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(Editor's Note: This is the first part of a two-part series. Visit our website next week for part 2)

The American College of Chest Physicians (ACCP) is the world's largest clinical cardiopulmonary and critical care medical society with more than 17,000 members. Based on results of clinical trials and the information they provide, ACCP has developed recommendations on the management of thromboembolic disorders. These evidence-based clinical practice guidelines include more than 600 recommendations for the prevention, diagnosis and treatment of thrombosis. The ninth edition of "Antithrombotic Therapy and Prevention of Thrombosis" addresses several clinical conditions-cardiovascular disease, atrial fibrillation, stroke, pregnancy, surgery and neonates and children.¹

The ACCP guideline uses a grading approach that requires the distinction between patient-important and surrogate outcomes.¹ This system classifies recommendations as strong (grade 1) or weak (grade 2) based on the estimates of risks, benefits and burdens. The quality of the evidence is then graded as high (grade A), moderate (grade B) or low (grade C), based on the strength of study design, consistency of result and directness of the evidence.²

Anti-Platelet Drugs
The ACCP guideline highlights the practical aspects of anti-platelet therapy, including optimum dosing and the risk/benefits of individual versus dual antiplatelet therapy in clinical settings, which is the result of randomized clinical trials. However, it does not provide specific management recommendations. The document discusses aspirin, dipyridamole, cilostazol, the thienopyridines and the glycoprotein IIb/IIIa antagonists in relation to the mechanisms of action, pharmacokinetics and pharmacodynamics.

1. "For lactating women using low-dose aspirin for vascular indications who wish to breast feed, we suggest continuing this medication (Grade 2C)."⁴
2. "We suggest that when aspirin is used for antiplatelet therapy in children, it is used in doses of 1 to 5 mg/kg per day (Grade 2C)."⁴
3. "In patients with a coronary stent who are receiving dual antiplatelet therapy and require surgery, we recommend deferring surgery for at least 6 weeks after placement of a bare-metal stent and for at least 6 months after placement of a drug-eluting stent instead of undertaking surgery within these time periods (Grade 1C)."⁴
4. "For patients with AF, including those with paroxysmal AF, who are at intermediate risk of stroke (e.g., CHADS2 score = 1), we recommend oral anticoagulation rather than no therapy (Grade 1B). We suggest oral anticoagulation rather than aspirin (75 mg to 325 mg once daily) (Grade 2B) or combination therapy with aspirin and clopidogrel (Grade 2B)."⁴

Oral Anticoagulant Therapy
The only available oral anticoagulant therapy for many decades has been the vitamin K antagonists (VKA). Much evidence is available on their efficacy in clinical settings. Recently introduced to the market are the new oral anticoagulant drugs-dabigatran, which is a direct thrombin inhibitor, and rivaroxaban, a direct Xa inhibitor.

Issues with the VKA include polymorphisms of the CYP2C9 gene that impact metabolize and drug-drug interactions. The Prothrombin Time (PT) is used to monitor VKA therapy based on vitamin K dependent (II, VII, IX, X) factor half-lives. In the attempt to standardize this test, the International Normalized Ratio (INR) based on the sensitivity of reagents (ISI) was developed. The College of American Pathologists recommends that labs use thromboplastin reagents that are at least moderately responsive (ISI 1.7) and reagent/instrument combinations for which the ISI has been established.⁵

Dabigatran is a prodrug that has been evaluated for the prevention of VTE in elective total knee or hip arthroplastic, in stroke prevention, or systemic embolism in nonvalvular atrial fibrillation (AF). In a double-blind study, dosing regimens of 110 mg and 150 mg were compared to warfarin (target INR, 2.0-3.0) in the RE-LY trial. Results demonstrated patients on warfarin were in their target range 64% of the time. The dose of dabigatran was directly related to its efficacy and bleeding risk, which was higher at 150 mg. Dabigatran had a reduced frequency of hemorrhagic stroke when compared with warfarin.⁵

Rivaroxaban is approved for the prevention of VTE in patients undergoing total hip or knee replacement surgery and is undergoing extensive clinical studies for the prevention of acute ischemic stroke in patients with AF. It has been found to be more effective than the low molecular weight heparin (LMWH) enoxaparin in preventing VTE after total hip or knee replacement surgery.⁵

Recommendations and grading from the oral anticoagulant guidelines are:

• "For patients sufficiently healthy to be treated as outpatients, we suggest initiating VKA therapy with warfarin 10 mg daily for the first 2 days followed by dosing based on international normalized ratio (INR) measurements rather than starting with the estimated maintenance dose (Grade 2C)."³
• "For patients initiating VKA therapy, we recommend against the routine use of pharmacogenetic testing for guiding doses of VKA (Grade 1B)."³
• "For patients taking VKAs with previously stable therapeutic INRs who present with a single out-of-range INR of 0.5 below or above therapeutic, we suggest continuing the current dose and testing the INR within 1 to 2 weeks (Grade 2C)."³
• "For patients treated with VKAs, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) rather than a lower (INR , 2) or higher (INR 3.0-5.0) range (Grade 1B)."³

References

1. D. Gutterman., D. Zelman Lewis, S., Guyatt, GH., Akl, EA., Crowther, M, Schünemann, HJ., Guttermann, DD, Introduction to the Ninth Edition: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest 2012;141; 48S-52S
2. Gordon, G., Gutterman, D., Baumann, MH., Addrizo-Harris, D., Hylek, EM., Philips, B., Raskob, G., Lewis, SZ., Hshuemann, H., Grading Strength of Recommendations and Quality of Evidence in Clinical Guidelines, Chest, 129: 2006, 1174-181.
3. Eikelboom , JW., Hirsh, J., Spencer, FA, Baglin , TP ,Weitz, J , Antiplatelet Drugs Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, CHEST 2012; 141(2)(Suppl):e89S-e119S
4. Guyatt,GH, Akl, EA, Crowther, M., Gutterman, DD., Schuünemann, HJ., Executive Summary : AntithromboticTherapy and Prevention of Thrombosis, 9th Clinical Practice Guidelines ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest 2012;141;7S-47S
5. Hylek, EM, Palareti, G., Ageno, W., Gallus, AS, Wittkowsky,A, Crowther, M., Oral Anticoagulant Therapy: Antithrombotic Evidence-Based Clinical Practice Guidelines: American College of Chest Physicians Therapy and Prevention of Thrombosis, 9th ed Chest 2012;141;e44S-e88S.