This is the current release of the guideline.

This guideline is updates a previous version: Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008 Jun;133(6 Suppl):454S-545S. [393 references]

Patients with venous thromboembolism (VTE), including deep venous thrombosis (DVT), pulmonary embolism (PE), acute upper-extremity deep venous thrombosis (UEDVT), incidentally diagnosed (asymptomatic) DVT or PE, superficial vein thrombosis, splanchnic vein thrombosis, and hepatic vein thrombosis, or complications of venous thromboembolism, including postthrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTPH)

Treatment/Management

Pharmacological Management

1. Low-molecular-weight heparin (LMWH)
   • Once- versus twice-daily administration
2. Intravenous (IV) or subcutaneous (SC) unfractionated heparin (UFH)
3. Fondaparinux
4. Vitamin K antagonist (VKA), with monitoring of international normalized ratio (INR)
5. Systemic thrombolytic therapy
6. Rivaroxaban
7. Dabigatran
8. Initiation and duration of therapy
9. In-hospital versus at-home initial treatment

Mechanical and Surgical Management

1. Ambulation
2. Elastic compression stockings, bandages, and sleeves
3. Intermittent pneumatic compression (IPC)
4. Catheter-directed thrombolysis (CDT)
5. Catheter-assisted embolectomy
6. Surgical pulmonary embolectomy with cardiopulmonary bypass
7. Inferior vena cava (IVC) filter
8. Pulmonary thromboendarterectomy

Defining the Clinical Questions—Population, Intervention, Comparator, and Outcome

The thrombosis expert on the Executive Committee along with the deputy editors took primary responsibility for defining the scope of the clinical questions that each article would address. For each question, the topic editor and deputy editor defined the relevant population, alternative management strategies (intervention and comparator), and the outcomes (i.e., population, intervention, comparator, and outcome [PICO] format). Each clinical question provided the framework for formulating study inclusion and exclusion criteria and guided the search for relevant evidence (systematic reviews and original studies). Panels typically restricted included studies to randomized controlled trials (RCTs) for intervention questions but included observational studies when there was a paucity of RCT data addressing an intervention and for questions of risk assessment. Readers can find these PICO questions in the first table of each article. One or more recommendations could be formulated for each clinical question.

Identifying the Evidence

To identify the relevant evidence, a team of methodologists and medical librarians at the Oregon Health & Science University Evidence-based Practice Center conducted literature searches of Medline, the Cochrane Library, and the Database of Abstracts of Reviews of Effects. For each article, the team conducted a search for systematic reviews and another for original studies encompassing the main populations and interventions for that article. These searches included studies indexed from week 1, January 2005, forward because Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th Edition (AT8) searches were carried out up to that date (search strategies are available on request). Many articles supplemented these searches with more-focused searches addressing specific clinical questions. When clinical questions had not been covered in AT8, searches commenced at a date relevant to each intervention.

Titles and abstracts retrieved from bibliographic database searches generally were screened in duplicate, and full-text articles were retrieved for further review. Consensus on whether individual studies fulfilled inclusion criteria was achieved for each study between two reviewers. If consensus could not be achieved, the topic editor and other topic panelists were brought into the discussion. Deputy editors reviewed lists of included studies from the database searches in order to identify any potentially missed studies. Additional studies identified were then retrieved for further evaluation.

Topic panels also searched the same bibliographic databases for systematic reviews addressing each PICO question. The quality of reviews was assessed using principles embodied in prior instruments addressing methodologic quality of systematic reviews, and wherever possible, current high-quality systematic reviews were used as the source of summary estimates. Reviews were also used to identify additional studies to complement the database searches.

Not stated

Grading of Recommendations Assessment, Development and Evaluation (GRADE) Approach to Rating Quality of Evidence

General Methods

Assessing Studies and Summarizing Evidence

Evaluating Risk of Bias in Individual Studies

The expert panel developed and applied uniform criteria for evaluating the risk of bias associated with individual randomized controlled trials (RCTs) based on the criteria recommended by the Cochrane Collaboration (Table 1 in the methodology companion [see the "Availability of Companion Documents" field]). Although all authors assessed risk of bias for individual studies, because of resource limitations, the panel summarized the results of the risk of bias for only a minority of the recommendations. Readers can find these assessments in the online data supplements. For most recommendations for which such tables were not developed, Evidence Profiles that typically provide information on the risk of bias in footnotes were developed.

The panel also developed specific criteria for assessing the risk of bias of observational studies (cohort studies with concurrent controls, cohort studies with historical controls, case-control studies, or case series). Again, these were based on the evidence-based domains recommended by the Cochrane Collaboration for observational studies.

Studies without internal comparisons were termed "cohort studies without internal controls" if they met the following criteria:

1. A protocol existed before the date of commencement of data collection.
2. A definition of inclusion and exclusion criteria was available.
3. The study reported the number of excluded patients.
4. The study conducted a standardized follow-up, including description of all of the following: schedule of follow-up, investigation of suspected outcomes, and criteria used to define outcomes.
5. The study reported all losses to follow-up.

The panel labeled studies that did not meet these criteria as "case series." No distinction was made between prospective and retrospective studies because although prospective studies may on average be of higher quality, individual prospective studies may have a significant risk of bias and specific retrospective studies may not. For questions related to risk assessment, the panel evaluated the risk of bias of individual studies using the following criteria: valid outcome assessment, including blinding when appropriate; adjustment for between-group differences; and minimal loss to follow-up.

Evaluating Quality of Bodies of Evidence

The expert panel assessed evidence across studies on an outcome-by-outcome basis using criteria suggested by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. The expert panel defined quality of evidence as their confidence in the estimate of the effect to support a recommendation. RCTs start as high-quality evidence and observational studies as low-quality evidence. Additional factors that affect this rating of quality include the risk of bias; precision, consistency, and directness of results; likelihood of publication bias; and presence of very large effects. The American College of Chest Physicians (ACCP) adaptation of the GRADE system differs only in that the quality of a body of evidence can be high (A), moderate (B), or low (C); GRADE also provides a category for very-low-quality evidence. See the "Rating Scheme for the Strength of the Evidence" field.

Often, the panel found that the quality of the evidence differed across outcomes. For example, in assessing the quality of evidence for thienopyridines vs warfarin in patients undergoing percutaneous coronary interventions, the panel determined the evidence to be of moderate quality for mortality, nonfatal myocardial infarction, and revascularization but of low quality for major bleeding.

The panel then made a rating of the quality of the entire body of evidence bearing on the effect of alternative management strategies for each clinical question. In other words, the panel assessed the quality across outcomes, including both benefits and harms. Quality for each recommendation was the lowest quality rating of the outcomes judged as critical (as opposed to important, but not critical).

Most patient-important outcomes in this guideline are binary or yes-no outcomes (death, stroke, venous thromboembolism [VTE], myocardial infarction, bleeding). In general, relative effects are similar across subgroups of patients, including those with varying baseline risk. The evidence summaries (Evidence Profiles and Summary of Findings tables), therefore, include a presentation of relative effects (where possible as relative risks because they are easier to understand than odds ratios [ORs]) of intervention vs control management strategies.

Trading off desirable and undesirable consequences (e.g., thrombosis vs bleeding) requires, however, estimates of absolute effect. For example, in patients with atrial fibrillation, warfarin results in a 66% relative risk reduction in nonfatal stroke. This comes at a cost of inconvenience, lifestyle restrictions, and risk of bleeding. For patients with a CHADS (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke) score of ≥3, the 66% relative risk reduction translates into an absolute reduction of 6.3% (63 in 1,000) per year. Virtually all patients will consider this worthwhile. On the other hand, for patients with a CHADS score of 0, the 66% reduction translates into an absolute risk reduction of only 0.5% (5 in 1,000) per year. Many patients may consider this reduction not worth the undesirable consequences of warfarin use.

The panel calculated absolute effects by applying relative risks to estimates of control group risk. For instance, if control group risk of thrombosis is 4% and relative risk with an intervention is 50%, then the absolute difference between intervention and control is 4% of 50% or 2%, and the number needed to treat to prevent an episode of thrombosis is 100/2 or 50. In many cases, the Summary of Findings tables present effects as events prevented (or caused) per 1,000 patients. In this hypothetical example, the effect would be 20 events per 1,000 patients.

Whenever valid prognostic data were available from observational studies, they were used to estimate control group risks. When credible results from observational and prognostic studies were not available, risk estimates from control groups of RCTs were used.

Considering Subgroup-Specific Relative and Absolute Effects

Whenever the expert panel identified credible evidence that the relative effects vary across distinguishable subgroups of patients (i.e., interaction between the intervention and a patient characteristic), the respective relative effects were considered separately. The panel then calculated the associated absolute effects.

Even when the relative effect is the same, the absolute magnitude of treatment effects may differ in patients with varying levels of risk. For instance, although the relative risk reduction of warfarin vs aspirin in stroke prevention for patients with atrial fibrillation is likely close to 50% across risk groups, this translates into an absolute risk reduction of <1% per year in the lowest-risk groups and ~5% per year in the highest-risk groups.

The expert panel included control group risks and absolute-effect estimates for different groups in the summaries of effect when (and only when) two conditions were present. First, they required validated prognostic models or, at the very least, credible strategies for clinicians to easily identify higher- and lower-risk patients. Second, the panel identified varying risk groups only when recommendations differed in strength or direction between groups. Both conditions were met, for instance, in the atrial fibrillation recommendations in which strong recommendations in favor of anticoagulation were restricted to the higher-risk patients.

Conducting Meta-analyses

When pooled estimates of effects were not available from existing high-quality systematic reviews, the panel performed meta-analyses if the data were sufficiently homogeneous. When pooling two studies, they used a fixed-effects model. When three or more studies were available for generating a pooled estimate, they used a random-effects model as the primary analysis and a fixed-effects model as a secondary analysis. If there were discrepancies between the two, the panel considered the following reasons: If there was substantial heterogeneity leading to wider confidence intervals (CIs) with the random-effects model, the panel considered that model more trustworthy, and if the discrepancy was due to a single large dominant study with a result substantially different from smaller studies, they considered the fixed-effects model more trustworthy. The panel also assessed statistical heterogeneity using both a χ² test and I² as well as assessed possible explanations of heterogeneity considering a priori-generated hypotheses.

Summary Tables

When resources permitted, the expert panel used a standardized approach for summarizing the evidence and methodology of individual studies. These summaries appear in the online data supplements. Wherever possible, the expert panel reported nonfatal events (e.g., nonfatal stroke) so that there is no overlap with the number of fatal events reported.

For a large number of recommendations, the expert panel summarized the quality of the body of evidence (see the "Rating Scheme for the Strength of the Evidence" field above) and estimates of relative and absolute effect of alternative management strategies using the methods of the GRADE Working Group. Evidence Profiles summarize the quality of the body of evidence and when evidence comes from randomized trials, generally include a presentation of reviewer assessment of risk of bias, precision, consistency, directness, and publication bias associated with each outcome. As specified in GRADE methodology, the overall quality of evidence represents the lowest quality of any critical outcome.

Evidence Profiles can be found in the online data supplement. The format for these tables was determined through a formal survey of panelists that evaluated the panelists' preferences for alternative presentations and the impact of these presentations on their understanding of the evidence. The text in the printed version of Antithrombotic Therapy and Prevention of Thrombosis, 9th ed (AT9) recommendations includes more succinct Summary of Findings tables, which include the overall quality assessment as well as the relative and absolute effect sizes for each outcome. Use of an associated computer program facilitated the production of the Evidence Profiles and Summary of Findings tables which are listed in the original guideline document.

Specific Methods for This Guideline

Presentation as Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE)

In addressing DVT, the expert panel first review studies that included (1) only patients who presented with symptomatic DVT or (2) patients who presented with DVT or PE (i.e., meeting the broader criterion of VTE). For the PE components, the panel review studies (and subgroups within studies) that required patients to have presented with symptomatic PE (who may also have had symptoms of DVT). For this reason and because more patients with VTE present with symptoms of DVT alone than with symptoms of PE (including those who also have symptoms of DVT), the DVT section deals with a larger body of evidence than the PE section.

In the evaluation of anticoagulant therapy, there are a number of justifications for inclusion of patients who present with DVT and PE in the same study, and for extrapolating evidence obtained in patients with one presentation of VTE (e.g., DVT) to the other presentation (e.g., PE). First, a majority of patients with symptomatic DVT also have PE (symptomatic or asymptomatic), and a majority of those with symptomatic PE also have DVT (symptomatic or asymptomatic). Second, clinical trials of anticoagulant therapy have yielded similar estimates for efficacy and safety in patients with DVT alone, in those with both DVT and PE, and in those with only PE. Third, the risk of recurrence appears to be similar after PE and after proximal DVT. Consequently, the results of all studies of VTE have been considered when formulating recommendations for short- and long-term anticoagulation of proximal DVT and PE (see Fig. 1 in the original guideline document), and these recommendations are essentially the same for proximal DVT or PE.

There are, however, some important differences between patients who present with PE and those who present with DVT that justify separate consideration of some aspects of the treatment of PE. First, the risk of early death (within 1 month) from VTE due to either the initial acute episode or recurrent VTE is much greater after presenting with PE than after DVT; this difference may justify more aggressive initial treatment of PE (e.g., thrombolytic therapy, insertion of an inferior vena cava [IVC] filter, more intensive anticoagulant therapy) compared with DVT. Second, recurrent episodes of VTE are about three times as likely to be PE after an initial PE than after an initial DVT (i.e., about 60% after a PE vs 20% after a DVT); this difference may justify more aggressive, or more prolonged, long-term therapy. Third, the long-term sequelae of PE are cardiorespiratory impairment, especially due to pulmonary hypertension, rather than post-thrombotic syndrome (PTS) of the legs or arms. These differences are most important for recommendations about the use of thrombus removal procedures (e.g., thrombolytic therapy) in patients who present with DVT and PE.

Outcomes Assessed

The outcomes important to patients considered for most recommendations are recurrent VTE, major bleeding, and all-cause mortality. These outcomes are categorized in two different ways in the evidence profiles. Whenever data were available, fatal episodes of recurrent VTE and bleeding were included in the mortality outcome, and nonfatal episodes of recurrent VTE and bleeding were reported separately in their own categories to avoid reporting an outcome more than once in an evidence profile. However, many original reports and published meta-analyses did not report fatal and nonfatal events separately. In this situation, the panel have reported the outcome categories of mortality, recurrent VTE, and major bleeding, with fatal episodes of VTE and bleeding included in both mortality and two specific outcomes (i.e., fatal episodes of VTE and bleeding are included in two outcomes of the evidence profile).

With both ways of reporting outcomes, the panel tried to specifically identify deaths from recurrent VTEs and major bleeds. As part of the assessment of the benefits and harms of a therapy, the panel generally assume that ~5% of recurrent episodes of VTE are fatal and that ~10% of major bleeds are fatal, and if the panel deviated from these estimates, they noted the reasons for so doing. We did not consider surrogate outcomes (e.g., vein patency) when there were adequate data addressing the corresponding outcome of importance to patients (e.g., postthrombotic syndrome [PTS]).

When developing evidence profiles, the panel tried to obtain the baseline risk of outcomes (e.g., risk of recurrent VTE or major bleeding) from observational studies because these estimates are most likely to reflect real-life incidence. In many cases, however, they used data from randomized trials because observational data were lacking or were of low quality. Methodologic issues specific to duration of anticoagulation are addressed in the section 3.1 of the original guideline under the subsection on general consideration in weighing the benefits and risks of different durations of anticoagulant therapy.

Refer to the original guideline for specific information on patient values and preferences and influence of bleeding risk and cost in developing the recommendations.

Composition and Selection of Topic Panel Members

The American College of Chest Physicians (ACCP) Antithrombotic Therapy and Prevention of Thrombosis, 9th ed (AT9) Executive Committee selected panel members for each article. A topic editor and a deputy editor led each of the AT9 panels issuing recommendations. The topic editor was the person primarily responsible for each article and was required to be a methodologist without serious financial or intellectual conflict of interest for any of the article's recommendations. In all but one case, the topic editor also was a clinician. The Executive Committee chose these individuals on the basis of their previous experience with guideline development and, in particular, their familiarity with methods developed by the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) Working Group. These topic editors and all panel members were approved by the ACCP Health and Science Policy (HSP) Committee after review of their conflict of interest disclosures.

Criteria for selection of the remainder of the panel members, including the deputy editor-thrombosis expert, were an established record in the relevant clinical or research area, international and gender representation, and an absence of financial conflicts of interest that were judged unacceptable. Some of the panelists had prior experience on ACCP guidelines in this area and represented the thrombosis community, but there was substantial turnover from the previous edition. After an international request for applications broadcast through multiple medical societies, the Executive Committee nominated individual topic editors and deputy editors and collaborated with them to identify and nominate other topic panel members.

The ACCP HSP Committee reviewed all nominees and approved all panel members after review of their curricula vitae and conflict of interest disclosures. Of 150 nominees, 137 were approved, 18 were approved with management of conflicts of interest (i.e., regular disclosures and review of ongoing conflicts as the process progressed), and 13 were disapproved as a result of the magnitude of financial conflicts of interest. Articles associated with recommendations included from seven to 14 panel members. Patients or representatives of specific stakeholder groups were not included on topic panels.

Each topic panel also included a frontline physician working in the relevant area who was neither an expert in thrombosis nor a methodologist or clinical investigator. These individuals were chosen in consultation with the topic editors and the ACCP HSP Committee. These clinicians were charged with the following: (1) proposing important real-world clinical questions on the prevention, diagnosis, and treatment of thrombosis that were not addressed in Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th Edition (AT8) and (2) reviewing the draft manuscripts and recommendations to assess the usability of the guidelines and the feasibility of implementation of AT9 recommendations.

To address issues of economic efficiency six health economist-physicians were included on the AT9 topic panels charged with making recommendations. These resource consultants were selected and approved through identical procedures to those for topic editors and panel members.

Ensuring Consistency Across Articles

A number of strategies were used to ensure consistency across articles, and one panel member participated extensively in the formulation of clinical questions for each article. To ensure consistency of judgments regarding bleeding, another panel member was responsible for standardizing the approach to bleeding outcomes and participated in multiple topic panels. Additionally, to ensure consistency in the trade-offs between thrombotic and bleeding events, all articles used the same ratings of values and preferences (described in more detail in the methodology companion [see the "Availability of Companion Documents" field]). Because some of the same evidence summaries were relevant to several articles, five individuals were chosen to participate in each of the articles addressing coronary artery disease, stroke, and peripheral arterial disease.

In AT9, prevention of venous thromboembolism (VTE) is addressed in three articles as opposed to a single article as was done in AT8. The prevention topic editors and deputy editors and those of the stroke article (which includes thromboprophylaxis recommendations) participated in multiple conference calls to develop and harmonize the approach to prevention and to ensure consistency among final recommendations. Topic editors consulted with one another when issues overlapped. For example, the decision regarding the use of a vitamin K antagonist, aspirin, and clopidogrel simultaneously in patients with atrial fibrillation, valvular disease, and intravascular stents is relevant for the atrial fibrillation, coronary, and peripheral arterial disease articles. Topic panels deferred to the Evidence-Based Management of Anticoagulant Therapy AT9 topic panel for recommendations related to the dosing and monitoring of anticoagulation therapies.

The AT9 Executive Committee met at least once a month and regularly issued statements of clarification of methods to topic editors and deputy editors (e.g., use of fixed- or random-effects models for meta-analysis), conflict of interest, preparation of tables, and issues of style and presentation. All these statements were communicated directly to the topic editors and deputy editors and made available in a central repository accessible to all AT9 panelists. The chair of the Executive Committee was available for resolving any challenging issues related to the aforementioned topics. Between September 2009 and September 2010, two members of the Executive Committee held regular (every 3 months), separate conference calls with each topic editor and deputy editor during which they addressed questions and concerns. Finally, the chair of the Executive Committee reviewed every article to ensure consistency of evidence presentation, evaluation, and writing style. Refer to the methodology companion for further information on the approach used to ensure consistent language in writing.

Formulating Recommendations

Following approaches recommended by the GRADE Working Group, the topic editor, in some cases aided by a panelist without conflicts, formulated the draft recommendations. The formulation of recommendations considered the balance between the desirable and undesirable consequences of an intervention; the quality of evidence; the variability in patient values and preferences; and, on occasion, resource use issues. The recommendations were graded as strong when desirable effects were much greater than undesirable effects or vice versa. Strong recommendations were worded as "The expert panel recommends" and labeled 1. Recommendations were graded as weak when desirable effects were not clearly greater or less great than undesirable effects. Weak recommendations were worded as "The expert panel suggests" and labeled 2. The rating of the quality of the evidence—high, A; moderate, B; or low, C—is provided with the strength of each recommendation.

Finalizing Recommendations

The topic panel members without primary conflicts discussed draft recommendations. Initial discussions generally led to a consensus at the article level on the quality of evidence and the direction and strength of recommendations. At least two members of the Executive Committee reviewed in detail drafts of articles, including recommendations. Written critiques were prepared and returned to the authors for revision. Articles were then made available to the entire AT9 panel.

Recommendations on which topic panels had difficulty coming to a consensus were discussed at a final conference in February 2011 attended by the topic editors and deputy editors and at least one other panel member from each article. Prior to the conference, all AT9 panelists updated their conflict of interest disclosures. The ACCP invited a number of clinical organizations with interest in the guideline topic to attend the final conference as observers.

At this final conference, a representative of each article presented potentially controversial issues in their article's recommendations. Following discussion, which included those present and those attending by video conference, all panelists without primary conflicts of interest voted on each recommendation. The voting process used a GRADE grid and required that for a strong recommendation, ≥80% of those voting had to agree that a strong recommendation was appropriate.

The AT9 Executive Committee members harmonized the articles and resolved remaining disagreements among them through facilitated discussion with topic editors and deputy editors without primary conflicts. All major correspondence and decisions at the final conference were recorded in written and audio formats and are available on request to science@chestnet.org.

See the methodology companion (see the "Availability of Companion Documents" field) for information on accounting for patient values and preferences in recommendations.

Strength of the Recommendations Grading System

*The guideline developers use the wording recommend for strong (Grade 1) recommendations and suggest for weak (Grade 2) recommendations.

General

Resource Use Issues

In addressing resource use (cost) issues in Antithrombotic Therapy and Prevention of Thrombosis, 9th ed (AT9), the expert panel followed previously developed principles. In particular, the panel restricted economic evaluation to recommendations in which it was plausible that resource use considerations might change the direction or strength of the recommendation and in which high-quality economic evaluations were available. When this was not the case, the panel did not consider resource use in the recommendations.

Six clinicians with the requisite expertise in decision and economic analyses participated in the guideline development process; each article had the benefit of one of these experts as a full committee member. The following subsections present key points in the process of considering resource allocation issues in the recommendations.

Overview of the Process

Panelists, in consultation with resource use consultants, determined questions for which resource use might change the direction or strength of recommendations. For those questions, the panel sought high-quality economic analyses. If such analyses were available, the panel applied the evidence regarding resource use to the relevant recommendation. If net costs or marginal cost-effectiveness ratios were very high, panelists considered rating down the quality of evidence for an intervention from high to low or possibly changing the direction of the recommendation using guides described in the section "Criteria for Resource Allocation Issues to Affect Recommendations—Thresholds for Cost-Effectiveness" in the methodology companion (see the "Availability of Companion Documents" field).

Identifying the Literature

The Oregon Health & Science University Evidence-based Practice Center conducted thorough literature searches for economic analyses relevant to the different AT9 articles. The resource use experts supplemented these by searches focused on the specific questions of interest for each article. The searches were conducted in Medline and the Cochrane Central Register of Clinical Trials. On the basis that data from studies appreciably more than a decade old would not reflect the current situation, searches were restricted to published studies from 1999 forward. Thus, bibliographic database searches encompassed publications from January 1999 forward: The end date varied across articles and ranged between November 2009 and March 2010 when the searches were executed.

Evaluating the Evidence

A standardized data extraction form was used to ensure uniform evaluation of the quality of relevant economic analyses. Quality assessment was based on published criteria and included specification of perspective of analysis (e.g., societal, health system), appropriateness of time horizon (preferably lifetime), use of high-quality evidence for probabilities and rates, use of high-quality sources for costs (e.g., primary data, Medicare payments, claims data as proxies), use of appropriate methods for measurement of preferences, and performance of sensitivity analyses to explore uncertainty (both deterministic and probabilistic).

Criteria for Resource Allocation Issues to Affect Recommendations—Thresholds for Cost-Effectiveness

The results of economic analyses may either increase the strength of an otherwise weak recommendation or weaken the strength of a strong recommendation. If cost-effectiveness studies bolstered an already strong recommendation, no change to the recommendation was necessary. The panel chose the following thresholds for cost-effectiveness considerations affecting recommendations:

1. When the clinical evidence warrants a strong recommendation for A over B:
   1. Strong recommendation favoring A when high-quality evidence from economic evaluations shows that A costs <3 times the gross domestic product (GDP) per capita (approximately US $150,000) per quality-adjusted life year (QALY) gained relative to B
   2. Weak recommendation favoring A when high-quality evidence from economic evaluations shows that A costs 3 to 5 times the GDP per capita (~$150,000-$250,000) per QALY gained relative to B
   3. Weak recommendation favoring B when high-quality evidence from economic evaluations shows that A costs >5 times the GDP per capita (~$250,000) per QALY gained relative to B
2. When the clinical evidence warrants a weak recommendation for A over B:
   1. Strong recommendation favoring A if A results in cost savings of >10% to 20% of the GDP per capita (~$5,000-$10,000) relative to B (Cost savings must represent all downstream costs and not just the actual cost of the intervention, and analysis must demonstrate a high level of confidence that there is a cost savings.)
   2. Continued weak recommendation favoring A when B is marginally more costly than A (<10% the GDP per capita)
   3. Continued weak recommendation favoring A when A costs 0 to 5 times the GDP per capita per QALY gained relative to B
   4. Weak recommendation favoring B if A costs >5 times the GDP per capita (~$250,000) per QALY gained relative to B

Extension of Economic Analyses to Low- and Middle-Income Countries

Although certain interventions may be cost-effective in high-income countries (e.g., <$20,000 per QALY gained), in poor countries, $20,000 gained per QALY may be prohibitive. The choice of a threshold will vary depending on who is making resource allocation decisions. To facilitate the use of already published cost-effectiveness analyses, the World Health Organization (WHO), through its WHO-CHOICE (Choosing Interventions that are Cost Effective) program has used criteria suggested by the Commission on Macroeconomics and Health. Interventions that cost <1 times the average per-capita income for a given country or region per QALY gained are considered very cost-effective. Interventions that cost up to three times the average per-capita income per QALY gained are still considered cost-effective, whereas those that exceed this level are not considered to be cost-effective. To facilitate this process, WHO has developed tables of such threshold values for different regions and countries around the world. Thus, the thresholds discussed in the previous section have been defined in terms of GDP per capita. Although referencing thresholds for cost-effectiveness to average per-capita income in middle- and low-income countries can help to extend results of economic analyses performed in high-income countries, such analyses may be less relevant in low-income countries because of significantly different material and labor costs and, thus, may be difficult to extrapolate. Furthermore, the comparator strategies may not be feasible or customary in these locales.

Specific to This Guideline

Health economic evaluations that have assessed initial treatment of DVT at home, although they have weaknesses (e.g., industry funded, not derived from trials in which low-molecular-weight heparin [LMWH] was used both in the hospital and at home, short time horizon [i.e., ≤3 months], and limited use of sensitivity analyses), all conclude that home treatment is cost-saving (about US $500-$2,500 per patient).

The American College of Chest Physicians (ACCP) Health and Science Policy (HSP) Committee established a process for the thorough review of all ACCP evidence-based clinical practice guidelines. After final review by the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed (AT9) Executive Committee, the guidelines underwent review by the Cardiovascular and Pulmonary Vascular NetWorks of the ACCP, the HSP Committee, and the ACCP Board of Regents. The latter two groups had the right of approval or disapproval but usually worked with the topic panelists and editors to make necessary revisions prior to final approval. Both the HSP Committee and the Board of Regents identified primary reviewers who read the full set of articles, and the remaining HSP Committee members were responsible for reviewing several articles each. The reviewers considered both content and methodology as well as whether there was balanced reporting and adherence to HSP Committee processes. All reviewers were vetted through the same conflict of interest disclosure and management process described in the "Description of Methods Used to Formulate the Recommendations" field. Finally, the Editor in Chief of CHEST read and forwarded the manuscripts for independent, external peer review prior to acceptance for publication. No recommendations or assessments of the quality of the evidence could be changed without the express approval of the topic panel members, AT9 Executive Committee, HSP Committee, and ACCP Board of Regents.

This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society on Thrombosis and Haemostasis.

The grades of recommendation (1A, 1B, 1C, 2A, 2B, 2C) and the approach to rating the quality of evidence are defined at the end of the "Major Recommendations" field.

Treatment of Acute Deep Vein Thrombosis (DVT)

Initial Anticoagulation of Acute DVT of the Leg

In patients with acute DVT of the leg treated with vitamin-K antagonist (VKA) therapy, the expert panel recommends initial treatment with parenteral anticoagulation (low-molecular-weight heparin [LMWH], fondaparinux, intravenous [IV] unfractionated heparin [UFH], or subcutaneous [SC] UFH) over no such initial treatment (Grade 1B).

Whether to Treat with Parenteral Anticoagulation While Awaiting the Results of Diagnostic Work-up for Venous Thromboembolism (VTE)

In patients with a high clinical suspicion of acute VTE, the expert panel suggests treatment with parenteral anticoagulants compared with no treatment while awaiting the results of diagnostic tests (Grade 2C).

In patients with an intermediate clinical suspicion of acute VTE, the expert panel suggests treatment with parenteral anticoagulants compared with no treatment if the results of diagnostic tests are expected to be delayed for more than 4 h (Grade 2C).

In patients with a low clinical suspicion of acute VTE, the expert panel suggests not treating with parenteral anticoagulants while awaiting the results of diagnostic tests, provided test results are expected within 24 h (Grade 2C).

Whether and How to Prescribe Anticoagulants to Patients with Isolated Distal DVT

In patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, the expert panel suggests serial imaging of the deep veins for 2 weeks over initial anticoagulation (Grade 2C).

In patients with acute isolated distal DVT of the leg and severe symptoms or risk factors for extension (see text), the expert panel suggests initial anticoagulation over serial imaging of the deep veins (Grade 2C).

Remarks: Patients at high risk for bleeding are more likely to benefit from serial imaging. Patients who place a high value on avoiding the inconvenience of repeat imaging and a low value on the inconvenience of treatment and on the potential for bleeding are likely to choose initial anticoagulation over serial imaging.

In patients with acute isolated distal DVT of the leg who are managed with initial anticoagulation, the expert panel recommends using the same approach as for patients with acute proximal DVT (Grade 1B).

In patients with acute isolated distal DVT of the leg who are managed with serial imaging, the expert panel recommends no anticoagulation if the thrombus does not extend (Grade 1B); the expert panel suggests anticoagulation if the thrombus extends but remains confined to the distal veins (Grade 2C); the expert panel recommends anticoagulation if the thrombus extends into the proximal veins (Grade 1B).

Timing of Initiation of VKA and Associated Duration of Parenteral Anticoagulant Therapy

In patients with acute DVT of the leg, the expert panel recommends early initiation of VKA (e.g., same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the international normalized ratio (INR) is 2.0 or above for at least 24 hours (Grade 1B).

Choice of Initial Anticoagulant Regimen in Patients With Proximal DVT

In patients with acute DVT of the leg, the expert panel suggests LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux).

Remarks: Local considerations such as cost, availability, and familiarity of use dictate the choice between fondaparinux and LMWH. LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH.

In patients with acute DVT of the leg treated with LMWH, the expert panel suggests once- over twice-daily administration (Grade 2C).

Remarks: This recommendation only applies when the approved once-daily regimen uses the same daily dose as the twice-daily regimen (i.e., the once-daily injection contains double the dose of each twice-daily injection). It also places value on avoiding an extra injection per day.

At-Home vs In-Hospital Initial Treatment of DVT

In patients with acute DVT of the leg and whose home circumstances are adequate, the expert panel recommends initial treatment at home over treatment in hospital (Grade 1B).

Remarks: The recommendation is conditional on the adequacy of home circumstances: well-maintained living conditions, strong support from family or friends, phone access, and ability to quickly return to the hospital if there is deterioration. It is also conditional on the patient feeling well enough to be treated at home (e.g., does not have severe leg symptoms or comorbidity).

Catheter-Directed Thrombolysis for Acute DVT

In patients with acute proximal DVT of the leg, the expert panel suggests anticoagulant therapy alone over catheter-directed thrombolysis (CDT) (Grade 2C).

Remarks: Patients who are most likely to benefit from CDT (see text in the original guideline document) and attach a high value to prevention of postthrombotic syndrome (PTS) and a lower value to the initial complexity, cost, and risk of bleeding with CDT are likely to choose CDT over anticoagulation alone.

Systemic Thrombolytic Therapy for Acute DVT

In patients with acute proximal DVT of the leg, the expert panel suggests anticoagulant therapy alone over systemic thrombolysis (Grade 2C).

Remarks: Patients who are most likely to benefit from systemic thrombolytic therapy (see text in the original guideline document), who do not have access to CDT, and who attach a high value to prevention of PTS, and a lower value to the initial complexity, cost, and risk of bleeding with systemic thrombolytic therapy, are likely to choose systemic thrombolytic therapy over anticoagulation alone.

Operative Venous Thrombectomy for Acute DVT

In patients with acute proximal DVT of the leg, the expert panel suggests anticoagulant therapy alone over operative venous thrombectomy (Grade 2C).

Anticoagulation in Patients Who Have Had Any Method of Thrombus Removal Performed

In patients with acute DVT of the leg who undergo thrombosis removal, the expert panel recommends the same intensity and duration of anticoagulant therapy as in similar patients who do not undergo thrombosis removal (Grade 1B).

Vena Cava Filters for the Initial Treatment of DVT

In patients with acute DVT of the leg, the expert panel recommends against the use of an inferior vena cava filter (IVC) filter in addition to anticoagulants (Grade 1B).

In patients with acute proximal DVT of the leg and contraindication to anticoagulation, the expert panel recommends the use of an IVC filter (Grade 1B).

In patients with acute proximal DVT of the leg and an IVC filter inserted as an alternative to anticoagulation, the expert panel suggests a conventional course of anticoagulant therapy if their risk of bleeding resolves (Grade 2B).

Remarks: The expert panel does not consider that a permanent IVC filter, of itself, is an indication for extended anticoagulation.

Early Ambulation of Patients with Acute DVT

In patients with acute DVT of the leg, the expert panel suggests early ambulation over initial bed rest (Grade 2C).

Remarks: If edema and pain are severe, ambulation may need to be deferred. The expert panel suggests the use of compression therapy in these patients (see "Compression Stockings and Bandages to Prevent PTS" below).

Long-term Anticoagulation of Acute DVT of the Leg

In patients with acute VTE who are treated with anticoagulant therapy, the expert panel recommends long-term therapy (see below for recommended duration of therapy) over stopping anticoagulant therapy after about 1 week of initial therapy (Grade 1B).

Duration of Long-term Anticoagulant Therapy

In patients with a proximal DVT of the leg provoked by surgery, the expert panel recommends treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B), (ii) treatment of a longer time-limited period (e.g., 6 or 12 months) (Grade 1B), or (iii) extended therapy (Grade 1B regardless of bleeding risk).

In patients with a proximal DVT of the leg provoked by a nonsurgical transient risk factor, the expert panel recommends treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B), (ii) treatment of a longer time-limited period (e.g., 6 or 12 months) (Grade 1B), and (iii) extended therapy if there is a high bleeding risk (see Table 2 in the original guideline document) (Grade 1B). The expert panel suggests treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Grade 2B).

In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor (see remarks below), the expert panel suggests treatment with anticoagulation for 3 months over treatment of a shorter period (Grade 2C) and recommends treatment with anticoagulation for 3 months over treatment of a longer time-limited period (e.g., 6 or 12 months) (Grade 1B) or extended therapy (Grade 1B regardless of bleeding risk).

In patients with an unprovoked DVT of the leg (isolated distal [see remarks below] or proximal), the expert panel recommends treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B). After 3 months of treatment, patients with unprovoked DVT of the leg should be evaluated for the risk-benefit ratio of extended therapy.

In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk (see Table 2 in the original guideline document), the expert panel suggests extended anticoagulant therapy over 3 months of therapy (Grade 2B).

In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a high bleeding risk (see Table 2 in the original guideline document), the expert panel recommends 3 months of anticoagulant therapy over extended therapy (Grade 1B).

In patients with a first VTE that is an unprovoked isolated distal DVT of the leg (see remarks below), the expert panel suggests 3 months of anticoagulant therapy over extended therapy in those with a low or moderate bleeding risk (see Table 2 in the original guideline document) (Grade 2B) and recommends 3 months of anticoagulant treatment in those with a high bleeding risk (Grade 1B).

In patients with a second unprovoked VTE, the expert panel recommends extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk (see Table 2 in the original guideline document) (Grade 1B), and the expert panel suggests extended anticoagulant therapy in those with a moderate bleeding risk (Grade 2B).

In patients with a second unprovoked VTE who have a high bleeding risk (see Table 2 in the original guideline document), the expert panel suggests 3 months of anticoagulant therapy over extended therapy (Grade 2B).

In patients with DVT of the leg and active cancer, if the risk of bleeding is not high, the expert panel recommends extended anticoagulant therapy over 3 months of therapy (Grade 1B), and if there is a high bleeding risk (see Table 2 in the original guideline document), the expert panel suggests extended anticoagulant therapy (Grade 2B).

Remarks: Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anticoagulant therapy; however, it is anticipated that not all patients who are diagnosed with isolated distal DVT will be given anticoagulants (see "Whether and How to Prescribe Anticoagulants to Patients with Isolated Distal DVT" above and in section 2.3 of the original guideline document). In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (e.g., annually).

Intensity of Anticoagulant Effect

In patients with DVT of the leg who are treated with VKA, the expert panel recommends a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR <2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B).

Choice of Anticoagulant Regimen for Long-term Therapy

In patients with DVT of the leg and no cancer, the expert panel suggests VKA therapy over LMWH for long-term therapy (Grade 2C). For patients with DVT and no cancer who are not treated with VKA therapy, the expert panel suggests LMWH over dabigatran or rivaroxaban for long-term therapy (Grade 2C).

In patients with DVT of the leg and cancer, the expert panel suggests LMWH over VKA therapy (Grade 2B). In patients with DVT and cancer who are not treated with LMWH, the expert panel suggests VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2B).

Remarks: Choice of treatment in patients with and without cancer is sensitive to the individual patient's tolerance for daily injections, need for laboratory monitoring, and treatment costs. LMWH, rivaroxaban, and dabigatran are retained in patients with renal impairment, whereas this is not a concern with VKA. Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to patients, may prove to be associated with better clinical outcomes than VKA and LMWH therapy. When these guidelines were being prepared (October 2011), postmarketing studies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, the expert panel gives a weak recommendation in favor of VKA and LMWH therapy over dabigatran and rivaroxaban, and the expert panel has not made any recommendations in favor of one of the new agents over the other.

Choice of Anticoagulant Regimen for Extended Therapy

In patients with DVT of the leg who receive extended therapy, the expert panel suggests treatment with the same anticoagulant chosen for the first 3 months (Grade 2C).

Treatment of Asymptomatic DVT of the Leg

In patients who are incidentally found to have asymptomatic DVT of the leg, the expert panel suggests the same initial and long-term anticoagulation as for comparable patients with symptomatic DVT (Grade 2B).

PTS of the Leg

Compression Stockings and Bandages to Prevent PTS

In patients with acute symptomatic DVT of the leg, the expert panel suggests the use of compression stockings (Grade 2B).

Remarks: Compression stockings should be worn for 2 years, and the expert panel suggests beyond that if patients have developed PTS and find the stockings helpful. Patients who place a low value on preventing PTS or a high value on avoiding the inconvenience and discomfort of stockings are likely to decline stockings.

Physical Treatment of PTS

In patients with PTS of the leg, the expert panel suggests a trial of compression stockings (Grade 2C).

In patients with severe PTS of the leg that is not adequately relieved by compression stockings, the expert panel suggests a trial of an intermittent compression device (Grade 2B).

Pharmacologic Treatment of PTS

In patients with PTS of the leg, the expert panel suggests that venoactive medications (e.g., rutosides, defibrotide, and hidrosmin) not be used (Grade 2C).

Remarks: Patients who value the possibility of response over the risk of side effects may choose to undertake a therapeutic trial.

Initial Treatment of Acute Pulmonary Embolism (PE)

Initial Anticoagulation for Acute PE

In patients with acute PE, the expert panel recommends initial treatment with parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH) over no such initial treatment (Grade 1B).

Whether to Treat with Parenteral Anticoagulation While Awaiting the Results of Diagnostic Work-up for PE

In patients with a high clinical suspicion of acute PE, the expert panel suggests treatment with parenteral anticoagulants compared with no treatment while awaiting the results of diagnostic tests (Grade 2C).

In patients with an intermediate clinical suspicion of acute PE, the expert panel suggests treatment with parenteral anticoagulants compared with no treatment if the results of diagnostic tests are expected to be delayed for more than 4 h (Grade 2C).

In patients with a low clinical suspicion of acute PE, the expert panel suggests not treating with parenteral anticoagulants while awaiting the results of diagnostic tests, provided that test results are expected within 24 h (Grade 2C).

Timing of Initiation of VKA and Associated Duration of Parenteral Anticoagulant Therapy

In patients with acute PE, the expert panel recommends early initiation of VKA (e.g., same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the INR is 2.0 or above for at least 24 h (Grade 1B).

Choice of Initial Parenteral Anticoagulant Regimen in Patients with PE

In patients with acute PE, the expert panel suggests LMWH or fondaparinux over IV UFH (Grade 2C for LMWH; Grade 2B for fondaparinux) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux).

Remarks: Local considerations such as cost, availability, and familiarity of use dictate the choice between fondaparinux and LMWH. LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH. In patients with PE where there is concern about the adequacy of SC absorption or in patients in whom thrombolytic therapy is being considered or planned, initial treatment with IV UFH is preferred to use of SC therapies.

In patients with acute PE treated with LMWH, the expert panel suggests once- over twice-daily administration (Grade 2C).

Remarks: This recommendation only applies when the approved once-daily regimen uses the same daily dose as the twice-daily regimen (i.e., the once-daily injection contains double the dose of each twice-daily injection). It also places value on avoiding an extra injection per day.

Early vs Standard Discharge of Patients with Acute PE

In patients with low-risk PE and whose home circumstances are adequate, the expert panel suggests early discharge over standard discharge (e.g., after first 5 days of treatment) (Grade 2B).

Remarks: Patients who prefer the security of the hospital to the convenience and comfort of home are likely to choose hospitalization over home treatment.

Systemic Thrombolytic Therapy for PE

In patients with acute PE associated with hypotension (e.g., systolic BP <90 mm Hg) who do not have a high bleeding risk, the expert panel suggests systemically administered thrombolytic therapy over no such therapy (Grade 2C).

In most patients with acute PE not associated with hypotension, the expert panel recommends against systemically administered thrombolytic therapy (Grade 1C).

In selected patients with acute PE not associated with hypotension and with a low risk of bleeding whose initial clinical presentation or clinical course after starting anticoagulant therapy suggests a high risk of developing hypotension, the expert panel suggests administration of thrombolytic therapy (Grade 2C).

In patients with acute PE, when a thrombolytic agent is used, the expert panel suggests short infusion times (e.g., a 2-h infusion) over prolonged infusion times (e.g., a 24-h infusion) (Grade 2C).

In patients with acute PE when a thrombolytic agent is used, the expert panel suggests administration through a peripheral vein over a pulmonary artery catheter (Grade 2C).

Catheter-Based Thrombus Removal for the Initial Treatment of PE

In patients with acute PE associated with hypotension and who have (i) contraindications to thrombolysis, (ii) failed thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (e.g., within hours), if appropriate expertise and resources are available, the expert panel suggests catheter-assisted thrombus removal over no such intervention (Grade 2C).

Surgical Embolectomy for the Initial Treatment of PE

In patients with acute PE associated with hypotension, the expert panel suggests surgical pulmonary embolectomy over no such intervention if they have (i) contraindications to thrombolysis, (ii) failed thrombolysis or catheter-assisted embolectomy, or (iii) shock that is likely to cause death before thrombolysis can take effect (e.g., within hours), provided surgical expertise and resources are available (Grade 2C).

Vena Cava Filters for the Initial Treatment of PE

In patients with acute PE who are treated with anticoagulants, the expert panel recommends against the use of an IVC filter (Grade 1B).

In patients with acute PE and contraindication to anticoagulation, the expert panel recommends the use of an IVC filter (Grade 1B).

In patients with acute PE and an IVC filter inserted as an alternative to anticoagulation, the expert panel suggests a conventional course of anticoagulant therapy if their risk of bleeding resolves (Grade 2B).

Remarks: The expert panel does not consider that a permanent IVC filter, of itself, is an indication for extended anticoagulation.

Long-term Treatment of PE

In patients with PE provoked by surgery, the expert panel recommends treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B), (ii) treatment of a longer time-limited period (e.g., 6 or 12 months) (Grade 1B), or (iii) extended therapy (Grade 1B regardless of bleeding risk).

In patients with PE provoked by a nonsurgical transient risk factor, the expert panel recommends treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B), (ii) treatment of a longer time-limited period (e.g., 6 or 12 months) (Grade 1B), and (iii) extended therapy if there is a high bleeding risk (see Table 2 in the original guideline document) (Grade 1B). The expert panel suggests treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (see Table 2 in the original guideline document) (Grade 2B).

In patients with an unprovoked PE, the expert panel recommends treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B). After 3 months of treatment, patients with unprovoked PE should be evaluated for the risk-benefit ratio of extended therapy.

In patients with a first VTE that is an unprovoked PE and who have a low or moderate bleeding risk (see Table 2 in the original guideline document), the expert panel suggests extended anticoagulant therapy over 3 months of therapy (Grade 2B).

In patients with a first VTE that is an unprovoked PE and who have a high bleeding risk, the expert panel recommends 3 months of anticoagulant therapy over extended therapy (Grade 1B).

In patients with a second unprovoked VTE, the expert panel recommends extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk (see Table 2 in the original guideline document) (Grade 1B), and the expert panel suggests extended anticoagulant therapy in those with a moderate bleeding risk (see Table 2 in the original guideline document) (Grade 2B).

In patients with a second unprovoked VTE who have a high bleeding risk (see Table 2 in the original guideline document), the expert panel suggests 3 months of therapy over extended therapy (Grade 2B).

In patients with PE and active cancer, if the risk of bleeding is not high (see Table 2 in the original guideline document), the expert panel recommends extended anticoagulant therapy over 3 months of therapy (Grade 1B), and if there is a high bleeding risk (see Table 2 in the original guideline document), the expert panel suggests extended anticoagulant therapy (Grade 2B).

Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (e.g., annually).

In patients with PE who are treated with VKA, the expert panel recommends a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR <2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B).

In patients with PE and no cancer, the expert panel suggests VKA therapy over LMWH for long-term therapy (Grade 2C). For patients with PE and no cancer who are not treated with VKA therapy, the expert panel suggests LMWH over dabigatran or rivaroxaban for long-term therapy (Grade 2C).

In patients with PE and cancer, the expert panel suggests LMWH over VKA therapy (Grade 2B). In patients with PE and cancer who are not treated with LMWH, the expert panel suggests VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2C).

Remarks: Choice of treatment in patients with and without cancer is sensitive to the individual patient's tolerance for daily injections, need for laboratory monitoring, and treatment costs. Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to patients, may prove to be associated with better clinical outcomes than VKA and LMWH therapy. When these guidelines were being prepared (October 2011), postmarketing studies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, the expert panel gives a weak recommendation in favor of VKA and LMWH therapy over dabigatran and rivaroxaban, and the expert panel has not made any recommendation in favor of one of the new agents over the other.

In patients with PE who receive extended therapy, the expert panel suggests treatment with the same anticoagulant chosen for the first 3 months (Grade 2C).

Treatment of Asymptomatic PE

In patients who are incidentally found to have asymptomatic PE, the expert panel suggests the same initial and long-term anticoagulation as for comparable patients with symptomatic PE (Grade 2B).

Chronic Thromboembolic Pulmonary Hypertension

Pulmonary Thromboendarterectomy, Anticoagulant Therapy, and Vena Cava Filter for the Treatment of Chronic Thromboembolic Pulmonary Hypertension (CTPH)

In patients with CTPH, the expert panel recommends extended anticoagulation over stopping therapy (Grade 1B).

In selected patients with CTPH, such as those with central disease under the care of an experienced thromboendarterectomy team, the expert panel suggests pulmonary thromboendarterectomy over no pulmonary thromboendarterectomy (Grade 2C).

Superficial Vein Thrombosis (SVT)

In patients with SVT of the lower limb of at least 5 cm in length, the expert panel suggests the use of a prophylactic dose of fondaparinux or LMWH for 45 days over no anticoagulation (Grade 2B).

Remarks: Patients who place a high value on avoiding the inconvenience or cost of anticoagulation and a low value on avoiding infrequent symptomatic VTE are likely to decline anticoagulation.

In patients with superficial vein thrombosis who are treated with anticoagulation, the expert panel suggests fondaparinux 2.5 mg daily over a prophylactic dose of LMWH (Grade 2C).

Acute Upper-Extremity DVT (UEDVT)

Acute Anticoagulation for UEDVT

In patients with acute UEDVT that involves the axillary or more proximal veins, the expert panel recommends acute treatment with parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH) over no such acute treatment (Grade 1B).

In patients with acute UEDVT that involves the axillary or more proximal veins, the expert panel suggests LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B).

Thrombolytic Therapy for the Initial Treatment of UEDVT

In patients with acute UEDVT that involves the axillary or more proximal veins, the expert panel suggests anticoagulant therapy alone over thrombolysis (Grade 2C).

Remarks: Patients who (i) are most likely to benefit from thrombolysis (see text in the original guideline document); (ii) have access to CDT; (iii) attach a high value to prevention of PTS; and (iv) attach a lower value to the initial complexity, cost, and risk of bleeding with thrombolytic therapy are likely to choose thrombolytic therapy over anticoagulation alone.

In patients with UEDVT who undergo thrombolysis, the expert panel recommends the same intensity and duration of anticoagulant therapy as in similar patients who do not undergo thrombolysis (Grade 1B).

Long-term Anticoagulation for UEDVT

In most patients with UEDVT that is associated with a central venous catheter, the expert panel suggests that the catheter not be removed if it is functional and there is an ongoing need for the catheter (Grade 2C).

In patients with UEDVT that involves the axillary or more proximal veins, the expert panel suggests a minimum duration of anticoagulation of 3 months over a shorter period (Grade 2B).

Remarks: This recommendation also applies if the UEDVT is associated with a central venous catheter that was removed shortly after diagnosis.

In patients who have UEDVT that is associated with a central venous catheter that is removed, the expert panel recommends 3 months of anticoagulation over a longer duration of therapy in patients with no cancer (Grade 1B), and the expert panel suggests this in patients with cancer (Grade 2C).

In patients who have UEDVT that is associated with a central venous catheter that is not removed, the expert panel recommends that anticoagulation is continued as long as the central venous catheter remains over stopping after 3 months of treatment in patients with cancer (Grade 1C), and the expert panel suggests this in patients with no cancer (Grade 2C).

In patients who have UEDVT that is not associated with a central venous catheter or with cancer, the expert panel recommends 3 months of anticoagulation over a longer duration of therapy (Grade 1B).

Prevention of PTS of the Arm

In patients with acute symptomatic UEDVT, the expert panel suggests against the use of compression sleeves or venoactive medications (Grade 2C).

Treatment of PTS of the Arm

In patients who have PTS of the arm, the expert panel suggests a trial of compression bandages or sleeves to reduce symptoms (Grade 2C).

In patients with PTS of the arm, the expert panel suggests against treatment with venoactive medications (Grade 2C).

Splanchnic Vein Thrombosis

In patients with symptomatic splanchnic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), the expert panel recommends anticoagulation over no anticoagulation (Grade 1B).

In patients with incidentally detected splanchnic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), the expert panel suggests no anticoagulation over anticoagulation (Grade 2C).

Hepatic Vein Thrombosis

In patients with symptomatic hepatic vein thrombosis, the expert panel suggests anticoagulation over no anticoagulation (Grade 2C).

In patients with incidentally detected hepatic vein thrombosis, the expert panel suggests no anticoagulation over anticoagulation (Grade 2C).

Definitions:

Grading of Recommendations Assessment, Development and Evaluation (GRADE) Approach to Rating Quality of Evidence

Strength of the Recommendations Grading System

*The guideline developers use the wording recommend for strong (Grade 1) recommendations and suggest for weak (Grade 2) recommendations.

None provided

The type of supporting evidence is identified and graded for each recommendation (see the "Major Recommendations" field).

Appropriate antithrombotic therapy and management of patients with venous thromboembolic disease

Risk Factors for Bleeding With and Contraindications to Use of Thrombolytic Therapy (Both Systemic and Locally Administered)

Major Contraindications^a

• Structural intracranial disease
• Previous intracranial hemorrhage
• Ischemic stroke within 3 months
• Active bleeding
• Recent brain or spinal surgery
• Recent head trauma with fracture or brain injury
• Bleeding diathesis

Relative Contraindications^b

• Systolic blood pressure (BP) >180 mm Hg
• Diastolic BP >110 mm Hg
• Recent bleeding (nonintracranial)
• Recent surgery
• Recent invasive procedure
• Ischemic stroke more than 3 months previously
• Anticoagulation (e.g., vitamin K antagonist [VKA] therapy)
• Traumatic cardiopulmonary resuscitation
• Pericarditis or pericardial fluid
• Diabetic retinopathy
• Pregnancy
• Age >75 y
• Low body weight (e.g., 60 kg)
• Female sex
• Black race

Among 32,000 Medicare patients (≥65 y) with myocardial infarction who were treated with thrombolytic therapy, the following factors were independently associated with intracranial hemorrhage: age ≥75 y (odds ratio [OR], 1.6), black race (OR, 1.6), female sex (OR, 1.4), previous stroke (OR, 1.5), systolic BP ≥160 mm Hg (OR, 1.8), women weighing ≤65 kg or men weighing ≤80 kg (OR, 1.5), and international normalized ratio (INR) >4 (OR, 2.2). The rate of intracranial hemorrhage increased from 0.7% with none or one of these risk factors to 4.1% with five or more of these risk factors. Among 32,000 patients with myocardial infarction who were treated with thrombolytic therapy in five clinical trials, the following factors were independently associated with moderate or severe bleeding: older age (OR, 1.04 per year), black race (OR, 1.4), female sex (OR, 1.5), hypertension (OR, 1.2), and lower weight (OR, 0.99/kg). The expert panel estimated that systemic thrombolytic therapy is associated with a relative risk (RR) of major bleeding of 3.5 within 35 d (RR, ~7 for intracranial bleeding); about three-fourths of the excess of major bleeds with thrombolytic therapy occur in the first 24 h.

^aThe presence of major contraindications usually precludes use of thrombolytic therapy and, consequently, these factors have not been well studied as risk factors for bleeding associated with thrombolytic therapy. The factors listed above are consistent with other recommendations for the use of thrombolytic therapy in patients with pulmonary embolism.

^bRisk factors for bleeding during anticoagulant therapy that are not included above are also likely to be relative contraindications to thrombolytic therapy. The increase in bleeding associated with a risk factor will vary with (1) severity of the risk factor (e.g., extent of trauma or recent surgery) and (2) temporal relationships (e.g., interval from surgery or a previous bleeding episode believed to decrease markedly after ~2 wk). Risk factors for bleeding at critical sites (e.g., intracranial, intraocular) or noncompressible sites are stronger contraindications for thrombolytic therapy.

An implementation strategy was not provided.

Not applicable: The guideline was not adapted from another source.

The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and sanofi-aventis US.

The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations.

American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel

Primary Authors: Clive Kearon, MD, PhD; Elie A. Akl, MD, MPH, PhD; Anthony J. Comerota, MD; Paolo Prandoni, MD, PhD; Henri Bounameaux, MD; Samuel Z. Goldhaber, MD, FCCP; Michael E. Nelson, MD, FCCP; Philip S. Wells, MD; Michael K. Gould, MD, FCCP; Francesco Dentali, MD; Mark Crowther, MD; and Susan R. Kahn, MD

Executive Committee: Gordon H. Guyatt, MD, FCCP (Chair); Elie A. Akl, MD, MPH, PhD; Mark Crowther, MD; David D. Gutterman, MD, FCCP; Holger J. Schünemann, MD, PhD, FCCP; Sandra Zelman Lewis, PhD, ACCP; Joe Ornelas, DC

Panelists: Walter Ageno, MD; Pablo Alonso-Coello, MD, PhD; Sonia S. Anand, MD, PhD; Juan I. Arcelus, MD, PhD; Trevor P. Baglin, MBChB, PhD; Alex A. Balekian, MD, MSHS; Shannon M. Bates, MDCM; Sergio Bellmunt, MD; Neera Bhatnagar, MLIS; Robert Bona, MD; Henri Bounameaux, MD; Anthony K. C. Chan, MBBS; Clifford W. Colwell Jr, MD; Anthony J. Comerota, MD; Deborah J. Cook, MD, MSc(Epi); Michael H. Criqui, MD, MPH; Catherine Curley, MD; Mary Cushman, MD; Ola E. Dahl, MD; Antonio L. Dans, MD; Bruce L. Davidson, MD, MPH, FCCP; Francesco Dentali, MD; James D. Douketis, MD, FCCP; Andrew S. Dunn, MD; Shanil Ebrahim, MSc; Mark H. Eckman, MD; John W. Eikelboom, MBBS; Yngve Falck-Ytter, MD; Margaret C. Fang, MD, MPH; Jason Fish, MD, MSHS; Charles W. Francis, MD; Stephen E. Fremes, MD, FCCP; Alexander S. Gallus, MBBS; David A. Garcia, MD; Alan S. Go, MD; Neil A. Goldenberg, MD, PhD; Samuel Z. Goldhaber, MD, FCCP; Steven Goodacre, MBChB, PhD; Joel M. Gore, MD; Michael K. Gould, MD, FCCP; Ian A. Greer, MD, FCCP; Randolph Guzman, MD, RVT; Jonathan L. Halperin, MD; John A. Heit, MD; Jack Hirsh, MD, FCCP; Anne Holbrook, MD, PharmD; Patricia A. Howard, PharmD; Michael Hughes, PhD; Elaine M. Hylek, MD, MPH; Rebecca N. Ichord, MD; Roman Jaeschke, MD; Amir K. Jaffer, MD; Milosz Jankowski, MD, PhD; Norman A. Johanson, MD; Janna M. Journeycake, MD, MSCS; Susan R. Kahn, MD; Paul J. Karanicolas, MD, PhD; Clive Kearon, MD, PhD; Pooja Khatri, MD; Russell C. Klein, MD; Michael J. Kovacs, MD; Regina Kunz, MD, MSc(Epi); Deirdre A. Lane, PhD; Eddy S. Lang, MDCM; Maarten G. Lansberg, MD, PhD; Hoang Le, MD, FCCP; Wendy Lim, MD; A. Michael Lincoff, MD; Lori-Ann Linkins, MD; Gregory Y. H. Lip, MD; Samantha MacLean, MSc; Regina Makdissi, MD; Warren J. Manning, MD; Michael Mayr, MD; Marian S. McDonagh, PharmD; Shelley McLeod, MSc; Catherine McGorrian, MBBCh, BAO; Saskia Middeldorp, MD, PhD; Paul Monagle, MBBS, MD, FCCP; COL Lisa K. Moores, MC, USA, FCCP; Sohail Mulla, BHSc; M. Hassan Murad, MD, MPH; Michael E. Nelson, MD, FCCP; Mai N. Nguyen-Huynh, MD; Susan L. Norris, MD, MPH; Ulrike Nowak-Göttl, MD; Martin J. O'Donnell, MB, PhD; Thomas L. Ortel, MD, PhD; Gualtiero Palareti, MD; Stephen G. Pauker, MD; Anne-Marie Prabulos, MD; Paolo Prandoni, MD, PhD; Fraser D. Rubens, MD; Charles M. Samama, MD, PhD, FCCP; Meyer Michel Samama, MD; Sam Schulman, MD, PhD; Neil E. Schwartz, MD, PhD; Daniel E. Singer, MD; Frank A. Sonnenberg, MD; Frederick A. Spencer, MD; Alex C. Spyropoulos, MD, FCCP; Scott M. Stevens, MD; Matthew D. Stevenson, PhD; Jack Sun, MD; Peter J. Svensson, MD, PhD; Kevin H. Teoh, MD; Per Olav Vandvik, MD, PhD; David L. Veenstra, PharmD, PhD; Sara K. Vesely, PhD; Jeffrey I. Weitz, MD, FCCP; Philip S. Wells, MD; Richard P. Whitlock, MD; Daniel M. Witt, PharmD, FCCP; Ann Wittkowsky, PharmD, FCCP; Sherry M. Wren, MD; John J. You, MD

All panelists were required to disclose both financial conflicts of interest, such as receipt of funds for consulting with industry, and intellectual conflicts of interest, such as publication of original data bearing directly on a recommendation. Financial and intellectual conflicts of interest were classified as primary (more serious) or secondary (less serious). The operational definition of primary intellectual conflicts of interest included authorship of original studies and peer-reviewed grant funding (government, not-for-profit organizations) directly bearing on a recommendation. The operational definition of primary financial conflicts of interest included consultancies, advisory board membership, and the like from industry. Topic editors had no primary conflicts of interest, as noted. Some deputy editors, who were clinical experts in the topic of the article, had relevant primary conflicts of interest. The American College of Chest Physicians (ACCP) Health and Science Policy (HSP) Committee deemed some of these conflicts serious enough to require "management." Management involved more frequent updates of disclosures than required of the approved panelists without any conflicts and recusal from activities relevant to that conflict.

Topic panel members, including the deputy editor, with primary conflicts related to a particular recommendation did not participate in the final deliberations that led to the decision regarding the direction or strength of a recommendation, nor did they vote on recommendations for which they were primarily conflicted. Panelists with primary conflicts could, however, participate in discussions and offer their opinions on interpretations of the evidence. Readers will find a record of panelist conflicts of interest on a recommendation-by-recommendation basis in the online data supplement.

In summary, the authors have reported to CHEST the following conflicts of interest: Dr Kearon is a consultant to Boehringer Ingelheim and has received peer-reviewed funding for studies in the treatment of VTE. Dr Bounameaux has received grant monies and honoraria for consultancy or lectures from Bayer Schering Pharma AG; Daiichi-Sankyo Co, Ltd; Sanofi-Aventis LLC; Pfizer Inc; Bristol-Myers Squibb; Servier; and Canonpharma Production Ltd. Dr Goldhaber has received funds from Eisai Co, Ltd; EKOS Corporation; Sanofi-Aventis LLC; and Johnson & Johnson. He serves as a consultant for Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Daiichi Sankyo Co, Ltd; Eisai Co, Ltd; EKOS Corporation; Medscape; Merck & Co, Inc; Portola Pharmaceuticals, Inc; and Sanofi-Aventis LLC. Dr Wells has received peer-reviewed and investigator-initiated industry research funding for projects related to venous thrombosis treatment. He has received honoraria for industry-sponsored (Bayer, Boehringer Ingelheim, Pfizer, BioMerieux, sanofi-aventis) talks pertaining to venous thrombosis and has attended advisory boards for Bayer, Boehringer Ingelheim, Pfizer and Bristol-Myers Squibb. Dr Crowther has served on various advisory boards, has assisted in the preparation of  educational materials, has sat on data safety management boards, and his institution has received research funds from the following companies: Leo Pharma A/S, Pfizer Inc, Boehringer Ingelheim GmbH, Bayer Healthcare Pharmaceuticals, Octapharm AG, CSL Behring, and Artisan Pharma. Personal total compensation for these activities over the past 3 years totals less than US $10,000. Dr Kahn has received peer-reviewed and investigator-initiated industry research funding for projects related to venous thrombosis and post-thrombotic syndrome prevention and treatment. She has received honoraria for industry-sponsored talks pertaining to venous thrombosis. Dr Akl is a member of and prominent contributor to the GRADE Working Group. Dr Comerota discloses that he is a consultant to and speaker for Covidien, Inc. Drs Prandoni, Nelson, Gould, and Dentali have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org .

This is the current release of the guideline.

This guideline is updates a previous version: Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008 Jun;133(6 Suppl):454S-545S. [393 references]

Electronic copies: Available to subscribers of Chest - The Cardiopulmonary and Critical Care Journal .

Print copies: Available from the American College of Chest Physicians, Products and Registration Division, 3300 Dundee Road, Northbrook IL 60062-2348.

The following are available:

• Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141;7S-47S.
• Introduction to the ninth edition: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical guidelines. Chest 2012;141;48S-52S.
• Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141;53S-70S.
• Patient values and preferences in decision making for antithrombotic therapy: a systematic review: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141;e1S-e23S.
• Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141;e44S-e88S.
• Antiplatelet drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141;e89S-e119S.
• New antithrombotic drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141;e120S-e151S.
• Approach to outcome measurement in the prevention of thrombosis in surgical and medical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141;e185S-e194S.

Electronic copies: Available to subscribers of Chest - The Cardiopulmonary and Critical Care Journal .

Print copies: Available from the American College of Chest Physicians, Products and Registration Division, 3300 Dundee Road, Northbrook IL 60062-2348.

None available

This summary was completed by ECRI on July 30, 2001. The information was verified by the guideline developer on October 17, 2001. This NGC summary was updated by ECRI on December 8, 2004. The updated information was verified by the guideline developer on January 12, 2005. This summary was updated by ECRI on March 6, 2007 following the U.S. Food and Drug Administration (FDA) advisory on Coumadin (warfarin sodium). This summary was updated by ECRI Institute on June 22, 2007 following the U.S. Food and Drug Administration (FDA) advisory on heparin sodium injection. This summary was updated by ECRI Institute on September 7, 2007 following the revised U.S. Food and Drug Administration (FDA) advisory on Coumadin (warfarin). This summary was updated by ECRI Institute on March 14, 2008 following the updated FDA advisory on heparin sodium injection. This NGC summary was updated by ECRI Institute on November 25, 2008. The updated information was verified by the guideline developer on January 7, 2009. This summary was updated by ECRI Institute on January 15, 2010 following the U.S. Food and Drug Administration (FDA) advisory on Voltaren Gel. This summary was updated by ECRI Institute on July 27, 2010 following the FDA drug safety communication on Heparin. This NGC summary was updated by ECRI Institute on May 2, 2012.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.