Management of Thromboembolic Disorders

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 special considerations in 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.

Antiplatelet efficacy for thrombosis prevention is known by these agents to inhibit pathways involved in platelet activation and aggregation. It is a challenge to balance these very effective agents and prevent complication of bleeding.³ Recommendations and grading in regard to anti-platelet therapy include:

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 metabolization 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 arthroplasty, 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

AACP 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

Thrombophilia and Pregnancy
Utilization of anticoagulation to prevent pregnancy complication is becoming more frequent in patients with hereditary thrombophilia. Combination therapy with aspirin also is used for the prevention of recurrent pregnancy loss in women with antiphospholipid antibodies. Treating pregnant patients with anticoagulation is challenging because of both maternal and fetal complications.⁶

Consideration must be given to the frequency, type of administration, side effects and risks and benefits of therapy in pregnancy. Harmful effects, including maternal bleeding, congenital malformations and burden of treatment, must be compared with the benefits of avoiding VTE or pregnancy loss.⁶

Directives in the AACP document include:

• "For women receiving anticoagulation for the treatment of VTE who become pregnant, we recommend LMWH over vitamin K antagonists during the first trimester (Grade 1A), in the second and third trimesters (Grade 1B), and during late pregnancy when delivery is imminent (Grade 1A)."⁶
• "For pregnant women with no prior history of VTE who are known to be homozygous for factor V Leiden or the prothrombin 20210A mutation and who do not have a positive family history for VTE, we suggest antepartum clinical vigilance and postpartum prophylaxis for 6 weeks with prophylactic- or intermediate dose LMWH or vitamin K antagonists targeted at INR 2.0 to 3.0 rather than routine care (Grade 2B)."⁵
• "For women with two or more miscarriages but without APLA or thrombophilia, we recommend against antithrombotic prophylaxis (Grade 1B)."⁵
• "For lactating women using LMWH, danaparoid, or r-hirudin who wish to breast-feed, we recommend continuing the use of LMWH, danaparoid, or r-hirudin (Grade 1B). "

New Antithrombotic Drugs
New antithrombotic drugs have been developed to provide better therapeutics without the limitations of existing anticoagulants. Most advances have occurred in the area of antiplatelet drugs and anticoagulants. Advances in fibrinolytic drugs have lagged.⁷

Antiplatelet agents include targets of thromboxane A2, ADP or thrombin receptors on platelets. ADP receptor antagonists, like clopidogrel, target P2Y 12, whereas the thrombin receptor antagonists target PAR-1.⁷

The mechanism of anticoagulation can be achieved by several routes. Initiation is blocked by drugs that target the tissue factor/factor VIIa complex. Propagation of coagulation is blocked by drugs that inhibit factor IXa or factor Xa, or their cofactors, factor VIIIa and factor Va. Other anticoagulants that target thrombin attenuate fibrin generation. These can be further subclassified as direct or indirect inhibitors. Direct inhibitors bind directly to the target enzyme and block substrate interactions, while indirect inhibitors bind to naturally occurring plasma cofactors, such as antithrombin or heparin cofactor II, accelerating their interaction with clotting enzymes.⁷

A better understanding of fibrinolysis has led to the development of new agents. This includes methods to enhance endogenous fibrinolysis that include inhibitors of type 1 plasminogen activator (PAI-1), urokinase plasminogen activator (u-PA), TAFIa, or activated factor XIII (factor XIIIa). New fibrinolytic agents include alfi meprase, V10153, plasmin and desmoteplase.⁷

Innovations in ACCP's 9th Edition of 'Antithrombotic Therapy and Prevention of Thrombosis'
ACCP guidelines contain evidence-based information that has been graded to enhance the quality and relevance of recommendations. Major innovations include:

1. Unconflicted methodologists as topic editors. Conflicted experts did not participate in final process of making recommendations.
2. Many evidence profile and summary of finding tables.
3. New insights into evidence (asymptomatic thrombosis, aspirin).
4. Quantitative specification of values and preferences based on systematic review of relevant evidence and formal preference rating exercise.
5. Article addressing diagnosis of DVT.¹

Donna D. Castellone is clinical science manager, Roche Diagnostics.

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 edChest 2012;141;e44S-e88S.
6. Prabulos, A, Vandvik, PO., Bates, SM., Greer, IA.,,Middeldorp,S., Veenstra, DL., VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest 2012;141;e691S-e736S
7. Weitz, JI., Eikelboom , JW., Samama., MM New Antithrombotic Drugs Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest 2012;141;e120S-e151S