Chest
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physician Evidence-Based Clinical Practice Guidelines Online Only ArticlesEvidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Section snippets
Summary of Recommendations
Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommendations sections to indicate recommendations that are newly added or have been changed since the publication of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.
2.1. For patients sufficiently healthy to be treated as outpatients, we suggest initiating vitamin K
Methods
The methods for the development of this article's recommendations follow those developed for the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.2 Although we aimed to summarize and use randomized controlled trial (RCT) evidence to inform recommendations for clinicians, we found only lower-quality evidence to address most of our questions. At the onset of our review process, our panel decided to limit
Initial Dose Selection—Loading Dose
Loading doses of VKA may be worth considering where rapid attainment of therapeutic international normalized ratio (INR) is required and considered safe, primarily for patients with VTE. Predictable and timely achievement of therapeutic INRs without increased risk of bleeding or recurrent thromboembolic events avoids the inconvenience and pain of prolonged administration of subcutaneous (SC) low-molecular-weight heparin (LMWH) and facilitates early patient discharge and eligibility for
Monitoring Frequency for VKAs
The frequency of long-term INR monitoring is influenced by patient compliance, changes in health status, the addition or discontinuation of interacting medications, changes in diet, the quality of dose-adjustment decisions, and whether the patient has demonstrated stable INRs.23, 24, 25 We define stable INRs as at least 3 months of consistent results with no need to adjust VKA dosing.26 Recall intervals for various clinical situations have not been extensively studied; rather, they evolved from
Optimal Therapeutic INR Range
The desired effect of VKA on the prothrombin time, expressed as INR, can be provided as a therapeutic range (eg, INR 2.0-3.0) or a therapeutic target (eg, INR 2.5). The former provides information on INR values considered acceptable for the patient, whereas the latter is intended to induce those managing anticoagulant therapy to strive for an ideal level.
In a systematic review of 19 studies (one RCT, five with analysis of INR-specific outcomes from RCTs, and 13 observational studies) reporting
VKA—Discontinuation of Therapy
There is a theoretical concern that abrupt VKA discontinuation may result in a temporary hypercoagulable state due to an imbalance in the rates of normalization of activity of the coagulation factors II, VII, IX, and X on the one hand and the natural inhibitors protein C and protein S on the other.143 Five small controlled trials (total n = 217) have addressed this issue.144, 145, 146, 147 The primary outcomes of four of the studies were laboratory results suggestive of a hypercoaguable state144
UFH—Dose Adjustment by Weight
Five RCTs compared initial IV UFH dosing according to a weight-based nomogram with a fixed-dose approach.149, 150, 151, 152, 153 The study by Jaff et al151 was excluded because no weight-adjusted group for the initial bolus was included. The study by Toth and Voll153 was excluded because the fixed dose varied by treating physician, and thromboembolic or bleeding complications were not specified. In the remaining three RCTs a total of 292 patients were randomized to either weight based or fixed
Should the Therapeutic Dose of LMWH Be Modified for Decreased Renal Function?
LMWH, as opposed to UFH, is primarily eliminated through renal excretion. We found no RCTs comparing a standard, body-weight-adjusted dose to a reduced dose of LMWH in severe renal insufficiency, defined as creatinine clearance < 30 mL/min.
A meta-analysis of 18 observational studies or subgroup analyses of studies using therapeutic doses of LMWH provides some indirect evidence on this patient population.157 On the basis of four of the studies, this review suggested that standard doses of LMWH
Fondaparinux Dose Management by Weight
Doses of heparins for the treatment of thrombosis often are administered according to patient body weight for both LMWH and UFH. Both total body weight and lean body weight have been used. In clinical trials, patients with morbid obesity (> 120-130 kg) often have been excluded. We did not identify any studies comparing weight-adjusted dosing of fondaparinux to standard doses not adjusted for weight. Two randomized trials for symptomatic venous thrombosis162, 163 used doses adjusted for the
Vitamin K for Patients Taking VKAs With High INRs Without Bleeding
The risk of bleeding increases significantly when the INR exceeds 4.5.165 In a retrospective review, patients with mechanical heart valves had a risk of adverse events that increased logarithmically from two per 100 patient-years at INR 2.5 to 4.9, to 4.8 per 100 patient-years for INR 5 to 5.5, then to 75 per 100 patient-years for INR ≥ 6.5.166 Similarly, a case-control analysis of adults sustaining intracerebral bleeding while on warfarin noted a doubling of intracerebral bleeding for every
Intensive Patient Education and Anticoagulation Outcomes
Intensive patient education (defined as dedicated patient education sessions beyond the usual VKA information distributed by pamphlet or the patient's usual provider) has been proposed to reduce adverse events related to anticoagulation and to improve TTR. Although better patient knowledge of anticoagulation has been associated with improved INR control, these were no randomized trials, and INRs were surrogate outcomes.208, 209
Seven RCTs (n = 1,195) compared supplemental patient education with
Acknowledgments
Author contributions: As Topic Editor, Dr Holbrook oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein
Dr Holbrook: served as Topic Editor.
Dr Schulman: served as Deputy Editor.
Dr Witt: served as a panelist.
Dr Vandvik:, served as a panelist.
Dr Fish: served as a frontline clinician.
Dr Kovacs: served as a panelist.
Dr Svensson: served as a panelist.
Dr Veenstra: served as a resource consultant.
Dr Crowther: served as a
References (216)
- et al.
Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines
Chest
(2012) - et al.
Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines
Chest
(2012) - et al.
Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines
Chest
(2012) - et al.
A 10 mg warfarin initiation nomogram is safe and effective in outpatients starting oral anticoagulant therapy for venous thromboembolism
Thromb Res
(2009) - et al.
Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism
Am J Cardiol
(2006) - et al.
Efficacy and safety of early versus late initiation of warfarin during heparin therapy in acute thromboembolism
Am Heart J
(1992) - et al.
Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition)
Chest
(2008) - et al.
Warfarin dose management affects INR control
J Thromb Haemost
(2009) - et al.
Reexamining the recommended follow-up interval after obtaining an in-range international normalized ratio value: results from the Veterans Affairs study to improve anticoagulation
Chest
(2011) Oral anticoagulation should be managed in the community with treatment aimed at standard therapeutic targets and increased recall intervals
J Thromb Haemost
(2008)
The interval between prothrombin time tests and the quality of oral anticoagulants treatment in patients with chronic atrial fibrillation
Thromb Res
Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin users
J Thromb Haemost
Outcomes and predictors of very stable INR control during chronic anticoagulation therapy
Blood
Warfarin for atrial fibrillation in community-based practise
J Thromb Haemost
Single-dose adjustment versus no adjustment of warfarin in stably anticoagulated patients with an occasional international normalized ratio (INR) out of range
Thromb Res
Warfarin dose reduction vs watchful waiting for mild elevations in the international normalized ratio
Chest
Incidence of thromboembolic complications in patients with mechanical heart valves with a subtherapeutic international normalized ratio
J Thorac Cardiovasc Surg
Daily vitamin K supplementation improves anticoagulant stability
J Thromb Haemost
Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin
Blood
Is long-term pharmacist-managed anticoagulation service efficient? A pragmatic randomized controlled trial
Am Heart J
Improving the quality of anticoagulation of patients with atrial fibrillation in managed care organizations: results of the managing anticoagulation services trial
Am J Med
Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy
Chest
Effect of study setting on anticoagulation control: a systematic review and metaregression
Chest
Self-monitoring of oral anticoagulation: a systematic review and meta-analysis
Lancet
A randomized comparison of a computer-based dosing program with a manual system to monitor oral anticoagulant therapy
Thromb Res
The effectiveness of warfarin dosing from a nomogram compared with house staff dosing
J Arthroplasty
Multicentre randomised study of computerised anticoagulant dosage. European Concerted Action on Anticoagulation
Lancet
An international multicenter randomized study of computer-assisted oral anticoagulant dosage vs. medical staff dosage
J Thromb Haemost
Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study
J Thromb Haemost
The cost-effectiveness of computer-assisted anticoagulant dosage: results from the European Action on Anticoagulation (EAA) multicentre study
J Thromb Haemost
Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines
Chest
Practical application of the 10-mg warfarin initiation nomogram
Blood Coagul Fibrinolysis
A randomized trial comparing 5-mg and 10-mg warfarin loading doses
Arch Intern Med
Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy
Ann Intern Med
Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial
Ann Intern Med
Intensive initial oral anticoagulation and shorter heparin treatment in deep vein thrombosis
Thromb Haemost
A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data
Clin Med Res
CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study
Clin Pharmacol Ther
Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation
Circulation
Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients
Pharmacogenet Genomics
Optimal loading dose for the initiation of warfarin: a systematic review
BMC Cardiovasc Disord
A policy model to evaluate the benefits, risks and costs of warfarin pharmacogenomic testing
Pharmacoeconomics
Cost-effectiveness of genotype-guided warfarin dosing for patients with atrial fibrillation
Circ Cardiovasc Qual Outcomes
Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation
Ann Intern Med
Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis
N Engl J Med
Early versus delayed introduction of oral vitamin K antagonists in combination with low-molecular-weight heparin in the treatment of deep vein thrombosis. a randomized clinical trial
Haemostasis
A computerized intervention to improve timing of outpatient follow-up: a multicenter randomized trial in patients treated with warfarin
J Gen Intern Med
Guidelines on oral anticoagulation: third edition
Br J Haematol
INR: Intervals of measurement can safely extend to 14 weeks
Clin Lab Haematol
A comparison between six- and four-week intervals in surveillance of oral anticoagulant treatment
Am J Clin Pathol
Cited by (0)
Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and sanofi-aventis US.
Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).