• December 3, 2008 – Innohep (tinzaparin): The U.S. Food and Drug Administration (FDA) has requested that the labeling for Innohep be revised to better describe overall study results which suggest that, when compared to unfractionated heparin, Innohep increases the risk of death for elderly patients (i.e., 70 years of age and older) with renal insufficiency. Healthcare professionals should consider the use of alternative treatments to Innohep when treating elderly patients over 70 years of age with renal insufficiency and deep vein thrombosis (DVT), pulmonary embolism (PE), or both.

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 – October 2008.

This guideline follows closely the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) [R] and the American Society of Regional Anesthesia and Pain Medicine guidelines. Areas of divergence from the American College of Chest Physicians guideline recommendations are the use of aspirin following orthopedic procedures.

The recommendations for venous thromboembolism prophylaxis are presented in the form of a Table with 9 components, accompanied by detailed annotations. Clinical highlights, the Table, "Thromboembolic Prophylaxis for Adult Patients", and selected annotations (numbered to correspond with the Table) follow.

Class of evidence (A-D, M, R, X) and conclusion grade (I-III, Not Assignable) definitions are provided at the end of the "Major Recommendations" field.

Clinical Highlights

1. All patients should be evaluated for venous thromboembolism risk upon hospital admission, change in level or care, change in providers, and prior to discharge. (Aim #1)
2. All patients should receive proper education regarding venous thromboembolism risk, signs and symptoms of venous thromboembolism, and prophylaxis methods available. (Aim #3 )
3. Early and frequent ambulation should be encouraged when possible in all patient groups. (Aim #5)
4. All medical and surgical/trauma patients who have a high or very high risks for venous thromboembolism should receive anticoagulation prophylaxis unless contraindicated. (Aim #9)
5. Aspirin alone is not recommended for routine venous thromboembolism prophylaxis following hip/knee arthroplasty but may be considered in combination with mechanical prophylaxis methods in patients without additional risk factors. Further study is needed. (Aim #10)
6. Aspirin and antiplatelet drugs are not recommended for venous thromboembolism prophylaxis in other surgical patients or medically ill patients. (Aim #6)
7. For all patients receiving spinal or epidural anesthesia, precautions should be taken when using anticoagulant prophylaxis to reduce the risk of epidural hematoma. (Aim #4)
8. Risk of venous thromboembolism development continues beyond hospitalization, and the need for post-discharge anticoagulation should be assessed. (Aim #8)

Thromboembolic Prophylaxis for Adult Patients

[R]

Abbreviations: CABG, coronary artery bypass graft; CrCl, creatinine clearance; hr, hours; INR, International Normalized Ratio; IV, intravenous; LMWH, low-molecular- weight heparin; preop, preoperative; postop, postoperative; sq, subcutaneous; VTE, venous thromboembolism

1. General Recommendations

   1-3. All Patients Should Be Encouraged to Ambulate as Early as Possible, and as Frequently as Possible

   Although no specific studies exist to document the value of patient education and early ambulation to reduce venous thromboembolism risk, the work group believes these measures are important for all venous thromboembolism risk patients, including those in the very-high-risk group.

   1-4. All Non-Ambulatory Patients Should Have, at a Minimum, Mechanical Prophylaxis – Unless Contraindicated

   Although mechanical prophylaxis devices have been evaluated extensively in clinical studies, their efficacy in venous thromboembolism prophylaxis remains unclear. These studies have often failed to define exactly what device was used, and frequently the devices were used in combination with other prophylaxis methods, making it difficult to prove their efficacy. Mechanical prophylaxis devices available for use include graded compression stockings, intermittent pneumatic compression devices and venous foot pumps. Graded compression stockings are frequently used in combination with either intermittent pneumatic compression or venous foot pump devices. The 2008 American College of Chest Physician guidelines identify both the advantages and the limitations of mechanical thromboprophylaxis modalities (see Table A, in the original guideline document). Mechanical prophylaxis devices, particularly graded compression stockings, can have harmful consequences, most commonly related to skin irritation and breakdown. The use of graded compression stockings is contraindicated in some patients (see Contraindications field). If mechanical prophylaxis is utilized, careful nursing assessment and care are essential to minimizing complications.

4. Special Situations – Dose Adjustment

   Fixed-dose prophylaxis in the morbidly obese (body mass index greater than or equal to 35) will likely result in underdosing. Current expert opinion suggests enoxaparin be increased by 25%. There are no dosing recommendations available for dalteparin or fondaparinux.

5. Special Situations -- Neuraxial Blockade

   Neuraxial blockade is not a contraindication for pharmacologic prophylaxis. It is important to consider the use and timing of medications with neuraxial blockade. When an epidural is used for anesthesia, it is most appropriate to wait until the catheter is removed before starting pharmacologic prophylaxis. Neuraxial blockade should generally be avoided in patients with a clinical bleeding disorder.

   General Guidelines:

   1. 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, numbness, incontinence) after injections, during infusions, and after discontinuation of infusions.
   2. Both insertion and removal of neuraxial catheters are significant events. The timing of those events and the timing of any anticoagulation drugs should be taken into consideration as well as the pharmacokinetics and pharmacodynamics of the specific anticoagulant drugs.
   3. The emergence of new drugs and unexpected clinical scenarios can render any guideline obsolete. Consultation with an anesthesiologist experienced in regional anesthesia is essential for novel situations.
   4. The American Society of Regional Anesthesia and Pain Medicine has developed extensive, peer-reviewed, guidelines for the practice of regional anesthesia in the presence of anticoagulation and can be used for detailed management. These guidelines are available at http://www.asra.com.

   [R]

   Neuraxial blockade (spinal or epidural anesthesia) is a valuable tool for both anesthesiologists and surgeons. The Cochrane Reviews and other sources have listed the usefulness of neuraxial blockade for both intraoperative anesthesia and postoperative analgesia. There are groups of patients that demonstrate improved morbidity and mortality with the use of regional rather than general anesthesia. Similarly the usefulness of venous thromboembolism prophylaxis in preventing morbidity and mortality in surgical patients has been well established. However, there is concern about an increased risk of perispinal hematoma in patients receiving antithrombotic medications for venous thromboembolism prophylaxis in the setting of neuraxial blockade.

   Perispinal hematoma is a rare but serious complication of neuraxial blockade. Thus, it is important to consider both the use and the timing of antithrombotic medications in these patients [D], [R].

   Thromboprophylactic Agents and Neuraxial Blockade

   1. Subcutaneous unfractionated heparin (5,000 units twice daily or three times daily):

      It is acceptable to place and maintain epidural catheters in patients on subcutaneous unfractionated heparin. Dosing should be such that the activity of the last dose is near its nadir. Epidural placement should be prior to starting the regimen or at least 6 to 8 hours after the last dose. When discontinuing the epidural catheter, an interval of at least 4 to 6 hours should have transpired since the last dose and the next heparin dose should be given no sooner than 1 to 2 hours after pulling the catheter.

   2. Low-molecular-weight heparin:

      Twice-daily thromboprophylactic regimens with enoxaparin or dalteparin preclude the use of epidural catheters. The catheter should be discontinued prior to the initiation of this regimen. It is permissible to maintain an epidural catheter on once-daily regimens as long as there is a protocol to closely monitor the patient. The initial dose should not be given for at least 12 hours after catheter placement. Catheter removal should also be 12 to 24 hours after the last low-molecular-weight heparin dose, and an interval of at least 2 hours should pass prior to giving the next dose.

   3. Warfarin

      Low levels of anticoagulation with warfarin permit retention of an epidural catheter, especially during the early stages of initiating warfarin therapy. It appears to be safe to discontinue the epidural catheter at international normalized ratio values up to 2.0, as long as it is within 48 hours of initiating warfarin therapy. Once beyond 72 hours of drug initiation, multiple coagulation factors beyond factor VII and protein C are affected, which necessitate a more conservative international normalized ratio value less than 1.5 in order to safely discontinue the epidural catheter.

   4. Fondaparinux:

      Inadequate data exist at this time regarding the maintenance of epidural catheters while employing this agent. Early data suggest that holding fondaparinux for 36 hours may allow safe epidural catheter removal. However, additional study is necessary before this can be endorsed. Currently, it is recommended that the epidural catheter be removed prior to initiating thromboprophylaxis with this drug.

   More detailed discussion of each of these points can be reviewed at http://www.asra.com.

6. Pharmacologic Prophylaxis: Hospitalized Non-Surgical Patients Including Burns

   Two recent meta-analyses of hospitalized medical patients showed a significant reduction in pulmonary embolism, a non-significant reduction in symptomatic deep vein thrombosis, and a non-significant increase in major bleeding. Anticoagulation prophylaxis had no effect in all-cause mortality [M].

   The ARTEMIS trial showed fondaparinux effective for non-surgical prophylaxis without increasing the risk of clinically relevant bleeding [A].

7. Pharmacologic Prophylaxis: General, Gynecologic and Urologic Surgery

   Studies, primarily in patients over 40 years of age, have shown that unfractionated heparin is as effective as low-molecular-weight heparin as an anticoagulant prophylactic agent for moderate- and high-risk surgical patients. [Conclusion Grade I: See Conclusion Grading Worksheet A – Annotation #7 (Selecting Heparin) in the original guideline document]

   Several studies have compared low-molecular-weight heparin with unfractionated heparin. A meta-analysis concluded that low-molecular-weight heparin doses of less than 3,400 anti-Xa units every day was as effective as unfractionated heparin. At higher doses, low-molecular-weight heparin was slightly superior in preventing venous thromboembolism but had an increased risk of hemorrhage (including major hemorrhage) [A]. The European Multicenter Trial concluded that 1,750 anti-Xa units of low-molecular-weight heparin (reviparin) was equivalent to 10,000 units unfractionated heparin, with a slightly decreased rate of bleeding (8.3% vs. 11.8%) [A].

   General surgical regimens have traditionally been begun preoperatively to increase efficacy. A recent study of low-molecular-weight heparin did not show an increased risk of bleeding complications when compared to postoperative administration [C].

   Traditionally, heparin regimens in general surgery have been continued while the patient is hospitalized.

   Refer to the original guideline document for more information.

9. Orthopedic Surgery

   Use of Aspirin Following Hip/Knee Arthroplasty

   Although it remains controversial, interest persists in the orthopedic community regarding the use of aspirin for venous thromboembolism prophylaxis following elective hip and knee arthroplasty. The debate over the use of aspirin for venous thromboembolism prophylaxis is occurring in Minnesota and across the U.S. The work group has provided a pro/con forum to illustrate this debate (see the original guideline document). The American College of Chest Physicians recommends against the use of aspirin alone. Aspirin alone is not recommended for routine venous thromboembolism prophylaxis following hip/knee arthroplasty but may be considered in combination with mechanical prophylaxis in patients without additional venous thromboembolism risk factors. Further study is needed.

   As the debate surrounding the use of aspirin continues, The American Academy of Orthopedic Surgeons has published recommendations on the prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty [R]. These recommendations are based on a systematic review of the literature conducted by the Center for Clinical Evidence Synthesis at Tufts New England Medical Center. The recommendations risk stratify patients based on venous thromboembolism risk (standard or elevated) and risk of major bleeding (standard or elevated). This risk stratification results in four patient groups:

   1. Standard venous thromboembolism risk, standard bleeding risk
   2. Elevated venous thromboembolism risk, standard bleeding risk
   3. Standard venous thromboembolism risk, elevated bleeding risk
   4. Elevated venous thromboembolism risk, elevated bleeding risk

   Recommended chemoprophylactic agents include (in alphabetical order) aspirin; low-molecular-weight heparin; synthetic pentasaccharides; and warfarin in all groups except the elevated venous thromboembolism risk, standard bleeding risk group. In this particular group, recommended agents include (in alphabetical order) low-molecular-weight heparin; synthetic pentasaccharides; and warfarin.

Definitions:

Conclusion Grades:

Grade I: The evidence consists of results from studies of strong design for answering the question addressed. The results are both clinically important and consistent with minor exceptions at most. The results are free of any significant doubts about generalizability, bias, and flaws in research design. Studies with negative results have sufficiently large samples to have adequate statistical power.

Grade II: The evidence consists of results from studies of strong design for answering the question addressed, but there is some uncertainty attached to the conclusion because of inconsistencies among the results from the studies or because of minor doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from weaker designs for the question addressed, but the results have been confirmed in separate studies and are consistent with minor exceptions at most.

Grade III: The evidence consists of results from studies of strong design for answering the question addressed, but there is substantial uncertainty attached to the conclusion because of inconsistencies among the results of different studies or because of serious doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from a limited number of studies of weak design for answering the question addressed.

Grade Not Assignable: There is no evidence available that directly supports or refutes the conclusion.

Classes of Research Reports:

1. 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

2. 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

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.

ICSI's conflict of interest policy and procedures are available for review on ICSI's website at www.icsi.org.

Electronic copies: Available from the Institute for Clinical Systems Improvement (ICSI) Web site.

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; e-mail: icsi.info@icsi.org.

• Venous thromboembolism prophylaxis. Executive summary. Bloomington (MN): Institute for Clinical Systems Improvement, 2008 Oct. 1 p. Electronic copies: Available from the Institute for Clinical Systems Improvement (ICSI) Web site.
• ICSI pocket guidelines. May 2007 edition. Bloomington (MN): Institute for Clinical Systems Improvement, 2007.

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; e-mail: icsi.info@icsi.org.

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