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## Complete Summary

#### GUIDELINE TITLE

Antithrombotic therapy supplement.

#### BIBLIOGRAPHIC SOURCE(S)

Institute for Clinical Systems Improvement (ICSI). Antithrombotic
therapy supplement. Bloomington (MN): Institute for Clinical Systems
Improvement (ICSI); 2007 Aug. 64 p. \[118 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Anticoagulation therapy
supplement. Bloomington (MN): Institute for Clinical Systems Improvement
(ICSI); 2006 Apr. 49 p.

### \*\* 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)

-   Conditions that require anticoagulation therapy (e.g., thrombosis)

-   Conditions that may result from anticoagulation therapy (e.g.,
    bleeding)

#### GUIDELINE CATEGORY

Management\
Prevention\
Risk Assessment

#### CLINICAL SPECIALTY

Cardiology\
Emergency Medicine\
Family Practice\
Hematology\
Internal Medicine\
Neurology

#### INTENDED USERS

Advanced Practice Nurses\
Allied Health Personnel\
Health Care Providers\
Health Plans\
Hospitals\
Managed Care Organizations\
Nurses\
Pharmacists\
Physician Assistants\
Physicians

#### GUIDELINE OBJECTIVE(S)

-   To provide a resource for the clinician in the use of antithrombotic
    drugs

-   To help physicians make risk-benefit treatment decisions

-   To serve as a tool to use for patients treated with anticoagulants

-   To bring about consistency in recommendations that are common to the
    scope of related Institute for Clinical Systems Improvement (ICSI)
    cardiovascular guidelines: [Atrial
    Fibrillation](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=10723&nbr=5585);
    [Heart Failure in
    Adults](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11531&nbr=5972);
    [Diagnosis and Initial Treatment of Ischemic
    Stroke](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11079&nbr=5842);
    [Diagnosis and Treatment of Chest Pain and Acute Coronary Syndrome
    (ACS)](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=10227&nbr=5390);
    [Venous
    Thromboembolism](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11284&nbr=5885),
    and [Venous Thromboembolism
    Prophylaxis](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11286&nbr=5887).

#### TARGET POPULATION

Any patient receiving anticoagulation therapy

**Note**: Refer to related National Guideline Clearinghouse (NGC)
summaries of the Institute for Clinical Systems Improvement (ICSI)
cardiovascular guidelines for specific target populations: [Atrial
Fibrillation](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=10723&nbr=5585);
[Heart Failure in
Adults](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11531&nbr=5972);
[Diagnosis and Initial Treatment of Ischemic
Stroke](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11079&nbr=5842);
[Diagnosis and Treatment of Chest Pain and Acute Coronary Syndrome
(ACS)](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=10227&nbr=5390);
[Venous
Thromboembolism](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11284&nbr=5885),
and [Venous Thromboembolism
Prophylaxis](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11286&nbr=5887).

#### INTERVENTIONS AND PRACTICES CONSIDERED

1.  Risk assessment (risk of thrombosis if untreated versus risk of
    bleeding if treated)

2.  Pre-treatment assessment, including complete blood count (CBC),
    platelet count, prothrombin time (PT), international normalized
    ratios (INRs), activated partial thromboplastin time (aPTT),
    creatine, liver enzymes, and albumin

3.  Anticoagulants

    -   Warfarin

    -   Unfractionated heparin (UFH)

    -   Low-molecular-weight heparin (LMWH)

    -   Synthetic pentasaccharide (fondaparinux)

    -   Alternative agents in selected cases: such as direct thrombin
        inhibitors, antiplatelet agents (oral and parenteral)

4.  Reversal of anticoagulation

    -   Vitamin K

    -   Fresh frozen plasma (FFP)

    -   Protamine sulfate

5.  Patient education

6.  Monitoring of anticoagulation therapy by establishing INRs or by
    using aPTTs or heparin assays or by performing periodic platelet
    counts

7.  Perioperative management including:

    -   Bridging therapy (e.g., taking a patient off warfarin in the
        perioperative setting and \"bridging\" with heparin)

    -   Management of neuraxial blockade

#### MAJOR OUTCOMES CONSIDERED

**Safety and Efficacy of Anticoagulation**

-   Risk and incidence of adverse effects of anticoagulation, (e.g.,
    major bleeding, skin necrosis, heparin induced thrombocytopenia)

-   Therapeutic anticoagulation levels (e.g., international normalized
    ratio \[INR\])

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

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

A literature search of clinical trials, meta-analysis, and systematic
reviews is performed.

#### 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

**Classes of Research Reports**:

A.  Primary Reports of New Data Collection:

> Class A:

-   Randomized, controlled trial

> Class B:

-   Cohort study

> Class C:

-   Nonrandomized trial with concurrent or historical controls

-   Case-control study

-   Study of sensitivity and specificity of a diagnostic test

-   Population-based descriptive study

> Class D:

-   Cross-sectional study

-   Case series

-   Case report

B.  Reports that Synthesize or Reflect upon Collections of Primary
    Reports:

> Class M:

-   Meta-analysis

-   Systematic review

-   Decision analysis

-   Cost-effectiveness analysis

> Class R:

-   Consensus statement

-   Consensus report

-   Narrative review

> Class X:

-   Medical opinion

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review

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

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

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

**New Guideline Development Process**

A new guideline, order set, and protocol is developed by a 6- to
12-member work group that includes physicians, nurses, pharmacists,
other healthcare professionals relevant to the topic, along with an
Institute for Clinical Systems Improvement (ICSI) staff facilitator.
Ordinarily, one of the physicians will be the leader. Most work group
members are recruited from ICSI member organizations, but if there is
expertise not represented by ICSI members, 1 or 2 members may be
recruited from medical groups or hospitals outside of ICSI.

The work group will meet for seven to eight three-hour meetings to
develop the guideline. A literature search and review is performed and
the work group members, under the coordination of the ICSI staff
facilitator, develop the algorithm and write the annotations and
footnotes and literature citations.

Once the final draft copy of the guideline is developed, the guideline
goes to the ICSI members for critical review.

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

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

**Critical Review Process**

Every newly developed guideline or a guideline with significant change
is sent to Institute for Clinical Systems Improvement (ICSI) members for
Critical Review. The purpose of critical review is to provide an
opportunity for the clinicians in the member groups to review the
science behind the recommendations and focus on the content of the
guideline. Critical review also provides an opportunity for clinicians
in each group to come to consensus on feedback they wish to give the
work group and to consider changes necessary across systems in their
organization to implement the guideline.

All member organizations are expected to respond to critical review
guidelines. Critical review of guidelines is a criterion for continued
membership within the ICSI.

After the critical review period, the guideline work group reconvenes to
review the comments and make changes, as appropriate. The work group
prepares a written response to all comments.

**Approval**

Each guideline, order set, and protocol is approved by the appropriate
steering committee. There is one steering committee each for
Respiratory, Cardiovascular, OB/GYN, and Preventive Services. The
Committee for Evidence-based Practice approves guidelines, order sets,
and protocols not associated with a particular category. The steering
committees review and approve each guideline based on the following:

-   Member comments have been addressed reasonably.

-   There is consensus among all ICSI member organizations on the
    content of the document.

-   Within the knowledge of the reviewer, the scientific recommendations
    within the document are current.

-   Either a critical review has been carried out, or to the extent of
    the knowledge of the reviewer, the changes proposed are sufficiently
    familiar and sufficiently agreed upon by the users that a new round
    of critical review is not needed.

Once the guideline, order set, or protocol has been approved, it is
posted on the ICSI Web site and released to members for use. Guidelines,
order sets, and protocols are reviewed regularly and revised, if
warranted.

**Document Revision Process**

ICSI scientific documents are revised every 12 -- 36 months as indicated
by changes in clinical practice and literature. Every 6 months, ICSI
checks with the work group to determine if there have been changes in
the literature significant enough to cause the document to be revised
earlier than scheduled.

Prior to the work group convening to revise the document, ICSI members
are asked to review the document and submit comments. During revision, a
literature search of clinical trials, meta-analysis, and systematic
reviews is performed and reviewed by the work group. The work group will
meet for 1-2 three-hour meetings to review the literature, respond to
member organization comments, and revise the document as appropriate.

If there are changes or additions to the document that would be
unfamiliar or unacceptable to member organizations, it is sent to
members to review prior to going to the appropriate steering committee
for approval.

**Review and Comment Process:**

ICSI members are asked to review and submit comments for every
guideline, order set, and protocol prior to the work group convening to
revise the document.

The purpose of the Review and Comment process is to provide an
opportunity for the clinicians in the member groups to review the
science behind the recommendations and focus on the content of the order
set and protocol. Review and Comment also provides an opportunity for
clinicians in each group to come to consensus on feedback they wish to
give the work group and to consider changes needed across systems in
their organization to implement the guideline.

All member organizations are encouraged to provide feedback on order
sets and protocol, however responding to Review and Comment is not a
criterion for continued membership within ICSI.

After the Review and Comment period, the work group reconvenes to review
the comments and make changes as appropriate. The work group prepares a
written response to all comments.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

**Note from the National Guideline Clearinghouse (NGC) and the Institute
for Clinical Systems Improvement (ICSI)**: For a description of what has
changed since the previous version of this guidance, refer to \"[Summary
of Changes Report \-- August -
2007](http://www.icsi.org/antithrombotic_therapy_supplement__guideline__14045/antithrombotic_therapy_supplement__summary_of_changes_.html).\"

These recommendations supplement the recommendations on anticoagulation
therapy provided in the National Guideline Clearinghouse (NGC) summaries
of the Institute for Clinical Systems Improvement (ICSI) guidelines:
[Atrial
Fibrillation](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=10723&nbr=5585);
[Heart Failure in
Adults](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11531&nbr=5972);
[Diagnosis and Initial Treatment of Ischemic
Stroke](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11079&nbr=5842);
[Diagnosis and Treatment of Chest Pain and Acute Coronary Syndrome
(ACS)](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=10227&nbr=5390);
[Venous
Thromboembolism](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11284&nbr=5885),
and [Venous Thromboembolism
Prophylaxis](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11286&nbr=5887).

Class of evidence (A-D, M, R, X) ratings are defined at the end of the
\"Major Recommendations\" field.

**Clinical Highlights**

-   There are no circumstances under which patients absolutely should or
    should not receive anticoagulation therapy. Clinicians must consider
    the risks and benefits of anticoagulation therapy for a patient
    based upon the individual\'s risk for thrombosis if not treated
    weighed against the risk of bleeding if treated. (*Introduction,
    Annotations #2, 3, 4, 12, 13, 14, 15, 26, 27, 29, 36, 37, 39, 46,
    47, 49, 55, 56, 58*)

-   In the initial phase of treatment for patients with active
    thrombosis (such as acute deep vein thrombosis \[DVT\]) or high risk
    of thrombosis, immediate-acting anticoagulant agents (unfractionated
    heparin \[UFH\]/low-molecular-weight heparin \[LMWH\]/fondaparinux)
    should be used concomitant with warfarin. (*Annotation #7*)

-   Loading doses and rapid induction of warfarin should be avoided.
    (*Annotation #7*)

-   Many prescription medications or over-the-counter remedies,
    including dietary supplements and herbs, may alter the effectiveness
    of anticoagulants (detected by the international normalized ratio
    \[INR\]) and/or reduce the effectiveness of platelets (not detected
    by the INR). (*Annotations #7; see also Annotations Appendices B, C,
    D in the original guideline document*)

-   Vitamin K may be used to reverse supratherapeutic anticoagulation
    with warfarin. The dose of vitamin K depends upon the degree of INR
    elevation and/or signs and symptoms of bleeding. Vitamin K can lead
    to warfarin resistance and subsequently to an increased risk of
    thromboembolism. (*Annotation #9*)

-   Regardless of the anticoagulant used, it is important that patients
    know they must always inform their physician and other health care
    providers that they are on anticoagulation therapy, especially if
    they are undergoing an invasive procedure. (*Annotations #10, 20,
    24, 34, 44, 54, 63; see also Appendix D in the original guideline
    document*)

-   Patients should be encouraged and empowered to play an active role
    in the self-management of their treatment. Self-management is best
    initiated and sustained through active involvement of patients and
    family members with their multidisciplinary health care team. This
    educational partnership should be encouraged to decrease potential
    risks and improve understanding of the importance of patient
    adherence to their treatment regimen. (*Annotation #10, 20, 24, 34,
    44, 54, 63; see also Appendix D in the original guideline document*)

-   Patients with mechanical heart valves and who are pregnant have
    complex anticoagulation needs and should be managed by an
    anticoagulation expert. (*Annotations #4,15*)

**Warfarin**

1.  **Introduction**

> Warfarin is used in the chronic management of patients with several
> types of thrombotic diseases. It produces its anticoagulant effect by
> inhibiting the vitamin K dependent production of clotting factors II,
> VII, IX, and X, and proteins C and S. Warfarin is not fully effective
> in the initial several days of therapy because of a delayed reduction
> in some of the clotting factors that it inhibits. In the initial phase
> of treatment for patients with active thrombosis (such as acute deep
> vein thrombosis \[DVT\]) or high risk of thrombosis, immediate acting
> anticoagulant agents (unfractionated heparin \[UFH\],
> low-molecular-weight heparin \[LMWH\], fondaparinux, direct thrombin
> inhibitors \[DTIs\]) should be used concomitantly with warfarin.
>
> When determining the efficacy and tolerability of warfarin in patients
> with non-valvular atrial fibrillation, the clinical trials excluded
> patients using the following criteria:
>
> **Table 1: Exclusion Criteria Used in Trials Evaluating the Efficacy
> and Tolerability of Anticoagulation in Patients with Non-valvular
> Atrial Fibrillation**

  -----------------------------------------------------------------------
  Active bleeding\
  Active peptic ulcer disease\
  Known coagulation defects\
  Thrombocytopenia (platelet less than 50,000/mm^3^) or platelet
  dysfunction\
  Recent hemorrhagic stroke\
  Noncompliant or unreliable patients\
  Patient is psychologically or socially unsuitable\
  Dementia or severe cognitive impairment\
  History of falls (three within the previous year or recurrent,
  injurious falls)\
  Excessive alcohol intake\
  Uncontrolled hypertension (greater than 180/100 mm Hg)\
  Daily use of nonsteroidal anti-inflammatory drugs (NSAIDs)\
  Planned invasive procedure or major surgery

  -----------------------------------------------------------------------

> The clinician will need to balance the potential increased risk in
> bleeding against the potential decreased risk of thromboembolism when
> evaluating warfarin therapy.
>
> ***Evidence supporting this recommendation is of class: R***

2.  **Contraindications**

> **Key Points**:

-   All contraindications are relative to a patient\'s risk for
    thrombosis weighed against their risk for bleeding while on
    anticoagulation therapy.

> **Warfarin Allergy or Intolerance**
>
> Acute rash, hepatitis, diarrhea, or nausea may indicate an allergy or
> intolerance to warfarin.
>
> **Hemorrhage**
>
> Anticoagulation with warfarin is contraindicated in patients with
> active hemorrhage with possible exceptions in certain circumstances
> such as disseminated intravascular coagulation as a result of
> malignancy. The decision to initiate anticoagulation should be
> individualized for patients with a history of recent hemorrhage.
> Again, this is dependent on circumstances including the type of
> hemorrhage and the indication for anticoagulation. Withholding
> anticoagulation for four to six weeks may be prudent for non-central
> nervous system bleeds. This duration may be longer for central nervous
> system (CNS) bleeds and needs to be assessed on a case-by case basis.
>
> See Appendix A, \"Risk Factors for Bleeding During Warfarin Therapy\"
> in the original guideline document and Annotation #3, \"Adverse
> Effects\" for additional information about predicting the risk of
> bleeding for individual patients.
>
> **Pregnancy**
>
> See Annotation #4, \"Pregnancy - Contraindicated.\"

3.  **Adverse Effects**

> **Key Points**:

-   The most common adverse effect of warfarin is bleeding. Risk factors
    for bleeding include patient-related and treatment-related factors.

> **Bleeding**
>
> Patients treated with usual doses of warfarin have a 2-4% risk per
> year of bleeding episodes requiring transfusion, and a 0.2% risk per
> year of fatal hemorrhage. Risk factors for bleeding include
> patient-related factors and treatment-related factors.
>
> **Patient-related factors** include age, previous episodes of
> bleeding, anemia (hematocrit \[HCT\] less than 30%), hypertension,
> heart disease, cerebrovascular disease, renal disease, history of
> gastrointestinal (GI) hemorrhage, active peptic ulcer disease or liver
> disease, recent or imminent surgery, trauma, excessive alcohol intake,
> unreliability, frequent or significant falls, regular use of NSAIDs,
> and use of other medications or natural remedies.
>
> The U.S. Food and Drug Administration (FDA) recently approved updated
> labeling for warfarin. The agency reports that people with variations
> in two genes, CYP2C9 and VKORC1, are individually responsible for
> 35-50% of the variable dose response to warfarin. These genetic
> variations affect the dose of warfarin that individual patients will
> need to achieve and maintain therapeutic INRs.
>
> While there is clinical evidence that the presence of these genetic
> variations may impact the choice of the initial warfarin dose, there
> are no trials, at present, that have shown using genetic testing will
> have an impact on short- and long-term safety and patient outcomes.
> The FDA has not made the testing for the two gene variations
> mandatory.
>
> The work group feels that more clinical trials are necessary before
> recommending routine testing of patients for these genetic variations.
> There are many other variables that influence a patient\'s response to
> warfarin therapy. Most important is that all patients initiating
> warfarin need frequent, careful monitoring to assess their response to
> this therapy.
>
> **Advanced patient age** and hypertension are two predictors of risk
> strongly related to the inherent risk of intracerebral hemorrhage in
> patients not receiving anticoagulation. Combined literature sources
> support age as a risk for intracerebral hemorrhage that increases by
> 1.85/year/decade, with particular caution above 75 years of age.
>
> **Treatment-related factors** include duration, intensity, and
> variability of warfarin treatment, concomitant use of aspirin, and
> support patients receive from their providers and home environments.
> Please refer to Appendix A, \"Risk Factors for Bleeding During
> Warfarin Therapy\" in the original guideline document for additional
> information on bleeding risk in anticoagulation therapy.
>
> Risk factors for bleeding should not be considered absolute
> contraindications to anticoagulant therapy. Some risk factors for
> bleeding (such as age) are also risk factors for thromboembolism.
> **The potential increased risk of bleeding must be balanced against
> the potential decreased risk of thromboembolism**.
>
> ***Evidence supporting this recommendation is of classes: A, B, C, D,
> R***
>
> **Skin Necrosis**
>
> Skin necrosis is a rare but serious complication of warfarin therapy
> that typically occurs on the third to eighth day of therapy. Warfarin
> should be discontinued in patients with evidence of skin necrosis.
>
> When warfarin-induced skin necrosis is suspected, patients should be
> placed on heparin therapy unless there is evidence of heparin induced
> thrombocytopenia (HIT).
>
> ***Evidence supporting this recommendation is of classes: D, R***
>
> **Purple Toe Syndrome**
>
> Purple toe syndrome and other manifestations of peripheral emboli may
> rarely complicate warfarin therapy, usually 3 to 10 weeks after
> initiation of therapy. Causes of purple toe syndrome other than
> warfarin should be considered when making a treatment decision. These
> include vasculitis, acute myocardial infarction (MI) with embolism,
> and diabetes mellitus.
>
> ***Evidence supporting this recommendation is of classes: D, R***
>
> **Less Serious Adverse Effects**
>
> Adverse effects that are less serious include alopecia, osteoporosis,
> gastrointestinal discomfort, and rash. Management of these adverse
> effects should be managed on an individual basis.
>
> ***Evidence supporting this recommendation is of classes: B, D***

4.  **Pregnancy - Contraindicated**

> Warfarin is contraindicated during pregnancy because it crosses the
> placenta causing teratogenicity and fetal bleeding.
>
> Unfractionated and low molecular weight heparins do not cross the
> placenta and do not cause teratogenicity or fetal bleeding. Therefore,
> UFH or a LMWH should be used in place of warfarin. A recent study has
> shown that two pregnant patients with mechanical heart valves had
> thrombotic complications when treated with LMWH. **Patients with
> mechanical heart valves and who are pregnant are at high risk and
> should be managed by an anticoagulation expert**.
>
> ***Evidence supporting this recommendation is of class: R***

5.  **Breast Feeding**

> The amount of warfarin in breast milk is too small to affect the baby.
> As a result, breastfeeding is safe for mothers taking warfarin and for
> their infants.

6.  **Monitoring**

> **Test**
>
> The INR is the preferred test for monitoring warfarin therapy.
>
> The INR is calculated from the Prothrombin Time (PT) as follows:
>
> (Patient PT/Mean Normal PT)^ISI^
>
> The International Sensitivity Index (ISI) is a measure of sensitivity
> of the thromboplastin. The manufacturer provides this information. The
> laboratory instrumentation used for INR testing may cause a clinically
> significant change in the ISI.
>
> **Limitations of INR**
>
> There are several recognized limitations of the test, including
> instrumentation effect on the ISI and erroneous reporting of the ISI
> by the thromboplastin manufacturer.
>
> **Timing and Frequency of INR Testing**
>
> During initiation and maintenance therapy with warfarin, the INR is
> best measured at least 16 hours after the dose of warfarin.
>
> INR determinations should be obtained monthly in most stable patients,
> and no more than six weeks should elapse between determinations.
>
> **Influence of Heparin and Lupus Anticoagulants on the INR**
>
> Prothrombin reagents contain a heparin neutralizer; however, presence
> of high concentrations of heparin in plasma samples (e.g., sample
> collected shortly after intravenous \[IV\] heparin bolus, or sample
> collected above an IV infusion of unfractionated heparin, or sample
> collected through a heparin-coated catheter \[central venous line or
> arterial line\]) will spuriously prolong the INR.
>
> Prothrombin reagents contain a high concentration of phospholipids;
> thus, presence of lupus anticoagulants typically does not affect the
> INR result.
>
> However, there are individual patients in whom lupus anticoagulants
> may spuriously prolong INR results obtained by some instrument-reagent
> combinations. In these patients, lupus anticoagulants can cause a
> prolongation of the PT and INR, resulting in a perceived
> overestimation of a patient\'s anticoagulation.
>
> **Alternatives to INR in Patients with Lupus Anticoagulants**
>
> For patients with a prolonged baseline PT/INR due to a lupus
> anticoagulant, alternatives to the INR have been evaluated.
> Measurement of chromogenic factor X levels or factor II levels may be
> helpful in the monitoring of warfarin therapy in selected patients
> with lupus anticoagulant. Both the chromogenic factor X and factor II
> levels may not be readily available.
>
> ***Evidence supporting this recommendation is of classes: A, D, R***
>
> **Blood Samples**
>
> Patient samples should be collected in 109 mmol/L (3.2%) sodium
> citrate when INR testing is performed on anticoagulated plasma.

-   The volume of sodium citrate in blood tubes used for collection of
    plasma INR testing should be adjusted when the patient\'s hematocrit
    is greater than 55%. Specimens with a high hematocrit will cause
    spuriously high INR values unless the citrate volume is adjusted.

-   Anticoagulated whole blood may be stored spun or unspun at room
    temperature for up to 24 hours prior to testing.

> ***Evidence supporting this recommendation is of classes: B, R***
>
> Refer to the original guideline document for information on
> instruments including point of care instruments and reagents.

7.  **Dosing**

> **Key Points**:

-   Patients receiving warfarin for the first time should begin at the
    patient\'s estimated average daily dose (typically 5 mg/day; range
    2.5 to 7.5 mg/day), with a recheck of INR in two to three doses.

-   Steady-state INR values will not be realized for up to three weeks
    following a dose adjustment.

> **Testing must be completed and results reviewed before initiation of
> warfarin:**

-   Complete blood count (CBC)

-   Platelet count

-   PT/INR

-   Activated partial thromboplastin time (aPTT)

-   Creatinine

> **Obtain if there is clinical suspicion of abnormal results based on
> patient history and physical:**

-   Liver enzymes (alanine transaminase \[ALT\], aspartate transaminase
    \[AST\], gamma-glutamyl transferase \[GGT\])

-   Albumin

> **General Principles of Warfarin Dosing**
>
> Loading doses and rapid induction of warfarin should be avoided.
> Warfarin (irrespective of INR) is not fully effective in the first
> several days of therapy because of a delayed decrease in several
> circulating clotting factors. Loading doses can increase a patient\'s
> risk of supratherapeutic INR and make it more difficult to determine a
> steady-state dose.
>
> See \"Patient Related Factors\" under Annotation #3\"Adverse Effect\"
> for a discussion of the updated labeling for warfarin.
>
> Patients at high risk of thrombosis, such as those with an active
> thrombotic process (e.g., venous thromboembolism \[VTE\]) or an
> underlying malignancy, should be treated with concomitant
> immediate-acting anticoagulant (UFH, LMWH, fondaparinux, DTIs) and
> warfarin therapy. Patients at lower thrombotic risk (e.g., atrial
> fibrillation without recurrent thromboembolism) can be initiated on
> warfarin alone.
>
> A single target INR value should be used as a goal endpoint. This will
> decrease the odds of a patient being above or below desirable range of
> INR. The target INR for most conditions is 2.5 with an acceptable
> range of 2.0 to 3.0. Other thrombotic conditions (e.g., mitral
> mechanical valves) have recommended targets of 3.0 (range 2.5 to 3.5).
> A table of recommended therapeutic ranges for oral anticoagulant
> therapy is available in Annotation #8, \"Recommended Therapeutic Range
> for Oral Anticoagulation Therapy\" in the original guideline document.
> Also, individual disease management guidelines such as [Atrial
> Fibrillation](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=10723&nbr=5585)
> and [Venous
> Thromboembolism](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11284&nbr=5885)
> give specific INR recommendations.
>
> The risk of bleeding for patients on warfarin increases substantially
> at INR values greater than 4.0. This risk is magnified if one or more
> risk factors are present. Consider hemorrhagic risk in all dosing
> decisions. Please refer to Appendix A, \"Risk Factors for Bleeding
> During Warfarin Therapy,\" of the original guideline document for more
> information on risk factors for bleeding during warfarin therapy.
>
> There is a significant increase in thromboembolism as INR values
> decrease below INR 1.7. Clinical risk and past medical history should
> be considered in all dosing decisions. Higher risk may require more
> aggressive dosing.
>
> In most cases, holding warfarin for 4 days prior to surgery results in
> an INR value of 1.2 or less. Expect advanced age and drug interactions
> to result in a slower decline. Patients with high risk of
> thromboembolism may need coverage with heparin for a portion of this
> time. For more information, see Annotation #65, \"Anticoagulation
> Bridging.\"
>
> Some equivalency studies have shown that substitution of generic
> warfarin for brand name Coumadin® may provide equivalent
> anticoagulation response if the manufacturer of the generic warfarin
> has followed the standards set for the name brand. Care must be taken
> to remain with either the brand name product or the same generic
> product. Do not switch from brand to generic or between generics.
>
> Prescription and over-the-counter medications can adversely affect the
> INR response to warfarin. Dietary supplements including herbal or
> natural remedies can change the INR response to warfarin and/or
> increase a patient\'s risk of bleeding. In these instances, additional
> monitoring may be needed. See Appendices B, \"Drug Interactions with
> Warfarin\" and C, \"Endogenous Interactions with Warfarin\" in the
> original guideline document for more information on drug interactions
> with warfarin.
>
> Mechanism of drug-drug interactions occur commonly by the cytochrome
> P450 enzyme metabolizing system. Metabolism of the object or substrate
> medication may either be induced or inhibited by the interacting drug.
> Induction will result in a diminished pharmacodynamic response, while
> inhibition will result in an increased pharmacodynamic response.
>
> Foods that contain moderate amounts of vitamin K may decrease the INR
> response to warfarin. Patients should be encouraged to not change
> their diet while taking warfarin and not change the amount of foods
> containing vitamin K they normally eat each day. See Annotation #10,
> \"Key Patient Education Components\" for a guide to educating patients
> regarding warfarin therapy.
>
> Direct thrombin inhibitors (hirudin, argatroban, bivalirudin) and
> heparins can affect the INR. See Annotations #35-44, \"Direct Thrombin
> Inhibitors\" for more information.
>
> ***Evidence supporting this recommendation is of classes: A, B, D,
> R***
>
> **Initiation of Warfarin**
>
> *Average Daily Dosing Technique (for patients not on heparin)*
>
> Average daily dosing technique is useful for patients off UFH and
> LMWH.
>
> A baseline INR value may be drawn to rule out underlying coagulopathy.
>
> Patients previously taking warfarin can be initiated at the previous
> dose.
>
> Patients receiving warfarin for the first time should begin at an
> average dose of 5 mg daily with a recheck of INR in two to three
> doses. Lower initiation doses should be considered for patients with
> any of the following factors: age greater than 75 years, multiple
> comorbid conditions, poor nutrition (low albumin), elevated INR when
> off warfarin, elevated liver function tests, or changing thyroid
> status. For patients who weigh more than 80 kg, a higher estimated
> average initial dose of 7.5 mg may be given. Higher initial dosing
> nomograms have not shown consistent benefit. Loading doses can
> increase a patient\'s risk of supratherapeutic INR and make it more
> difficult to determine a steady-state dose.
>
> See \"Patient Related Factors\" under Annotation #3\"Adverse Effect\"
> for a discussion of the updated labeling for warfarin.
>
> If the INR is 2.0 or greater after the first 3 doses, consider
> decreasing the dose by one-half. Always search for causes of rapid
> rise in INR such as poor nutritional status, infection, or systemic
> disease process. See Appendix C in the original guideline document for
> more information on endogenous interactions with warfarin.
>
> Subsequent INR values are determined at two to three times weekly for
> one to two weeks, then less often depending on the stability of the
> INR result.
>
> Steady state anticoagulation occurs between 6 to 12 days. Expect obese
> patients and patients of advanced age to take longer to reach steady
> state.
>
> ***Evidence supporting this recommendation is of classes: A, B, D,
> R***
>
> *Flexible Daily Dosing Technique (for patients on heparin)*
>
> The flexible daily dosing technique is useful for patients on
> concomitant UFH or a LMWH.
>
> A baseline INR value may be drawn to rule out underlying coagulopathy.
>
> Patients are given daily doses of warfarin, adjusted according to the
> daily INR, until a weekly dose can be determined.
>
> The dose-response relationship is best interpreted when there are at
> least 16 hours between dose and laboratory draw.
>
> ***Evidence supporting this recommendation is of class: D***
>
> *Maintenance Dosing of Warfarin*
>
> An assessment of clinical variables known to affect the INR (including
> a change of patient adherence, change of other medications \[e.g.,
> amiodarone\], change of food or alcohol consumption, change of
> activity level) should be made with each dose adjustment. Always
> search for the cause of out-of-range values and address them before
> adjusting the dose.
>
> Expect a 15% dose adjustment to result in an approximately 1.0 INR
> change. Likewise, a 10% dose adjustment will result in an approximate
> 0.7 to 0.8 INR change.
>
> Steady-state INR values will not be realized for up to 3 weeks
> following a dose adjustment.
>
> Patients with INR values by [+]{.underline} 0.5 INR out-of-range
> should be considered for more frequent monitoring and should have a
> repeat INR within seven days.
>
> If two consecutive weekly INR values are within range and there has
> not been a change in clinical variables known to effect the INR, the
> interval between draws may be gradually increased to monthly, and not
> more than 6 weeks.
>
> *Options for Dosing and Management*
>
> Anticoagulation clinics have been shown to significantly reduce
> patients\' risks of adverse events.
>
> Though traditionally, warfarin has been monitored at a central
> laboratory and managed by the patient\'s physician, new monitoring and
> management options have emerged.
>
> Anticoagulation clinics staffed by pharmacists/registered nurses (RNs)
> have been shown to significantly reduce patients\' risks of adverse
> events.
>
> Computer-assisted dosing has been slow to develop, but may someday
> improve the quality of anticoagulation adjustments and offer superior
> management for difficult or high-risk patients.
>
> Selected point-of-care instruments have received FDA approval for
> patient self-testing.
>
> While some patients may prefer self-management, clinical experience,
> reimbursement, and research are insufficient to support widespread
> implementation of patient self-management. Further research is needed
> to better identify appropriate candidates for self-management, and to
> delineate the key components of education and support.
>
> ***Evidence supporting this recommendation is of classes: A, B, C, D,
> R***

8.  **Recommended Therapeutic Range for Oral Anticoagulation**

> Recommended therapeutic range for oral anticoagulation therapy is
> provided in the original guideline document.

9.  **Correction of Supratherapeutic Anticoagulation Caused by
    Warfarin**

> Supratherapeutic anticoagulation may occur with patients taking
> warfarin. Vitamin K may be used to reverse the effects of warfarin;
> however, vitamin K can lead to warfarin resistance and, subsequently,
> to an increased risk of thromboembolism.
>
> ***Evidence supporting this recommendation is of classes: A, B, C, D,
> R***
>
> **Important Considerations for Vitamin K Dosing**
>
> In an outpatient clinic setting, oral vitamin K is the preferred route
> of administration.
>
> In a hospital setting, when patients are ill or taking nothing by
> mouth, intravenous vitamin K may be the preferred route of
> administration. To avoid anaphylactic reactions, vitamin K should be
> given over 30 minutes in a mixture of dextrose 5% in water (D5W) 50 mL
> under monitored conditions. It is not necessary to premedicate with
> corticosteroids or antihistamines.
>
> Administration of vitamin K by subcutaneous or intramuscular
> injections is not recommended due to unpredictable absorption which
> can lead to erratic correction of the INR and resistance to warfarin.
>
> Refer to Table 2 in the original guideline document for details on
> correction of supratherapeutic warfarin anticoagulation caused by
> warfarin.
>
> ***Evidence supporting this recommendation is of classes: B, C, R***

10. **Key Patient Education Components**

> Mechanism of action of warfarin: it depletes certain coagulation
> factor proteins in the blood.
>
> Time of day to take warfarin: it should be taken at approximately the
> same time each day. Due to the short half-life of factor VII and its
> influence on the INR, this is especially important if the patient will
> have an INR drawn the next morning.
>
> Explanation of INR, target range, and regular testing
>
> Signs and symptoms of bleeding and that the provider should be
> contacted immediately if bleeding signs are present.
>
> Need to notify provider if illness, injury, or change in physical
> status occurs.
>
> Need to inform all their health care providers of anticoagulation
> therapy, especially if potentially undergoing an invasive procedure,
> surgery or dental work.
>
> **Drug interactions**:

-   What to do if a new medication is initiated or a medication is
    discontinued, especially if the interaction with warfarin is
    unknown: check INR within three to four days.

-   Drugs that affect the absorption of warfarin

-   Drugs that increase or decrease the effect of warfarin

-   Common over-the-counter medication interactions, including aspirin,
    NSAIDs, acetaminophen, natural or herbal remedies, laxatives,
    antacids, and multivitamin preparations containing vitamin K

> Role of vitamin K and the importance of consistency of vitamin K rich
> foods in the diet rather than avoidance of vitamin K rich foods
>
> Importance of minimizing trauma risk associated with activities at
> high risk for injury
>
> Effect of exercise: increased activity results in decreased effect of
> the drug
>
> Effect of personal habits: alcohol, chewing tobacco, etc.
>
> Effect of certain conditions: congestive heart failure, thyroid
> disease, gastroenteritis, and diarrhea
>
> Importance of self-monitoring: maintain a log of INRs, dose of
> warfarin, etc.
>
> Medic Alert® bracelet/necklace and warfarin ID card.
>
> See Appendix D in the original guideline for a guide to patient
> education regarding warfarin therapy.

**Heparin (Unfractionated and Low-Molecular-Weight Heparin)**

11. **Introduction**

> Heparin\'s (UFH, LMWH) anticoagulant effect is due to the presence of
> a pentasaccharide sequence which potentiates the action of
> antithrombin III leading to inactivation of several clotting
> factors\--primarily factors Xa and IIa. Heparins have relatively rapid
> onset of action compared to warfarin and are often the first drug used
> in acute thrombotic situations.
>
> UFH is derived from porcine or bovine sources. It has variable
> absorption, metabolism, and pharmacokinetics and effects on
> anticoagulation. Monitoring is required in most patients treated with
> this drug.
>
> LMWH are depolymerized byproducts of UFH. Pharmacological advantages
> of LMWH relate to superior absorption and consistent dose effect
> response.

12. **Contraindications**

> Active major bleeding including intracerebral hemorrhage within past
> two weeks, subarachnoid hemorrhage until definitively treated
>
> Thrombolytics given within past 24 hours for acute stroke
>
> Hypersensitivity to heparin or pork products
>
> Heparin-induced thrombocytopenia (HIT)
>
> Renal failure (LMWH and fondaparinux)

13. **Precautions**

> Active or history of recent gastrointestinal ulceration and hemorrhage
>
> Bacterial endocarditis
>
> Bleeding diathesis
>
> Concomitant therapy with agents that inhibit platelets
>
> Congenital or acquired bleeding disorders
>
> Hemorrhagic stroke
>
> Status post brain, spinal, or ophthalmologic surgery
>
> Uncontrolled arterial hypertension
>
> Diabetic retinopathy

14. **Adverse Effects**

> **Key Points**:

-   Heparin-induced thrombocytopenia (HIT) should be suspected in
    patients who develop a skin lesion reaction at the injection site,
    have a systemic reaction to a bolus administration of heparin, or
    develop a greater than 50% decrease in platelet count from baseline
    labs while on heparin.

-   All heparin should be stopped in patients suspected of having HIT
    until antibody test results are available.

-   If the patient is on concomitant warfarin and HIT is suspected, the
    warfarin should be stopped, the warfarin effects corrected, and
    patient started on DTI therapy.

> **Bleeding**
>
> Risk of bleeding increases with treatment-related factors such as
> dose, duration, and use of thrombolytics and/or antiplatelet agents,
> and patient-related factors including age over 70 years, recent trauma
> or surgery, coagulopathy, peptic ulcer, neoplasm, or renal failure.
>
> ***Evidence supporting this recommendation is of classes: A, R***
>
> **Heparin-Induced Thrombocytopenia (HIT)**
>
> HIT is an immune-mediated reaction to heparins. It occurs in 2 to 3%
> of patients treated with UFH and less than 1% of patients treated with
> LMWH. This syndrome can be associated with paradoxical increased risk
> for venous and arterial thrombosis. Patients who develop HIT without
> associated thrombosis will have a significant risk for thrombosis in
> the subsequent 100 days. Patients with a history of HIT should not be
> treated with UFH or LMWH.
>
> HIT should be suspected in patients who develop a skin lesion reaction
> at the injection site, have a systemic reaction to a bolus
> administration of heparin, or develop a greater than 50% decrease in
> platelet count from baseline labs while on heparin.
>
> Delayed-onset HIT is an increasingly recognized form of this disorder.
> Patients with delayed-onset HIT typically present with thromboembolic
> complications one to two weeks (range 5 to 40 days) after receiving
> their last dose of LMWH or UFH. They frequently display mild or
> moderate thrombocytopenia. When HIT is not recognized as the etiology
> of the thromboembolic complication, the patient is frequently
> rechallenged with heparin, causing significant worsening of the
> thrombosis, as well as the thrombocytopenia. These patients typically
> have very high titers of HIT-related antibodies. The possibility of
> delayed onset HIT should be considered in any patient presenting with
> thromboembolism after a recent hospitalization.
>
> In vitro data have not demonstrated cross reactivity of fondaparinux
> with HIT antibodies. However, there is one report of HIT with
> fondaparinux.
>
> Patients suspected of having any form of HIT should have their heparin
> stopped while antibody testing for HIT is performed. Patients with a
> high clinical probability of having HIT should be treated with an
> appropriate alternative anticoagulant before antibody test results are
> available. Direct thrombin inhibitors (DTIs) are the alternative
> anticoagulant of choice for patients with HIT. Three brands are FDA
> approved: argatroban, lepirudin (Refludan®), and most recently
> bivalirudin (Angiomax®).
>
> If a patient is receiving warfarin when there is a high clinical
> probability of HIT, the warfarin should be stopped. The warfarin
> effect should be reversed with vitamin K and DTI therapy should be
> initiated. Low maintenance doses of warfarin can be restarted during
> DTI therapy after the platelet count has significantly improved and
> there is clinical improvement in the patient\'s thrombosis. There
> should be at least a five-day overlap of the DTIs and warfarin. The
> DTI therapy should be continued until the platelet count stabilizes.
>
> See Annotations #35\--44, \"Direct Thrombin Inhibitors\" for more
> information.
>
> ***Evidence supporting this recommendation is of class: R***

15. **Pregnancy**

> **Adverse Effects in Pregnancy**
>
> UFH and LMWH do not cross the placenta and therefore do not cause
> teratogenicity or fetal bleeding, though bleeding at the
> uteroplacental junction is possible.
>
> **Patients with mechanical heart valves and who are pregnant are at
> high risk and should be managed by an anticoagulation expert**. A
> study has shown that two pregnant patients with mechanical heart
> valves had thrombotic complications when treated with LMWH. Because of
> this, the FDA and the manufacturer have warned that enoxaparin is not
> presently indicated for use in prophylaxis for heart valve patients
> who are pregnant. However, the available data sets, clinical trials,
> reviews, and registry data suggest that, compared with UFH, LMWHs may
> be safe and effective agents in pregnant women with mechanical heart
> valves.
>
> The American College of Chest Physicians (ACCP) recommends that women
> requiring long-term anticoagulation with warfarin who are attempting
> pregnancy be monitored with frequent pregnancy tests. They recommend
> substituting UFH or a LMWH for warfarin when pregnancy is achieved.
> LMWHs cause less HIT and bone loss during pregnancy than UFH.
>
> The pharmacokinetics of LMWH in pregnancy is significantly altered.
> Consideration should be given to monitoring the anti-Xa activity at 12
> to 15 weeks and 30 to 33 weeks.
>
> When possible, patients using UFH or a LMWH should have a planned
> delivery. UFH should be discontinued 6 hours prior to a planned
> delivery. LMWH should be discontinued 24 hours prior to a planned
> delivery.
>
> ***Evidence supporting this recommendation is of class: R***

16. **Breast Feeding**

> Heparin is not secreted in breast milk and can be given safely to
> nursing mothers.
>
> ***Evidence supporting this recommendation is of class: R***

**Unfractionated Heparin**

17. **Monitoring**

> UFH treatment of thrombosis can be monitored using an activated
> partial thromboplastin time (aPTT) or heparin assay. The recommended
> test for monitoring UFH, including the therapeutic range for the test,
> should be provided by the laboratory. Of note, aPTT results vary among
> institutions due to differences in laboratory instruments and
> reagents. The aPTT therapeutic range should correspond to a plasma
> heparin concentration of 0.3 to 0.7 units/mL by an anti-Xa inhibition
> assay (0.2 to 0.4 units/mL by protamine titration assay).
>
> Heparin assays are being increasingly used for monitoring UFHs in the
> treatment of venous thromboembolism. The suggested target therapeutic
> range is 0.35 to 0.7 units/mL by the anti-Xa inhibition assay.
> Monitoring unfractionated heparin using a heparin assay may be
> indicated when the expected aPTT prolongation is not observed despite
> high doses of UFH (greater than 35,000 U unfractionated heparin in 24
> hours), when the pretreatment aPTT is prolonged or when a lupus
> anticoagulant has been previously documented in the patient.
>
> Patients receiving UFH or a LMWH should be monitored for HIT with a
> platelet count beginning at baseline, then every other day. A platelet
> count of less than 50% of baseline may indicate the development of
> HIT.
>
> **Note**: Patients who have not received heparin within the previous
> three months are unlikely to develop HIT within the first three days
> of treatment; however, patients who have received heparin within three
> months may develop HIT more rapidly. Unfortunately, patients are not
> always aware that they have received heparin (with surgery, central
> intravenous catheters, etc.) For the sake of safety and simplicity,
> the workgroup recommends a platelet count every other day for all
> patients receiving UFH or a LMWH. See Annotation #14, \"Adverse
> Effects\" for more information on adverse effects.
>
> ***Evidence supporting this recommendation is of classes: B, R***

18. **Dosing**

> **Testing must be completed and results reviewed before initiation of
> UFH:**
>
> Complete blood count (CBC)/platelet count
>
> PT/INR
>
> aPTT
>
> Creatinine
>
> **Obtain if there is clinical suspicion of abnormal results based on
> patient history and physical:**
>
> Liver enzymes (ALT, AST, GGT)
>
> Albumin
>
> Weight-based, institution specific nomograms are strongly recommended
> for patients on therapeutic intravenous UFH. Each institution must
> develop its own nomograms based upon their unique specific therapeutic
> ranges. See Appendix E in the original guideline document for an
> example of a heparin nomogram.
>
> **A standard weight-based protocol for heparin administration should
> not be used for patients receiving parenteral platelet receptor
> glycoprotein IIb/IIIa antagonist (abciximab or ReoPro®), tirofiban
> (Aggrastat®), eptifibatide (Integrilin®), and/or thrombolytics
> (alteplase or Activase®)**. Treating physicians should refer to the
> specific agent\'s package insert or their institution protocols for
> the specific agent\'s heparin protocol.
>
> Before administering UFH, the patient\'s height in centimeters and
> weight in kilograms and any adverse reactions to drugs or food,
> including a description of the reaction, should be noted.
>
> Before administering UFH, draw hemoglobin/hematocrit, platelet count,
> aPTT, and PT.
>
> **Initiation of UFH**
>
> An initial bolus dose of heparin is recommended followed by IV
> infusion, with the exception of acute stroke. The use of heparin in
> patients with acute stroke is evolving. See the NGC summary of the
> ICSI guideline [Diagnosis and Initial Treatment of Ischemic
> Stroke](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11079&nbr=5842).
> Note the time of initial heparin bolus.
>
> After initial IV bolus of heparin, begin maintenance drip per
> institutional protocols.
>
> **Maintenance**
>
> Obtain an aPTT level or heparin assay six hours after the initiation
> of IV heparin drip. Adjust the IV drip according to institutional
> protocols.
>
> ***Evidence supporting this recommendation is of classes: A, B***

19. **Correction of Supratherapeutic Anticoagulation Caused by UFH**

> Protamine sulfate administered by slow IV infusion over 10 minutes
> reverses the anticoagulation effects of unfractionated heparin.
>
> [Bolus dose of UFH (units) divided by 100 = protamine
> dose]{.underline}\
> Hourly infusion rate of UFH (units) divided by 40 = protamine dose
>
> Anaphylaxis occurs in 1% of patients who have previously received
> protamine (such as NPH insulin). Other adverse effects include
> hypotension.
>
> ***Evidence supporting this recommendation is of class: R***

20. **Key Patient Educational Components**

> Importance of understanding heparin assays, INRs, and target ranges
>
> Know and watch for signs of bleeding

**Low Molecular Weight Heparin (LMWH)**

21. **Monitoring**

> Patients receiving LMWH are at lower risk of developing HIT than
> patients receiving UFH. The need for platelet count monitoring during
> LMWH therapy depends on the indication for anticoagulation.
> Postoperative patients receiving LMWH and medical/obstetrical patients
> receiving LMWH following at least one dose of UFH (including UFH IV
> flushes) within the past 100 days infrequently experience HIT.
> Therefore, a baseline platelet count followed by platelet counts every
> two to three days is recommended until the LMWH is discontinued or
> until day 14 of therapy, whichever comes first.
>
> Medical and obstetrical patients receiving only LMWH rarely develop
> HIT. After a baseline platelet count, routine platelet count
> monitoring is not required. If there is clinical uncertainty about
> whether the patient may have received UFH, community standard is to
> monitor platelet counts monthly.
>
> All patients receiving any form of heparin should be instructed to
> immediately seek medical attention if signs or symptoms of venous
> thromboembolism are suspected.
>
> ***Evidence supporting this recommendation is of class: R***

22. **Dosing**

> **Testing must be completed and results reviewed before initiation of
> LMWH**:
>
> Complete blood count (CBC)/Platelet count
>
> PT/INR
>
> aPTT
>
> Creatinine
>
> **Obtain if there is clinical suspicion of abnormal results based on
> patient history and physical**:
>
> Liver enzymes (ALT, AST, GGT)
>
> Albumin
>
> LMWH should not be administered by intramuscular injection.
>
> Therapeutic doses of a LMWH are different from prophylactic doses.
>
> Doses of different LMWHs are not interchangeable.
>
> The anticoagulant effect of LMWH can extend beyond 24 hours after
> administration.
>
> The dose should be modified for patients with impaired renal function.
> It may be necessary to monitor the anti-Xa level in these patients.
> LMWHs are relatively contraindicated in patients with a creatinine
> clearance less than 30 or who are receiving dialysis. To calculate the
> estimated creatinine clearance, use the Cockcroft-Gault equation as
> follows:
>
> **In men**:
>
> Creatinine clearance =
>
> [(140 - age) x weight in kg]{.underline}\
> (72 x serum creatinine)
>
> **In women**:
>
> Creatinine clearance =
>
> [(140 - age) x weight in kg x 0.85]{.underline}\
> (72 x serum creatinine)
>
> The optimal dose of LMWH has not been established in patients with low
> body weight (less than 50 kg) (possibly higher than usual dose),
> obesity (possibly lower than usual dose), or pregnancy (changing dose
> due to changing creatinine clearance). It may be necessary to monitor
> the anti-Xa level in these patients.
>
> ***Evidence supporting this recommendation is of classes: D, R***
>
> Refer to Table 3 in the original guideline document for therapeutic
> dosing of LMWH and Table 4 for prophylactic dosing of LMWH.

23. **Correction of Supratherapeutic Anticoagulation Caused by LMWH**

> No agent, including fresh frozen plasma (FFP) and vitamin K, is
> effective for complete reversal of supratherapeutic anticoagulation
> with LMWH. Reversal of LMWH with protamine sulfate is incomplete, with
> neutralization of 60 to 75% at most. However, protamine should be
> considered for patients with severe life-threatening bleeding.
> Anaphylaxis occurs in 1% of patients who have previously received
> protamine (such as NPH insulin). Other adverse effects include
> hypotension.
>
> If LMWH has been administered within the last 8 hours:
>
> First dose: 1 mg protamine per 100 anti-Xa units LMWH\* administered
> by slow IV infusion over 10 minutes
>
> Second dose: 0.5 mg protamine per 100 anti-Xa units LMWH\*
> administered by slow IV infusion over 10 minutes
>
> \* 1 mg enoxaparin - approximately 100 antifactors Xa units
>
> Smaller doses are needed if the LMWH was administered more than eight
> hours ago.
>
> ***Evidence supporting this recommendation is of class: R***

24. **Key Patient Education Components**

> Over-the-counter and prescription drugs which should not be taken
> while on LMWH
>
> Importance of understanding heparin assay, INRs, and target ranges
>
> Know and watch for signs of bleeding
>
> Proper technique for injecting LMWH
>
> Restrictions for other conditions including DVT, stroke, or coronary
> artery disease (CAD). Refer to related ICSI guidelines for more
> information
>
> Importance of adhering to prescribed regimen
>
> Tables of patient education resources, along with patient and
> provider-oriented websites, are attached in the Support for
> Implementation section of the original guideline document.

**Synthetic Pentasaccharide (Fondaparinux)**

26. **Contraindications**

> Active major bleeding including intracerebral hemorrhage within past
> two weeks, subarachnoid hemorrhage until definitively treated
>
> Thrombolytics given within past 24 hours for acute stroke
>
> **Renal Failure**
>
> Fondaparinux has a long elimination half-life and there is no antidote
> for reversal; therefore, patients who may require rapid reversal are
> not candidates for this therapy.

27. **Precautions**

> Active or history of recent gastrointestinal ulceration and hemorrhage
>
> Bacterial endocarditis
>
> Bleeding diathesis
>
> Concomitant therapy with agents that inhibit platelets
>
> Congenital or acquired bleeding disorders
>
> Hemorrhagic stroke
>
> Status post brain, spinal, or ophthalmologic surgery
>
> Uncontrolled arterial hypertension
>
> Diabetic retinopathy

28. **Adverse Effects**

> Anemia has been reported in some patients receiving fondaparinux.
> Asymptomatic elevation in AST and ALT associated with an increase in
> bilirubin can occur in a small percentage of patients.

29. **Pregnancy**

> The safety of fondaparinux in pregnant women is unknown. Limited
> clinical experience suggests that fondaparinux may cross the placental
> barrier resulting in low but measurable anti-Xa activity in the
> umbilical cord.
>
> ***Evidence supporting this recommendation is of class: R***

30. **Breast-Feeding**

> Animal studies have shown secretion of fondaparinux in breast milk. It
> is unknown if humans secrete fondaparinux in breast milk.

31. **Monitoring**

> The heparin assay (anti-Xa) has been used to monitor effects of
> fondaparinux; however, in most clinical situations, monitoring may not
> be necessary. Indications for monitoring of fondaparinux include renal
> insufficiency (calculated creatinine clearance less than 30), low body
> weight (less than 50 kg), and obesity. There is limited data on use of
> fondaparinux in pregnancy.
>
> A platelet count should be obtained prior to the initiation of
> fondaparinux. Antibodies to fondaparinux rarely interact with platelet
> factor 4. There is one report of HIT with fondaparinux. Fondaparinux
> is not recommended for patients with platelets less than 100,000 mm^3^
> due to the overall increased risk of bleeding.
>
> Fondaparinux may cause transient elevations in serum
> aminotransferases. This effect is reversible and routine monitoring is
> not recommended.
>
> Additional information on fondaparinux is included in the NGC summary
> of the ICSI guideline [Venous Thromboembolism
> Prophylaxis](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=11286&nbr=5887).

32. **Dosing**

> **Testing must be completed and results reviewed before initiation of
> fondaparinux**:
>
> Complete blood count (CBC)/Platelet count
>
> PT/INR
>
> aPTT
>
> Creatinine
>
> **Obtain if there is clinical suspicion of abnormal results based on
> patient history and physical**:
>
> Liver enzymes (ALT, AST, GGT)
>
> Albumin
>
> Therapeutic doses are different than prophylactic dosing.
>
> Fondaparinux is not recommended for patients with platelets less than
> 100,000 mm^3^
>
> The dose of fondaparinux should be modified in patients with renal
> impairment. Fondaparinux is relatively contraindicated in patients
> with a creatinine clearance less than 30 mL/min. Fondaparinux should
> not be used in patients who are receiving dialysis.
>
> Fondaparinux is not recommended for patients weighing less than 50 kg.
>
> The optimal dose of fondaparinux has not been established in patients
> with obesity (possibly lower than usual dose). It may be necessary to
> monitor the anti-Xa level in these patients.
>
> There is limited data on use of fondaparinux in pregnancy.
>
> See Table 5 in the original guideline document for information on FDA
> approval status, indications, and dosing of fondaparinux.
>
> ***Evidence supporting this recommendation is of classes: A, M***

33. **Correction of Supratherapeutic Anticoagulation Caused by
    Fondaparinux**

> There is no antidote for excessive bleeding due to fondaparinux.
> Recombinant factor VIIa has shown promise as a possible antidote in
> studies utilizing healthy volunteers. Enzymes capable of degrading
> heparin have also been investigated as a future treatment for
> excessive bleeding due to fondaparinux.
>
> ***Evidence supporting this recommendation is of classes: A, D, R, Not
> Assignable***

34. **Key Patient Education Components**

> Importance of understanding fondaparinux and target ranges
>
> Know and watch for signs of bleeding
>
> Proper technique for injecting fondaparinux
>
> Restrictions for other conditions including DVT, stroke, or CAD.
> Please refer to the related ICSI guidelines for more information.
>
> Importance to adhering to prescribed regimen

**Direct Thrombin Inhibitors**

35. **Introduction**

> Direct thrombin inhibitors (DTIs) are a relatively new class of
> anticoagulant drugs. They exert their anticoagulant effect by directly
> attaching to and inhibiting both free and fibrin-bound thrombin.
> Potential advantages of these drugs over UFH are inhibition of fibrin
> (clot) bound thrombin, a more predictable anticoagulant response, and
> no effect on platelet factor 4. DTIs are presently approved for use in
> patients with active HIT and those with a previous history of HIT who
> require anticoagulation therapy.
>
> It is strongly recommended that consultation with a hematologist or
> anticoagulation expert is done when using these new anticoagulant
> drugs because of both drug and disease complexities.

36. **Contraindications**

    -   Active major bleeding

    -   Hypersensitivity to hirudin

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37. **Precautions**

    -   Severe hypertension

    -   History of recent major surgery

    -   History of recent major bleeding

    -   History of recent cerebrovascular accident

    -   Liver dysfunction (argatroban)

    -   Renal dysfunction (lepirudin)

    -   Gastrointestinal (GI) ulceration

    -   Patients with repeat courses may require more frequent
        monitoring due to antibody formation (lepirudin)

    -   Rare case reports of anaphylaxis with reexposure to lepirudin

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38. **Adverse Effects**

    -   Hemorrhage

    -   Patients with repeat courses may require more frequent
        monitoring due to antibody formation (lepirudin)

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39. **Pregnancy**

    -   Unknown

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40. **Breast-Feeding**

    -   Unknown

> **Types of Direct Thrombin Inhibitors**
>
> *Argatroban (Acova®)*
>
> This is a small molecular weight reversible inhibitor of the active
> site of thrombin (univalent). This agent is excreted normally in
> patients with renal insufficiency, but the dose must be reduced in
> patients with hepatic failure.
>
> *Bivalirudin (Angiomax®)*
>
> This is a semisynthetic bivalent inhibitor of thrombin. However,
> unlike hirudin, bivalirudin produces only transient reversal of
> thrombin and a shorter half-life. It has minimal renal excretion.
>
> *Lepirudin (recombinant hirudin) (Refludan®)*
>
> This is a potent specific inhibitor of thrombin that forms a slowly
> reversible complex with the enzyme by binding to both its active site
> and an exosite focus (bivalent effect). It is cleared predominantly by
> the kidneys with a half-life of 40 minutes post IV dose and 120
> minutes post subcutaneous dose. It has almost irreversible binding to
> thrombin and has been associated with an increased risk of major
> bleeds in one study.

41. **Monitoring**

    -   The aPTT testing is commonly used to monitor DTIs.

    -   The ecarin clotting time has been shown to be a **superior
        test** for monitoring recombinant hirudin therapy. However,
        these tests are not yet widely available in clinical
        laboratories.

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42. **Dosing**

> **Testing must be completed and results reviewed before initiation of
> direct thrombin inhibitors**:
>
> CBC/platelet count
>
> PT/INR
>
> aPTT
>
> Creatinine
>
> **Obtain if there is clinical suspicion of abnormal results based on
> patient history and physical**:
>
> Liver enzymes (ALT, AST, GGT)
>
> Albumin

-   **Argatroban (Acova®)**

> Argatroban has a short half-life (less than 1 hour) and is dosed at 2
> micrograms/kg/min with adjustments to maintain aPTT at 1.5 to 3.0
> times normal (not to exceed 100s).

-   **Bivalirudin (Angiomax®)**

> Bivalirudin is dosed as a 1.0 mg/kg IV bolus, followed by 2.5
> mg/kg/hour for 4 hours, followed by 0.2 mg/kg/hour infusion
> thereafter.

-   **Lepirudin (recombinant hirudin) (Refludan®)**

> The drug is dosed at 0.4 mg/kg bolus IV, followed by 0.15 mg/kg/hour
> IV with adjustments to maintain aPTT at 1.5 to 2.5 times the median of
> the laboratory normal range. This range may not be appropriate if the
> patient\'s aPTT is elevated at baseline.

43. **Correction of Supratherapeutic Anticoagulation Caused by DTIs**

> The major side effect of DTIs is bleeding. This appears to be more
> significant with the irreversible inhibitor Lepirudin and less so with
> the reversible inhibitors. There is no antidote for these medications
> should bleeding occur, which further supports the use of agents with a
> short half-life.
>
> ***Evidence supporting this recommendation is of class: R***

44. **Key Patient Education Components**

> Importance of understanding aPTT and target ranges
>
> Know and watch for signs of bleeding

**Antiplatelet Agents**

45. **Introduction**

> Platelet involvement with pathologic thrombosis and vascular occlusion
> in both venous and arterial systems has been a recognized target and
> challenge for therapeutic intervention. Antiplatelet drugs provide
> relatively safe and variably efficacious alternatives for reduction of
> excessive risk in several common clinical conditions, notably cardiac
> and cerebral atherothrombosis. In modern clinical practice,
> antiplatelet drugs play a role with other means of risk reduction in
> both primary and secondary prevention of vascular morbidity, and in
> selected acute event-management situations. There is substantial basic
> scientific and clinical trial data available to make rational and
> selective management decisions for individual patients in all
> conceivable settings of clinical practice. Even more ongoing clinical
> trials offer a dynamic evolving knowledge base for mundane therapeutic
> choices, a moving target of expertise.
>
> **Principles**:

1.  Antithrombotic therapeutic benefit is relative to individual patient
    morbidity, tolerance, and hemorrhagic risk.

2.  In general, individual patient thrombotic risk must exceed 3% per
    year to realize a clinically meaningful benefit from antiplatelet
    drugs.

> For specific treatment recommendations, please see the related ICSI
> guidelines.
>
> **Oral Agents**

-   Aspirin

-   Clopidogrel

-   Dipyridamole

> **Parenteral Agents**

-   Platelet glycoprotein IIb/IIIa antagonists

> Refer to the original guideline document for information on the
> mechanism of action of antiplatelet agents.

**Antiplatelet Agents -- Oral**

46. **Contraindications**

    -   Major hemorrhage

    -   Hypersensitivity to NSAIDs \[aspirin\]

    -   Platelet count less than 50,000

    -   Syndrome of asthma, rhinitis, and nasal polyps

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47. **Precautions**

    -   Patients at risk of increased bleeding from trauma, surgery or
        other pathological condition (particularly gastrointestinal and
        intraocular)

    -   Alcohol use (three or more drinks/day)

    -   Pregnancy (third trimester)

    -   Gastrointestinal symptoms, peptic ulcer disease

    -   Renal failure

    -   Severe hepatic insufficiency

    -   Concomitant use of more than one antithrombotic drug

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48. **Adverse Effects**

> Combination of aspirin and clopidogrel and/or combination with
> warfarin or other anticoagulant have been shown to increase the risk
> of major bleeding.
>
> **Aspirin**
>
> Hemorrhage, with underlying hemostatic defects: uremia, hemophilia,
> anticoagulation therapy. Hemorrhage, without defects: odds ratio (OR)
> 1.6 in high-risk patients.
>
> Gastric irritation: dose-related

-   No better with coated or buffered tablets.

> Influence of concomitant COX-2 inhibitors/NSAIDs

-   Withhold NSAIDs for 30 minutes after taking aspirin

> **Clopidogrel**
>
> Thrombotic thrombocytopenic purpura (TTP), sometimes life-threatening,
> may occur, usually within two weeks of treatment initiation.
>
> Hemorrhage 9%; severe in 1%-2%/year of chronic treatment
>
> Thrombocytopenia
>
> Allergic rash
>
> Diarrhea
>
> **Dipyridamole**
>
> Systemic vasodilation, with secondary dizziness, syncope, myocardial
> ischemia
>
> Headache
>
> Hemorrhage is NOT a common problem
>
> ***Evidence supporting this recommendation is of classes: A, D, M***

49. **Pregnancy**

> Third-trimester risks of placental separation and hemorrhage
>
> ***Evidence supporting this recommendation is of class: A***

50. **Breast-Feeding**

> Clinical experience limited; risks cannot be entirely ruled out.

51. **Monitoring**

> In most clinical situations, monitoring of oral antiplatelet agents is
> not required. There are no laboratory methods that have been shown
> effective in monitoring antiplatelet activity in patients. In patients
> where the risk of bleeding is a concern, monitoring may include:

-   CBC/platelet count

-   Fecal blood testing

-   Template bleeding time test

52. **Dosing**

> **Aspirin**
>
> For all clinically important endpoint events, oral doses ranging
> between 81-325 mg/day are sufficient. Higher doses thought in the past
> to be required for clinical effects have been shown to be unnecessary,
> and are undesirable because of dose-related gastric and hemorrhagic
> side effects.
>
> **Aspirin Resistance**
>
> Some patients at risk, as well as volunteer subjects, have shown
> variably submaximal responses to aspirin, as assessed by bleeding time
> and *in vitro* laboratory evaluations of platelet response to ADP
> (adenosine diphosphate) and other activating agents. Methodologic and
> statistical issues of sampling, and the functional limitations of
> available laboratory tests, are likely explanation for the failure to
> observe such variable dosing requirements in clinical trials.
>
> The ultimate evidence of aspirin resistance would be occurrence of
> thrombosis and treatment failure, although the presumption of
> resistance is confounded by the many other factors promoting
> thrombogenesis at local tissue sites.
>
> **Clopidogrel**
>
> Loading dose with 300-600 mg results in more rapid effectiveness, but
> no scientifically established ideal loading schedule is available. A
> patient-selective phenomenon of \"resistance\" has been observed, as
> with aspirin, but again no reliable laboratory test of antiplatelet
> effect can be recommended.
>
> When using clopidogrel and aspirin in combination, 81 mg dose of
> aspirin should be used.
>
> **Dipyridamole**
>
> Antiplatelet oral dosing as Aggrenox®, containing 200 mg
> modified-release dipyridamole plus 25 mg aspirin. Standard-release
> oral dipyridamole is considered to be unreliable due to erratic
> absorption.
>
> ***Evidence supporting this recommendation is of class: A***

53. **Correction of Supratherapeutic Anticoagulation Caused by Oral
    Antiplatelet Agents**

> Platelet infusion

54. **Key Patient Education Components**

> Importance of understanding antiplatelet agents and target ranges
>
> Know and watch for signs of bleeding
>
> Restrictions for other conditions including DVT, stroke, or CAD.
> Please refer to related ICSI guidelines for more information
>
> Importance to adhering to prescribed regimen

**Antiplatelet Agents \-- Parenteral**

55. **Contraindications**

    -   Bleeding diathesis or oral anticoagulant use within seven days

    -   Cerebrovascular accident (CVA) within two years

    -   History of vasculitis

    -   Intracranial tumor, arteriovenous malformation or aneurysm

    -   Major surgery or trauma

    -   Severe uncontrolled hypertension

    -   Thrombocytopenia

    -   Active or recent internal bleeding

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56. **Precautions**

    -   Concomitant administration with thrombolytics, oral
        anticoagulants, NSAIDs, dipyridamole and other antiplatelet
        drugs increases the risk of bleeding.

    -   A low-dose, weight-adjusted heparin regimen is recommended to
        minimize the risk of bleeding.

    -   Minimize arterial and venous punctures, intramuscular (IM)
        injections and use of urinary catheters, nasotracheal
        intubation, nasogastric tubes and automatic blood pressure
        cuffs.

    -   Arterial sheath should not be removed unless aPTT is 50 seconds
        or less, OR the activated clotting time is 175 seconds or less,
        and heparin has been discontinued for at least two hours.

    -   Full-dose heparin should be stopped at least two hours before
        femoral artery sheath removal and adequate hemostasis achieved.

    -   Patients should be maintained on adequate bed rest following
        sheath removal or discontinuation of IIB/IIIA.

    -   Thrombocytopenia has been observed; platelet counts should be
        monitored.

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57. **Adverse Effects**

> Major bleeding
>
> Thrombocytopenia \[less than 50,000\] 1%-2%, usually asymptomatic

58. **Pregnancy**

> Little information is known and not all platelet glycoprotein
> antagonist drugs have been studied. All studies to date have been
> animal studies.

59. **Breast-Feeding**

> Little information is known but it does not appear that parenteral
> antiplatelet drugs are excreted in breast milk.

60. **Monitoring**

> In most clinical situations, monitoring of oral antiplatelet agents is
> not required. There are no laboratory methods that have been shown
> effective in monitoring antiplatelet activity in patients. In patients
> where the risk of bleeding is a concern, monitoring may include:

-   CBC/platelet count

-   Fecal blood testing

-   Template blood bleeding time test

61. **Dosing**

> **Abciximab**
>
> IV bolus 0.25mg/kg plus 0.125 microgm/kg/min infusion; effective in
> 80% or more in percutaneous coronary intervention (PCI) subjects
>
> Half-life at 30 minutes; 65% attachment to platelet surface
>
> Peak effects at 2 hours: receptor blockade, aggregation, bleeding time
>
> Recovery over 12 to 48 hours
>
> **Tirofiban**
>
> IV bolus 0.4 microgm/kg/min x 30 min, then 0.1 microgm/kg/min
>
> Renal clearance issues (less than 30 mL/min)
>
> **Eptifibatide**
>
> IV bolus 180 microgm/kg, infusion 2 microgm/kg/min
>
> Return to normal variable, usually within one hour of discontinuation
> of infusion

62. **Correction of Supratherapeutic Anticoagulation Caused by
    Parenteral Antiplatelet Agents**

> Platelet infusion

63. **Key Patient Education Components**

> Importance of understanding antiplatelet agents and target ranges.
>
> Know and watch for signs of bleeding.
>
> Restrictions for other conditions including DVT, stroke or CAD. Please
> refer to related ICSI guidelines for more information.
>
> Importance to adhering to prescribed regimen.

64. **Mechanical Heart Valves in Patients Who Are Pregnant**

> Patients with mechanical heart valves who are pregnant or attempting
> to become pregnant are at high risk and should be managed by an
> anticoagulation expert. A study has shown that two patients who were
> pregnant and had mechanical heart valves had thrombotic complications
> when treated with LMWH. Because of this, the FDA and the manufacturer
> have warned that enoxaparin is not presently indicated for use in
> prophylaxis for heart valves patients who are pregnant.

**Perioperative Management**

65. **Anticoagulation Bridging**

>  

  ------------------------------------------------------------------------------
  **PERIOPERATIVE                   **Procedure   
  ANTICOAGULATION**                 Bleeding      
                                    Risk**        
  -------------------------- ------ ------------- ------------------------------
                                    **LOW**       **HIGH**

  **Patient Thromboembolic   LOW    Continue      Hold Warfarin 4 Days Prior To
  Risk**                            Warfarin      The Procedure (see Table #6.
                                                  \"Recommended Bridging
                                                  Schedule,\" below)

                             HIGH   Continue      Bridging
                                    Warfarin      
  ------------------------------------------------------------------------------

> **Risk of Thrombotic Complications in the Absence of Anticoagulation
> Therapy**

  -----------------------------------------------------------------------
  **Condition**                              **%Thrombotic Risk
                                             (Annualized)**
  ------------------------------------------ ----------------------------
  Atrial fibrillation (low risk)             1

  Atrial fibrillation (average risk)         5

  Atrial fibrillation (high risk)            12

  Aortic valve prosthesis (dual-leaflet \--  10-12
  St. Jude)                                  

  Aortic valve prosthesis (single-leaflet    23
  \-- Bjork-Shiley)                          

  Mitral valve prosthesis (dual-leaflet \--  22
  St. Jude)                                  

  Multiple prosthesis (St. Jude)             91
  -----------------------------------------------------------------------

> **Low Bleeding Risk Procedures**
>
> For most dental procedures, a review of the literature has shown that
> in most cases no change in warfarin is needed. It may be reasonable to
> allow the patient to \"drift\" to the low end of their therapeutic INR
> prior to a dental procedure with a high risk of bleeding.
>
> Local bleeding may be controlled with a variety of techniques
> including pressure, biting on tea bags, gelatin sponges, and topical
> thrombin. Other means of local hemostasis control include tranexamic
> acid mouthwash or epsilon aminocaproic acid packing.
>
> Other examples of procedures with low bleeding risk include skin
> biopsies and cataract surgery. Patients who have procedures that are
> of low bleeding risk can be continued on warfarin anticoagulation
> without interruption.
>
> For gynecologic and orthopedic surgical patients at low risk for
> bleeding, the warfarin dose may be lowered four to five days before
> surgery and the surgery performed at a lower INR (INR 1.3-1.5). The
> warfarin dose can be increased to the previous dose postoperatively.
>
> **Low Thromboembolic Risk Patients**
>
> Patients with low thromboembolic risk, such as patients with atrial
> fibrillation without prior cerebrovascular accident or other
> thromboembolic event, may stop warfarin 4 doses prior to the procedure
> and resume warfarin the evening of surgery. Low thromboembolic risk
> patients undergoing procedures that require perioperative UFH or LMWH
> for VTE prophylaxis should receive the recommended prophylaxis in
> addition to resumption of warfarin.
>
> **High Bleeding Risk Procedures for High Thromboembolic Risk Patients
> \-- Bridging**
>
> **Table 6: Recommended Bridging Schedule**
>
> Please be aware that this schedule is not FDA-approved and there are
> no randomized controlled trials that have studied the efficacy of this
> schedule. An individual\'s history of thromboembolism will assist with
> the decision-making. In general, plan to skip 4 doses prior to the
> invasive procedure.

  ------------------------------------------------------------------------
  **Days Before   **Warfarin**    **INR**         **Full Dose\*\* LMWH\*
  Procedure**                                     or Therapeutic UFH**
  --------------- --------------- --------------- ------------------------
  5 days prior to Last dose       Check if not    4-5 days before
  procedure                       done within 2   procedure, start after
                                  weeks prior     first missed warfarin
                                                  dose if at very high
                                                  risk of thrombosis.

  4 days prior to None            None            4-5 days before
  procedure                                       procedure, start after
                                                  first missed warfarin
                                                  dose if at very high
                                                  risk of thrombosis.

  3 days prior to None            None            AM and PM dose
  procedure                                       

  2 days prior to None            None            AM and PM dose
  procedure                                       

  1 day prior to  None            Check INR; if   AM dose. If UFH is
  procedure                       INR greater     continuous IV infusion,
                                  than 1.5,       discontinue five hours
                                  consider 1-2.5  before surgery. For p.m.
                                  mg Vitamin K by dose -- if subcutaneous
                                  mouth.          UFH or LMWH, discontinue
                                                  dose 12 hours before
                                                  surgery.

  Procedure       Resume at       None            Start at least 12 hours
                  regular dose                    post procedure \-- see
                  that evening                    Annotation #19 of
                                                  guideline

  1 day after     Regular dose    As indicated    Restart if hemostasis
  procedure                       \-- may be      achieved
                                  skipped         

  2 days after    Regular dose    As indicated    Restart if hemostasis
  procedure                                       achieved

  3 days after    Regular dose    As indicated    Continue until INR
  procedure                                       greater than minimum
                                                  acceptable x 2 day

  4 days after    Regular dose    Daily until INR Discontinue
  procedure                       greater than    
                                  2.0, then as    
                                  indicated       
  ------------------------------------------------------------------------

> \*If enoxaparin is used as the LMWH, dosing is every 12 hours (a.m.
> and p.m.). Once a day dosing is used if the LMWH is tinzaparin or
> dalteparin
>
> \*\* Therapeutic refers to full-dose UFH and LMWH for venous
> thrombosis and not cardioembolic prevention.
>
> ***Evidence supporting this recommendation is of classes: D, R***

66. **Perioperative Management of Antiplatelet Agents**

> Patients receiving anti-platelet agents should have these agents
> stopped 2 to 10 days prior to a procedure:

-   Clopidogrel 7 days prior to surgery

-   Aspirin 7-10 days prior to surgery

-   Ibuprofen 2 days prior to surgery

> Cilostazol (Pletal®) does not appear to prolong bleeding times and has
> no effect on platelet counts in healthy adults.

67. **Neuraxial Blockade Management (Spinal/Epidural)**

> New challenges in the management of the anticoagulated patient
> undergoing neuraxial blockade have arisen as medical standards for the
> prevention of perioperative venous thromboembolism were established.
> Likewise, as more efficacious anticoagulants and antiplatelet agents
> have been introduced, patient management has become more complex.
>
> Regional anesthesia should be avoided in patients with a history of
> abnormal bleeding or if taking medications that affect hemostasis
> (e.g., aspirin, NSAIDs, platelet inhibitors, warfarin).
>
> Bleeding or hematomas within the spinal column may result when a
> heparin product or fondaparinux is used concurrently with spinal or
> epidural anesthesia or spinal puncture. The risk for complication
> increases with placement or removal of catheters in the spinal canal
> and by traumatic or repeated epidural or spinal puncture. Use of other
> drugs affecting the blood clotting mechanism such as NSAIDs, platelet
> inhibitors or other anticoagulants also increases the risk of
> complication.
>
> **General Guidelines**:

-   All patients who receive neuraxial blockade should be monitored
    closely for developing back pain or signs and symptoms of spinal
    cord compression (weakness, saddle numbness, incontinence) after
    injections, during infusions and after discontinuation of infusions.

-   Both insertion and removal of neuraxial catheters are significant
    events. The timing of those events and the timing of any
    antithrombotic drugs should be taken into consideration, as well as
    the pharmacokinetics and pharmacodynamics of the specific drugs
    used.

-   The emergence of new drugs and unexplained clinical scenarios can
    render any guideline obsolete. Consultation with an anesthesiologist
    experienced in regional anesthesia is essential for novel
    situations.

-   The American Society of Regional Anesthesia and Pain Medicine (ASRA)
    has developed extensive, peer-reviewed guidelines for the practice
    of regional anesthesia in the presence of antithrombotic therapy and
    can be used for detailed management. These guidelines are available
    at [http:/www.asra.com](http://www.asra.com/).

> Spinal hematomas after neuraxial blockade are very rare (3 in 850,000
> in one study) and therefore are difficult to attribute cause and
> effect. The FDA has received 43 reports of patients with spinal or
> epidural hematoma after receiving the LMWH enoxaparin. This has
> prompted the FDA to ask LMWH manufacturers to include warning labels
> for this complication.
>
> ***Evidence supporting this recommendation is of classes: D, R, Not
> Assignable***
>
> **Warfarin with Neuraxial Blockade**
>
> There is no increased risk of perispinal hematoma in patients
> receiving warfarin postoperatively. However, the mean time to catheter
> removal was approximately 36 hours, and the majority of patients did
> not have an INR above 1.5 at the time of removal.
>
> The ASRA guideline ([http://www.asra.com](http://www.asra.com/))
> indicates removal of catheter when INR is less than 1.5 with INR
> checks perioperatively and daily if the first dose of coumadin was
> given greater than 24 hours preoperatively.
>
> **Heparin with Neuraxial Blockade**
>
> In general, the most critical time for risk of perispinal hematoma is
> with indwelling catheter insertion and removal.
>
> **Unfractionated Heparin**
>
> Unfractionated heparin for VTE prophylaxis in patients receiving
> neuraxial blockade does not appear to have significant risk. The ASRA
> guideline indicates no change in approach to patients receiving UFH.
> If the patient has received four or more days of UFH preoperatively,
> he/she should be assessed for heparin-induced thrombocytopenia.
> Optimally, the insertion of an epidural catheter occurs after three to
> four half-lives of the drug has elapsed. Depending on the drug and the
> renal clearance of the patient, this can be 12 to 24 hours for UFH or
> LMWH. An epidural catheter should be removed when the anticoagulation
> effect is at its minimum, approximately two hours before the next
> scheduled injection.
>
> Anticoagulation therapy may be resumed two hours after the catheter
> has been removed.
>
> **Low-Molecular-Weight Heparin**
>
> Low-molecular-weight heparin for VTE prophylaxis in patients receiving
> neuraxial blockade has some potential issues. In 1997, the U.S. FDA
> issued a physician advisory for LMWH and risk of spinal hematoma. The
> agency described 43 U.S. patients who developed perispinal hematoma
> after receiving the LMWH enoxaparin for VTE prophylaxis. Many of these
> patients developed permanent neurologic sequelae despite 65% receiving
> aggressive therapy and laminectomy. The median age of the patients was
> 78 years, and 78% of the patients were women. The potential risk
> factors were many, including presence of underlying hemostatic
> disorder, traumatic needle or catheter insertion, repeated needle
> insertion attempts or a bloody return in the catheter, catheter
> insertion or removal in the setting of significant anticoagulation,
> concurrent use of other antithrombotic agents, use of continuous
> epidural catheters, anticoagulant dosages and vertebral column
> abnormalities. There were not large enough patient numbers to develop
> prevalence data nor establish relative risk for any of the individual
> risk factors. Therefore, no specific conclusions could be made.
>
> **Newer Anticoagulant Drugs**
>
> The use of the newer factor Xa inhibitor, fondaparinux, or the
> thrombin inhibitors related to hirudin, is a relative contraindication
> to all regional anesthesia. The emergence of other newer anticoagulant
> drugs requires that each be evaluated with regard to its safety in
> combination with regional anesthesia. In all such circumstances,
> consultation with an anesthesiologist experienced in regional
> anesthesia is recommended.
>
> **Antiplatelet Agents with Neuraxial Blockade**
>
> Antiplatelet medications, including NSAIDs, thienopyridine derivatives
> (ticlopidine and clopidogrel) and platelet glycoprotein IIb/IIIa
> antagonists (abciximab, eptifibatide, tirofiban) exert diverse effects
> on platelet function. The pharmacologic differences make it impossible
> to extrapolate between the groups of drugs regarding the practice of
> neuraxial blockade.
>
> There is no wholly accepted test, including the bleeding time, that
> will guide antiplatelet therapy. Careful preoperative assessment of
> the patient to identify alterations of health that might contribute to
> bleeding is crucial. These conditions include a history of easy
> bruisability/excessive bleeding, female gender and increased age.

-   NSAIDs appear to represent no added significant risk for the
    development of spinal hematoma in patients having epidural or spinal
    anesthesia. The use of NSAIDs alone does not create a level of risk
    that will interfere with the performance of neuraxial blocks.

-   At this time, there do not seem to be specific concerns as to the
    timing of single-shot or catheter techniques in relationship to the
    dosing of NSAIDs, postoperative monitoring or the timing of
    neuraxial catheter removal.

-   The actual risk of spinal hematoma with clopidogrel and the
    glycoprotein IIb/IIIa antagonists is unknown. Based on labeling and
    surgical reviews, the suggested time interval between
    discontinuation of therapy and neuraxial blockade is 14 days for
    ticlopidine and 7 days for clopidogrel.

-   Platelet glycoprotein IIb/IIIa inhibitors exert a profound effect on
    platelet aggregation. Following administration, the time to normal
    platelet aggregation is 24 to 48 hours for abciximab and 4 to 8
    hours for eptifibatide and tirofiban. Neuraxial techniques should be
    avoided until platelet function has recovered. Glycoprotein IIb/IIIa
    antagonists are contraindicated within four weeks of surgery. Should
    one be administered in the postoperative period (following a
    neuraxial technique), the patient should be carefully monitored
    neurologically.

> The concurrent use of other medications affecting clotting mechanisms,
> such as oral anticoagulants, unfractionated heparin and LMWH, may
> increase the risk of bleeding complications. Cyclooxygenase-2
> inhibitors have minimal effect on platelet function and should be
> considered in patients who require anti-inflammatory therapy in the
> presence of anticoagulation.
>
> ***Evidence supporting this recommendation is of classes: B, D, R, Not
> Assignable***

68. **Key Patient Education Components**

> If a patient is to receive bridging therapy, the patient or a
> caregiver must show proficiency in the injection technique and
> proficiency with adhering to the perioperative schedule.

**Definitions**:

**Classes of Research Reports**:

A.  Primary Reports of New Data Collection:

> Class A:

-   Randomized, controlled trial

> Class B:

-   Cohort study

> Class C:

-   Nonrandomized trial with concurrent or historical controls

-   Case-control study

-   Study of sensitivity and specificity of a diagnostic test

-   Population-based descriptive study

> Class D:

-   Cross-sectional study

-   Case series

-   Case report

B.  Reports that Synthesize or Reflect upon Collections of Primary
    Reports:

> Class M:

-   Meta-analysis

-   Systematic review

-   Decision analysis

-   Cost-effectiveness analysis

> Class R:

-   Consensus statement

-   Consensus report

-   Narrative review

> Class X:

-   Medical opinion

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is classified for selected
recommendations (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Guideline implementation may help the clinician make risk-benefit
treatment decisions regarding anticoagulation therapy and appropriately
manage patients on anticoagulation therapy to maximize safety and
efficacy.

#### POTENTIAL HARMS

-   The major potential side effect of anticoagulation therapy is
    bleeding either from supratherapeutic effect or by accentuating the
    blood loss of patients with an existing source of bleeding.

-   The major potential harm of withholding anticoagulation therapy is
    risk for thrombosis.

-   Refer to the \"Major Recommendations\" field for additional details.

-   Refer to Annotation Appendix B of the original guideline document
    for a list of drugs interacting with warfarin and a description of
    the mechanism of interaction with warfarin.

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

There are no absolute contraindications to anticoagulant therapy. The
decision to treat a patient with anticoagulant drugs takes into account
an individual patient\'s risk for thrombosis if not treated weighed
against the risk of bleeding while on anticoagulation therapy.

Refer to Annotations 2, 4, 12, 26, 36, 46, and 55 in the \"Major
Recommendations\" section for relative contraindications to
antithrombotic therapy.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   These clinical guidelines are designed to assist clinicians by
    providing an analytical framework for the evaluation and treatment
    of patients, and are not intended either to replace a clinician\'s
    judgment or to establish a protocol for all patients with a
    particular condition. A guideline will rarely establish the only
    approach to a problem.

-   This clinical guideline should not be construed as medical advice or
    medical opinion related to any specific facts or circumstances.
    Patients are urged to consult a health care professional regarding
    their own situation and any specific medical questions they may
    have.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

Once a guideline is approved for general implementation, a medical group
can choose to concentrate on the implementation of that guideline. An
action group is formed when a topic is selected as an initiative.  In
addition to the action group goals and measures, each medical group sets
specific goals they plan to achieve in improving patient care based on
the particular guideline(s).Each medical group shares its experiences
and supporting measurement results within the action group. This sharing
facilitates a collaborative learning environment. Action group learnings
are also documented and shared with interested medical groups within the
collaborative.

Currently, action groups may focus on one guideline or a set of
guidelines such as hypertension, lipid treatment, and tobacco cessation.

#### IMPLEMENTATION TOOLS

Patient Resources\
Pocket Guide/Reference Cards

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\
Patient-centeredness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Institute for Clinical Systems Improvement (ICSI). Antithrombotic
therapy supplement. Bloomington (MN): Institute for Clinical Systems
Improvement (ICSI); 2007 Aug. 64 p. \[118 references\]

#### ADAPTATION

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

#### DATE RELEASED

2001 Sep (revised 2007 Aug)

#### GUIDELINE DEVELOPER(S)

Institute for Clinical Systems Improvement - Private Nonprofit
Organization

#### GUIDELINE DEVELOPER COMMENT

Organizations participating in the Institute for Clinical Systems
Improvement (ICSI): Affiliated Community Medical Centers, Allina Medical
Clinic, Altru Health System, Aspen Medical Group, Avera Health,
CentraCare, Columbia Park Medical Group, Community-University Health
Care Center, Dakota Clinic, ENT Specialty Care, Fairview Health
Services, Family HealthServices Minnesota, Family Practice Medical
Center, Gateway Family Health Clinic, Gillette Children\'s Specialty
Healthcare, Grand Itasca Clinic and Hospital, HealthEast Care System,
HealthPartners Central Minnesota Clinics, HealthPartners Medical Group
and Clinics, Hutchinson Area Health Care, Hutchinson Medical Center,
Lakeview Clinic, Mayo Clinic, Mercy Hospital and Health Care Center,
MeritCare, Mille Lacs Health System, Minnesota Gastroenterology,
Montevideo Clinic, North Clinic, North Memorial Care System, North
Suburban Family Physicians, Northwest Family Physicians, Olmsted Medical
Center, Park Nicollet Health Services, Pilot City Health Center, Quello
Clinic, Ridgeview Medical Center, River Falls Medical Clinic, Saint
Mary\'s/Duluth Clinic Health System, St. Paul Heart Clinic, Sioux Valley
Hospitals and Health System, Southside Community Health Services,
Stillwater Medical Group, SuperiorHealth Medical Group, University of
Minnesota Physicians, Winona Clinic, Ltd., Winona Health

ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425;
telephone, (952) 814-7060; fax, (952) 858-9675; e-mail:
<icsi.info@icsi.org>; Web site: [www.icsi.org](http://www.icsi.org/).

#### SOURCE(S) OF FUNDING

The following Minnesota health plans provide direct financial support:
Blue Cross and Blue Shield of Minnesota, HealthPartners, Medica,
Metropolitan Health Plan, PreferredOne and UCare Minnesota. In-kind
support is provided by the Institute for Clinical Systems Improvement\'s
(ICSI) members.

#### GUIDELINE COMMITTEE

Cardiovascular Steering Committee

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Work Group Members*: Bruce Burnett, MD (Work Group Leader) (Park
Nicollet Health Services) (Internal Medicine); Stephen Kopecky, MD (Mayo
Clinic) (Cardiology); Colleen Morton, MD (Health Partners Medical Group)
(Hematology); Rajiv Pruthi, MD (Mayo Clinic) (Hematology); John Butler,
MD (HealthPartners Medical Group) (Internal Medicine); Mark Morrow, MD
(Aspen Medical Group) (Internal Medicine); John Davenport, MD (Park
Nicollet Health Services) (Neurology); Timothy Miley, MD (Park Nicollet
Health Services) (Pathology); Jill Strykowski, RPh, MS (Park Nicollet
Health Services) (Pharmacy); Sherri Huber, MT (ASCP) (Institute for
Clinical Systems Improvement) (Facilitator)

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

In the interest of full disclosure, the Institute for Clinical Systems
Improvement (ICSI) has adopted a policy of revealing relationships work
group members have with companies that sell products or services that
are relevant to this guideline topic. The reader should not assume that
these financial interests will have an adverse impact on the content of
the guideline, but they are noted here to fully inform readers. Readers
of the guideline may assume that only work group members listed below
have potential conflicts of interest to disclose.

No work group members have potential conflicts of interest to disclose.

ICSI\'s conflict of interest policy and procedures are available for
review on ICSI\'s website at [www.icsi.org](http://www.icsi.org/).

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Anticoagulation therapy
supplement. Bloomington (MN): Institute for Clinical Systems Improvement
(ICSI); 2006 Apr. 49 p.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [Institute for Clinical Systems
Improvement (ICSI) Web
site](http://www.icsi.org/guidelines_and_more/guidelines__order_sets___protocols/).

Print copies: Available from ICSI, 8009 34th Avenue South, Suite 1200,
Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675;
Web site: [www.icsi.org](http://www.icsi.org/); e-mail:
<icsi.info@icsi.org>.

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   Anticoagulation therapy supplement. Executive summary. Bloomington
    (MN): Institute for Clinical Systems Improvement, 2007 Aug. 1 p.
    Electronic copies: Available from the [Institute for Clinical
    Systems Improvement (ICSI) Web
    site](http://www.icsi.org/antithrombotic_therapy_supplement__guideline__14045/antithrombotic_therapy_supplement__executive_summary_.html).

-   ICSI pocket guidelines. April 2006 edition. Bloomington (MN):
    Institute for Clinical Systems Improvement, 2006. 298 p.

Print copies: Available from ICSI, 8009 34th Avenue South, Suite 1200,
Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675;
Web site: [www.icsi.org](http://www.icsi.org/); e-mail:
<icsi.info@icsi.org>.

#### PATIENT RESOURCES

The following is available:

-   Patient education guide to warfarin therapy. Appendix D:
    Anticoagulation therapy supplement. Bloomington (MN): Institute for
    Clinical Systems Improvement (ICSI); 2007 Aug.

Electronic copies: Available in Portable Document Format (PFD) from the
[Institute for Clinical Systems Improvement (ICSI) Web
site](http://www.icsi.org/guidelines_and_more/guidelines__order_sets___protocols/cardiovascular/antithrombotic_therapy_supplement__guideline__14045/antithrombotic_therapy_supplement_guideline.html).

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 August 26, 2002. The
information was verified by the guideline developer on September 23,
2002. This summary was updated by ECRI on May 7, 2004, July 14, 2005,
and on May 17, 2006. 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 NGC summary
was updated by ECRI Institute on November 28, 2007. 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 (abstracted Institute for Clinical Systems Improvement
\[ICSI\] Guideline) is based on the original guideline, which is subject
to the guideline developer\'s copyright restrictions.

The abstracted ICSI Guidelines contained in this Web site may be
downloaded by any individual or organization. If the abstracted ICSI
Guidelines are downloaded by an individual, the individual may not
distribute copies to third parties.

If the abstracted ICSI Guidelines are downloaded by an organization,
copies may be distributed to the organization\'s employees but may not
be distributed outside of the organization without the prior written
consent of the Institute for Clinical Systems Improvement, Inc.

All other copyright rights in the abstracted ICSI Guidelines are
reserved by the Institute for Clinical Systems Improvement, Inc. The
Institute for Clinical Systems Improvement, Inc. assumes no liability
for any adaptations or revisions or modifications made to the abstracts
of the ICSI Guidelines.

### DISCLAIMER

#### NGC DISCLAIMER

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All guidelines summarized by NGC and hosted on our site are produced
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<http://www.guideline.gov/about/inclusion.aspx> .

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Date Modified: 11/3/2008