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Q: Should patients receiving warfarin for the treatment of a DVT or PE be bridged with heparin or low-molecular heparin when warfarin is interrupted for a surgery or procedure?

A: The American College of Chest Physicians (ACCP) recommends: In patients with a mechanical heart valve or atrial fibrillation or VTE at high risk for thromboembolism, we recommend bridging anticoagulation with therapeutic-dose SC LMWH or IV UFH over no bridging during temporary interruption of VKA therapy (Grade 1C); we suggest therapeutic-dose SC LMWH over IV UFH (Grade 2C). In patients with a mechanical heart valve or atrial fibrillation or VTE at moderate risk for thromboembolism, we suggest bridging anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV UFH, or low-dose SC LMWH over no bridging during temporary interruption of VKA therapy (Grade 2C); we suggest therapeutic-dose SC LMWH over other management options (Grade 2C). In patients with a mechanical heart valve or atrial fibrillation or VTE at low risk for thromboembolism, we suggest low-dose SC LMWH or no bridging over bridging with therapeutic-dose SC LMWH or IV UFH (Grade 2C).¹

Although bridging anticoagulation for warfarin interruption around a surgery or procedure is common, there are no trials that have evaluated the safety or efficacy of this practice. Three randomized clinical trials are underway to help answer this question, but, none of these trials is evaluating patients that are anticoagulated for venous thromboembolic disease.²

How to categorize a patient that is being treated for a DVT or PE is somewhat subjective. The ACCP guidelines suggest a high risk of recurrent DVT or PE during warfarin interruption if the initial diagnosis of venous thromboembolic disease was less than 3 months ago, moderate risk at 3-12 months and low risk if more than 12 months ago.¹ Older estimates from mathematical modeling set high risk as less than 1 month, moderate risk at 1 to 3 months and low risk as greater than 3 months.³

An observational study of a large group of California patients showed that most DVT and PE reoccur in the first 3 months after initial hospitalization for venous thromboembolism⁴ and this predilection for early recurrence has been shown in clinical trials comparing warfarin to low molecular weight heparin⁵ and newer experimental anticoagulants.⁶

Clinical Applicability
Patients with a diagnosis of acute DVT or PE in the past 3 months are at highest risk of recurrence if warfarin is to be interrupted for a surgery. The procedure should be delayed if possible. The ACCP guidelines are a very reasonable guide to which patients should receive bridging anticoagulation therapy. Unfortunately, there are no trials on the horizon to answer this question in this group of patients.

1. Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). American College of Chest Physicians. Chest. 2008;133(6 Suppl):299S-339S.
2. www.clinicaltrials.gov. Accessed December 2009.
3. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med. 1997;336(21):1506-11.
4. White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107(23 Suppl 1):I4-8.
5. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. N Engl J Med. 2003;349(2):146-153.
6. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. The RE-COVER Study Group. N Engl J Med. 2009 [epub ahead of print].

Q: How long should a patient with a DVT be treated?

A: There are 4 types of clinical scenarios that can help guide the length of DVT treatment: provoked, cancer related, recurrent, and idiopathic (non-provoked).

Provoked DVT are felt to be "caused" by a high-risk clinical situation such as surgery or pregnancy. It is less clear if less severe clinical "causes" should be classified as provoked. Examples are long plane flights, low-dose estrogen use, or lower extremity immobilization after an injury. Patients with these less clear provocations have been shown to have lower rates of recurrence than patients who develop a DVT after surgery.¹ The American College of Chest Physicians (ACCP) recommend 3 months of anticoagulation for patients with a provoked DVT.²

Cancer is a well known powerful risk factor for the development of DVT and the ACCP guidelines² recommend continued anticoagulation until the cancer is resolved, which can be difficult to determine. Of note, these patients should be treated with a low-molecular weight heparin for the first 3 to 6 months which has a 9% absolute reduction in recurrence compared to warfarin treatment.^2,3

Recurrent DVT should be treated indefinitely as shown in a landmark trial by Schulman and colleagues.⁴ However, it is important that the subtleties of the guidelines are appreciated. Patients with recurrent idiopathic (non-provoked) DVT should be treated indefinitely, but not those with recurrent provoked DVT.²

Idiopathic DVT is common and accounts for 25 to 40% of all DVT. Patients who suffer a first proximal DVT should be considered for indefinite treatment², however, guidelines recommend treatment for 3 months for those with a first distal DVT.² The recurrence rate of DVT is 7 to 10% per year in patients with a first proximal idiopathic DVT. There have been 3 main strategies to help define which patients should continue long term anticoagulation. Patients with a positive d-dimer test performed 1 month after stopping anticoagulation have an 11% annual rate of recurrence which can be reduced to a rate of 2% with re-initiation of anticoagulation; patients with a negative d-dimer still had a significant recurrence rate of 4.4%.⁵ Tailoring the length of anticoagulation based on the presence of residual vein thrombosis seen on periodic follow-up ultrasound has shown promise, unfortunately the absolute rates of recurrence were not reported in the subset of patients with idiopathic DVT and patients who had recanalization of the thrombus still had a substantial rate of recurrence once anticoagulation was stopped.⁶ Performing a hypercoagulable work-up makes pathophysiologic sense, however, patients with and without thrombophilia appear to have the same recurrence rates once anticoagulation is stopped.⁷

Clinical Applicability
All patients with a DVT need periodic follow-up to balance the risk of DVT recurrence and bleeding. Patients with provoked DVT should be treated for 3 months; those with cancer-related thrombosis should continue treatment until the cancer is resolved; recurrent idiopathic proximal DVT should be treated indefinitely; and the first episode of idiopathic unprovoked proximal DVT should also be considered for indefinite treatment because d-dimer, periodic follow-up ultrasounds, or hypercoagulable testing have not been able to identify a group of patients at very low risk of recurrence.

1. Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet. 2003;362(9383):523-526.
2. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). American College of Chest Physicians. Chest. 2008;133(6 Suppl):454S-545S. Erratum in: Chest. 2008;134(4):892.
3. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. N Engl J Med. 2003;349(2):146-153.
4. Schulman S, Granqvist S, Holmström M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med. 1997;336(6):393-398.
5. Palareti G, Cosmi B, Legnani C, et al. D-dimer testing to determine the duration of anticoagulation therapy. PROLONG Investigators. N Engl J Med. 2006;355(17):1780-1789. Erratum in: N Engl J Med. 2006;355(26):2797.
6. Prandoni P, Prins MH, Lensing AW, et al. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. AESOPUS Investigators. Ann Intern Med. 2009;150(9):577-585.
7. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005;293(19):2352-61.

Q: Should patients be prescribed compression stockings after a DVT?

A: Postthrombotic or postphlebitic syndrome can be a cause of major morbidity in patients that suffer a proximal DVT of the legs. In a landmark observation, Prandoni and colleagues showed a 28% rate of postthrombotic syndrome 5 years after the diagnosis of DVT and 9% of the patients had severe symptoms manifested by venous ulcers.¹

The American College of Chest Physicians guidelines state²:
"For a patient who has had a symptomatic proximal DVT, we recommend the use of an elastic compression stocking with an ankle pressure gradient of 30 to 40 mm Hg if feasible (Grade 1A). Compression therapy, which may include use of bandages acutely, should be started as soon as feasible after starting anticoagulant therapy and should be continued for a minimum of 2 years, and longer if patients have symptoms of PTS. (Note: feasibility, both short and long term, refers to ability of patients and their caregivers to apply and remove stockings.)"

Two randomized trials have evaluated the efficacy of elastic compression stockings in the prevention of postthrombotic symptoms in patients with first proximal DVT. The first study by Branjes and colleagues³ compared made-to-measure stockings worn for 2 years to no treatment and found mild to moderate symptoms in 20% of the stocking group and 47% in the no stocking group.

The second study by Prandoni and colleagues⁴ yielded similar data: rates of postthrombotic syndrome were 25% in the stocking group and 49% in the no stocking group. Of note, this study used off the shelf stockings (less expensive) and evaluated postthrombotic syndrome using a validated signs and symptoms measure.¹

One important aspect of these trials is the subjective nature of the post thrombotic syndrome and the lack of blinding. The SOX trial will attempt to resolve this methodological weakness by using a placebo, non-compression stocking to help eliminate the potential bias in evaluation of postthrombotic symptoms.⁵

Clinical Applicability
Until further trial results are available, all patients should be offered off-the-shelf below the knee 30-40 mm Hg pressure stockings to be worn for at least 2 years after the diagnosis of first proximal DVT. These stockings are difficult to pull on, hot, uncomfortable and unattractive for many patients; however, they have the potential to prevent the symptoms of postthrombotic syndrome.

1. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125(1):1-7.
2. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). American College of Chest Physicians. Chest. 2008;133(6 Suppl):454S-545S. Erratum in: Chest. 2008;134(4):892.
3. Brandjes DP, Büller HR, Heijboer H, et al. Randomized trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349(9054):759-762.
4. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the postthrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141(4):249-56.
5. http://clinicaltrials.gov/ct2/show/NCT00143598?term=sox&rank=4. Accessed December 2009.

Q: Can I use a D-dimer blood test to diagnose DVT?

A: D-dimer is a breakdown product of a thrombus and is an indirect marker of an active clot. A very sensitive assay will detect a thrombus, but there are many other conditions that can cause a false positive result. A negative D-dimer test can rule out DVT. However, this test should not be used to confirm DVT since its specificity is low.

The D-dimer test should only be used to rule OUT thrombosis in patients with a low clinical suspicion of DVT, calculated using the modified Well's criteria. The original Well's criteria¹ classified the pretest (clinical) probability into low, moderate, and high categories. The modified Well's system classifies patients as likely or unlikely to have DVT. These modified criteria were used in a randomized trial that assessed the diagnostic value of the D-dimer test.² Patients who were clinically unlikely to have DVT did not benefit from an ultrasound test if their D-dimer result was negative. Their rate of VTE (0.4%) during 3 months of follow-up was comparable to the "unlikely" patients who received standard ultrasound evaluation (1.4%, P = 0.16).

Clinical applicability
Patients presenting with symptoms of DVT should be classified as likely or unlikely to have the disease with the modified Well's criteria. Those patients who are unlikely to have DVT should have a highly sensitive D-dimer test. Patients with a negative D-dimer result can be safely managed without anticoagulation or further testing.

1. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet. 1997;350(9094):1795-1798.
2. Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349(13):1227-1235.

Q: Is ultrasound useful to determine if a patient should continue anticoagulation after 3-6 months of treatment for a non-provoked (idiopathic) DVT?

A: DVT can be considered a chronic disease and 30% of patients will develop recurrence within 8 years if anticoagulation is not continued.¹ Current guidelines recommend continued anticoagulation for patients after the first episode of idiopathic DVT.² The clinical challenge is to define an effective strategy to identify which patients are at high risk for recurrence and test the efficacy and safety of extended anticoagulation. D-dimer testing and evaluation of residual thrombus after initial treatment of DVT are 2 strategies used to identify patients at high risk of recurrence.

Prandoni and colleagues³ performed a randomized trial to help evaluate the utility of ultrasound testing to guide the length of anticoagulation with vitamin K antagonist in patients with DVT. Patients in the study had a first proximal DVT that was either provoked or non-provoked (idiopathic). Patients with provoked DVT were randomized to therapy lasting 3 months or until follow-up ultrasounds showed recanalization of the residual thrombus. Patients with idiopathic DVT were randomized to therapy lasting 6 months or until recanalization of the residual thrombus. The primary outcome was recurrent DVT or PE.

Patients in the fixed length treatment group had a 17.8% recurrence rate and this was reduced to 12.3% in the group with tailored therapy based on recanalization of the residual thrombus (adjusted hazard ratio, 0.64 [95% CI, 0.39 to 0.99]) after a mean of 33 months follow up. Patients with idiopathic DVT seemed to gain the most benefit from this strategy; however the study was not large enough to analyze patients with idiopathic and provoked DVT separately.

Bottom line answer: Non-surgical patients in the hospital do not need routine platelet monitoring when LMWH or fondaparinux is used. If unfractionated heparin is used, policies should ensure platelet surveillance.

Clinical applicability
Even with serial ultrasound guided therapy, which includes stopping anticoagulation when the residual thrombus has recanalization, patients had a rate of recurrence of approximately 4% per year (12.3% over 33 months). If this rate is not acceptable, anticoagulation should be continued indefinitely as long as the bleeding risk is low. A similar recurrence rate was observed in patients monitored with the d-dimer test. Patients with a negative d-dimer result who had received at least 3 months of anticoagulation and who had been followed for 2 years, had an annual risk of recurrent VTE of 3.5%.⁴

1. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125(1):1-7.
2. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; American College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):454S-545S. Erratum in: Chest. 2008 Oct;134(4):892.
3. Prandoni P, Prins MH, Lensing AW, et al; AESOPUS Investigators. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med. 2009;150(9):577-585.
4. Verhovsek M, Douketis JD, Yi Q, et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med. 2008 Oct 7;149(7):481-490, W94.

Q: Our hospital wants to be compliant with the Joint Commission's National Patient Safety Goals and we are building the required hospital policies. We would like to know if there are any thromboprophylaxis situations that do not require platelet monitoring to detect heparin-induced thrombocytopenia.

A: One of The Joint Commission's mandatory 2009 National Patient Safety Goals 03.05.01 requires that: The hospital has a written policy that addresses baseline and ongoing laboratory tests that are required for heparin and low molecular weight heparin therapies.¹ Platelet monitoring falls into this category and we can look to the American College of Chest Physicians' guidelines to assist in building hospital protocols.

Heparin and, to a lesser extent, low molecular weight heparin (LMWH) can cause heparin-induced thrombocytopenia (HIT) which is an antibody-mediated adverse effect of thromboprophylaxis with heparin and can lead to venous and arterial thrombosis. The risk is highest in the postoperative patient receiving unfractionated heparin, and is lowest in the medical or obstetric patient receiving LMWH. The ACCP recommendations for platelet monitoring state: For medical/obstetrical patients who are receiving only LMWH, or medical patients who are receiving only intravascular catheter UFH flushes (HIT risk < 0.1%), we suggest clinicians do not use routine platelet count monitoring (Grade 2C).²

Although fondaparinux is not addressed in the National Patient Safety Goals or the VTE Core Measure set, the ACCP recommends: For patients who are receiving fondaparinux thromboprophylaxis or treatment, we recommend that clinicians do not use routine platelet count monitoring (Grade 1C).²

Bottom line answer: Non-surgical patients in the hospital do not need routine platelet monitoring when LMWH or fondaparinux is used. If unfractionated heparin is used, policies should ensure platelet surveillance.

1. The Joint Commission 2009 National Patient Safety Goals Hospital Program. Available at: http://www.jointcommission.org/PatientSafety/NationalPatientSafetyGoals/09_hap_npsgs.htm. Accessed August 2009.
2. Warkentin TE, Greinacher A, Koster A, Lincoff AM; American College of Chest Physicians. Chest. 2008;133(6 Suppl):340S-380S.

Q: Postthrombotic syndrome (PTS) (previously called postphlebitic syndrome) is a common disorder associated with much morbidity. How common is symptomatic PTS?

A: The incidence of symptomatic PTS has been debated. Recently Shrier et al (2009) conducted a study of PTS in a prospective, multicenter, cohort study of 387 patients using a Villalta scale at 1 month and up to 24 months after acute DVT.

• The study was conducted in patients with objectively diagnosed symptomatic DVT of the lower limb presenting to emergency departments, outpatient clinics, or in inpatient wards of 8 affiliated hospitals in Quebec and Ontario.
• The severity of PTS was modeled using the Villalta scoring: none (0-4), mild (5-9), moderate (10-14), and severe (> 14)
• Symptomatic PTS occurred in 48% of patients within 1 month of the index DVT event. Most patients categorized as none or mild at the 1-month follow-up visit after the index event were also in the none or mild categories at the end of follow-up, whereas about half of the patients categorized as moderate or severe at 12 months improved to none or mild at the end of follow-up
• Patients who had worse 1-month postthrombotic severity category had higher average scores over time
• There was considerable patient variability over time; however, PTS 1-month Villalta score was strongly predictive of Villalta score during follow-up, as was extensive thrombosis (common femoral or iliac vein)
• Data were collected on the use of compression stockings during follow up, but the study was not able to assess whether this influenced PTS. The effect of anticoagulation therapy on PTS risk could not be ascertained.
• PTS is associated with decreased physical activity level at 2 years

Reference:

Shrier I, Kahn SR, Steele RJ. Effect of early physical activity on long-term outcome after venous thrombosis. Clin J Sport Med. 2009;19(6):487-493.

Q: Many organizations are working diligently to comply with the multitude of regulatory requirements of the Centers for Medicare and Medicaid Services (CMS), The Joint Commission's National Patient Safety Goals, and Agency for Healthcare Research and Quality (AHRQ) Safe Practices. In order to meet the expectations, one must anticipate and overcome several barriers. What are the common mistakes made by organizations?

A: The most common mistakes institutions make in designing VTE prophylaxis orders:

• Point-based models generally get low adherence if the practitioner is required to assess the categories and make a quantitative conclusion. One exception to this may be an electronic alert system, where the data are put into the electronic chart by the practitioner and the computer generates a risk score. Orders with too much guidance tend to be ignored, as do those with too many levels of risk. Protocols with too little guidance have limited use. Some orders consist of a list of possible interventions, without assistance in choosing which prophylaxis might be most appropriate for different levels of risk and how special circumstances such as bleeding risk impact the decision. The risk level assessment and prophylaxis choices should be part of the same instrument. Separation can lead to inadequate prophylaxis, as the evaluation must be made multiple times. The patient should be evaluated at different points in the course of the treatment to maintain a continuum of care, but each time the risk evaluation and treatment decision should be closely linked.
• Mechanical prophylaxis has an appropriate role, especially in moderate or high-risk patients with risk of bleeding. In one meta-analysis, intermittent pneumatic compression reduced the rate of DVT by 60% in postoperative patients. On the other hand, thigh-length graduated compression stockings did not reduce the risk of deep vein thrombosis in hospitalized immobile patients admitted within 1 week of acute stroke. These findings and the recommendations of the 2008 American College of Chest Physicians (ACCP) guidelines make it clear that mechanical prophylaxis can play a positive role but must be used judiciously.
• New protocols should supplant older ones, not be added to them. This housekeeping should be done by the implementation committee in the ongoing effort to maintain a simple system that maximizes positive patient outcomes. After implementation, the system should be monitored and revised to address problems that might arise. The iterations of evaluation and revision lead to improvement.

Q: What are some of The Joint Commission's newest VTE measures and when were they implemented?

A: A 6-component VTE measure set has been approved by The Joint Commission and is available for selection by hospitals to meet core measure set accreditation requirements. The measurement set which took effect May 1, 2009 is as follows:

• Prophylaxis
• VTE-1: VTE prophylaxis
• VTE-2: VTE prophylaxis in the ICU
• Treatment
• VTE-3: patients with overlap of anticoagulation therapy
• VTE-4: patients receiving UFH with platelet count monitoring and adjustment of medication by nomogram/protocol
• VTE-5: discharge instructions
• Outcome
• VTE-6: incidence of potentially preventable hospital-acquired VTE

In addition, on October 1, 2009, the stroke and VTE measures became ORYX^® core measure sets for the purpose of meeting the performance measurements for accreditation.

• Hospitals are required to collect and transmit data to The Joint Commission for a minimum of 4 ORYX^® core measures. Accredited hospitals may select stroke or VTE as one of their required 4 ORYX^® core measure sets.

Reference:

The Joint Commission. Current NHQM Manual. Accessed November 2009.

Q: Epidural anesthesia is commonly and appropriately used in patients at varying levels of VTE risk. What interventions and recommendations exist to minimize the risk of bleeding in these patients?

A: Neuraxial blockade has several advantages over systemic opioids, but the risk of spinal or epidural hematoma may be increased with the concomitant use of antithrombotic drugs. Therefore, these agents must be used cautiously in patients with neuraxial blockade.¹ Guidelines from the American Society of Regional Anesthesia and Pain Medicine (ASRA) contain the following recommendations²:

1. Subcutaneous UFH: No contraindication, consider delaying heparin until after block if technical difficulty is anticipated
2. LMWH: Twice daily dosing-LMWH 24 hours after surgery, regardless of technique; remove neuraxial catheter 2 hours before first LMWH dose
3. Warfarin: Document normal INR after discontinuation (prior to neuraxial technique); remove catheter when INR < 1.5 (initiation of therapy)

Of course before initiating thromboprophylaxis, it is important to evaluate the risk of bleeding, and patients should be assessed for contraindications that could increase that risk. The risk factors for spinal hematoma in neuraxial blockade include:

• Known systemic bleeding disorder
• Hemorrhagic or traumatic tap
• Indwelling epidural catheters
• Additional doses of LMWH (ie, bid dosing)
• Concomitant use of medications that may impair hemostasis
• Communication gap between providers

1. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest. 2008;133(6_suppl):381S-453S.
2. Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med. 2003;28(3):172-197.

Q: Which hospitalized patients should be included in our prophylaxis program? Of special interest are psychiatric inpatients and obstetrics patients (both c-section and normal vaginal deliveries).

A: Hundreds of randomized, controlled studies have demonstrated that prophylaxis against thromboembolism is efficacious. Despite this evidence and expert recommendations, more than 50% of medical and surgical inpatients do not receive thromboprophylaxis or are treated suboptimally.¹

VTE is considered one of the most preventable causes of morbidity and mortality in hospitalized patients. As a result, The Joint Commission (formerly the Joint Commission on the Accreditation of Healthcare Organizations [JCAHO]) now expects hospitals to demonstrate compliance with recommendations for DVT prevention. Similarly, beginning in 2009, the Center for Medicare and Medicaid Services will not reimburse hospitals for the added costs of care for patients who develop DVT after orthopedic surgeries.

Certain factors confer particular risk for DVT, including prior VTE events, surgery, cancer, and prolonged immobility. A useful resource to guide clinicians in the prevention and management of VTE is the 8th edition of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, which was released in June 2008.²

The risk of VTE is high in many hospitalized patients who do not generally receive prophylaxis. General medical and surgical patients have a DVT prevalence of 10% to 40%. Although the majority of hospitalized patients have at least one identifiable predisposing factor for DVT, Goldhaber¹ reported that 16% of patients with documented DVT had no comorbidities. The most common risks described in that study were systemic hypertension, surgery within the past 3 months, immobility within the past 30 days, cancer, and obesity. Based on patient outcomes and cost effectiveness, many studies support routine preventive treatment for hospitalized patients at increased risk for VTE.

The current guidelines provide prophylaxis recommendations determined by risk factors. Patients admitted to the hospital with at least one of these risk factors should receive thromboprophylaxis with low-molecular weight heparin (LMWH), low-dose unfractionated heparin (LDUH), or fondaparinux. When anticoagulation is contraindicated, such as in patients with active bleeding, a high risk of bleeding, or impaired coagulation, prophylaxis should include mechanical measures with either GCS or IPC.³

Anticoagulant therapy is indicated during pregnancy for the prevention of VTE, for the prevention of systemic embolism in patients with mechanical heart valves, and in combination with aspirin for the prevention of recurrent pregnancy loss in women with antiphospholipid antibodies.⁴ The use of anticoagulant therapy during pregnancy is challenging because of the potential for fetal and maternal complications. Although cesarean section is likely to be a risk factor for VTE, the risk for symptomatic events attributable to cesarean section appears very modest and is similar to that seen in low-risk surgical patients for whom no routine thromboprophylaxis other than mobilization is recommended.⁴ Additional factors may increase the risk of VTE associated with cesarean section, and when it is performed emergently, the risk of VTE is approximately double that of an elective procedure.⁴ The level of risk with multiple factors is not clearly established. Addition of multiple other risk factors (increased age, prior VTE, obesity, thrombophilia, lower limb paralysis, immobilization, extended surgery such as hysterectomy, preeclampsia, and comorbid medical conditions such as heart failure) is likely to place the patient at moderate to high risk for VTE. Thus, a thrombosis risk assessment should be performed in all women undergoing cesarean section to determine the need for thromboprophylaxis. In patients without additional thrombosis risk factors undergoing cesarean section, anticoagulant thromboprophylaxis is not recommended, and early mobilization should be encouraged. In the presence of moderate risk, either pharmacologic or nonpharmacologic strategies for prevention may be used.⁴ If the risk is high, then pharmacologic strategies should be added to mechanical prophylaxis.

1. Goldhaber SZ, Tapson VF; DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol. 2004;93(2):259-262.
2. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):381S-453S.
3. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med. 1991;151(5):933-938.
4. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsch J; American College of Chest Physicians. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133:844S-886S.

Q: What is the correct duration of therapy for patients with VTE (deep vein thrombosis) and is there a role for ultrasound to guide management?

A: The optimal duration of warfarin for first DVT is hotly debated. The important PREVENT trial¹ showed that low-intensity warfarin therapy given to patients with VTE (initiated after 6.5 months of full-dose warfarin therapy) reduced the risk of VTE recurrence by 64% over a mean period of 2 years.

The multi-center AESOPUS trial² asked whether ultrasonographic (USG) detection of residual thrombi could be used to guide the duration of anticoagulation and reduce the rate of VTE recurrence. Patients who experienced a first DVT were treated with 3 months of oral anticoagulant. Patients who completed this period without an event were randomized to fixed-duration or flexible-duration warfarin treatment. The fixed-group individuals with secondary DVT received 3 months of warfarin, and those with unprovoked DVT received 6 months of therapy. The flexible-duration group's therapy was terminated at 3 months if their USG showed vein re-canalization. Patients whose veins had not re-canalized at 3 months received additional USG at 3 and 9 months (for secondary DVT) or at 3, 9, 15, and 21 months (for unprovoked DVT).

After 33 months of follow-up, the recurrent DVT risk was 12% in the flexible-duration group, significantly lower than 17% in the fixed group. This indicates an advantage of continuing warfarin in patients who do not have re-canalization. However, an editorial points out that patients with idiopathic DVT need indefinite warfarin, and those with provoked DVT need "time-limited" warfarin. Follow-up USG may be reasonable in this group to determine the length of warfarin treatment. It is important to recognize that patients with previous thromboembolism, permanent risk factors for thrombosis, and thrombophilic abnormalities other than factor V Leiden and prothrombin mutation were excluded.

I use low-intensity warfarin after 3 months of high-intensity treatment, following the PREVENT trial results. When ultrasound data are available for provoked VTE I take it into consideration, but I do not routinely order USG. If additional research supports the AESOPUS study this could change.

1. Ridker PM, et al; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348(15):1425-1434.
2. Prandoni P, et al; AESOPUS Investigators. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med. 2009;150(9):577-585.

Q: Is it acceptable to monitor medical inpatients closely and perform screening ultrasounds when symptoms of DVT appear, instead of providing prospective prophylaxis?

A: Unfortunately, it is not. In a prospective contemporary assessment of DVT, the DVT-FREE Registry confirmed that many patients with ultrasound-documented DVT do not have typical symptoms or at least those symptoms do not indicate DVT. Furthermore, routine ultrasound is time-consuming, expensive, and notoriously insensitive in the two areas of high concern in medical inpatients: asymptomatic patients and those with calf-only DVT. Patients at risk of developing VTE in the hospital should be prophylaxed; screening patients is expensive and not clinically rewarding.

Reference:
1.Kucher N, et al. Risk factors associated with symptomatic pulmonary embolism in a large cohort of deep vein thrombosis patients. Thromb Haemost. 2005;93(3):494-498.

Q: What is the role of mechanical (nonpharmacological) methods of prophylaxis for VTE in nonsurgical patients?

A: In general, mechanical methods of VTE prophylaxis are inferior to pharmacologic prophylaxis. Mechanical methods are useful in two settings: (1) patients who cannot receive pharmacologic prophylaxis because their risk of bleeding is too high (this is often the case in some surgical populations); (2) patients who are at particularly high risk of VTE, or those for whom a DVT or PE would be catastrophic because of their comorbidities. These patients may in fact benefit from the use of concomitant pharmacologic and mechanical prophylaxis.

Reference:
1.Geerts WH, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133;381-453.

Q: I have a 75-year-old female patient with diabetes, obesity, and COPD who was admitted for bilateral pneumonia. A central venous line was placed in the right subclavian vein while the patient was in the MICU. During hospitalization, the patient developed marked right upper extremity swelling DVT. An ultrasound confirmed a RUE DVT. Should this patient be treated with thrombolysis, standard anticoagulation management, or by simply removing the CVL?

A: The approach to patients with upper extremity DVT is controversial, primarily due to a lack of randomized trials assessing management, and a perception that UE DVT is unlikely to lead to PE. Though the rate of embolization may be lower than for lower extremity DVT, the risk of embolization is still substantial, acute and long-term anticoagulation is required. Small cohort studies suggest that a standard approach, (ie, acute anticoagulation with SC LMWH or IV heparin with long-term anticoagulation with warfarin, as used for lower extremity DVT) is effective. This approach is preferred over thrombolysis, as thrombolytics have not consistently shown a benefit compared to standard therapy, and some studies have noted high rates of bleeding and/or recurrence. Similarly, simply removing the CVL and not administering anticoagulation is not recommended for most patients due to lack of studies proving efficacy. Patients with UE DVT should be transitioned to warfarin, though there is also a lack of evidence on the optimal duration. In general, a process of selecting a duration of oral anticoagulation should mirror that for lower extremity DVT. The CVL generally does not need to be removed if it is functioning well and still medically necessary. For the patient in this scenario, the CVL could be removed. This eliminates a transient risk factor and a 3-month course of anticoagulants would be appropriate.

Q: The patient is an 83-year-old female with a history of hypertension, diabetes, and osteoarthritis. The patient had an idiopathic PE 14 months ago and has been on warfarin since that time. The patient is scheduled to undergo a total hip replacement. Her INR 1 week prior to surgery is 2.5. What is the best management of the patient's warfarin peri-operatively?

A: Management of anticoagulation in the peri-operative period is a common and controversial clinical challenge. Simply withholding warfarin is simple and inexpensive, but exposes the patient to a period of subtherapeutic anticoagulation. Administering SC low-molecular-weight heparin or IV heparin while warfarin is withheld (known as bridging therapy) reduces the time the patient is at high risk for thrombosis, but increases the risk of bleeding for most procedures and is costly. Physicians need to base their decision on the estimated risk of clotting and bleeding and the consequences of these complications should they occur. The American College of Chest Physicians (ACCP) guidelines can help clinicians choose a rational strategy that can minimize the overall risks to the patient (Douketis JD, et al. Chest. 2008;133:299S-339S). The guidelines use the available evidence to categorize patients on warfarin into low, intermediate, and high risk for thromboembolism without anticoagulation. The patient in this scenario would be categorized as low risk, as she had a single VTE > 12 months ago. In addition, peri-operative bridging would increase her risk for major bleeding, particularly if the heparin were given within 24 hours of major surgery. The best management for this patient would be to simply withhold warfarin for 5 days prior to surgery and restart warfarin the night of surgery provided hemostasis is adequate.

Q: I have a 42-year-old female patient who was admitted with an acute DVT. There were no precipitating factors, such as recent surgery, and a hypercoagulable work-up was negative. The patient was treated with low-molecular-weight heparin and warfarin, and was discharged home on LMWH one day after admission. The LMWH was discontinued when the INR was 2.0, at which time the patient's symptoms had improved. What is the role of D-dimer in determining how long to treat this patient with warfarin?

A: Studies have consistently found that indefinite therapy after an acute venous thromboembolism results in fewer recurrences than does a 3-6 month course of warfarin. Based on these studies, the American College of Chest Physicians (ACCP) guidelines suggest indefinite therapy for patients who have no increased risk of bleeding and for whom the INR management is not problematic. However, some clinicians continue to treat for a shorter interval (such as 3-6 months) due to concerns about bleeding risks on lifelong warfarin. The D-dimer assay can help clinicians choose an appropriate time course. A positive D-dimer test approximately 1 month after stopping warfarin predicts a significantly increased risk of recurrence and identifies a subgroup of patients who may benefit from indefinite anticoagulation. Conversely, a negative result is reassuring and can help identify patients at a lower risk of recurrent VTE. For those patients where it is unclear if indefinite therapy is preferred, a D-dimer test done after stopping warfarin can help guide this decision.

Q: Is there data or rationale for overlapping warfarin with LMWH, UFH, or fondaparinux for VTE prophylaxis post hip or knee orthopedic surgery?

A: Current ACCP guidelines recommend prophylaxis with LMWH, fondaparinux, or adjusted dose vitamin K antagonists (VKA) for total hip and knee arthroplasty; UFH is not recommended in these populations as it has been found less efficacious than the aforementioned strategies. VKA dosing should begin the day before or the day of surgery and should achieve a target INR 2.0-3.0 within 72 hours post-op. If the INR is not realized at 72 hours, full dose anticoagulation with LMWH or UFH should be used until the therapeutic target is reached. This is the protocol that provides level 1A evidence in support of vitamin K antagonists in this population.

Some practitioners have started prophylactic LMWH or fondaparinux post-op at the same time as vitamin K antagonists until the INR goal is reached. To my knowledge, there are no randomized controlled studies comparing this approach to standard evidence-based recommendations. One would hypothesize that this would provide better prophylaxis than traditional vitamin K antagonist alone. In such protocols, the patient was converted to full dose LMWH or fondaparinux if the vitamin K antagonist was insufficient to reach the therapeutic goal at 72 hours.

It should be noted that the AAOS also supports the use of lower dose warfarin (INR target 1.5-2.0) as well as mechanical prophylaxis combined with aspirin for VTE prophylaxis in patients undergoing total hip or knee arthroplasty. The ACCP does not share this view.

Q: Do you currently treat patients with uncomplicated pulmonary emboli as outpatients or as accelerated discharge within 24-48 hours? If so, what are your exclusion/inclusion criteria?

A: Yes, I treat PE patients as outpatients or facilitated discharge. To qualify, all patients must meet basic discharge criteria: normal vital signs, ability to ambulate on room air, ability to eat and drink, and be competent to execute basic activities of daily living. In addition, patients must have the ability to obtain and self inject LMWH (or have a proxy arranged). The patient must have a home and a phone, and have credible adherence to protocols and follow-up. The patient must also be willing to go home.

Important exclusions include morbid obesity (over 120 kg) and significant renal impairment (creatinine clearance rate < 30-40 ml/min), as both of these problems can decrease predictability of weight-based dosing.

Q: Is it acceptable to stop VTE prophylaxis for medical patients at the time of hospital discharge?

A: Meta-analyses confirm the overall net benefits of short-term anticoagulant prophylaxis (typically 6-14 days) in medical patients. However, the modern hospitalization is shorter, which raises the question of whether hospital prophylaxis for 3-4 days affords the same protection. Various surgical populations are already known to benefit from extended prophylaxis outside the hospital.^1-6 For medical patients, the start and overall length of the "at risk" period for VTE is unlikely to be restricted to hospital stay. Population studies demonstrate that the most frequent variable found in patients diagnosed with symptomatic community VTE is hospitalization within 30 days of diagnosis, suggesting the "at risk" period could be as long as 4 weeks after hospital discharge.^7,8

The EXCLAIM trial⁹ directly evaluated this question in an international, multicenter, randomized, placebo-controlled trial. It enrolled 5,105 acutely-ill patients with recent reduced mobility; patients received enoxaparin 40 mg subcutaneously once daily for 10+/-4 days and then received the same enoxaparin regimen or placebo for an additional 28+/-4 days. The primary efficacy endpoint was the incidence of asymptomatic deep-vein thrombosis (DVT) detected by routine standardized ultrasonography at the end of the double-blind period, symptomatic DVT, symptomatic pulmonary embolism (PE), or fatal PE during the double-blind period. Secondary efficacy endpoints include the incidence of VTE at 3 months and the incidence of mortality up to 6 months after enrollment. The primary safety endpoint was major hemorrhagic complications during the same period. Compared to placebo (n = 2062), the extended duration enoxaparin group (n = 2052) had a 44% relative risk reduction in overall VTE events (2.8% vs. 4.9%; P = 0.0011), including a significant 73% relative risk reduction in symptomatic VTE (0.3% vs. 1.1%; P = 0.0044). The significant reduction in risk of VTE persisted to 90 days (3.0% vs. 5.2%; P = 0.0015). All cause mortality at 6 months did not differ between the groups. The extended duration enoxaparin group had more total bleeding events (5.7% vs. 3.8%; P = 0.007), including major bleeding (0.6% vs 0.15%; P = 0.024).

These results confirm that the "at risk" period for medical patients discharged from the hospital is longer than 6-14 days, and that this risk can be effectively reduced with thromboprophylaxis.^1-9 In addition, this study indirectly addressed the question of whether shorter courses of prophylaxis (ie, 3-4 days) are adequate compared to the routinely studied 6-14 days of prophylaxis. It doesn't seem plausible that prophylaxis courses shorter than 6-14 days will be as efficacious in "at risk" medical patients, when the results of EXCLAIM demonstrate that 6-14 days is inadequate compared to 28 days. As such, all providers should try to ensure that discharged medical patients receive a minimum of 6 days of prophylaxis.

1. Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind randomized comparison. The North American Fragmin Trial Investigators. Arch Intern Med. 2000;160:2208-2215.
2. Comp PC, Spiro TE, Friedman RJ, et al; Enoxaparin Clinical Trial Group. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group. J Bone Joint Surg Am. 2001;83-A:336-345.
3. Hull RD, Pineo GF, Stein PD, et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med. 2001;135:858-869.
4. Eriksson BI, Lassen MR, PENTasaccharide in HIp-FRActure Surgery Plus Investigators. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2003;163:1337-1342.
5. Bergqvist D, Jonsson B. Cost-effectiveness of prolonged administration of a low molecular weight heparin for the prevention of deep venous thrombosis following total hip replacement. Value Health. 1999;2:288-294.
6. Bergqvist D, Agnelli G, Cohen AT, et al; ENOXACAN II Investigators. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002;346:975-980.
7. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160:809-815.
8. Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med. 2007;167:1471-1475.
9. Hull RD, Schellong SM, Tapson VF, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recent reduced mobility: the EXCLAIM study. Presented at: 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland. Late-breaking clinical trials, abstract O-S-001.

Q: Should individual patient risk assessment guide thrombosis prophylaxis or does it suffice to prescribe prophylaxis according to broad groups?

A: The 2008 ACCP guidelines identify major groups at risk for thrombosis and recommend specific thromboprophylaxis for each. For example, patients undergoing major general surgery or major orthopedic surgery are at high risk.¹ This approach simplifies prophylaxis, which is required for most patients.

The guidelines are based on randomized controlled clinical trials in well–defined populations. Many patients are excluded for reasons including a past history of thrombosis, cancer, or multiple comorbidities. The conclusions are strong for that particular population, but may not apply to others. Many patients encountered in clinical practice do not fit the inclusion criteria, are not covered by the clinical trial conclusions, and thus need individualized thromboprophylaxis. The guidelines point out that treatment that differs from the established guidelines may be appropriate for patients who do not fit the clinical trial criteria. This emphasizes the importance of individual patient risk assessment, as VTE is the number one preventable cause of death in hospitalized patients. Therefore, VTE risk assessment should be part of a proper history and physical exam to increase the odds for success of an operation or medical treatment plan. A low–risk procedure in a high–risk patient may carry the same risk as a high–risk procedure in a low–risk patient but these combinations have not all been tested in RCTs and no guideline recommendations are available.

In order to address these issues we have developed a patient risk assessment that accounts for most of the known risk factors and assigns a weight to each factor to produce a risk score.^{2, 3} This score is based on studies of the effects of weight, age, length of surgery, cancer, and hormonal therapy on thrombosis. The risk score has been validated in a number of studies in medical and surgical patients.^4-6 Using the score can help guide the initiation, type, duration, and intensity of prophylaxis. A recent study examined the correlation of the score with the 30 day incidence of proven DVT in surgical patients.⁷ The risk assessment score should be helpful in selecting which patients should receive out–of–hospital prophylaxis.

1. Geerts WH, Pineo GF, Heit JA. Prevention of venous thromboembolism: the Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2005;106:910.
2. Arcelus JI, Candocia S, Traverso CI, Fabrega F, Caprini JA, Hasty JH. Venous thromboembolism prophylaxis and risk assessment in medical patients. Semin Thromb Hemost. 1991;17 Suppl 3:313-318.
3. Caprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon. 2005;51:70-78.
4. Zakai NA, Wright J, Cushman M. Risk factors for venous thrombosis in medical inpatients: validation of a thrombosis risk score. J Thromb Haemost. 2004;2:2156-2161.
5. Seruya M, Venturi ML, Iorio ML. Efficacy and safety of venous thromboembolism prophylaxis in the highest risk plastic surgery patients. Plast Reconstr Surg. 2008;122:1701-1708.
6. Hatef D, Kenkel J, Nguyen M. Thromboembolic risk assessment and the efficacy of enoxaparin prophylaxis in excisional body contouring surgery. Plast Reconstr Surg. 2008;122:269-279.
7. Bahl V, Hu H, Henke PK, Wakefield TW, Campbell DAJ. A validation study of a retrospective venous thromboembolism risk scoring method. Submitted 2009.

Q: What are the clinical manifestations of venous thromboembolism (VTE)?

• Pulmonary embolism (PE) is an uncommon but potentially lethal complication that may occur in close to 300,00 patients annually and is associated with a 34% incidence of sudden death.¹ It was also estimated that at least one-third of these fatal emboli occurred out-of-hospital. The prevalence of PE at autopsy has not changed over 3 decades. The frequency of unsuspected PE in patients at autopsy has not diminished. Even among patients who die from PE, the PE is usually unsuspected. Such patients, however, typically have advanced disease. Among moribund patients, incidental PE is rarely diagnosed. Patients who suffer sudden unexplained catastrophic events in the hospital are a group in whom the diagnosis might be suspected more frequently if physicians maintain a high index of suspicion.²

• Pulmonary hypertension has been estimated to occur in 4% of individuals who survive PE and may result in decreased quality-of-life due to breathing issues. Often the diagnosis is suggested by unexplained dyspnea on exertion following recovery from a PE.³

• Deep venous thrombosis is another manifestation of VTE that can result in significant changes in lifestyle, including anticoagulant treatment, stockings, dietary, travel, or activity restrictions. There is an increased risk for recurrence if surgery is required or illness occurs, requiring hospitalization. Rarely phlegmasia cerulea or alba dolens develops, which may result in loss of a limb due to venous gangrene.

• Patients who suffer a postoperative DVT and have another operation may face the prospect of a recurrent DVT over 60% of the time in at least one study.⁴

• The post-thrombotic syndrome (PTS) is a complication that occurs in about 25% of patients following a DVT and is disabling in 7% of patients. Some of these complications take months or years to develop.⁵ Clinical manifestations include leg swelling, varicose veins, and chronic skin changes including leg ulcers. Recurrent DVT increases the incidence of PTS by 6-fold.⁶

• Non-hemorrhagic stroke is yet another manifestation of VTE that can develop when a clot breaks off from the arm, leg, or pelvic veins and travels to the right heart and goes through a patent foramen ovale to the left atrium and then into the systemic circulation. Often these clots go to the brain, resulting in a stroke.⁷

• In conclusion, thrombosis prophylaxis is frequently advised to prevent fatal PE. All too often the physician forgets that the real goal of thrombosis prophylaxis is to prevent the many faces of VTE, which may occur long after the initial thrombotic event.

1. Heit JA, Cohen AT, Anderson FA, Jr, on Behalf of the VTE Impact of Assessment Group. Estimated annual number of incident and recurrent, non-fatal and fatal venous thromboembolism (VTE) events in the US. Blood. 2005;106:910.
2. Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest. 1995;108(4):978-981.
3. Heresi GA, Dweik RA. Pulmonary hypertension: evaluation and management. Compr Ther. 2007;33(3):150-161.
4. Borow M, Goldson HJ. Prevention of postoperative deep venous thrombosis and pulmonary emboli with combined modalities. Am Surg. 1983;49(11):599-605.
5. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125(1):1-7.
6. Nicolaides AN, Breddin HK, Fareed J, et al. Prevention of venous thromboembolism. International Consensus Statement. Guidelines compiled in accordance with the scientific evidence. Int Angiol. 2001;20(1):1-37.
7. Salinger MH, Feldman TE, Salinger MH, Feldman TE. Patent foramen ovale: the missing link between deep venous thrombotic disease and embolic stroke. Disease-A-Month. 2005;51(2-3):94-103.

Q: Which patients should receive pharmacologic prophylaxis following hospital discharge?

A: There is good evidence in patients having abdominal cancer operations that VTE is the most common cause of death at 30 days after surgery.¹ Two randomized prospective clinical trials have demonstrated that the total VTE incidence is significantly reduced with 30 days of prophylactic LMWH compared to 7 days of LMWH following abdominal surgery for cancer.^{2, 3}

Patients with active cancer receiving chemotherapy are also at risk. This is particularly true for patients with multiple myeloma who are treated with thalidomide or lenalidomide and dexamethasone.⁴

Another clinical situation where there is excellent evidence for extended out-of-hospital prophylaxis is following certain major orthopedic procedures. A number of studies document the significantly lower venographic and clinical VTE incidence in patients receiving 30 days of LMWH compared to 7 days of prophylaxis.^{5, 6} These effects are more dramatic for total hip replacement compared to total knee replacement. There is also good evidence to suggest 30 days of prophylaxis in patients having hip fracture surgical repair.⁷

Carmody and colleagues have indicated that bariatric surgery patients frequently suffer VTE following hospital discharge. The authors recommend continuing LMWH prophylaxis in these surgical patients following discharge. The duration is not specified, but most of the VTE occurrences were seen in the first month.⁸ Borkgren-Okonek and his associates recommend a 2-tier program of prophylaxis using LMWH continued for 10 days after discharge.⁹

Seruya found in a Caprini score of 4 or more 15% of 1156 plastic surgery patients treated by the same surgeon. The incidence of proven VTE events in this group was 7.5% and the authors recommend LMWH prophylaxis to be continued for 7-10 days postoperatively for patients with high scores.¹⁰

Finally in medically ill hospitalized patients who are discharged with ongoing thrombosis risk, 30 days of LMWH prophylaxis has been shown to reduce the VTE incidence with a slight increase in the risk of bleeding.¹¹

1. Agnelli G, Bolis G, Capussotti L, et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surgery. 2006;243(1):89-95.
2. Bergqvist D, Agnelli G, Cohen AT, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. New Engl J Med. 2002;346(13):975-980.
3. Rasmussen MS, Jorgensen LN, Wille-Jorgensen P, et al. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study. J Thromb Haemost. 2006;4(11):2384-2390.
4. Knop S, Gerecke C, Liebisch P, et al. Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood. 2009;113(18):4137-4143.
5. Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators. Arch Intern Med. 2000;160(14):2208-2215.
6. Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet. 2001;358(9275):9-15.
7. Eriksson BI, Bauer KA, Lassen MR, Turpie AG; Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med. 2001;345(18):1298-1304.
8. Carmody BJ, Sugerman HJ, Kellum JM. Pulmonary embolism complicating bariatric surgery; detailed analysis of a single institutions 24 year experience. J Am Coll Surg. 2006;203(6):831-837.
9. Borkgren-Okonek MJ, Hart RW, Pantano JE, Rantis PC. Enoxaparin prophylaxis in gastric bypass patients; extended duration, dose stratification, and antifactor Xa activity. Surg Obes Relat Dis. 2008;4:625-631.
10. Seruya M, Venturi ML, Iorio ML Davison SP. Efficacy and safety of venous thromboembolism prophylaxis in highest risk plastic surgery patients. Plast Reconstr Surg. 2008;122:1701-1708.
11. Hull R. Extended duration of anticoagulation in the medically ill. ISTH Clinical Congress Geneva Switzerland. 2007:s-001.

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