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## Complete Summary

#### GUIDELINE TITLE

The pharmacology and management of the vitamin K antagonists: The
Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

#### BIBLIOGRAPHIC SOURCE(S)

Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The
pharmacology and management of the vitamin K antagonists: the Seventh
ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004
Sep;126(3 Suppl):204S-33S. \[329 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15383473)

#### GUIDELINE STATUS

This is the current release of the guideline.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [February 28, 2008, Heparin Sodium
    Injection](http://www.fda.gov/medwatch/safety/2008/safety08.htm#HeparinInj2):
    The U.S. Food and Drug Administration (FDA) informed the public that
    Baxter Healthcare Corporation has voluntarily recalled all of their
    multi-dose and single-use vials of heparin sodium for injection and
    their heparin lock flush solutions. Alternate heparin manufacturers
    are expected to be able to increase heparin production sufficiently
    to supply the U.S. market. There have been reports of serious
    adverse events including allergic or hypersensitivity-type
    reactions, with symptoms of oral swelling, nausea, vomiting,
    sweating, shortness of breath, and cases of severe hypotension.

-   [August 16, 2007, Coumadin
    (Warfarin)](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Warfarin):
    Updates to the labeling for Coumadin to include pharmacogenomics
    information to explain that people\'s genetic makeup may influence
    how they respond to the drug.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Thromboembolic disorders including the following:

-   Primary and secondary venous thromboembolism

-   Systemic embolism in patients with prosthetic heart valves or atrial
    fibrillation

-   Acute myocardial infarction in high-risk men

-   Stroke, recurrent infarction, or death in patients with acute
    myocardial infarction

-   Systemic embolism in high-risk patients with mitral stenosis

#### GUIDELINE CATEGORY

Management\
Prevention\
Treatment

#### CLINICAL SPECIALTY

Cardiology\
Critical Care\
Emergency Medicine\
Family Practice\
Internal Medicine

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

-   To describe the antithrombotics effects of vitamin K antagonists
    (VKAs)

-   To provide evidence-based recommendations concerning the monitoring
    of anticoagulation intensity, the clinical applications of VKA
    therapy, and the optimal therapeutic range of VKAs

#### TARGET POPULATION

Patients requiring oral anticoagulant therapy

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Pharmacotherapy**

1.  Vitamin K antagonists (VKAs)\*

2.  Low-molecular-weight heparin (LMWH)

3.  Unfractionated heparin (UFH)

4.  Reversal of VKAs:

    -   Vitamin K1

    -   Fresh plasma

    -   Prothrombin complex concentrate

    -   Recombinant factor VIIa

5.  Tranexamic acid mouthwash

6.  Epsilon amino caproic acid mouthwash

*\*Note: Since warfarin is the most commonly used VKA worldwide,
warfarin was used interchangeably with VKA or coumarin.*

**Monitoring**

1.  Prothrombin time (PT)

2.  International normalized ratio (INR)

#### MAJOR OUTCOMES CONSIDERED

-   Incidence of thrombosis

-   Recurrent thromboembolism

-   Incidence of major and minor hemorrhage

-   Time to achieve therapeutic international normalized ratio (INR)

-   Anticoagulant response

-   Maintenance dose

-   Time in the therapeutic range (TTR)

-   Cost effectiveness

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

**Process of Searching for Evidence**

Defining the clinical question provided the framework for formulating
eligibility criteria that guided the search for relevant evidence. Prior
to searching for the evidence, methodological experts and librarians
reviewed each question to ensure that the librarians could derive a
comprehensive search strategy.

In specifying eligibility criteria, authors not only identified
patients, interventions, and outcomes, but also methodological criteria.
For most therapeutic studies, authors restricted eligibility to
randomized controlled trials (RCTs).

For many questions, RCTs did not provide sufficient data, and article
authors also included observational studies. This was also true when
randomized trials were not the most appropriate design to use for
addressing the research question. In particular, randomized trials are
not necessarily the best design to understand risk groups (e.g., the
baseline or expected risk of a given event for certain subpopulations).
Because there are no interventions examined in questions about
prognosis, one replaces interventions by the exposure, which is time.

**Identifying the Evidence**

To identify the relevant evidence, a team of librarians at the
University at Buffalo conducted comprehensive literature searches. For
each question the authors provided, the librarians developed sensitive
(but not specific) search strategies, including all languages, and
conducted separate searches for systematic reviews, RCTs, and, if
applicable, observational studies. The librarians searched the Cochrane
Database of Systematic Reviews, the Database of Abstracts of Reviews of
Effectiveness and Cochrane Register of Controlled Trial, the ACP Journal
Club, MEDLINE, and Embase for studies published between 1966 and June
2002 in any language. To filter MEDLINE and Embase search results for
RCT evidence, the librarians used the search strategy developed by the
Cochrane Collaboration (full strategy available in Appendix online at:
<http://www.chestjournal.org/content/vol126/3_suppl_1>).

For observational studies, they restricted their searches to human
studies. Searches were not further restricted in terms of methodology.
While increasing the probability of identifying all published studies,
this sensitive approach resulted in large number of citations for many
of the defined clinical questions. Therefore, trained research
assistants screened the citation list developed from the search and
removed any apparently irrelevant citations. These irrelevant citations
included press news, editorials, narrative reviews, single case reports,
animal studies (any nonhuman studies), and letters to the editor.
Authors included data from abstracts of recent meetings if reporting was
transparent and all necessary data for the formulation of a
recommendation were available. The guideline developers did not
explicitly use Internet sources to search for research data.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

The rating scheme framework captures the trade-off between benefits and
risks (1 or 2) (and the methodological quality of the underlying
evidence (A, B, C+, or C). See \"Rating Scheme for the Strength of the
Recommendations.\"

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

**Summarizing Evidence**

The electronic searches also included searching for systematic reviews.
If authors were satisfied with a recent high-quality systematic review,
evidence from that review provided a foundation for the relevant
recommendation.

Pooled analyses from high-quality systematic reviews formed, wherever
possible, the evidence base of the recommendations. Pooling offers the
advantage of obtaining more precise estimates of treatment effects and
allows for a greater generalizability of results. However, pooling also
bears the risk of spurious generalization. In general, the summary
estimates of interest were the different types of outcomes conveying
benefit and downsides (i.e., risk, burden, and cost).

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus (Consensus Development Conference)

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

The strength of any recommendation depends on the following two factors:
the trade-off between the benefits and the risks, burdens, and costs;
and the strength of the methodology that leads to the treatment effect.
The guideline developers grade the trade-off between benefits and risks
in the two categories: 1, in which the trade-off is clear enough that
most patients, despite differences in values, would make the same
choice; and 2, in which the trade-off is less clear, and individual
patients\' values will likely lead to different choices.

When randomized trials provide precise estimates suggesting large
treatment effects, and the risks and costs of therapy are small,
treatment for average patients with compatible values and preferences
can be confidently recommended.

If the balance between benefits and risks is in doubt, methodologically
rigorous studies providing **Grade A** evidence and recommendations may
still be weak (**Grade 2**). Uncertainty may come from less precise
estimates of benefit, harm, or costs, or from small effect sizes.

There is an independent impact of validity and consistency, and the
balance of positive and negative impacts of treatment on the strength of
recommendations. In situations in which there is doubt about the value
of the trade-off, any recommendation will be weaker, moving from **Grade
1** to **Grade 2**.

**Grade 1** recommendations can only be made when there is a relatively
clear picture of both the benefits and the risks, burdens, and costs,
and when the balance between the two clearly favors recommending or not
recommending the intervention for the typical patient with compatible
values and preferences. A number of factors can reduce the strength of a
recommendation, moving it from **Grade 1** to **Grade 2**. Uncertainty
about a recommendation to treat may be introduced if the following
conditions apply: (1) the target event that is trying to be prevented is
less important (confident recommendations are more likely to be made to
prevent death or stroke than asymptomatic deep vein thrombosis); (2) the
magnitude of risk reduction in the overall group is small; (3) the
probability of the target event is low in a particular subgroup of
patients; (4) the estimate of the treatment effect is imprecise, as
reflected in a wide confidence interval (CI) around the effect; (5)
there is substantial potential harm associated with therapy; or (6)
there is an expectation for a wide divergence in values even among
average or typical patients. Higher costs would also lead to weaker
recommendations to treat.

The more balanced the trade-off between benefits and risks, the greater
the influence of individual patient values in decision making. Virtually
all patients, if they understand the benefits and risks, will take
aspirin after experiencing a myocardial infarction (MI) or will comply
with prophylaxis to reduce the risk of thromboembolism after undergoing
hip replacement. Thus, one way of thinking about a **Grade 1**
recommendation is that variability in patient values is unlikely to
influence treatment choice in average or typical patients.

When the trade-off between benefits and risks is less clear, individual
patient values may influence treatment decisions even among patients
with average or typical preferences.

**Grade 2** recommendations are those in which variation in patient
values or individual physician values will often mandate different
treatment choices, even among average or typical patients. An
alternative, but similar, interpretation is that a **Grade 2**
recommendation suggests that clinicians conduct detailed conversations
with patients to ensure that their ultimate recommendation is consistent
with the patient\'s values.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

  ------------------------------------------------------------------------------
  **Grade of         **Clarity of     **Methodological   **Implications**
  Recommendation**   Risk/Benefit**   Strength of        
                                      Supporting         
                                      Evidence**         
  ------------------ ---------------- ------------------ -----------------------
  **1A**             Clear            Randomized         Strong recommendation;
                                      controlled trials  can apply to most
                                      (RCTs) without     patients in most
                                      important          circumstances without
                                      limitations        reservation

  **1C+**            Clear            No RCTs, but       Strong recommendation;
                                      strong RCT results can apply to most
                                      can be             patients in most
                                      unequivocally      circumstances
                                      extrapolated, or   
                                      overwhelming       
                                      evidence from      
                                      observational      
                                      studies            

  **1B**             Clear            RCTs with          Strong recommendation;
                                      important          likely to apply to most
                                      limitations        patients
                                      (inconsistent      
                                      results,           
                                      methodological     
                                      flaws\*)           

  **1C**             Clear            Observational      Intermediate-strength
                                      studies            recommendation; may
                                                         change when stronger
                                                         evidence is available

  **2A**             Unclear          RCTs without       Intermediate-strength
                                      important          recommendation; best
                                      limitations        action may differ
                                                         depending on
                                                         circumstances or
                                                         patients\' or societal
                                                         values

  **2C+**            Unclear          No RCTs, but       Weak recommendation;
                                      strong RCT results best action may differ
                                      can be             depending on
                                      unequivocally      circumstances or
                                      extrapolated, or   patients\' or societal
                                      overwhelming       values
                                      evidence from      
                                      observational      
                                      studies            

  **2B**             Unclear          RCTs with          Weak recommendation;
                                      important          alternative approaches
                                      limitations        likely to be better for
                                      (inconsistent      some patients under
                                      results,           some circumstances
                                      methodological     
                                      flaws\*)           

  **2C**             Unclear          Observational      Very weak
                                      studies            recommendation; other
                                                         alternatives may be
                                                         equally reasonable
  ------------------------------------------------------------------------------

*\*These situations include RCTs with both lack of blinding and
subjective outcomes, where the risk of bias in measurement of outcomes
is high, or RCTs with large loss to follow-up.*

#### COST ANALYSIS

While conference participants agreed that recommendations should reflect
economic considerations, incorporating costs is fraught with difficult
challenges. For most recommendations, formal economic analyses are
unavailable. Even when analyses are available, they may be
methodologically weak or biased. Furthermore, costs differ radically
across jurisdictions, and even sometimes across hospitals within
jurisdictions.

Because of these challenges, the guideline developers consider economic
factors only when the costs of one therapeutic option over another are
substantially different within major jurisdictions in which clinicians
make use of their recommendations. As a result, in jurisdictions in
which resource constraints are severe, alternative allocations may serve
the health of the public far better than some of the interventions that
are designated as **Grade 1A**. This will likely be true for all less
industrialized countries and, with the increasing promotion of expensive
drugs with marginal benefits, may be increasingly true for wealthier
nations. Furthermore, recommendations change (either in direction or
with respect to grade) only when the guideline developers believe that
costs are high in relation to benefits. Instances in which costs have
influenced recommendations are labeled in the \"values and preferences\"
statements associated with the recommendation.

**Cost-Effectiveness of Usual Care (UC) vs. Anticoagulation Management
Service (AMS)**

Because of improved outcomes with fewer hospitalizations and emergency
department visits, the management of anticoagulation by an AMS may prove
to be more cost-effective, as demonstrated by a number of investigators
suggesting a \"cost avoidance\" of approximately \$1,000 per patient
year of therapy. These observations need to be validated by randomized
studies.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The guideline authors formulated draft recommendations prior to the
conference that served as the foundation for authors to work together
and critique the recommendations. Drafts of all articles including draft
recommendations were available for review during the conference. A
representative of each article presented potentially controversial
issues in their recommendations at plenary meetings. Article authors met
to integrate feedback, to consider related recommendations in other
articles, and to revise their own guidelines accordingly. Authors
continued this process after the conference until they reached agreement
within their groups and with other author groups who had provided
critical feedback. Finally, the editors of this supplement harmonized
the articles and resolved remaining disagreements through facilitated
discussion.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

The rating scheme is defined at the end of the \"Major Recommendations\"
field.

Please refer to the original full-length guideline document for a
detailed description of the pharmacology and monitoring of vitamin K
antagonists (VKAs), the pharmacokinetics and pharmacodynamics of
warfarin (including genetic and environmental factors), the
antithrombotics effect of VKAs, monitoring anticoagulation intensity,
and clinical applications of VKA therapy.

**The Appropriate Dose for Initiation of Oral Coagulants**

1.  The guideline developers suggest the initiation of oral
    anticoagulation with doses between 5 and 10 mg for the first 1 or 2
    days for most individuals, with subsequent dosing based on the
    international normalized ratio (INR) response (**Grade 2B**).

**Anticoagulation in the Elderly**

1.  In the elderly, for patients who are debilitated, malnourished, have
    congestive heart failure, or have liver disease, the guideline
    developers suggest the use of a starting dose of [\<]{.underline}5
    mg (**Grade 2C**).

**Frequency of Monitoring Oral Anticoagulation Therapy**

1.  The guideline developers suggest starting INR monitoring after the
    initial two or three doses of oral anticoagulation therapy (**Grade
    2C**).

2.  For patients who are receiving a stable dose of oral anticoagulants,
    the guideline developers suggest monitoring at an interval of no
    longer than every 4 weeks (**Grade 2C**).

**Management of Dosing When the INR is Nontherapeutic**

1.  For patients with INRs above the therapeutic range, but \<5.0 who
    have no significant bleeding, lower the dose or omit the dose,
    monitor more frequently, and resume therapy at a lower dose when the
    INR is in the therapeutic range. If only minimally above the
    therapeutic range, no dose reduction may be required (all **Grade
    2C**).

2.  For patients with INRs of [\>]{.underline}5.0 but \<9.0 who have no
    significant bleeding, omit the next one or two doses, monitor more
    frequently, and resume therapy at a lower dose when the INR is in
    the therapeutic range. Alternatively, omit a dose and administer
    vitamin K1 (1 to 2.5 mg orally), particularly if the patient is at
    an increased risk of bleeding. If more rapid reversal is required
    because the patient requires urgent surgery, vitamin K1
    ([\<]{.underline}5 mg orally) can be given with the expectation that
    a reduction of the INR will occur in 24 hours. If the INR is still
    high, additional vitamin K1 (1 to 2 mg orally) can be given (all
    **Grade 2C**).

3.  For patients with INRs of [\>]{.underline}9.0 and no significant
    bleeding, hold warfarin therapy and administer a higher dose of
    vitamin K1 (5 to 10 mg orally) with the expectation that the INR
    will be reduced substantially in 24 to 48 hours. Monitor the patient
    more frequently and use additional vitamin K1 if necessary. Resume
    therapy at a lower dose when INR is in the therapeutic range (all
    **Grade 2C**).

4.  In patients with serious bleeding and elevated INRs, the guideline
    developers recommend holding warfarin therapy and administering
    vitamin K1 (10 mg by slow intravenous \[IV\] infusion) supplemented
    with fresh plasma, prothrombin complex concentrate, or recombinant
    factor VIIa, depending on the urgency of the situation. Vitamin K1
    administration can be repeated every 12 hours (all **Grade 1C**).

5.  In patients with life-threatening bleeding and elevated INRs, the
    guideline developers recommend holding warfarin therapy and
    administering prothrombin complex concentrate or recombinant factor
    VIIa supplemented with vitamin K1 (10 mg by slow IV infusion).
    Repeat the procedure if necessary, depending on the INR (**Grade
    1C**).

6.  In patients with mild to moderately elevated INRs who have no major
    bleeding, the guideline developers suggest that vitamin K be
    administered orally rather than subcutaneously (SC) (**Grade 1A**).

**Management of Dosing When an Invasive Procedure is Required**

1.  For patients with a low risk of thromboembolism, stop warfarin
    therapy approximately 4 days before they undergo surgery, allow the
    INR to return to near-normal values, briefly use postoperative
    prophylaxis (if the intervention increases the risk of thrombosis)
    with a low dose of unfractionated heparin (UFH) (5,000 U SC) or a
    prophylactic dose of low-molecular-weight heparin (LMWH), and
    simultaneously begin warfarin therapy. Alternatively, a low dose of
    UFH or a prophylactic dose of LMWH also can be used preoperatively
    (all **Grade 2C**).

2.  For patients with an intermediate risk of thromboembolism, stop
    warfarin approximately 4 days before surgery, allow the INR to fall,
    cover the patient beginning 2 days preoperatively with a low dose of
    UFH (5,000 U SC) or a prophylactic dose of LMWH, and then commence
    administration of a low dose of UFH (or LMWH) and warfarin
    postoperatively. (**Grade 2C**).

3.  For patients with a high risk of thromboembolism, stop warfarin
    therapy approximately 4 days before surgery to allow the INR to
    return to normal at the time of surgery, and begin therapy with a
    full dose of UFH or a full dose of LMWH as the INR falls
    (approximately 2 days preoperatively). UFH can be administered as an
    SC injection on an outpatient basis and as a continuous IV infusion
    after hospital admission in preparation for surgery and should be
    discontinued approximately 5 hours before surgery with the
    expectation that the anticoagulant effect will have worn off at the
    time of surgery. An alternative is to continue to use SC UFH or LMWH
    preoperatively and to stop therapy 12 to 24 h before surgery with
    the expectation that the anticoagulant effect will be very low or
    have worn off at the time of surgery, then commence administering a
    low dose of UFH (or LMWH) and warfarin postoperatively (**Grade
    2C**).

4.  For patients with a low risk of bleeding, continue warfarin therapy
    at a lower dose and operate at an INR of 1.3 to 1.5. The dose of
    warfarin can be lowered 4 or 5 days before surgery. Warfarin therapy
    then can be restarted postoperatively, supplemented with a low dose
    of UFH (5,000 U SC) or a prophylactic dose of LMWH, if necessary
    (**Grade 2C**).

5.  In patients who are undergoing dental procedures with a need to
    control local bleeding, the guideline developers suggest the use of
    tranexamic acid mouthwash (**Grade 2B**) or epsilon amino caproic
    acid mouthwash without interrupting anticoagulant therapy (**Grade
    2B**).

**Therapeutic Range in the Presence of a Lupus Inhibitor**

1.  In patients who have a lupus inhibitor and who have no additional
    risk factors and have not failed to respond to therapy, the
    guideline developers suggest a therapeutic target INR of 2.5 (INR
    range, 2.0 to 3.0) (**Grade 2B**). In patients who have recurrent
    thromboembolic events with a therapeutic INR or other additional
    risk factors for thromboembolic events, the guideline developers
    suggest a target INR of 3.0 (INR range, 2.5 to 3.5) (**Grade 2C**).

**Models of Anticoagulation Monitoring and Management**

1.  The guideline developers recommend that physicians who manage oral
    anticoagulation therapy do so in a systematic and coordinated
    fashion, incorporating patient education, systematic INR testing,
    tracking, follow-up, and good patient communication of results and
    dosing decisions (**Grade 1C+**).

**[Definitions]{.underline}**

  ------------------------------------------------------------------------------
  **Grade of         **Clarity of     **Methodological   **Implications**
  Recommendation**   Risk/Benefit**   Strength of        
                                      Supporting         
                                      Evidence**         
  ------------------ ---------------- ------------------ -----------------------
  **1A**             Clear            Randomized         Strong recommendation;
                                      controlled trials  can apply to most
                                      (RCTs) without     patients in most
                                      important          circumstances without
                                      limitations        reservation

  **1C+**            Clear            No RCTs, but       Strong recommendation;
                                      strong RCT results can apply to most
                                      can be             patients in most
                                      unequivocally      circumstances
                                      extrapolated, or   
                                      overwhelming       
                                      evidence from      
                                      observational      
                                      studies            

  **1B**             Clear            RCTs with          Strong recommendation;
                                      important          likely to apply to most
                                      limitations        patients
                                      (inconsistent      
                                      results,           
                                      methodological     
                                      flaws\*)           

  **1C**             Clear            Observational      Intermediate-strength
                                      studies            recommendation; may
                                                         change when stronger
                                                         evidence is available

  **2A**             Unclear          RCTs without       Intermediate-strength
                                      important          recommendation; best
                                      limitations        action may differ
                                                         depending on
                                                         circumstances or
                                                         patients\' or societal
                                                         values

  **2C+**            Unclear          No RCTs, but       Weak recommendation;
                                      strong RCT results best action may differ
                                      can be             depending on
                                      unequivocally      circumstances or
                                      extrapolated, or   patients\' or societal
                                      overwhelming       values
                                      evidence from      
                                      observational      
                                      studies            

  **2B**             Unclear          RCTs with          Weak recommendation;
                                      important          alternative approaches
                                      limitations        likely to be better for
                                      (inconsistent      some patients under
                                      results,           some circumstances
                                      methodological     
                                      flaws\*)           

  **2C**             Unclear          Observational      Very weak
                                      studies            recommendation; other
                                                         alternatives may be
                                                         equally reasonable
  ------------------------------------------------------------------------------

*\*These situations include RCTs with both lack of blinding and
subjective outcomes, where the risk of bias in measurement of outcomes
is high, or RCTs with large loss to follow-up.*

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

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

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Appropriate monitoring and management of patients who require treatment
with vitamin K antagonists (VKAs)

#### POTENTIAL HARMS

-   Refer to Table 2 of the original guideline document entitled \"Drug
    and Food Interactions with Warfarin by Level of Supporting Evidence
    and Direction of Interaction\" for information on potentiation,
    inhibition, and no effect interactions.

-   Refer to Table 3 of the original guideline document entitled
    \"Enzyme-inducing Drug Interactions with Warfarin\" for information
    on inducing agents, isoenzyme induced, expected onset, anticipated
    dosage adjustments, and expected offset.

-   Refer to Table 4 of the original guideline document entitled
    \"Potential Problems with International Normalized Ratio (INR)
    (Causes of Erroneous INR)\" for information on problems with INR
    monitoring.

-   Bleeding, the most feared and major complication of oral
    anticoagulant therapy, is closely related to the intensity of
    anticoagulation.

-   High doses of vitamin K1, though effective, may lower the INR more
    than is necessary and may lead to warfarin resistance for a week or
    more.

-   Intravenous (IV) injection of vitamin K1 may be associated with
    anaphylactic reactions, although such reactions have even been
    described with non-IV routes of administration.

-   Other than hemorrhage, the most important side effect of warfarin is
    skin necrosis. This uncommon complication is usually observed on the
    third to eighth day of therapy, and is caused by extensive
    thrombosis of the venules and capillaries within the subcutaneous
    fat.

-   A variant of this syndrome also attributed to a severe,
    warfarin-induced, depletion of protein C is the occurrence of venous
    limb gangrene during warfarin treatment of cancer-associated deep
    vein thrombosis.

-   Refer to Tables 8, 9, and 10 of the original guideline document for
    information on the frequency of major hemorrhage/thromboembolism in
    patients managed under an anticoagulation management service (AMS),
    the frequency of major hemorrhage/thromboembolism in patients
    managed under usual care vs. AMS, and the frequency of major
    hemorrhage/thromboembolism in patients managed under usual care,
    respectively.

**Subgroups Most Likely to Experience Harms**

Several patient characteristics have been shown to be associated with
higher odds of bleeding during anticoagulation therapy. The patient
factor that most consistently has been demonstrated to be predictive of
major bleeding is a history of bleeding (especially gastrointestinal
\[GI\] bleeding). Other factors that have been shown to be associated
include a history of stroke and the presence of a serious comorbid
condition such as renal insufficiency, anemia, or hypertension.

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

The management of patients with warfarin-induced skin necrosis who
require lifelong anticoagulant therapy is problematic. Therapy with
warfarin is considered to be contraindicated, and long-term heparin
therapy is inconvenient and is associated with osteoporosis.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

**Interpreting the Recommendations**

Clinicians, third-party payers, institutional review committees, or the
courts should not construe these guidelines in any way as absolute
dictates. In general, anything other than a **Grade 1A** recommendation
indicates that the article authors acknowledge that other
interpretations of the evidence, and other clinical policies, may be
reasonable and appropriate. Even **Grade 1A** recommendations will not
apply to all circumstances and all patients. For instance, the guideline
developers have been conservative in their considerations of cost and
have seldom downgraded recommendations from **Grade 1** to **Grade 2**
on the basis of expense. As a result, in jurisdictions in which resource
constraints are severe, alternative allocations may serve the health of
the public far better than some of the interventions that are designated
as **Grade 1A**. This will likely be true for all less industrialized
countries and, with the increasing promotion of expensive drugs with
marginal benefits, may be increasingly true for wealthier nations.

Similarly, following **Grade 1A** recommendations will at times not
serve the best interests of patients with atypical values or preferences
or of those whose risks differ markedly from those of the usual patient.
For instance, consider patients who find anticoagulant therapy extremely
aversive, either because it interferes with their lifestyle (e.g.,
prevents participation in contact sports) or because of the need for
monitoring. Clinicians may reasonably conclude that following some
**Grade 1A** recommendations for anticoagulation therapy for either
group of patients will be a mistake. The same may be true for patients
with particular comorbidities (e.g., a recent gastrointestinal bleed or
a balance disorder with repeated falls) or other special circumstances
(e.g., very advanced age) that put them at unusual risk.

The guideline developers trust that these observations convey their
acknowledgment that no recommendations or clinical practice guidelines
can take into account the often compelling and unique features of
individual clinical circumstances. No clinician, and no body charged
with evaluating a clinician\'s actions, should attempt to apply these
recommendations in a rote or blanket fashion.

**Limitations of Guideline Development Methods**

The limitations of these guidelines include the possibility that some
authors followed this methodology more closely than others, although the
development process was centralized and supervised by the editors.
Second, it is possible that the guideline developers missed relevant
studies despite the comprehensive searching process. Third, the
guideline developers did not centralize the methodological evaluation of
all studies to facilitate uniformity in the validity assessments of the
research incorporated into these guidelines. Fourth, if high-quality
meta-analyses were unavailable, the guideline developers did not
statistically pool primary study results using meta-analysis. Finally,
sparse data on patient preferences and values, resources, and other
costs represent additional limitations that are inherent to most
guideline development methods.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

**Guideline Implementation Strategies**

A full review of implementation strategies for practice guidelines is
provided in the companion document entitled \"Antithrombotic and
Antithrombolytic Therapy: From Evidence to Application.\" The review
suggests that there are few implementation strategies that are of
unequivocal, consistent benefit, and that are clearly and consistently
worth resource investment. The following is a summary of the
recommendations (see \"Major Recommendations\" for a definition of the
recommendation grades).

To encourage uptake of guidelines, the guideline developers recommend
that appreciable resources be devoted to distribution of educational
material (**Grade 2B**).

They also suggest that:

-   Few resources be devoted to educational meetings (**Grade 2B**)

-   Few resources be devoted to educational outreach visits (**Grade
    2A**)

-   Appreciable resources be devoted to computer reminders (**Grade
    2A**)

-   Appreciable resources be devoted to patient-mediated interventions
    to encourage uptake of the guidelines (**Grade 2B**)

-   Few resources be devoted to audit and feedback (**Grade 2B**)

#### IMPLEMENTATION TOOLS

Personal Digital Assistant (PDA) Downloads\
Quick Reference Guides/Physician Guides\
Resources\
Slide Presentation\
Tool Kits

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness\
Staying Healthy

#### IOM DOMAIN

Effectiveness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The
pharmacology and management of the vitamin K antagonists: the Seventh
ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004
Sep;126(3 Suppl):204S-33S. \[329 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15383473)

#### ADAPTATION

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

#### DATE RELEASED

2004 Sep

#### GUIDELINE DEVELOPER(S)

American College of Chest Physicians - Medical Specialty Society

#### SOURCE(S) OF FUNDING

Funding was provided through an unrestricted educational grant by
AstraZeneca LP, Aventis Pharmaceuticals, GlaxoSmithKline, Bristol-Myer
Squibb/Sanofi-Synthelabo Partnership, and Organon Sanofi-Synthelabo LLC.

#### GUIDELINE COMMITTEE

American College of Chest Physicians Consensus Panel on Antithrombotic
and Thrombolytic Therapy

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Primary Authors*: Jack Ansell, MD; Jack Hirsh, MD, FCCP; Leon Poller,
MD; Henry Bussey, PharmD, FCCP; Alan Jacobson, MD;  Elaine Hylek, MD

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Dr. Ansell has received research funding from AstraZeneca, Aventis,
Sanofi-Synthelabo-Organon, Bristol-Myers Squibb. Dr. Ansell has received
honoraria for his participation on advisory boards and/or as a speaker
at educational events from AstraZeneca, Aventis,
Sanofi-Synthelabo-Organon, Wyeth Ayerst, Yamanouchi, Roche Diagnostics,
HemoSense, International Technedyne.

Dr. Hirsh has received research funding from AstraZeneca and has
received honararia for his participation on advisory boards and/or as a
speaker at educational events from AstraZeneca.

Dr. Poller is employed in an honorary capacity as Professor in the
University of Manchester. He receives research funding only from the
European Community and Manchester Thrombosis Research Foundation, a
registered charity. No honoraria have been received from industry for
the past 3 years.

Dr. Bussey has received research funding from Aventis,
Organon-Sanofi-Synthelabo, AstraZeneca, Bristol-Myers Squibb, Bertek
Pharmaceuticals, and Novartis and has participated on advisory boards
and/or research steering committees for Aventis,
Organon-Sanofi-Synthelabo, and AstraZeneca. He also has received
speaking honoraria from and/or served as a consultant for Aventis,
AstraZeneca, Bristol-Myers Squibb, and Organon-Sanofi-Synthelabo.

Dr. Jacobson has received research funding from AstraZeneca,
Bristol-Myers Squibb, Aventis, Sanofi, Organon, Roche Diagnostics,
Hemosense, International Technidyne, and Lifescan, and has received
honoraria for his participation on advisory boards and/or as a speaker
at educational events from AstraZeneca, Aventis, Bristol-Myers Squibb,
and Lifescan.

Dr. Hylek has received research funding from Pfizer and Bristol-Myers
Squibb and has received honoraria for participation as a speaker at an
educational event from Bristol-Myers Squibb.

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [Chest - The Cardiopulmonary and
Critical Care
Journal](http://www.chestjournal.org/content/vol126/3_suppl/).

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

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   The Seventh ACCP Conference on Antithrombotic and Thrombolytic
    Therapy. Evidence-based guidelines. Northbrook, IL: ACCP, 2004 Sep.

-   Methodology for guideline development for the Seventh American
    College of Chest Physicians Conference on Antithrombotic and
    Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

-   Applying the grades of recommendation for antithrombotic and
    thrombolytic therapy: The Seventh ACCP Conference on Antithrombotic
    and Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

-   Hemorrhagic complications of anticoagulant treatment: The Seventh
    ACCP Conference on Antithrombotic and Thrombolytic Therapy.
    Northbrook, IL: ACCP, 2004 Sep.

-   Antithrombotic and thrombolytic therapy: from evidence to
    application: The Seventh ACCP Conference on Antithrombotic and
    Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

-   Platelet-active drugs: the relationships among dose, effectiveness,
    and side effects: The Seventh ACCP Conference on Antithrombotic and
    Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

Electronic copies: Available from the [Chest - The Cardiopulmonary and
Critical Care Journal Web
site](http://www.chestjournal.org/content/vol126/3_suppl/).

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

The following is also available:

-   Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy:
    Evidence-based guidelines; quick reference guide. Northbrook, IL:
    ACCP, 2004 Sep. Personal Digital Assistant (PDA) download available
    at [ACCP Web site](http://accp.apprisor.com/dlselect.cfm).

Additional implementation tools are also available:

-   Clinical resource: antithrombotic and thrombolytic therapy.
    Northbrook, IL. ACCP, 2004. Ordering information: Available from the
    [ACCP Web
    site](http://www.chestnet.org/education/guidelines/products.php).

#### PATIENT RESOURCES

The following is available:

-   A patient\'s guide to antithrombotic and thrombolytic therapy. In:
    Clinical resource: antithrombotic and thrombolytic therapy.
    Northbrook (IL): American College of Chest Physicians (ACCP). 2004.

Ordering information is available from the [ACCP Web
site](http://www.chestnet.org/education/guidelines/products.php).

Please note: This patient information is intended to provide health
professionals with information to share with their patients to help them
better understand their health and their diagnosed disorders. By
providing access to this patient information, it is not the intention of
NGC to provide specific medical advice for particular patients. Rather
we urge patients and their representatives to review this material and
then to consult with a licensed health professional for evaluation of
treatment options suitable for them as well as for diagnosis and answers
to their personal medical questions. This patient information has been
derived and prepared from a guideline for health care professionals
included on NGC by the authors or publishers of that original guideline.
The patient information is not reviewed by NGC to establish whether or
not it accurately reflects the original guideline\'s content.

#### NGC STATUS

This NGC summary was completed by ECRI on November 19, 2004. The
information was verified by the guideline developer on January 12, 2005.
This summary was updated by ECRI on December 7, 2005 following the U.S.
Food and Drug Administration (FDA) advisory on NovoSeven. 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.

#### COPYRIGHT STATEMENT

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

### DISCLAIMER

#### NGC DISCLAIMER

The National Guideline Clearinghouse™ (NGC) does not develop, produce,
approve, or endorse the guidelines represented on this site.

All guidelines summarized by NGC and hosted on our site are produced
under the auspices of medical specialty societies, relevant professional
associations, public or private organizations, other government
agencies, health care organizations or plans, and similar entities.

Guidelines represented on the NGC Web site are submitted by guideline
developers, and are screened solely to determine that they meet the NGC
Inclusion Criteria which may be found at
<http://www.guideline.gov/about/inclusion.aspx> .

NGC, AHRQ, and its contractor ECRI Institute make no warranties
concerning the content or clinical efficacy or effectiveness of the
clinical practice guidelines and related materials represented on this
site. Moreover, the views and opinions of developers or authors of
guidelines represented on this site do not necessarily state or reflect
those of NGC, AHRQ, or its contractor ECRI Institute, and inclusion or
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Readers with questions regarding guideline content are directed to
contact the guideline developer.

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Date Modified: 11/10/2008