What are the current recommendations from the American College of Chest Physicians for thromboembolism prophylaxis in orthopedic surgery patients?

Introduction

The ninth edition of Antithrombotic Therapy and Prevention of Thrombosis: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines was released in February 2012, 4 years since the last update. The ACCP guidelines have been the cornerstone of antithrombotic therapy, providing extensive evidence-based recommendations for the treatment and prophylaxis of thromboembolic conditions affecting both venous and arterial systems since 1986. In this edition, the prevention of venous thromboembolism (VTE) in orthopedic patients has been separated out as its own section with more details and specific guidelines than previous editions.

The ninth edition is unique in that it includes the new antithrombotic agents such as the oral direct thrombin inhibitor (e.g., dabigatran) and oral direct factor Xa inhibitors (e.g., rivaroxaban and apixaban).1 Dabigatran is an oral direct thrombin inhibitor and is Food and Drug Administration (FDA)-approved for stroke prevention in atrial fibrillation.2 Although not FDA-approved, dabigatran has been studied in several trials for thromboembolism prophylaxis in patients undergoing total hip arthroscopy (THA) and total knee arthroscopy (TKA). Rivaroxaban is an oral direct factor Xa inhibitor approved for prevention of VTE after THA and TKA (10 mg daily) and for stroke prevention in atrial fibrillation (15 mg daily).3 Apixaban is also an oral direct factor Xa inhibitor, and although it has not yet been approved by the FDA, it has been approved in Europe for prevention of VTE after THA and TKA.1

The ACCP guidelines use the following grading system for the strength and evidence of the recommendations1:

• 1A: Strong recommendation, high-quality evidence; benefits clearly outweigh risk and burdens or vice versa
• 1B: Strong recommendation, moderate-quality evidence; benefits clearly outweigh risk and burdens or vice versa
• 1C: Strong recommendation, low- or very-low-quality evidence; benefits clearly outweigh risk and burdens or vice versa
• 2A: Weak recommendation, high-quality evidence; benefits closely balanced with risks and burden
• 2B: Weak recommendation, moderate-quality evidence; benefits closely balanced with risks and burden
• 2C: Weak recommendation, low- or very-low-quality evidence; uncertainty in the estimates of benefits, risks, and burden; benefits, risk, and burden may be closely balanced.

Orthopedic surgery and risk of thromboembolism

TKA and THA are becoming increasingly frequent procedures; for THA alone, there are 200,000 procedures done per year in the United States.1 THA and hip fracture surgery (HFS) have the highest risk of VTE among the orthopedic surgeries and although rare, there are still mortalities associated with VTE. The estimated rates of VTE without prophylaxis is 1.8% for symptomatic deep vein thrombosis (DVT) and 1% for pulmonary embolism (PE) during the first 7 to 14 days post-orthopedic surgery. The risk increases further after surgery, up to 4.3% at 35 days after orthopedic surgery with no prophylaxis. When incorporating the VTE occurrence up to 35 days, it is estimated that post-orthopedic surgery without prophylaxis, a patient would have a 2.8% risk of DVT and 1.5% risk of PE, for a total VTE risk of 4.3%.

Risk factors for VTE include previous VTE, cardiovascular disease, Charlson comorbidity index ≥3, a body mass index (BMI) >25 kg/m2 , every 5 years over age 40, advanced age ≥85 years, and varicose veins.1 A negative risk factor for VTE is ambulation before day 2 of surgery. It is to note that for major orthopedic surgery, the surgery-specific VTE risks far outweigh other risk factors mentioned. Known risk factors for bleeding include: previous major bleeding, severe renal failure, concomitant antiplatelet agent, and surgical factors (i.e., history of or difficult-to-control surgical bleeding, extensive surgical dissection, and revision surgery).

Recommendations 1

The recommendations for prophylaxis of VTE from the ninth edition of the ACCP guidelines are summarized below.

Major Orthopedic Surgeries:

• TKA/THA:
  • Antithrombotic prophylaxis for a minimum of 10 to 14 days is recommended compared to no prophylaxis: low molecular weight heparin (LMWH), fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose unfractionated heparin (LDUH), adjusted-dose vitamin K antagonist (VKA) (all Grade 1B), or an intermittent pneumatic device (IPCD) (Grade 1C).
  • Use of LMWH is preferred to the other agents recommended (Grade 2B/2C).
• HFS:
  • Antithrombotic prophylaxis for a minimum of 10 to 14 days is recommended compared to no prophylaxis: LMWH, fondaparinux, LDUH, adjusted-dose VKA, aspirin (all Grade 1B), or an intermittent pneumatic device (IPCD) (Grade 1C).
  • Use of LMWH in preferred to the other agents recommended (Grade 2B/2C).
• Apixaban or dabigatran (alternatively rivaroxaban or adjusted-dose VKA if apixaban or dabigatran are unavailable) are recommended as alternatives in patients unwilling to receive injections or an IPCS (all Grade 1B).
• In patients with increased risk of bleeding (see above), use of an IPCD or no prophylaxis rather than pharmacologic treatment is suggested (Grade 2C).
• Extending the thromboprophylaxis in the outpatient period for up to 35 days from the day of surgery rather than only 10 to 14 days is suggested (Grade 2B).
• Using dual prophylaxis with an antithrombotic agent and an IPCD during the hospital stay is recommended (Grade 2C).
• If receiving LMWH as thromboprophylaxis, recommend starting either 12 hours or more preoperatively or 12 hours or more postoperatively rather than within 4 hours or less preoperatively or 4 hours or less postoperatively (Grade 1B).
• The use of intravena cava (IVC) filter for primary prevention over no thromboprophylaxis in patients with an increased bleeding risk or contraindications to both pharmacologic and mechanical thromboprophylaxis is NOT recommended (Grade 2C).
• Comparison of agents:
  • LDUH vs LMWH: LMWH may reduce symptomatic VTE from 16 per 1,000 with LDUH to 13 per 1,000 without an increase in major bleeding.
  • VKA vs LMWH: LMWH resulted in 3 fewer events per 1,000 than VKA, but LMWH is associated with possible increase of 4 major bleeding events per 1,000. However, in extended prophylaxis data up to 6 weeks, almost 4 times as many major nonfatal bleeds were observed with VKA compared to LMWH.
  • Aspirin vs LMWH: Aspirin (325 mg twice daily and 650 mg twice daily) had more asymptomatic DVTs compared to LMWH. The rate of PE was too low for analysis and no major bleeding occurred in either group. However, indirect comparison of trials of LMWH and aspirin against placebo showed greater relative efficacy of LMWH.
  • Fondaparinux vs LMWH: No difference in reducing VTE events but fondaparinux may increase major bleeding events by 9 per 1,000. Caution with fondaparinux in patients weighing <50 kg and elderly and frail patients due to increased bleeding.
  • Rivaroxaban vs LMWH: Rivaroxaban (10 mg/day) resulted in 5 fewer symptomatic DVT per 1,000 over LMWH but with 9 more major bleeding events. Rivaroxaban lacks long-term safety data and has not been evaluated in HFS.
  • Rivaroxaban vs placebo for extended prophylaxis: Rivaroxaban or LMWH were administered for 12 days with rivaroxaban continued for additional 22 days vs placebo. The rivaroxaban group had 12 fewer per 1,000 symptomatic VTEs, but there exists uncertainty about major bleeding rates due to the definition of major bleeding in the study. The benefits may be offset by higher bleeding rate of rivaroxaban compared with placebo.
  • Dabigatran vs LMWH: No differences between LMWH and dabigatran 220 mg twice daily were seen for symptomatic VTEs or major bleeding events. Dabigatran 150 mg twice daily resulted in 2 additional symptomatic VTE events per 1,000, but was offset by 4 additional major bleeding events per 1,000 when compared to LMWH group. Overall, dabigatran is similar to LMWH in efficacy and bleeding risks, but long-term experience with LMWH favors its use.
  • Apixaban vs LMWH: Apixaban (2.5 mg twice daily) resulted in 7 fewer symptomatic DVT per 1,000 over LMWH without increase in risk of major bleeding, but no differences were seen in VTE risks when all nonfatal and fatal VTEs were combined. As apixaban lacks long-term experience, LMWH is still the agent of choice. Apixaban has not been evaluated in HFS.

Table. Summary of recommendations.1

Abbreviations: DUS, Doppler ultrasound screening; IPCD, intermittent pneumatic device; IVC, intravena cava; LDUH, low-dose unfractionated heparin; LMWH, low molecular weight heparin; THA, total hip arthroscopy; TKA, total knee arthroscopy; VKA, vitamin K antagonist.

Summary

In comparing the pharmacologic and mechanical interventions for major orthopedic surgeries, the agent with similar or superior properties with little risk of bleeding and extensive clinical experience is LMWH. Extending the duration of thromboprophylaxis from 10 to 14 days to up to 35 days had additional reductions in the risk of VTE with a similar safety profile. In the case that LMWH is not available or cannot be used (e.g., for heparin-induced thrombocytopenia), reasonable alternatives include apixaban, dabigatran, rivaroxaban, VKA, fondaparinux, IPCD, or ICPD in combination with low-dose aspirin. Choice of an alternative is based on several factors, including relative effectiveness, risk of bleeding, and issues that may interfere with adherence.

References

1. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e278S-e325S.

2. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2012

3. Xarelto [package insert]. Guarbo, Puerto Rico: Janssen Pharmaceuticals, Inc.; 2011.

Written by: Yun Jeong Lee, PharmD
                  PGY1 Pharmacy Practice Resident

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Which drugs have been associated with causing thrombocytopenia?

Introduction

Drug-induced thrombocytopenia (DITP) has been reported with a number of medications.1-3 Data suggest that DITP occurs in 10 out of 1 million people each year. The incidence may actually be higher in the elderly or hospitalized patients. DITP is usually seen within 1 to 2 weeks after starting a new medication and presents as a sudden drop in platelets, often as low as <20,000/microL. Patients may exhibit bleeding from the nose and gums, or gastrointestinal or urinary tract. In rare cases, bleeding can be fatal.

Mechanism of action

Drugs associated with thrombocytopenia usually accelerate platelet destruction through drug-dependant antibodies.1,2 There are multiple mechanisms that these drugs can bind to platelets and cause DITP. Table 1 describes these various mechanisms.

Table 1. Mechanisms of drug-induced thrombocytopenia.1,2

Abbreviations:Fab=Fragment antigen binding, Fc=fragment crystallizable region

DITP should be suspected in any case of acute thrombocytopenia with no specific identified cause. When evaluating a patient for DITP, it is important to obtain a complete medication history to determine the causative agent.1,2 The pharmacist should question the patient specifically about quinine, sulfonamides, herbal products, and non-prescription drug use. Patients generally must be exposed to the drug for 5 to 7 days to produce sensitization in a first exposure so understanding the time course of medication exposure is critical.

Drugs that cause DITP

Table 2 provides a summary of the most common agents that have been reported to cause DITP, although over 100 drugs have been linked to DITP. 1 In addition to drugs causing thrombocytopenia there are reports of herbal remedies and food causing this condition. Quinine from tonic water has been associated with thrombocytopenia as well as some Chinese herbal teas containing jui.

Table 2. Medications that cause thrombocytopenia 1,2,4,5

Treatment

Other than discontinuation of the drug, additional treatment for DITP is usually not required.1-3 In most cases, platelet counts return to normal levels within 5 to 7 days of discontinuing the causative agent. In some cases of severe bleeding or platelet counts <10,000/microL, platelet transfusions may be required. Patients should be counseled to avoid any further exposure to the medication associated with the thrombocytopenia.

References

1. Aster RH, Boougie DW. Drug-induced thrombocytopenia. N Engl J Med 2007;357(6):580-587.

2. Kenney B, Stack G. Drug-induced thrombocytopenia. Arch Pathol Lab Med. 2009;133(2):309-314.

3. Aster RH, Curtis BR, McFarland JG, Bougie DW. Drug-induced immune thrombocytopenia: Pathogenesis, diagnosis and management. J Thromb Haemost. 2009;7(6):911-918.

4. George JN, Aster RH. Drug-induced thrombocytopenia:pathogenesis, evaluation, and management. Hematology. ASH Education Book. 2009; 2009(1):153-158.

5. George JN. Drug-induced thrombocytopenia. In: UpToDate, Basow DS (Ed), UpToDate, Waltham, MA. 2012.

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What are the new drug interaction dosing recommendations for statins?

Introduction

In recent months, the Food and Drug Administration (FDA) has released numerous safety alerts regarding new drug interaction data for statins. 1-4 Some alerts have focused specifically on simvastatin and lovastatin1-3 and another resulted in updates to product labeling of most statins to reflect new data for interactions between statins and hepatitis C or human immunodeficiency virus (HIV) protease inhibitors. 4 A review of this new drug interaction data is presented in this article.

Simvastatin update

In June 2011, the FDA announced new dosage restrictions for simvastatin along with additional contraindications concerning use of the drug with certain other medications or above certain doses with other drugs.1In terms of new drug interactions, the FDA noted that the risk of myopathy is higher when simvastatin is administered with certain agents. Specifically, simvastatin is a cytochrome (CYP) 450 3A4 substrate, and strong CYP3A4 inhibitors are predicted to significantly increase simvastatin exposure. Because of this interaction, the agency stated that simvastatin should never be used with posaconazole and 3 drugs were moved from a "do not exceed simvastatin 10 mg" category to an absolute contraindication (gemfibrozil, cyclosporine, and danazol).1 In addition, dosing limits for simvastain were lowered for amiodaraone, verapamil, and diltiazem (to a maximum of simvastatin 10 mg daily) and added for amlodipine and ranolazine (to a maximum of simvastatin 20 mg daily).

However, in December of 2011, the dose limitation for simvastatin was increased from 10 mg back to 20 mg when coadministered with amiodarone. 2 This change was a result of the FDA noting that unlike other interacting drugs, there were no pharmacokinetic or clinical trial data to support the simvastatin dose reduction to 10 mg when used with amiodarone. Based on this assessment, the agency determined that the simvastatin dose limitation, when taken with amiodarone, should be restored to 20 mg. The new simvastatin dosing considerations are summarized in Table 1.1,2

Table 1. Simvastatin dosing considerations. 1,2

Abbreviations: HIV, human immunodeficiency virus.

Lovastatin update

In February 2012, the label for lovastatin was updated as a result of the June 2011 label revisions to simvastatin-containing products because of the physicochemical and pharmacokinetic similarities between lovastatin and simvastatin.3 As with simvastatin, lovastatin is also a CYP3A4 substrate and strong CYP3A4 inhibitors are predicted to significantly increase lovastatin exposure. Based on this prediction, the FDA updated the lovastatin labeling with changes similar to those observed for simvastatin; these changes are summarized in Table 2.

Table 2. Lovastatin dosing considerations. 3

Abbreviations: HIV, human immunodeficiency virus.

Class labeling changes

Finally, in March 2012, the FDA released new recommendations for avoiding drug interactions with statins and HIV or hepatitis C protease inhibitors. 4 When taken together, protease inhibitors can raise blood levels of statins and place patients at an increased risk for myopathy. The agency reported that the labels for protease inhibitors and the affected statins have been updated to contain consistent information, including dosing recommendations, about these drug-drug interactions.

The FDA cautioned that lovastatin or simvastatin should never be taken with HIV and hepatitis C protease inhibitors (as reflected in Tables 1 and 2 above) and that atorvastatin and rosuvastatin doses should be limited.4 No dosage adjustments are needed if protease inhibitors are coadministered with pravastatin or pitavastatin. There are no data for fluvastatin. A summary of the label changes related to this FDA alert are presented in Table 3.

Table 3. Statin dosing considerations. 4

Abbreviations: HIV, human immunodeficiency virus.

Summary

Clinicians should be familiar with these revised dosing recommendations for statins, so as to minimize the risk of myopathy in patients receiving concomitant interacting agents. If patients must receive an interacting drug, consider switching to a statin with less potential for drug-drug interactions such as pitavastatin or pravastatin. In addition, keep in mind the revised dosing limitations for simvastatin and lovastatin when using these drugs with agents that interact with the CYP3A4 pathway.

References

1. FDA drug safety communication: new restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. U.S. Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm. Accessed March 27, 2012.

2. FDA drug safety communication: revised dose limitation for Zocor (simvastatin) when taken with amiodarone. U.S. Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm283137.htm. Accessed March 27, 2012.

3. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. U.S. Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. Accessed March 27, 2012.

4. FDA drug safety communication: interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. U.S. Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm. Accessed March 27, 2012.

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