New Guidelines for Antithrombotic Therapy
Highlights from the 7^th ACCP Conference on Antithrombotic and Thrombolytic Therapy

Holger J. Schunemann, M.D., Ph.D., and Jack Hirsh, M.D., FCCP

Dr. Schunemann is Associate Professor of Medicine and Social and Preventive Medicine at the University of Buffalo at New York and of Clinical Epidemiology and Biostatistics at McMaster University, Hamilton, Canada.

Dr. Hirsh is Professor Emeritus of Medicine at Henderson Research Centre, McMaster University, Hamilton, Canada.

Introduction

In September 2004, the American College of Chest Physicians (ACCP) published the proceedings of the "Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines." The proceedings of the ACCP Consensus Conference provide an extensive critical review of the literature related to management of thromboembolic disorders, including venous thromboembolism, arterial thrombosis, and systemic arterial embolism. It includes chapters on thrombosis in pregnancy and on pediatric thrombosis. Each section concludes with a detailed summary that not only documents the therapeutic recommendations but also assigns a grade for each recommendation.

Clinical thrombosis has come a long way since the first publication of the guidelines in 1986. The number of antithrombotic agents available to the clinician has trebled, the rigor with which they are evaluated has improved dramatically, and the ACCP grading system for making recommendations has been refined. Rigorous studies in most fields have resulted in new and strong evidence-based recommendations. This article describes new developments since the previous ACCP guidelines, published in 2001. The guideline panel introduced major changes to strengthen the methodology used for the literature search.¹ The search process is now more comprehensive, transparent, and explicit. Since the 2001 publication, the grading system has been refined further.²

The recommendation to use (or not use) a particular treatment is based on the trade-off between benefits on the one hand and risks and/or costs on the other. If, after weighing all of the evidence, experts are very certain that benefits do, or do not, outweigh risks, burden, and costs, they make a strong recommendation -- in our formulation, Grade 1. If they are less certain of the magnitude of the benefits and risks, burden, and costs, and thus their relative impact, they make a weaker Grade 2 recommendation.

The grading system also provides information about the underlying quality of the evidence. There are four methodologic grades: A, B, C, and C+. Consistent results from randomized clinical trials (RCTs) generate Grade A recommendations, observational studies with very strong effects or secure generalization from RCTs Grade C+, inconsistent results from RCTs Grade B, and observational studies Grade C. The panel now downgrades recommendations from A to B for recommendations in favor of treatments that carry more risk, inconvenience, and cost than the alternatives if sample size is small or event rates are low. Specifically, if the results are not statistically significant (two-tailed p-value greater than 0.05) or if addition of a small number of adverse events to the treatment arm would render a result non-significant. A Grade 1 recommendation is downgraded to a Grade 2 if the downsides of treatment as reflected in toxicity, inconvenience, or costs are such that many people would consider that the benefits of the treatment are offset by the downsides. In addition, the conference has adopted a terminology expressing the strength of the recommendation. We now use the terms "we recommend" for strong recommendations (Grade 1A, 1C+, 1B, 1C) and "we
suggest" for weaker recommendations (2A, 2C+, 2B, 2C). A novelty is the explicit description of values and preferences that underlie specific recommendations. When tradeoffs between benefits and risks are less clear, individual patient values may influence treatment decisions even among patients with average or typical preferences. For example, in considering the duration of anticoagulation after an episode of idiopathic deep venous thrombosis, patients may make different choices depending on the relative value they place on avoiding a fatal pulmonary embolus, on avoiding bleeding, and on the inconvenience and worry associated with repeated testing to determine the intensity of anticoagulation.

Highlights of the Developments Since Publication of the 6th ACCP Antithrombotic Therapy Conference

Heparin and Its Mechanisms of Actions

Although low molecular weight heparins (LMWHs) have several advantages over unfractionated heparin, dose-finding trials are lacking in special populations, such as patients with renal failure. If enoxaparin is chosen for thromboprophylaxis in a patient with renal failure, the 40 mg daily dose seems preferable to the 30 mg twice daily dose.

Pharmacology & Management of the Vitamin K Antagonists (VKA)

Several recommendations regarding the appropriate dose for initiation of oral anticoagulants changed from the previous conference.³ These include: (1) Initiation of oral anticoagulation with doses between 5 mg and 10 mg for the first one or two days for most individuals, with subsequent dosing based on the INR response (Grade 2B). In the elderly, patients who are debilitated, malnourished, have congestive heart failure, or have liver disease, the panel suggests use of a starting dose below 5 mg (Grade 2C); and (2) for patients with a lupus inhibitor who have no additional risk factors and no failure of therapy, the panel suggests maintenance of a therapeutic target INR of 2.5 (range of 2.0 - 3.0) over higher intensity anticoagulation (Grade 2B).

New Anticoagulants

One of the most notable new developments is ximelegatran, the first available oral direct thrombin inhibitor.⁴ A prodrug of the active site-directed thrombin inhibitor melagatran, ximelagatran undergoes rapid biotransformation to the active compound melagatran after it is absorbed. Ximelagatran is administered orally in twice-daily dosing. Coagulation monitoring is not required because ximelagatran produces a very predictable anticoagulant response. Although the ACCP guidelines do not yet include specific recommendations for or against the use of ximelegatran, they review the results of the randomized trials in patients with knee and hip arthroplasty, ST-elevation or non-ST-elevation MI, in DVT, and in atrial fibrillation. The studies suggest a promising role of ximelagatran for several indications. The most important known side effect of ximelagatran is elevation of liver enzymes.

Heparin-Induced Thrombocytopenia

The guidelines now dedicate an entire chapter to the pronlem of heparin-induced thrombocytopenia (HIT).⁵ Monitoring, prevention, treatment, and diagnosis of HIT are discussed.

Prevention of Venous Thromboembolism (VTE)

For the first time, the ACCP guidelines make specific recommendations for long distance travelers (flights longer than six hours).⁶ These recommendations are generally based on lower quality evidence. The panel recommends avoidance of constrictive clothing around the lower extremities or waist, avoiding dehydration, and frequent calf muscle stretching (Grade 1C). If active prophylaxis is considered because of perceived increased risk of venous thrombosis, the guideline panel suggests pre-flight, properly-fitted, below-knee graduated compression stockings, providing 15-30 mm Hg of pressure at the ankle (Grade 2B), or a single prophylactic dose of LMWH, injected prior to departure (Grade 2B). The panel recommends against the use of aspirin for VTE prevention associated with travel (Grade 1B).

In orthopedic patients, several randomized controlled studies have investigated the efficacy of fondaparinux, a new selective Factor Xa inhibitor. The panel now recommends one of three anticoagulants: LMWH, fondaparinux, or adjusted-dose warfarin or other vitamin K antagonist (all Grade 1A). For patients undergoing hip fracture surgery, they recommend the routine use of fondaparinux (Grade 1A), LMWH (Grade 1C+), warfarin or other VKA (Grade 2B), or low dose unfractionated heparin (Grade 1B).

New recommendations are discussed for patients undergoing knee arthroscopy. The panel suggests clinicians do not use routine thromboprophylaxis in these patients, other than early mobilization (Grade 2B), because the evidence does not indicate clear benefit from routine prophylaxis in these patients. Only for patients who are at higher than usual risk, based on pre-existing VTE risk factors or following a prolonged or complicated knee arthroscopy, the panel suggest thromboprophylaxis with LMWH (Grade 2B).

Antithrombotic Therapy for Venous Thromboembolic Disease

Numerous new recommendations are available for patients with venous thromboembolic disease.⁷ The main new recommendations concern the duration and type of anticoagulation for DVT and PE.
The new key recommendations are:

• Patients with first-episode idiopathic DVT should be considered for indefinite anticoagulant therapy (Grade 2A).
• The dose of warfarin or other VKA should be adjusted to maintain a target INR of 2.5 (INR range 2.0 and 3.0) for all treatment durations (Grade 1A).
• The panel recommends against high-intensity warfarin or other VKA therapy (INR range 3.1 to 4.0) (Grade 1A) and against low-intensity therapy (INR range 1.5 to 1.9) compared to INR range of 2.0 to 3.0 (Grade 1A).
• In patients with acute DVT, subcutaneously administered unfractionated heparin (UFH) can be used as an adequate alternative to intravenous unfractionated heparin (UFH) (Grade 1A).
• In patients with acute DVT treated with LMWH, the panel recommends against routine monitoring with antifactor Xa level measurements (Grade 1A).
• In patients with DVT, the panel recommends against the routine use of intravenous thrombolytic treatment (Grade 1A). However, in selected patients such as those with massive ileo-femoral DVT at risk of limb gangrene secondary to venous occlusion, the panel suggest intravenous thrombolysis (Grade 2C).
• For patients with objectively confirmed non-massive PE, acute treatment with subcutaneous LMWH or intravenous unfractionated heparin (UFH) is recommended (both Grade 1A).

Atrial Fibrillation (AF)

The new developments include a recommendation for therapy with aspirin at 325 mg per day in patients with persistent or paroxysmal AF under age 65 years and with no other risk factors (Grade 1B).⁸

Valvular Heart Disease

There are no important changes to the recommendations regarding valvular disease and valve replacement.⁹ As described in the introduction, randomized controlled trials are few and far between.

Stroke

The recommendations regarding the use of antiplatelet agents in ischemic stroke have changed. In patients who have experienced a non-cardioembolic stroke or transient ischemic attack (TIA), the panel recommends treatment with an antiplatelet agent¹⁰ (Grade 1A) for the prevention of recurrent cardiovascular events. Aspirin at a dose of 50-325 daily, the combination of aspirin, 25 mg, and extended-release dipyridamole, 200 mg twice daily, or clopidogrel (75 daily) are all acceptable options for initial therapy. In patients receiving aspirin who are at moderate-to-high risk of gastrointestinal bleeding complications, the panel recommends using low doses of aspirin, i.e. 50 to 100 mg daily (Grade 1C+). The panel suggests the use of the combination of aspirin and extended-release dipyridamole (25/200 mg twice daily) over aspirin (Grade 2A), and clopidogrel over aspirin (Grade 2B) for patients who have experienced a non-cardioembolic stroke or TIA. For most patients with non-cardioembolic stroke or TIA, the panel recommends antiplatelet agents over oral anticoagulation (Grade 1A). However, in patients with well documented pro-thrombotic disorders, the panel suggests oral anticoagulation over antiplatelet agents (Grade 2C).

Coronary Artery Disease, Coronary Thrombolysis, and Percutaneous Coronary Intervention (PCI)

In patients with non-ST-elevation acute coronary syndrome (NSTE ACS), if diagnostic catheterization will be delayed or when coronary bypass surgery will not occur until > five days, the panel recommends clopidogrel as bolus therapy (300 mg), followed by 75 mg daily for nine-12 months in addition to aspirin (Grade 1A).¹¹ In NSTE ACS patients in whom angiography will take place within 24 hours, the panel suggests beginning clopidogrel after coronary anatomy has been determined (Grade 2A). For patients who have received clopidogrel and are scheduled for coronary bypass surgery, it recommends discontinuing clopidogrel for five days prior to the scheduled surgery (Grade 2A).

In health care settings where pre-hospital administration of fibrinolytic therapy is feasible and primary angioplasty is not available, the panel recommends pre-hospital administration of fibrinolytic therapy only (Grade 1A).¹²

For long-term treatment after PCI in patients who receive antithrombotic agents such as clopidogrel or warfarin, the panel recommends lower-dose aspirin (75 to 100 mg daily) (Grade 1C+).¹³ In patients with low atherosclerotic risk, such as those with isolated coronary lesions, the panel recommends clopidogrel for at least two weeks after placement of a bare metal stent (Grade 1A), for two to three months after placement of a sirolimus-eluting stent (Grade 1C+), and six months after placement of a paclitaxel-eluting stent (Grade 1C).

Saphenous Vein and Internal Mammary Artery Bypass Grafts

The guideline panel now recommends for patients undergoing CABG for NSTE ACS clopidogrel at 75 mg daily for nine - 12 months following the procedure in addition to treatment with aspirin (Grade 1A).¹⁴ For patients undergoing CABG who have no other indication for warfarin or other VKA, the panel suggests clinicians not administer warfarin or other VKA(Grade 2B).

Peripheral Arterial Occlusive Disease

For patients with disabling intermittent claudication who do not respond to conservative measures and who are not candidates for surgical or catheter-based intervention, the panel suggests cilostazol (Grade 2A).¹⁵ The panel suggests that clinicians not use cilostazol in patients with less disabling claudication (Grade 2A).

Pregnancy

Few additional studies have been published for treatment of thrombotic disease in pregnant women.¹⁶ The guideline panel makes a stronger recommendation that women with acute VTE be treated with either adjusted-dose LMWH throughout pregnancy or IV unfractionated heparin (bolus followed by a continuous infusion to maintain the aPTT in the therapeutic range) for at least five days, followed by adjusted-dose unfractionated heparin or LMWH for the remainder of the pregnancy (Grade 1C+). Anticoagulants should be given for at least six weeks postpartum.

Pediatric Patients

The sparseness of studies providing evidence for recommendations in pediatric patients remains striking. The few available high quality studies deal with catheterization and Kawasaki's disease. For prophylaxis during cardiac catheterization, there is a recommendation against aspirin therapy (Grade 1B).¹⁷ For neonates and children with peripheral arterial catheters in situ, the panel recommends low-dose heparin through the catheter, preferably by continuous infusion, (Grade 1A). In children with Kawasaki's disease, the panel recommends aspirin in high doses initially (80 to 100 mg/kg/d during the acute phase, up to 14 days) and then in lower doses (3 to 5 mg/kg/d for seven weeks or longer) (Grade 1C+) as well as IV gamma globulin within ten days of onset of symptoms (Grade 1A).¹⁸

General considerations

While conference participants recognized that recommendations should reflect economic considerations, for most recommendations formal economic analyses were unavailable. Even when analyses were available, they often were methodologically weak or biased. In addition, costs differ dramatically across jurisdictions (sometimes even across hospitals within jurisdictions). For example, cost for LMWH are high in the United States, but low in most European countries. Thus, in instances when small benefits accrue to patients from use of LMWH in comparison to unfractionated heparin, the choice in favor of LMWH may be clear in Europe, but much less clear in North America. These considerations are again reflected in the values and preference statements.¹⁹ The ACCP is establishing a task force to develop strategies for optimal integration of cost data in future guidelines.

Summary

The ACCP antithrombotic guidelines conference has come a long way since the first publication of the guidelines in 1986. While evidence on which recommendation are made remains weak in fields of pediatric thrombosis, thrombosis in pregnancy, and thrombosis in valvular heart disease, rigorous studies in other fields have generated new and strong evidence-based recommendations for many indications.

References

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