority that are applicable to most patients in most circumstances, they have been accepted as providing a high level of evidence.

Moderate level of evidence was considered to be provided by RCT with less consistent results, limited power, or other methodological problems, which were directly applicable to the target population as well as by RCT extrapolated to the target population from a different group of patients. Low level of evidence was considered to be provided by well-conducted observational studies with consistent results that were directly applicable to the target population.

Review of the literature using the levels of evidence as defined above has revealed areas of lack of evidence or low level evidence and a number of key questions that require to be addressed by future studies. They are stated throughout the document and are summarized in the final section (chapter 24).

Costs

Because this is an international document not focused on the clinical practice of one country or continent and because of the variability in costs in different parts of the world, we have refrained from incorporating consideration of costs or cost-effectiveness in our recommendations. We believe that decisions about costs and resource allocations for health care interventions are more appropriately made by individual health care systems. However, recognizing that health care systems do not have unlimited resources, we have included a section that summarizes available cost-effectiveness evidence for primary prevention and treatment of VTE (chapter 23) that can be used by appropriate decision makers.

Outcomes

Evidence is presented for outcomes such as the incidence of asymptomatic DVT at screening symptomatic DVT or PE, fatal PE, overall mortality, and development of the postthrombotic syndrome (PTS) when available. The decision to use asymptomatic DVT as well as symptomatic DVT or PE is a subjective one based on the following arguments.

The relationship between asymptomatic and symptomatic VTE including PE has been known for some time.^4–6 Reduction in the incidence of asymptomatic DVT has been shown to be associated with a reduction of symptomatic DVT and PE.^7–9 Large studies, such as the international multicenter trial, that were powered to study efficacy on fatal PE have demonstrated that reduction in silent DVT is accompanied by reduction in clinical DVT, clinical PE, and fatal PE. ¹⁰ Another example is the meta-analysis of VKA in orthopedic surgery, ¹¹ which showed a risk ratio (RR) of 0.56 (95% confidence interval [CI] 0.37-0.84) for DVT and 0.23 for PE (95% CI 0.09-0.59) compared to placebo. The VKAs were less effective than low-molecular-weight heparin (LMWH) in preventing total DVT (RR 1.51; 95% CI 1.27-1.79) and proximal DVT (RR 1.51; 95% CI 1.04-2.17). The ratio between reduction in the incidence of DVT and incidence of PE observed in different general surgical, orthopedic, and medical patients as a result of different methods of prophylaxis is not constant, but this is not a valid argument to discard the end point of silent DVT. Thus, regulatory authorities have recognized asymptomatic proximal DVT as a valid endpoint of clinical trials and drug evaluation. As clinical practice and our knowledge base on VTE evolved, so did the regulatory requirements for product approval. A confounding factor is the use of symptomatic events to assess efficacy in trials where ultrasound or venography are also used to detect asymptomatic DVT, because these investigations introduce bias due to treatment of patients with the detected asymptomatic DVT, which suppresses and underestimates the true incidence of symptomatic VTE. The same applies to the current opinion of regulatory bodies and authorities that favors weighting recommendations for effectiveness of prophylaxis or treatment based on symptomatic VTE and mortality. Treating symptomatic DVT (it would be unethical not to treat) suppresses the true effect on mortality. Relatively few PE occur in patients with symptomatic DVT. The majority of PE including fatal PE occurs in patients with asymptomatic DVT. Thus, asymptomatic DVT is an important stage of thromboembolic disease that has not yet manifested itself. Demonstration that asymptomatic below knee DVT is associated with subsequent development of the PTS,^12,13 that 20% of the asymptomatic calf DVT extend proximal to the knee if untreated, ¹⁴ and that 18% of the symptomatic calf DVT are associated with proximal extension or recurrence ¹⁵ also validates adoption of such end points for efficacy evaluation. Because the PTS results in a marked reduction of quality of life and suffering and because there is emerging evidence that it can be prevented by DVT prophylaxis, adequate treatment of lower limb DVT, and prevention of DVT recurrence, we have devoted a separate section to it (chapter 21). Based on the above arguments, we have strived for objectivity in using the evidence present and available, rather than absent (very few studies are powered for mortality as an end point), which results in a large number of recommendations based on high level of evidence for preventing DVT, PE, or recurrent VTE. Such an approach provides clinically important distinctions to guide clinicians concerning prophylactic and treatment regimens.This document presents the evidence in a concise format and attempts to indicate not only the magnitude of the effect of different prophylactic regimens in terms of absolute, as well as relative risk, but also the quality of the studies in terms of the level of evidence: high, moderate, or low. Information on safety (clinically relevant and or major bleeding and other adverse effects) is also provided. We believe that lack of evidence for mortality should not detract from objective evidence of morbidity.

Low–Molecular-Weight Heparins

Regulatory bodies in Europe and North America consider the various LMWHs (both originator and generics) to be distinct drug products. They require clinical validation for specific indications for each drug. Each LMWH must be dosed according to the manufacturer’s label and recommendations. Therapeutic interchange among these products is not appropriate. In our recommendations, we have often used the term LMWH dosed as per label because different LMWHs have been shown to be equally effective and because they have been grouped together in the majority of meta-analyses. The choice of a particular LMWH should be made locally and should be based on the magnitude of the clinical effect, level of evidence, approval by the regulatory authorities for each indication and cost.

Generic LMWHs are pending review or are under review, while some have been approved by individual regulatory affairs agencies. The food and drug administration in the United States has approved a generic LMWH under the generic pathway of approval. On the other hand, the European medicines agency (EMA) and Canadian Regulatory authorities require approval by the biosimilar pathway that may include clinical trial evidence. Neither the EMA nor the Canadian Regulatory authorities have approved any generic LMWH. Other jurisdictions such as Central America, South America, and India have approved generic heparins without clinical trials.