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Bloomfield HE, Taylor BC, Krause A, et al. Safe and Effective Anticoagulation in the Outpatient Setting: A Systematic Review of the Evidence [Internet]. Washington (DC): Department of Veterans Affairs (US); 2011 Feb.

METHODS

SEARCH STRATEGY

We searched Ovid MEDLINE using the search strategies outlined below. For Key Question 1 we searched the <1950 to 2010> database, downloaded the results and then excluded pre-1996 references. For Key Question 2, we searched the <1950 to 2010> database, limited the results to references from 2005-2010 in the search string and then downloaded the results for further inclusion/exclusion determination. This search was limited to articles published after 2004 because of the availability of a 2007 technology assessment report directly related to this question.2 For Key Question 3, we searched the <1996 to 2010> database and then downloaded the results for further inclusion/exclusion determination. For all three Key Questions, the initial literature search was completed in 2009. All searches were updated in March 2010 using identical search strategies. The literature search for Key Question 2 was updated again in October 2010. We also searched the Cochrane Library and identified additional citations from reference lists of relevant articles.

Search Strategy – Key Question #1

  1. warfarin.mp. or exp Warfarin/
  2. coumadin.mp.
  3. coumarin.mp. or exp Coumarins/
  4. exp anticoagulants/ or anticoagul*.mp.
  5. or/1-4
  6. Ambulatory Care Facilities/
  7. Outpatient Clinics, Hospital/
  8. 6 or 7
  9. 5 and 8
  10. (anticoagul* adj clinic*).mp.
  11. 9 or 10

Search Strategy – Key Question #2

  1. exp anticoagulants/
  2. (warfarin or coumadin or coumarin).mp.
  3. (oral adj anticoagul$).mp.
  4. or/1-3
  5. self administration/
  6. drug administration schedule/
  7. international normalized ratio/
  8. near patient test$.mp.
  9. point of care systems/
  10. self test$.mp.
  11. self manage$.mp.
  12. drug monitoring/
  13. primary health care/
  14. (primary care or general practice or general practitioner$).mp.
  15. or/5-14
  16. 4 and 15
  17. limit 16 to yr=”2005 -Current”

Search Strategy – Key Question #3:

  1. (warfarin or coumadin or coumarin).mp.
  2. exp HEMORRHAGE/ or hemorrhag*.mp.
  3. exp CEREBROVASCULAR TRAUMA/
  4. bleed$.mp.
  5. stroke.mp.
  6. or/2-6
  7. 1 and 7
  8. risk factor*.mp. or exp Risk Factors/
  9. predict*.mp. or exp Risk/
  10. 9 or 10
  11. 8 and 11
  12. cohort stud*.mp. or exp Cohort Studies/
  13. prospective stud*.mp. or exp Prospective Studies/
  14. random*.mp. or exp Randomized Controlled Trial/
  15. or/13-15
  16. 12 and 16

Trained researchers reviewed the titles and abstracts identified by the literature search to identify articles published in the English language, in peer-reviewed journals, and related to one of the key questions. For KQ1 and KQ2, we included articles that involved an outpatient, adult population receiving chronic (defined as more than 3 months) anti-coagulation therapy. For KQ3, we further limited the inclusion criteria to studies that involved warfarin therapy, reported results by risk factor status, and had a study population of at least 25 cases of serious bleeding. For all questions, we excluded case series, case reports, qualitative reports, narrative reviews, and editorials or letters. Full-text versions of potentially relevant articles were obtained for further review (see Figures 2, 3, and 4) and trained researchers extracted data from articles that met inclusion criteria.

Figure 2. Literature Flow Diagram for Key Question 1.

Figure 2

Literature Flow Diagram for Key Question 1.

Figure 3. Literature Flow Diagram for Key Question 2.

Figure 3

Literature Flow Diagram for Key Question 2.

Figure 4. Literature Flow Diagram for Key Question 3.

Figure 4

Literature Flow Diagram for Key Question 3.

DATA EXTRACTION

For studies related to Key Questions 1 and 2, we extracted data on study design, country of origin, funding source, indications for anticoagulation, sample characteristics, interventions, mortality, thromboembolic events, major bleeding events, patient satisfaction, quality of life, laboratory measures of anticoagulation quality (i.e., percent time within the therapeutic range, percent of INR values within the therapeutic range, and INR variability), hospitalizations, outpatient and emergency room utilization, outpatient laboratory utilization, and long-term care admissions.

For Key Question #1a, we extracted data on ratio of staff to patient load; qualifications of staff and leadership; organizational structure of clinic; frequency and type (e.g., face-to-face versus phone) of contact with patient; frequency and timing of INR checks; use of computer-based algorithms to adjust dosing; timeliness of follow-up of abnormal INRs; patient education; use of genetic information to tailor therapy; protocols for use of vitamin K; clinic volume; hypercoagulation workups (e.g., Factor V Leiden); and use of technologies such as Interactive Voice Recording.

For Key Question #3, we extracted data on study characteristics, patient factors (e.g., age, gender, level of education); indication for anti-coagulation (atrial fibrillation; deep vein thrombosis/pulmonary embolism – either first or recurrent and with or without precipitating factors; mechanical heart valve; TIA/stroke; other); indices measuring severity of illness, functional status, and co-morbidity; time above therapeutic range; type of anticoagulant used; frequency and type of monitoring; concomitant use of anti-platelet agents; concomitant use of other medications; and setting within which patient is monitored (specialized anticoagulation clinic or not).

QUALITY ASSESSMENT

The quality of the individual randomized studies was assessed by the following: 1) adequate allocation concealment, denoted by central allocation, including telephone, web-based and pharmacy controlled randomization or use of sequentially numbered, opaque, sealed envelopes; 2) blinding of key study personnel (i.e., providers and/or study personnel who adjudicated outcomes blinded to group assignment); 3) analysis by intention-to-treat (i.e., all subjects counted in group to which they were randomized in the outcomes analyses); and 4) reporting of number of withdrawals/dropouts by group assignment.

DATA SYNTHESIS

For Key Question #1, analyses using a DerSimonian and Laird random-effects model, which assumes that the true treatment effects in the individual trials may vary from each other, were conducted in Review Manager Version 5.0.3 A random-effects model is an analytical approach that incorporates heterogeneity that cannot be readily accounted for. Statistical heterogeneity between trials was assessed using the I2 test. An I2 score of 50 or greater indicates substantial heterogeneity.4

For Key Question #2, clinical outcomes data were pooled and analyzed in Review Manager Version 5.0.3 Because of low event rates for several clinical outcomes, we used Peto odds ratios (fixed effects model). Weighted mean differences were calculated using a random effects model using the Comprehensive Meta-Analysis software© (Biostat, Inc., Englewood, NJ). Statistical heterogeneity between trials was assessed using the I2 test; a score of 50% or greater suggests moderate to substantial inconsistency among studies.4 In order to explore heterogeneity we performed subgroup analyses and tested for interactions. The extent of publication bias was evaluated through visual inspection of funnel plot asymmetry and the linear regression–based test proposed by Egger.5

PEER REVIEW

A draft version of this report was sent to our Technical Expert Panel members and to three peer reviewers. Reviewer comments were addressed and our responses incorporated into the final report (Appendix A).

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Cover of Safe and Effective Anticoagulation in the Outpatient Setting
Safe and Effective Anticoagulation in the Outpatient Setting: A Systematic Review of the Evidence [Internet].
Bloomfield HE, Taylor BC, Krause A, et al.
Washington (DC): Department of Veterans Affairs (US); 2011 Feb.

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