Objective

Overview

This web-based, case-based continuing education program applies clinical practice guidelines and recent research results to venous thromboembolism patient cases.

The program is designed to be interactive with questions posed to the participant at several points. After responding to each question, you will see the correct response, as well as how others have answered the questions. Please respond to each question, even if you are unsure of your answer. These questions are for educational purposes only; your answers will not impact your CE credit for the program.

CE Information

Target Audience

This continuing education activity was planned to meet the needs of pharmacists who treat, instruct, or otherwise participate in the care of patients with or at risk for venous thromboembolism.

Continuing Education Accreditation

The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program provides 1.0 hour (0.10 CEU) of continuing education credit (program number 204-000-07-435-H01). Upon completion of the online case study and post-program survey, participants may print their official ASHP CE statements. This program is available for continuing education credit from May 31, 2009 to March 11, 2011.


Planned and conducted by ASHP Advantage and supported by an educational grant from sanofi-aventis U.S. 

 

Contact ASHP Advantage for assistance or questions.

Copyright 2007 • Trademark • ASHP Privacy Policy

 

Learning Objectives

Learning Objectives

After completing this activity, the participant should be able to:

1. Evaluate the risk for venous thromboembolism (VTE) in a patient with an acute medical condition and determine whether VTE prophylaxis is warranted.
2. Recommend a prophylactic drug therapy regimen for a patient at risk for VTE and evaluate the patient’s response to treatment.
3. Identify a possible adverse effect from anticoagulant therapy and discuss the impact on healthcare costs and an appropriate intervention to manage the adverse effect.
4. Identify the best approach to ensure that VTE risk assessment and prophylaxis are provided for hospital patients. 
5. Recommend drug therapy for a patient who experiences VTE.
   

Introduction

Introduction

Venous thromboembolism (VTE) is the most common preventable cause of hospital death.¹ Evidence-based guidelines for the prevention of VTE have been developed.² However, VTE prophylaxis is underused in hospitalized patients (especially those with acute medical illness) despite the availability of these guidelines.^3-7 Various governmental and private organizations, including the Centers for Medicare and Medicaid Services (CMS), National Quality Forum, and Joint Commission on Accreditation of Healthcare Organizations (Joint Commission), have recognized and taken steps to address the problem by establishing the Surgical Care Improvement Project, Joint Commission National Patient Safety Goals, and National Consensus Standards for the Prevention and Care of Venous Thromboembolism.

Efforts by pharmacists to educate physicians and nurses about VTE risk assessment and prophylaxis have been shown to improve the rates and appropriateness of VTE prophylaxis.⁸ A variety of other active strategies have been used to improve VTE prophylaxis rates, including computer-assisted decision making and implementation of clinical practice guidelines with auditing and feedback to the clinician.^9,10 Passive dissemination of guidelines is inadequate. Reductions in the incidence of VTE without increasing the risk of bleeding have been observed with the use of active strategies.^9,10 A combination of active strategies to remind clinicians to assess VTE risk and assist clinicians in the selection of appropriate VTE prophylaxis is most effective for preventing VTE.¹¹

Health system pharmacists can play a vital role in ensuring that clinical practice guidelines are followed in their practice settings. The following patient case illustrates the application of principles for VTE risk assessment and prophylaxis.

Patient Case

Patient Case

KH is a 49-year-old Caucasian woman who presents to the emergency department with shortness of breath, severe chest pain on inspiration, abdominal pain, fever and productive cough.  Her past medical history includes asthma and chronic obstructive pulmonary disease (COPD) for which she takes the following medications:

Preadmission Medications

Theophylline 200 mg orally twice daily
Montelukast 10 mg orally once daily
Ipratropium bromide four 17-mcg puffs by oral inhalation four times daily
Advair Diskus (fluticasone 250 mcg and salmeterol 50 mcg) by oral inhalation twice daily
Guaifenesin 1.2 g orally every 12 hours
Prednisone 40 mg orally once daily in the morning
Albuterol two 90-mcg inhalations as needed for exercise-induced bronchospasm, not to exceed 12 inhalations in a 24-hour period

Patient Case (Cont.)

Social History

Divorced mother with one child (10 years old)
No alcohol consumption
No cigarette smoking history
Unemployed
Lives with sister

Physical Examination

Temperature: 104.5°F
Heart rate: 120 beats per minute
Respiratory rate: 36-40 breaths per minute
Blood pressure: 110/60 mm Hg
Pulse oximetry: 86%
Height: 5’1”
Weight: 180 lb (82 kg)

Review of Systems

Significant for decreased appetite and oral intake for the past week
Chest pain on inspiration
ECG: no changes
Cardiac biomarkers: negative
No hemoptysis
No rash

Patient Case (Cont.)

A chest computed tomography scan is negative for pulmonary embolism. The nature of chest pain, lack of ECG changes and negative test results for cardiac biomarkers exclude the possibility of myocardial infarction as the cause for KH’s chest pain. COPD exacerbation is the diagnosis. KH is admitted to the hospital for treatment with the following medications:

Admission Medication Orders

Hydrocortisone 100 mg i.v. every 8 hours
Ceftriaxone 1 g i.v. every 12 hours
Azithromycin 500 mg i.v. X 1
Azithromycin 250 mg i.v. every 24 hours
Albuterol 2.5 mg + ipratropium bromide 0.5 mg by nebulizer every 6 hours
Albuterol 2.5 mg by nebulizer every hour as needed for breathing difficulty
Acetaminophen 650 mg orally every 4-6 hours as needed for pain

Question 1

Question 1

Which of the following characteristics besides prolonged bed rest places this patient at increased risk for VTE?

Question 2

Question 2

Is VTE prophylaxis indicated for KH?

Question 3

Question 3

Which of the following interventions are among the options recommended by ACCP for patients like KH?

Question 4

There are several therapeutic options for VTE prophylaxis in patients with acute medical illness, including low-dose UFH (5000 units s.c. three times daily) and LMWH.²  Enoxaparin 40 mg s.c. once daily for 6-14 days reduced the risk for VTE by 63% compared with placebo in a study of patients with acute medical illness.¹³  This regimen was at least as effective as low-dose UFH 5000 units s.c. three times daily for the prevention of VTE in patients like KH with severe respiratory disease or heart failure.¹⁵  Fewer adverse effects were associated with enoxaparin compared with UFH.  In the PREVENT study, a 45% reduction in the relative risk of VTE was associated with dalteparin 5000 units s.c. once daily for 14 days compared with placebo in patients with acute medical illness.¹⁶

Question 4

Which of the following drug regimens is recommended for VTE prophylaxis in KH?

Screen 10

Concerns have been raised about the potential for an increased risk for VTE due to inadequate prophylaxis when using fixed doses of LMWH in obese patients like KH.¹⁷ In a study of the use of enoxaparin (40 mg s.c. once daily) for VTE prophylaxis in orthopedic patients with total knee replacement, total hip replacement, or trauma, the incidence of VTE was significantly higher (32%) in obese patients (defined as a BMI >32 kg/m²) than nonobese patients (17%).¹⁸ These findings suggest the need for larger enoxaparin doses in obese patients who require VTE prophylaxis than the fixed doses recommended for all patients. Weight-based dosing of enoxaparin (1 mg/kg s.c. every 12 hours) has been used successfully for the treatment of VTE (i.e., to prevent recurrence of VTE) in obese patients weighing up to 155 kg (341 lb) .¹⁹

In the PREVENT study of fixed doses of dalteparin 5000 units/day s.c. for 14 days in acutely ill medical patients, the incidence of VTE was the same (2.8%) in obese patients (defined as a BMI >= 30 kg/m² for men and >= 28.6 kg/m² for women) and non-obese patients.^16,20 However, the effect of dalteparin was attenuated by BMI values of 40 kg/m² or higher.

A pharmacokinetic study of enoxaparin in healthy volunteers found no major differences between obese and nonobese subjects that would warrant dose adjustment in obese patients.²¹ The obese subjects weighed up to 144 kg (317 lb) . Anti-factor Xa assays in patients receiving weight-based doses of dalteparin or tinzaparin for the treatment of VTE or other disorders requiring anticoagulation demonstrated that increases in body weight up to 190 kg (418 lb) did not affect the response.^22-24

According to ACCP guidelines, an increase in LMWH by 25% should be considered for very obese patients (i.e., patients with a total body weight >190 kg .¹⁷ If anti-factor Xa monitoring is available, LMWH therapy in very obese patients should be dosed according to total body weight with dose adjustments based on anti-factor Xa levels. If anti-factor Xa monitoring is not available, LMWH therapy in very obese patients should be dosed according to total body weight; if bleeding occurs, doses should be reduced. In the case of KH, if LMWH therapy was chosen, dosing would be based on her total body weight of 82 kg (e.g., enoxaparin 82 mg s.c. every 12 hours) without anti-factor Xa monitoring.

Question 5

Approximately 10 days after KH began treatment with UFH 5000 units s.c. three times daily she developed left leg swelling (Figure 3) and discomfort. Her platelet count had decreased by 77% from baseline (Figure 4).

Figure 3. Swelling in KH’s Left Leg

Figure 4. Change in Platelet Count in KH.

Question 5

Which of the following scenarios is likely and tests should be ordered?

Screen 12

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse effect associated with heparin therapy that increases the risk for thrombosis.²⁵  The reaction is the result of heparin binding to platelet factor-4 (PF-4), a chemokine stored in platelet α-granules. Heparin-PF-4 complexes are antigenic and they bind to HIT antibodies, causing platelet activation and aggregation. HIT should be suspected in patients receiving heparin therapy and developing signs or symptoms of thrombus formation within 5-14 days after initiating heparin therapy (or earlier if heparin therapy has been used previously in the patient).²⁶  Ultrasonography of lower extremity veins is recommended for patients with strongly suspected (or confirmed) HIT.²⁵  Platelet count monitoring (for a reduction in platelet count by 50% or more) also is recommended to detect HIT.²⁵

Question 6

HIT and subsequent DVT are potentially serious consequences of heparin therapy. The most serious acute complication of DVT is PE. Long-term complications after DVT include recurrent DVT, post-thrombotic syndrome (persistent edema, pain, purpura, dermatitis, pruritus, cellulitis, and ulceration), and death.²⁷  HIT also is costly. In a retrospective analysis of medical patients receiving UFH or LMWH for VTE prophylaxis, the incidence of HIT was 0.51% and 0.084%, respectively, a difference that is significant.²⁸   Although the incidence of HIT is low with both UFH and LMWH, the average cost of a hospital admission in which HIT developed was significantly higher ($56,364) than that for a hospital admission not involving HIT ($15,231). A cost savings of $13.88 per patient was associated with the use of LMWH instead of UFH for VTE prophylaxis.

Simply stopping heparin therapy is an inadequate remedy in patients with HIT because the risk for thrombosis persists.²⁶  Heparin should be discontinued and a direct thrombin inhibitor (lepirudin, argatroban, or bivalirudin) should be initiated.²⁵  Warfarin should not be initiated until the platelet count returns to near normal because warfarin depletes protein C, a natural anticoagulant, resulting in a hypercoagulable state.²⁶   Skin necrosis and limb gangrene may develop if warfarin is initiated too early.²⁶ Warfarin loading doses should be avoided. Warfarin therapy should be initiated using a low maintenance dose (not to exceed 5 mg).²⁵

Question 6.

Which of the following is recommended for KH?

Screen 14

 Treatment with the direct thrombin inhibitor should be continued in KH until an international normalized ratio (INR) in the therapeutic range (2.0-3.0) is achieved with warfarin therapy, with an overlap of at least 5 days between the direct thrombin inhibitor and warfarin therapies.²⁹ Because this was KH’s first DVT incident and it was associated with a transient cause (HIT, acute medical illness, and prolonged bed rest), warfarin therapy should be continued for 3 months.¹⁷

KH responds to antibiotic therapy, and her shortness of breath, severe chest and abdominal pain, fever, and productive cough resolve. She is discharged from the hospital with recommendations to make appointments with her physician and at the laboratory and prescriptions for the following medications:

Discharge Medications

 Warfarin 5 mg orally once daily
Theophylline 200 mg orally twice daily
Montelukast 10 mg orally once daily
Ipratropium bromide four 17-mcg puffs by oral inhalation four times daily
Advair Diskus (fluticasone 250 mcg and salmeterol 50 mcg) by oral inhalation twice daily
Guaifenesin 1.2 g orally every 12 hours
Prednisone 50 mg orally once daily in the morning
Albuterol two 90-mcg inhalations as needed for exercise-induced bronchospasm, not to exceed 12 inhalations in a 24-hour period

Question 7

Question 7

Which of the following is the most effective approach for reducing the incidence of VTE in hospitalized patients like KH?

Review Question

 

Review Question

Which of the following statements about pharmacologic prophylaxis for VTE is correct?

Review Question

 Review Question

Which of the following interventions should be used for a patient at risk for VTE who has a bleeding disorder?

Screen 18

 

Patient Case

 
JL is a 58-year-old woman who arrives at the emergency department with a chief complaint of severe right leg pain. She reports recently returning from a lengthy vacation to Australia, but denies injury. Her past medical history includes hypertension for which she takes hydrochlorothiazide and osteoarthritis for which she takes acetaminophen.

Preadmission Medications

Hydrochlorothiazide 25 mg once daily
Acetaminophen 650 mg every 4-6 hours as needed for osteoarthritis pain

Screen 19

Social History

Married with one grown child
Consumes alcohol occasionally at social functions
No history of cigarette smoking
Employed as a flight attendant

Physical Examination

Temperature: 98.1°F
Heart rate: 100 beats per minute
Respiratory rate: 25-30 breaths per minute
Blood pressure: 135/80 mm Hg
Pulse oximetry: 99%
Height: 5’5”
Weight: 132 lb (60 kg)

Review of Systems

On physical examination, the patient’s right lower extremity is swollen from the ankle to the mid-thigh, with moderate discoloration and a palpable cord. She has no shortness of breath or chest pain.

Question 8

 Question 8

Leg ultrasonography is indicated for JL because her presentation is consistent with DVT.

Screen 21

 Ultrasonography reveals that JL has DVT of the right lower calf (Figure 5). According to ACCP, the primary therapy for acute DVT is anticoagulation to prevent thrombus extension and early and late recurrence of DVT and PE.²⁹  Long-term treatment in the chronic phase involves continuation of anticoagulation because the incidence of symptomatic thrombus extension or VTE recurrence in patients with DVT is 15% to 50% without such treatment.²⁹

At least 5 days of i.v. or s.c. UFH or s.c. LMWH are recommended by ACCP during the acute phase of VTE.^29,30 Warfarin should be initiated at the same time as UFH or LMWH, and it should be continued during the chronic phase, with a target INR of 2.0-3.0.²⁹ Once the INR is stable and it exceeds 2.0, UFH or LMWH therapy may be discontinued.

 

 

Figure 5. Lower Extremity Ultrasound Positive for DVT

Screen 22

 The use of LMWH for initial VTE treatment is recommended over UFH by ACCP, preferably on an outpatient basis or as an inpatient if necessary.²⁹ These recommendations are based on studies demonstrating that LMWH therapy at home is as safe and effective as UFH therapy in the hospital, and home LMWH therapy is associated with shorter hospital stays, lower costs, and better quality of life.²⁹

Question 9 - Screen 22

 

Question 9

LMWH and warfarin therapy are prescribed for JL. Which of the following is the minimum duration of LMWH therapy for JL?

Screen 23

 The recommended dosage of enoxaparin for the treatment of patients like JL who have acute DVT without PE is 1 mg/kg s.c. every 12 hours or 1.5 mg/kg s.c. every 24 hours.^19,31 A reduced dosage of 1 mg/kg s.c. once daily is recommended for patients with severe renal impairment (creatinine clearance <30 mL/min).³¹

Question 10 - Screen 23

 Which of the following enoxaparin dosage regimens could be used for JL who has normal renal function and weighs 60 kg?

Question 11 - Screen 24

 Question 11

If JL had severe renal impairment, which of the following enoxaparin dosage regimens could be used?

Question 12 - screen 25

 Question 12

When should JL begin warfarin therapy?

Screen 26

 According to ACCP guidelines, long-term treatment with warfarin for 3 months is recommended for patients with a first episode of DVT caused by a transient (reversible) risk factor.²⁹ Treatment for at least 6-12 months is recommended for patients with an idiopathic first DVT episode.

Question 13 - Screen 26

 Question 13

Which of the following is the appropriate duration of warfarin therapy for JL?

Screen 27

 Pharmacist-managed anticoagulation management services for hospital inpatients have been shown to significantly reduce deaths, bleeding complications, the need for blood transfusions, hospital length of stay, and costs.^33,34 A cost savings of $8 for every dollar invested in these services has been projected.³³

Question 14 - Screen 27

Question 14

Which of the following would be a likely impact of pharmacist-managed anticoagulation management services if JL received LMWH and warfarin therapy on an inpatient basis?

Screen 28

 Malignancy in patients with DVT significantly increases the risk of recurrent VTE and death compared with patients with DVT and no malignancy.³⁵ In the CLOT study of patients with cancer and acute, symptomatic proximal DVT, PE, or both, dalteparin alone for 6 months (200 IU/kg s.c. once daily for 1 month, followed by approximately 150 IU/kg s.c. once daily for 5 months) was significantly more effective than dalteparin 200 IU/kg s.c. once daily for 5-7 days plus a coumarin derivative for 6 months (with a target INR of 2.5) in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding.³⁶ The 6-month mortality rate did not differ significantly between the two treatment groups.

Long-term LMWH therapy is recommended by ACCP for at least the first 3-6 months in patients with cancer and VTE.²⁹ Anticoagulant therapy (i.e., warfarin) should be continued indefinitely or until the cancer resolves.²⁹

Question 15 - screen 28

 Question 15

If JL was found to have a malignancy when her DVT was diagnosed, what would be the minimum duration of her LMWH therapy?

Question 16 - Screen 29

 Question 16

If JL was found to have a malignancy when her DVT was diagnosed, what would be the minimum duration of her warfarin therapy?

Screen 30

 The ACCP guidelines do not reflect the results of recent clinical studies of fondaparinux. In a 3-month, non-inferiority study of patients with acute symptomatic DVT, single daily s.c. doses of fondaparinux (5.0 mg for patients weighing <50 kg, 7.5 mg for patients weighing 50-100 kg, and 10.0 mg for patients weighing >100 kg) were at least as effective and safe as enoxaparin 1 mg/kg s.c. twice daily for preventing symptomatic recurrent VTE complications.³⁰

Question 17 - Screen 30

 Question 17

Which of the following fondaparinux regimens could have been recommended instead of LMWH for JL who weighs 60 kg?

Screen 31

 Fondaparinux is contraindicated in patients with severe renal impairment.³⁷ It is eliminated primarily by the kidneys, and its elimination half-life is increased substantially by renal failure, which can lead to accumulation of anti-factor Xa activity and bleeding complications.

Question 18 - Screen 31

 Question 18

If JL had severe renal impairment (creatinine clearance <30 mL/min), which of the following fondaparinux regimens could have been recommended instead of LMWH for her (JL weighs 60 kg)?

Screen 32

JL’s husband is taught to administer the s.c. enoxaparin injections, and JL is discharged with prescriptions for enoxaparin, warfarin, and her preadmission medications for hypertension and osteoarthritis.

Appointments are scheduled for laboratory follow-up, with plans to discontinue the enoxaparin once the INR is stable and exceeds 2.0 (and enoxaparin has been given for at least 5 days).

Discharge Medications

 Hydrochlorothiazide 25 mg once daily
Acetaminophen 650 mg every 4-6 hours as needed for osteoarthritis pain
Enoxaparin 60 mg s.c. every 12 hours
Warfarin 5 mg once daily

References

Case Study Complete

This completes the case-study.  If you would like to see a print-friendly summary of the case study, please click here.  Reference are provided below.  Thank you for your participation!

References

1. 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; 151:933-8.

2. Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004; 126(3 suppl):338S-400S.

3. 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; 93:259-62.

4. Monreal M, Kakkar AK, Caprini JA et al. The outcome after treatment of venous thromboembolism is different in surgical and acutely ill medical patients. Findings from the RIETE registry. J Thromb Haemost. 2004; 2:1892-8.

5. Tapson VF, Decousus H, Bergmann JF et al. The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE): Venous Thromboembolism Prophylaxis Practices in Acutely Ill Medical Patients. Blood. 2004; 104:11. Abstract #1762. http://meeting.bloodjournal.org/cgi/content/abstract/104/11/1762?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=tapson&searchid=1&FIRSTINDEX=0&volume=104&issue=11&resourcetype=HWCIT (accessed 2007 Mar 20).

6. Aujesky D, Guignard E, Pannatier A et al. Pharmacological thromboembolic prophylaxis in a medical ward: room for improvement. J Gen Intern Med. 2002; 17:788-91.

 
7. Arnold DM, Kahn SR, Shrier I. Missed opportunities for prevention of venous thromboembolism: an evaluation of the use of thromboprophylaxis guidelines. Chest. 2001; 120:1964-71.

8. Dobesh PP, Stacy ZA. Effect of a clinical pharmacy education program on improvement in the quantity and quality of venous thromboembolism prophylaxis for medically ill patients. J Manag Care Pharm. 2005; 11:755-62.

9. Kucher N, Koo S, Quiroz R et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005; 352:969-77.

10. Labarere J, Bosson JL, Brion JP et al. Validation of a clinical guideline on prevention of venous thromboembolism in medical inpatients: a before-and-after study with systematic ultrasound examination. J Intern Med. 2004; 256:338-48

11. Tooher R, Middleton P, Pham C et al. A systematic review of strategies to improve prophylaxis for venous thromboembolism in hospitals. Ann Surg. 2005; 241:397-415.

12. Cohen AT, Alikhan R, Arcelus JI et al. Assessment of venous thromboembolism risk and the benefits of thromboprophylaxis in medical patients. Thromb Haemost. 2005; 94:750-9.

13. Samama MM, Cohen AT, Darmon JY et al. comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med. 1999; 341: