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Antithrombotic Therapy and Prevention of Thrombosis, 9th Ed: American College of Chest Physician Evidence-Based Clinical Practice Guidelines Online Only Articles |

Evidence-Based Management of Anticoagulant TherapyAnticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines FREE TO VIEW

Anne Holbrook, MD, PharmD; Sam Schulman, MD, PhD; Daniel M. Witt, PharmD, FCCP; Per Olav Vandvik, MD, PhD; Jason Fish, MD, MSHS; Michael J. Kovacs, MD; Peter J. Svensson, MD, PhD; David L. Veenstra, PharmD, PhD; Mark Crowther, MD; Gordon H. Guyatt, MD
Author and Funding Information

From the Division of Clinical Pharmacology and Therapeutics (Dr Holbrook), Department of Medicine (Drs Holbrook, Schulman, Crowther, and Guyatt), and Department of Epidemiology and Biostatistics (Drs Holbrook and Guyatt), McMaster University, Hamilton, ON, Canada; Department of Pharmacy (Dr Witt), Kaiser Permanente Colorado, Denver, CO; Department of Medicine (Dr Vandvik), Innlandet Hospital Trust, Gjøvik, Norway; Department of Internal Medicine (Dr Fish), University of California Los Angeles, Los Angeles, CA; Department of Medicine (Dr Kovacs), University of Western Ontario, London, ON, Canada; Department for Coagulation Disorders (Dr Svensson), University of Lund, University Hospital, Malmö, Sweden; and Department of Pharmacy (Dr Veenstra), University of Washington, Seattle, WA.

Correspondence to: Anne Holbrook, MD, PharmD, Division of Clinical Pharmacology and Therapeutics, McMaster University, c/o Centre for Evaluation of Medicines, 105 Main St E, P1 Level, Hamilton, ON, L8N 1G6, Canada; e-mail: holbrook@mcmaster.ca


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).


Chest. 2012;141(2_suppl):e152S-e184S. doi:10.1378/chest.11-2295
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Background:  High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices.

Methods:  The methods of this guideline follow those described in 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 in this supplement.

Results:  Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education.

Conclusions:  We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

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 antagonist (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).

2.2. For patients initiating VKA therapy, we recommend against the routine use of pharmacogenetic testing for guiding doses of VKA (Grade 1B).

2.3. For patients with acute VTE, we suggest that VKA therapy be started on day 1 or 2 of LMWH or UFH therapy rather than waiting for several days to start (Grade 2C).

3.1. For patients taking VKA therapy with consistently stable INRs, we suggest an INR testing frequency of up to 12 weeks rather than every 4 weeks (Grade 2B).

3.2. 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).

3.3. For patients with stable therapeutic INRs presenting with a single subtherapeutic INR value, we suggest against routinely administering bridging with heparin (Grade 2C).

3.4. For patients taking VKAs, we suggest against routine use of vitamin K supplementation (Grade 2C).

3.5. (Best Practices Statement) We suggest that health-care providers who manage oral anticoagulation therapy should do so in a systematic and coordinated fashion, incorporating patient education, systematic INR testing, tracking, follow-up, and good patient communication of results and dosing decisions.

3.6. For patients treated with VKAs who are motivated and can demonstrate competency in self-management strategies, including the self-testing equipment, we suggest patient self-management (PSM) rather than usual outpatient INR monitoring (Grade 2B). For all other patients, we suggest monitoring that includes the safeguards in our best practice statement 3.5.

3.7. For dosing decisions during maintenance VKA therapy, we suggest using validated decision support tools (paper nomograms or computerized dosing programs) rather than no decision support (Grade 2C).

Remarks: Inexperienced prescribers may be more likely to improve prescribing with use of decision support tools than experienced prescribers.

3.8. For patients taking VKAs, we suggest avoiding concomitant treatment with nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase (COX)-2-selective NSAIDs, and certain antibiotics (see Table 8) (Grade 2C).

For patients taking VKAs, we suggest avoiding concomitant treatment with antiplatelet agents except in situations where benefit is known or is highly likely to be greater than harm from bleeding, such as patients with mechanical valves, patients with acute coronary syndrome, or patients with recent coronary stents or bypass surgery (Grade 2C).

4.1. 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).

4.2. For patients with antiphospholipid syndrome with previous arterial or venous thromboembolism, we suggest VKA therapy titrated to a moderate-intensity INR range (INR 2.0-3.0) rather than higher intensity (INR 3.0-4.5) (Grade 2B).

5.0. For patients eligible to discontinue treatment with VKA, we suggest abrupt discontinuation rather than gradual tapering of the dose to discontinuation (Grade 2C).

6.1. For patients starting IV unfractionated heparin (UFH), we suggest that the initial bolus and the initial rate of the continuous infusion be weight adjusted (bolus 80 units/kg followed by 18 units/kg per h for VTE; bolus 70 units/kg followed by 15 units/kg per h for cardiac or stroke patients) or use of a fixed dose (bolus 5,000 units followed by 1,000 units/h) rather than alternative regimens (Grade 2C).

6.2. For outpatients with VTE treated with subcutaneous (SC) UFH, we suggest weight-adjusted dosing (first dose 333 units/kg, then 250 units/kg) without monitoring rather than fixed or weight-adjusted dosing with monitoring (Grade 2C).

7.1. For patients receiving therapeutic LMWH who have severe renal insufficiency (calculated creatinine clearance < 30 mL/min), we suggest a reduction of the dose rather than using standard doses (Grade 2C).

8.1. For patients with VTE and body weight over 100 kg, we suggest that the treatment dose of fondaparinux be increased from the usual 7.5 mg to 10 mg daily SC (Grade 2C).

9.1.

(a) For patients taking VKAs with INRs between 4.5 and 10 and with no evidence of bleeding, we suggest against the routine use of vitamin K (Grade 2B).

(b) For patients taking VKAs with INRs > 10.0 and with no evidence of bleeding, we suggest that oral vitamin K be administered (Grade 2C).

9.2. For patients initiating VKA therapy, we suggest against the routine use of clinical prediction rules for bleeding as the sole criterion to withhold VKA therapy (Grade 2C).

9.3. For patients with VKA-associated major bleeding, we suggest rapid reversal of anticoagulation with four-factor prothrombin complex concentrate (PCC) rather than with plasma. (Grade 2C).

We suggest the additional use of vitamin K 5 to 10 mg administered by slow IV injection rather than reversal with coagulation factors alone (Grade 2C).

This article deals with the evidence regarding managing anticoagulant therapy, that is, oral vitamin K antagonists (VKAs), heparins, and fondaparinux. Separate articles address the pharmacology of these drugs.1 The questions that we address reflect those commonly posed in clinical practice.

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 the recommendations to questions in which evidence met a minimum threshold for quality: at least one comparative study with ≥ 50 patients per group with contemporaneous or historical controls reporting on patient-important outcomes or closely related surrogates. Despite this low threshold, evidence was unavailable for several important clinical management questions. When randomized trials were available, confidence in estimates often decreased because of indirectness (surrogate outcomes) and imprecision (wide CIs).

This article does not address anticoagulation management issues specific to pregnancy or to children. Issues believed to be specific to a particular diagnosis, such as VTE or atrial fibrillation, are dealt with in those specific articles of this supplement. Table 1 presents the questions for which we found evidence that met our quality threshold, including the relevant populations, interventions, comparators, and outcomes.

Table Graphic Jump Location
Table 1 —Structured Clinical Questions

AMS = anticoagulant management service; APS = antiphospholipid syndrome; aPTT = activated partial thromboplastin time; LMWH = low-molecular-weight heparin; FFP = fresh frozen plasma; INR = international normalized ratio; PCC = prothrombin complex concentrate; PICO = population, intervention, comparator, and outcome; UFH = unfractionated heparin; VKA = vitamin K antagonist; VKORC1 = vitamin K epoxide reductase complex 1.

2.1 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 outpatient dosing nomograms. Two large case series5,6 involving a total of 1,054 outpatients suggest that a nomogram specifying a 10-mg loading dose is safe, with a recurrent VTE rate of 1.9% and a major bleeding rate of 1.0% at 3 months follow-up.5 However, pooling across both studies suggests that only 49.3% of participants followed the nomogram completely.

Table 2 and Table S1 (tables that contain an “S” before the number denote supplementary tables not contained in the body of the article and available instead in an online data supplement; see the “Acknowledgments” for more information) summarizes our confidence in effect estimates and main findings from a meta-analysis of five RCTs of loading dose vs no loading dose of warfarin.711 The table shows that clinical outcomes, where documented, were similar between the groups. The studies typically measured time to therapeutic range of anticoagulation as the primary outcome and the patients were mainly those starting treatment (not prophylaxis) for VTE. Many of those treated as inpatients at the time of the study would, in current practice, be treated as outpatients.

Table Graphic Jump Location
Table 2 —[Section 2.1] Warfarin 10 mg Loading Dose Nomogram Compared With Warfarin 5 mg Loading Dose Nomogram for Warfarin Initiation7,8,10,11

GRADE = Grades of Recommendations, Assessment, Development, and Evaluation. See Table 1 legend for expansion of other abbreviation.

a 

All pooled studies included only patients with acute VTE. Studies from which data could be pooled are Kovacs et al,9 Quiroz et al,10 and Schulman et al.11

b 

Minimal loss to follow-up; adherence to intention-to-treat principle in two of three studies; follow-up period short but adequate for this outcome; any lack of blinding should not impact objective outcome (laboratory value, INR); adequate allocation concealment; sample size calculations reported for two of three studies.

c 

Results based on only three studies; one study shows no difference; one shows statistically significant reduction in time to therapeutic INR; and one had two parts to it, where one showed statistically significant reduction and the other did not.

d 

Mean follow-up period of 5 d for patients in the loading dose warfarin group from Schulman et al11 (this was the shortest period, only mean is available).

e 

Data collectors unblinded.

f 

Indirect given application aimed at outpatients with VTE; follow-up period is very short in two of three studies (5 d-2 wk).

g 

No studies were powered to detect differences in bleeding events between groups. Number of events is too sparse to draw any conclusions.

h 

Very small number of events; risk difference calculated.

i 

OR not estimable; absolute risk difference calculated.

Two studies by a single group7,8 compared a 10-mg loading dose to 5 mg daily for the first 2 days. Both included primarily inpatients, and one did not report recurrent VTE.8 The concentrations of protein C and factor VII, but not those of factor II or X, decreased faster in the 10-mg group than in the 5-mg group8; an increased risk of recurrent thromboembolism, however, has not been demonstrated in any of the studies presumably because initiation overlaps with heparin or LMWH. Quiroz et al10 compared 5 vs 10 mg initial warfarin dosing in 50 inpatients and reported no difference in median time to two consecutive therapeutic INRs. This study had only a 2-week follow-up and excluded 322 of the 372 patients screened. Another study compared loading dose vs standard warfarin initiation for patients with VTE and showed a shorter time to a therapeutic INR (3.3 vs 4.3 days).11 Finally, Kovacs et al9 found that the use of a 10- vs 5-mg initiation nomogram with 210 outpatients resulted in shorter mean time to therapeutic INR of 4.2 vs 5.6 days. The proportion therapeutic by day 5 was also significantly better at 86% vs 45% in the 10- vs 5-mg group, respectively. All studies followed the initiation period with INR-based dose adjustment.

Recommendation

2.1. 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 INR measurements rather than starting with the estimated maintenance dose (Grade 2C).

2.2 Initial Dose Selection and Pharmacogenetic Testing

Selection of the initial and maintenance doses of VKA therapy usually has been based on subjective estimates of patient age, size, nutritional status, and organ function. In section 2.1, we suggest a standard short loading dose for outpatients. Theoretically, individual patient pharmacogenetic testing of CYP2C9 (cytochrome P450 2C9), which is involved with VKA metabolism and VKORC1 (vitamin K epoxide reductase complex 1, the VKA target), might improve VKA therapy through more-accurate dose selection. There are four RCTs of pharmacogenetic testing-based dosing vs standard dosing; all addressed warfarin initiation.1215 The studies included patients with artificial heart valves, atrial fibrillation, or acute VTE. All studies were small (total n = 544). None showed any difference in thrombotic events, major bleeding, or survival (Table S2).

Hillman et al12 conducted a pilot study of 38 patients. Caraco et al13 randomized 283 patients but excluded 92 for reasons such as failure to follow warfarin dosing instructions. Huang et al15 included 121 valve inpatients and showed improvement in time to therapeutic range; the control group, however, used a substandard 2.5-mg daily regimen. Anderson et al,14 who had the highest methodologic quality, studied inpatients in which the control group experienced close INR monitoring following a loading-dose strategy. The investigators found no difference in time in therapeutic range or time to therapeutic range. A systematic review also concluded that there is a lack of evidence to support using pharmacogenetic testing to guide VKA dosing.16

Several recent economic evaluations have assessed the cost-effectiveness of pharmacogenetic testing to guide VKA (warfarin) initiation.1719 The results of these studies estimated the incremental cost at ∼$50,000 to $170,000 per quality-adjusted life year gained, but in sensitivity analyses, the incremental cost-effectiveness ratios were as high as $200,000 to $300,000 per quality-adjusted life year and included scenarios in which pharmacogenetic testing led to poorer patient outcomes. These results would be judged as not cost-effective by most drug policy experts.

Recommendation

2.2. For patients initiating VKA therapy, we recommend against the routine use of pharmacogenetic testing for guiding doses of VKA (Grade 1B).

2.3 Initiation Overlap for Heparin and VKA

Historically, clinicians administered IV unfractionated heparin (UFH) to inpatients for 5 to 7 days with subsequent initiation of a VKA, leading to a total duration of IV UFH of 10 to 14 days. More recently, VKA therapy has been initiated on the first or second day of heparin therapy, leading to shorter durations of heparin and earlier discharge from the hospital.

Table 3 (and Table S3) summarizes the evidence from a meta-analysis of 807 patients in four RCTs addressing this issue (F. Qayyum, unpublished data, 2011). These trials compared early start (day 1 or 2 of heparin) vs late start (days 3-10 of heparin) for the VKA therapy together with UFH or LMWH therapy. Two studies20,21 enrolled patients with DVT only, one enrolled patients with DVT or pulmonary embolism (PE),22 and the fourth included patients with left ventricular mural thrombosis.22 There were no differences between early vs late initiation of VKA for the outcomes of recurrent VTE, major bleeding, or death. Patients assigned to early initiation of VKA spent a mean of 4 fewer days in the hospital than patients assigned to late initiation of VKA. No studies have assessed early vs late initiation of VKA therapy in the outpatient setting, but we consider the results of the meta-analysis to be applicable to outpatients.

Table Graphic Jump Location
Table 3 —[Section 2.3] VKA Started Early vs Late With Heparin in Patients With Acute Thromboembolism

PE = pulmonary embolism; RR = risk ratio. See Table 2 legend for expansion of other abbreviation.

a 

For three out of four studies, concealment of allocation was unclear. Lack of blinding of health-care professionals in some studies.

b 

The value for I2 test for death was 55%, and therefore, it was rated down for inconsistency.

c 

The 95% confidence intervals around the absolute risk values were very wide for this outcome.

d 

Potential limitations in design for this outcome: allocation sequence concealment was not reported in three out of four studies; health-care professionals blinded in only one study (Hull et al20) (outcome assessors were blinded in three of four studies).

Recommendation

2.3. For patients with acute VTE, we suggest that VKA therapy be started on day 1 or 2 of LMWH or UFH therapy rather than wa