A systematic review of clinical practice guidelines on the use of low molecular weight heparin and fondaparinux for the treatment and prevention of venous thromboembolism: Implications for research and policy decision-making

Background Venous thromboembolism (VTE) is a major global cause of morbidity and mortality. Low molecular weight heparin (LMWH) and fondaparinux (FDP) are frequently used to treat and prevent VTE and have a variety of safety and practical advantages over other anticoagulants, including use in outpatient settings. These medications are commonly listed on drug formularies, which act as a gateway for health plan prescription coverage by outlining the circumstances under which patients will be covered for specific drugs and drug products. Because patient access to medications is impacted by the nature of their listing on formularies, they must be rigorously reviewed and modernized as new evidence emerges. Methods As part of a broader drug class review team, we completed a systematic review of clinical practice guidelines to determine whether the recommendations they reported aligned with the indications listed for the coverage of LMWH and FDP in an outpatient drug formulary. Guideline quality was assessed using the Appraisal of Guidelines for Research & Evaluation (AGREE) II tool. Recommendation matrices were used to systematically compare, categorize, and summarize included recommendations. Results Twenty-seven guidelines were included from which 168 eligible recommendations were identified. Generally, AGREE II domains were adequately addressed; however, domain five (applicability) was poorly addressed. Most recommendations were based on moderate- to low-quality/limited evidence and reported on the use of LMWHs generally; few reported on specific agents. Conclusions Our findings contributed to the recommendation that the formulary listing for LMWH and FDP be streamlined to include coverage for specific outpatient indications. The paucity of available evidence on the comparative efficacy of specific LMWH agents against each other and FDP limited agent-specific listing recommendations, highlighting the need for high-quality comparative studies on this topic.


Grading System Strength of Recommendation Level of Evidence
Watson et al.
(2015) [5] Grading of Recommendations Assessment Development and Evaluation (GRADE) [2] 1-Strong: clinicians are very certain that benefits do, or do not, outweigh risks and burdens. 2-Weak: clinicians believe that benefits and risks and burdens are finely balanced, or appreciable uncertainty exists about the magnitude of benefits and risks A-High: further research is very unlikely to change our confidence in the estimate of effect B-Moderate: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate C-Low: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate D-Very Low: any estimate of effect is very uncertain Whitlock et al. (2012) [6] American College of Chest Physicians (ACCP) modified approach to Grading of Recommendations Assessment, Development and Evaluation (GRADE) [7] 1: Strong-experts are very certain that benefits do or do not outweigh risks, burden, and costs 2: Weak-experts are less certain that of the magnitude of the benefits and risks, burden, and costs and their relative impacts A: high-quality evidence-randomized controlled trials and highquality observational studies with large, consistent, effects B: moderate-quality evidence C: low quality or very low-quality evidence  [8] American College of Chest Physicians (ACCP) modified approach to Grading of Recommendations Assessment, Development and Evaluation (GRADE) [7] 1: Strong-experts are very certain that benefits do or do not outweigh risks, burden, and costs 2: Weak-experts are less certain that of the magnitude of the benefits and risks, burden, and costs and their relative impacts A: high-quality evidence-randomized controlled trials and highquality observational studies with large, consistent, effects B: moderate-quality evidence C: low quality or very low-quality evidence  [9] American College of Chest Physicians (ACCP) modified approach to Grading of Recommendations Assessment, Development and Evaluation (GRADE) [7] 1-strong: experts are very certain that benefits do or do not outweigh risks, burden, and costs 2-weak: experts are less certain that of the magnitude of the benefits and risks, burden, and costs and their relative impacts A: high-quality evidence-randomized controlled trials and highquality observational studies with large, consistent, effects B: moderate-quality evidence C: low quality or very low-quality evidence

Falck-Ytter et al.
(2012) [10] American College of Chest Physicians (ACCP) modified approach to Grading of Recommendations Assessment, Development and Evaluation (GRADE) [7] 1: Strong-experts are very certain that benefits do or do not outweigh risks, burden, and costs 2: Weak-experts are less certain that of the magnitude of the benefits and risks, burden, and costs and their relative impacts A: high-quality evidence-randomized controlled trials and highquality observational studies with large, consistent, effects B: moderate-quality evidence C: low quality or very low-quality evidence A-good evidence to recommend the clinical preventive action B-fair evidence to recommend the clinical preventive action C-evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making D-fair evidence to recommend against the clinical preventive action E-good evidence to recommend against the clinical preventive action L-insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making I-at least one properly randomized controlled trial II-1-well-designed controlled trials without randomization II-2-well-designed cohort (prospective or retrospective) or casecontrol studies, preferably from more than one centre or research group II-3-comparisons between times or places with or without the intervention or dramatic results in uncontrolled experiments III-opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees  [18] American Heart Association clinical practice methodology Jacobs et al (2013) [19] and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [20][21][22] Strong-most patients should receive the recommended treatment Weak-different choices will be appropriate for different patients; management decision should be made in concert with the patient's values and preferences I-benefit >>> risk, procedure or treatment should be performed or administered IIa-benefit >> risk-additional studies with focused objectives are needed; it is reasonable to perform the procedure or administer the treatment IIb-benefit ≥ risk-additional studies with broad objectives are needed, and additional registry data would be helpful; procedure or treatment may be considered III-no benefit or III-harm: procedure or treatment should not be performed or administered because it is not helpful and may be harmful  [26] Method outlined by the United States Preventative Services Task Force [27] A: based on good and consistent scientific evidence B: based on limited or inconsistent scientific evidence C: based primarily on consensus and expert opinion I-at least one properly designed randomized controlled trial II-1: well-designed controlled trials without randomization II-2: well-designed cohort or case-control analytic studies, preferably from more than one center or research group II-3: multiple time-series with or without the intervention. Could include 'dramatic' results in uncontrolled experiments also could be regarded as this type of evidence III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees  [33] The American Society of Clinical Oncology [34] A-evidence of type I or consistent findings from multiple studies of types II, III, IV B-evidence of types II, III, or IV and findings are generally consistent C-evidence of types II, III, or IV but findings are inconsistent D-little or no systematic empirical evidence I-meta-analysis of multiple, well-designed, controlled studies -randomised trials with low false positive and low false-negative errors II-at least one well-designed experimental study -randomised trials with high false-positive and/or negative errors (low power) III-well-designed, quasi-experimental studies such as nonrandomised, controlled single group, pre-post, cohort, time, or matched case-control studies IV-evidence is from well-designed, non-experimental studies such as comparative and correlational descriptive and case studies

V-evidence from case reports and clinical examples Greenberg et al. (2014) [35]
Not reported I-generally should be performed II-may be reasonable to perform III-generally should not be performed Not reported 1. Strongly agree ("strongly recommend") 2. Somewhat agree ("recommend") 3. Neutral ("recommend") 4. Somewhat disagree ("recommend") 5. Strongly disagree ("suggest") Ia-systematic review of randomized controlled trials Ib-individual randomized controlled trials with narrow confidence intervals IIa-systematic reviews of cohort studies IIb-individual cohort studies or low-quality randomized controlled trials IIIa-systematic reviews of case-control studies IIIb-individual case-control studies IV-case series V-expert opinion or formal consensus Nicolaides et al. (2013) [38] Three main reference articles were used as guidance [39][40][41]

Not reported
High-randomized controlled trials with consistent results, or systematic reviews that were directly applicable to the target population.
Moderate-randomized controlled trials with less consistent results, limited power or other methodological problems, which were directly applicable to the target population -randomized controlled trials extrapolated to the target population from different group of patients Low-well-conducted observational studies with consistent results that were directly applicable to the target population The Scottish Intercollegiate Guidelines Network (SIGN) (2014) [16] Grading of Recommendations Assessment Development and Evaluation (GRADE) [2,29] A: At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results B: A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+ C: A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++ D: Evidence level 3 or 4; or Extrapolated evidence from studies 1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1+ High quality meta-analyses, systematic reviews, or RCTs with a low risk of bias 1-Meta-analyses, systematic reviews, or RCTs with a high risk of bias 2++ High quality systematic reviews of case control or cohort studies High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal 2+ Well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal 2-Case control or cohort studies with a high risk of confounding or  [42] Grading of Recommendations Assessment Development and Evaluation (GRADE) [2] 1A -strong recommendation 1B -strong recommendation 1C -strong recommendation 2A -weak recommendation 2B -weak recommendation 2C -weak recommendation 1A-high-quality evidence according to EBM* 1B-moderate-quality evidence according to EBM 1C-low-or very low-quality scientific evidence 2A-high-quality evidence according to EBM (further studies probably will not have any significant influence on changes in suggested treatment method) 2B-moderate-quality evidence according to EBM (further studies may have significant influence on changes in suggested treatment method) 2C-low-or very low-quality scientific evidence (further studies probably will have significant influence on changes in suggested treatment method)