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Effectiveness of interventions for the implementation of thromboprophylaxis in hospitalised patients at risk of venous thromboembolism: an updated abridged Cochrane systematic review and meta-analysis of randomised controlled trials
  1. Susan R Kahn1,
  2. Gisele Diendéré2,
  3. David R Morrison2,
  4. Alexandre Piché3,
  5. Kristian B Filion1,
  6. Adi J Klil-Drori1,2,
  7. James Douketis4,
  8. Jessica Emed5,
  9. André Roussin6,7,
  10. Vicky Tagalakis2,8,
  11. Martin Morris9,
  12. William Geerts10
  1. 1 Medicine, McGill University, Montreal, Quebec, Canada
  2. 2 Centre of Excellence in Thrombosis and Anticoagulation Care (CETAC), Clinical Epidemiology of the Lady Davis Institute for Medical Research, Montreal, Quebec, Canada
  3. 3 Department of Mathematics and Statistics, McGill University, Montreal, Quebec, Canada
  4. 4 Medicine, McMaster University, Hamilton, Ontario, Canada
  5. 5 Nursing, Jewish General Hospital, Montreal, Quebec, Canada
  6. 6 Medicine, University of Montreal, Montreal, Quebec, Canada
  7. 7 Thrombosis Canada, Whitby, Ontario, Canada
  8. 8 Internal Medicine and Medicine, McGill University, Montreal, Quebec, Canada
  9. 9 Schulich Library of Physical Sciences, Life Sciences and Engineering, McGill University, Montreal, Quebec, Canada
  10. 10 Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  1. Correspondence to Dr Susan R Kahn; susan.kahn{at}mcgill.ca

Abstract

Objective To assess the effectiveness of system-wide interventions designed to increase the implementation of thromboprophylaxis and decrease the incidence of venous thromboembolism (VTE) in hospitalised medical and surgical patients at risk of VTE.

Design Systematic review and meta-analysis of randomised controlled trials (RCTs).

Data sources Medline, PubMed, Embase, BIOSIS, CINAHL, Web of Science, CENTRAL, DARE, EED, LILACS and clinicaltrials.gov without language restrictions from inception to 7 January 2017, as well as the reference lists of relevant review articles.

Eligibility criteria for selecting studies RCTs that evaluated the effectiveness of system-wide interventions such as alerts, multifaceted, education, and preprinted orders when compared with no intervention, existing policy or another intervention.

Results We included 13 RCTs involving 35 997 participants. Eleven RCTs had data available for meta-analysis. Compared with control, we found absolute increase in the prescription of prophylaxis associated with alerts (21% increase, 95% CI [15% to 275%]) and multifaceted interventions (4% increase, 95% CI [3% to 11%]), absolute increase in the prescription of appropriate prophylaxis associated with alerts (16% increase, 95% CI [12% to 20%]) and relative risk reductions (risk ratio 64%, 95% CI [47% to 86%]) in the incidence of symptomatic VTE associated with alerts. Computer alerts were found to be more effective than human alerts, and multifaceted interventions with an alert component appeared to be more effective than multifaceted interventions without, although comparative pooled analyses were not feasible. The quality of evidence for improvement in outcomes was judged to be low to moderate certainty.

Conclusions Alerts increased the proportion of patients who received prophylaxis and appropriate prophylaxis, and decreased the incidence of symptomatic VTE. Multifaceted interventions increased the proportion of patients who received prophylaxis but were found to be less effective than alerts interventions.

Trial registration number CD008201.

  • thromboembolism
  • epidemiology
  • anticoagulation
  • internal medicine
  • public health
  • vascular medicine

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Strengths and limitations of this study

  • This review was conducted following the Cochrane Handbook for Systematic Reviews of Interventions.

  • We included all randomised controlled trials relevant to our research question.

  • We preferentially accounted for clustering designs using the intracluster correlation coefficient (ICC) where available. ICCs were not provided in many study reports, leading to confidence intervals that may be narrower than if clustering had been accounted for.

  • The quality of the evidence in this updated review was limited by the methodological quality of included trials.

Introduction

Compared with persons in the community, hospitalised medical and surgical patients are at approximately 50% higher risk of developing venous thromboembolism (VTE), which includes deep venous thrombosis (DVT)1 2 and pulmonary embolism (PE). VTE that occurs during or within 3 months after hospitalisation underlies >50% of all cases of the population burden of VTE.3–5 VTE is a frequent complication in hospitalised medical and surgical patients, a leading cause of mortality and morbidity in hospitalised patients (60 000–100 000 deaths per year),6 a leading cause of increased hospital costs (at least $600 million per year) and length of hospital stay, and PE is the third leading cause of preventable death and disability in hospital.7–11

The appropriate use of thromboprophylaxis in hospitalised patients at risk of VTE has been shown to be safe, effective and cost-effective. Therefore, many international clinical practice guidelines have recommended the use of thromboprophylaxis (eg, pharmacologic and/or mechanical modalities) in targeted groups of hospitalised medical and surgical patients at risk of VTE.12–21 The prevention of VTE was ranked as the number 1 of 79 strategies aimed to improve patient safety in hospitals,22 and interventions to increase thromboprophylaxis prescriptions have been classified as a strongly encouraged patient safety practice.23 24 Nonetheless, a clear gap exists between the available evidence and the implementation of the appropriate use of thromboprophylaxis into day-to-day clinical practice.25–33 System-wide interventions, by reaching the healthcare system as a whole, could help to improve prescription of appropriate thromboprophylaxis and ultimately reduce the risk of VTE in hospitalised medical and surgical patients at risk of VTE.34

In our previous Cochrane systematic review, we assessed the effectiveness of various system-wide interventions designed to increase the implementation of thromboprophylaxis in hospitalised medical and surgical patients at risk of VTE.35 We identified various system-wide interventions such as simple distribution of guidelines, audit and feedback (eg, review of performance); preprinted orders (eg, written, predefined orders, which can be completed by the physician on paper or electronically); the use of automatic reminder systems that include alerts (eg, human alerts, by a trained nurse, pharmacist or staff member; or computer, electronic alerts); multifaceted approaches that combine different types of interventions (eg, combination of education, audit and feedback and alerts) and educational interventions, which focus on the teaching and learning process by organising educational events (eg, grand rounds, self-administered courses).

This article presents the results of an update of our previous Cochrane review on the effectiveness of system-wide interventions designed to increase the use of thromboprophylaxis and decrease the incidence of VTE in hospitalised medical and surgical patients at risk of VTE. In this updated review, we focus exclusively on the higher level of evidence provided by randomised controlled trials (RCTs), whereas our previous review also included observational studies. The implementation of effective interventions could help clinicians and other healthcare professionals to improve the use of appropriate thromboprophylaxis in hospitalised medical and surgical patients at risk of VTE, and thereby reduce the morbidity and mortality associated with this preventable hospital complication.

Methods

This is an abridged, stand-alone version of an updated Cochrane systematic review.36 The protocol and the previous Cochrane review can be accessed from the Cochrane Library.35 37

Inclusion criteria

Study type

We included all types of RCTs, namely RCTs with random or quasi-random (eg, pseudo-randomisation such as even or odd date of birth) methods of allocation of interventions, which either randomised individuals (eg, parallel group, crossover or factorial design RCTs) or groups of individuals (cluster RCTs [CRTs]), and whose interventions aimed to increase the use of prophylaxis and/or appropriate prophylaxis, and/or decrease the proportion of symptomatic or asymptomatic VTE in hospitalised adult patients. The control group comparison could be ‘no intervention’, an existing policy or another type of intervention.

Studies were included only if the following characteristics were met: (1) the study design, population and intervention were clearly described; (2) study data were provided separately by intervention group and for VTE outcomes and (3) VTE was diagnosed using objective and accepted criteria. Studies and abstracts could be in any language. We excluded observational studies, studies in which the intervention was a simple distribution of published guidelines, and studies whose interventions were not clearly described.

Participants

Participants included hospitalised acutely and critically ill adult medical or surgical inpatients (age range, 18–99 years), their physicians, residents or nurses, or, in the case of CRTs, the cluster unit (eg, ward, hospital and physician practice).

Interventions

Any strategies targeted to individuals or to cluster units that aimed to increase the use of thromboprophylaxis in hospitalised patients at risk of VTE and/or decrease the rate of symptomatic or asymptomatic VTE. Examples of interventions include alerts (eg, computer alerts or human alerts), multifaceted interventions (eg, combination of education, audit and feedback and alert), educational interventions (eg, grand rounds, self-administered course) and preprinted orders interventions (eg, written predefined orders that can be completed by the physician on paper or electronically if they choose to).

Outcomes

The primary outcome of interest was the increase in the proportion of patients who received either pharmacologic or mechanical prophylaxis.

Secondary outcomes

  1. Increase in the proportion of patients who received appropriate prophylaxis (defined by study authors as appropriate according to consensus, local or international thromboprophylaxis guidelines) (note: ‘appropriate prophylaxis’ signifies that the patient received the proper treatment whether or not he/she received prophylaxis, ie, received prophylaxis in an at-risk patient, or did not receive prophylaxis in a low-risk patient).

  2. Decrease in the proportion of patients who develop any, symptomatic or asymptomatic, VTE.

  3. Decrease in the number of deaths.

  4. Safety of the intervention.

Search methods

We did a systematic literature database search in Medline (Ovid), PubMed, Embase (Ovid), BIOSIS Previews (Ovid), CINAHL, Web of Science, Cochrane (including the Cochrane Central Register of Controlled Trials), the Database of Abstracts of Reviews of Effects and the NHS Economic Evaluation Database, Latin American and Caribbean Health Sciences Literature and clinicaltrials.gov from inception to 28 July 2015. After 28 July 2015, we updated the literature search monthly until 7 January 2017, when our database was closed. The search strategies comprised a combination of Medical Subject Headings or their equivalent (where available), keywords, truncations and Boolean operators (see online supplement). We also hand searched the reference lists of relevant retrieved studies including narrative and systematic reviews to find additional potentially relevant articles from inception to 7 January 2017. Studies of any languages were searched.

Supplementary file 1

Study selection

Two review authors independently reviewed titles, abstracts and full texts of each study and indicated on a Study Eligibility Form if it should be included, excluded or undecided. Disagreements regarding study inclusion were resolved by discussion between the two review authors and, if necessary, by involving a third independent review author.

Data extraction and handling of missing data

Two review authors independently extracted data from the included articles. The data obtained for each study were entered in duplicate into two identical databases that were designed by Information Management Services of the Lady Davis Institute in Montréal, Canada. The two databases were compared for inaccuracies and any data entry errors were corrected. If agreement on the data entered for a given data field could not be reached between the two extractors, a third extractor was consulted. A third, final database was populated with the final corrected data.

The data abstraction form included the following:

  1. Description of study design: parallel-group, cross‐over, cluster or factorial design, including cluster unit and intracluster correlation (ICC) if available.

  2. Description of the randomisation procedure (unit of randomisation and analysis).

  3. Description of study period, years of enrolment, year of publication, duration and completeness of follow‐up.

  4. Description of study setting (hospital or centre characteristics): number of centres, university‐affiliated hospital, community hospital, physician practice, type of healthcare system (public vs private), departments included.

  5. Description of physicians: number of physicians, physician specialties.

  6. Description of patients: patient types (medical, surgical, trauma, other), inclusion and exclusion criteria, number of patients screened and included, average age, percent male, comorbidities and individual VTE risk profile (eg, age, sex, cancer patient and cardiac patient).

  7. Description of study intervention (active and control arms): type of intervention (alerts, multifaceted interventions, educational interventions, preprinted orders, other), intervention components (alert, no alert), type of alert (computer alert, human alert), timing of intervention (before or concurrent with intervention group).

  8. Description of VTE prophylaxis: pharmacological (type, dose), mechanical, appropriateness (definition and assessment).

  9. Method of VTE screening and diagnosis.

  10. Description of study outcomes (raw data and effect estimates).

  11. Risk of bias (ROB).

Time point of outcome assessment

We used the end-of-trial follow-up for all outcomes as all included studies were CRTs or parallel group trials, and there were no cross-over trials. For withdrawals whether or not due to adverse events, we used the longest on-treatment follow-up data available. For studies with more than one time point of outcome assessment, we used the most recent follow-up data.

Risk of bias of studies

The methodological quality of included trials was independently assessed by two review authors based on the Cochrane Collaboration’s tool for assessing the ROB.38 Disagreements were resolved by discussion with co-authors. We assessed all seven domains that are potential sources of bias, and rated them as high, low or unclear ROB. We assessed all items listed as other potential sources of bias such as trial design biases (eg, carry-over in cross-over trials, selective reporting bias in multiple intervention studies and recruitment bias in CRT); early study stopping for benefit; severe baseline imbalances and inappropriate influence of study funders that may compromise the internal validity of the study.38 We also assessed the overall ROB for each of the included studies (see online supplementary table S1).

Data analysis

We evaluated the effectiveness of system-wide interventions by calculating pooled risk difference (RD) for the outcomes ‘proportions of participants who received prophylaxis (RP)’ and ‘proportions of participants who received appropriate prophylaxis (RAP)’ or risk ratio (RR) for outcomes with expected low events rates such as VTE, mortality and safety based on the Cochrane Handbook recommendations for the choice of measure of effect.38 We calculated a summary statistic for each intervention category (alerts, multifaceted interventions, educational interventions and preprinted orders) and associated outcome using a random-effects model when there were sufficient studies to pool results (≥3 studies). To account for potential synergistic effects of multiples interventions, multifaceted interventions with an alert component (either computer alert or human alert) were compared with multifaceted interventions that did not include an alert component.

We used Review Manager V.5.3 and SAS V.9.4 for all data analyses. We preferentially used effect estimates for which the variance had been adjusted to account for the clustered nature of the data. Adjustment for the clustered design was feasible only for the meta-analysis of multifaceted interventions. One of the included studies evaluated more than one intervention.39 Meta-analysis was performed within the control group and each intervention group as recommended in the Cochrane Handbook. We did not use statistical methods to impute missing values or model missing data. Four original investigators were contacted for missing data40–43; only two of them were able to provide additional data.41 43 To assess heterogeneity, we estimated the I² statistic, which determines the percentage of variability between studies in the effect estimate that is above and beyond what is expected through sampling error (ie, chance).

Quality of evidence (GRADE)

We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the quality of evidence for each outcome that we were able to meta-analyse, with the quality of evidence graded from high (best) to very low (worst).44 The five GRADE considerations (ROB, indirectness of evidence, inconsistency of results, imprecision of results and publication bias) were assessed according to the methods and recommendations in the Cochrane Handbook.38 To mitigate publication bias, unpublished data were also searched through conference abstracts and congress communications. Original investigators of included trials were also contacted to request missing and unpublished data. We examined funnel plots centred around the pooled studies effect (either RD or RR) to assess the potential for publication bias.

Patient and public involvement

Patients and the public were not involved in the development or conduct of this systematic review. However, we are planning to involve patients in the dissemination of results via interactive exchanges between healthcare providers, patient partners, clinicians and policy-makers.

Results

Included studies

From the 12 920 records identified, 16 RCTs published up to 7 January 2017 were potentially relevant to our research question, of which 13 RCTs involving a total of 35 997 participants met our inclusion criteria (figure 1). This included five new trials since our last review published in 2013.35 Characteristics of included studies are reported in table 1.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for Cochrane review updates demonstrating the outcomes of the search process, and the inclusion of studies in the updated Cochrane systematic review and meta-analysis. CDSR, Cochrane Database of Systematic Reviews; CENTRAL, Central Register of Controlled Trials; CINAHL, Cumulative Index to Nursing and Allied Health Literature; DARE, Database of Abstracts of Reviews of Effects; LILACS, Latin American and Caribbean Health Sciences Literature; NHSEED, NHS Economic Evaluation Database; RCT, randomised controlled trial; VTE, venous thromboembolism.

Table 1

Characteristics of the included studies

The following type of interventions and comparisons were reported in the 13 trials (detailed descriptions of study interventions are shown in table 2):

Table 2

Description of study interventions

  • Six trials evaluated an alert intervention compared with the standard of care. Of these, three used a computer alert41 45 46 and the other three, a person such as a trained nurse, a pharmacist or a hospital staff member as a human alert.47–49

  • Six trials evaluated a multifaceted intervention that combined different types of interventions such as education, audit and feedback and alert, compared with the standard of care39 42 43 50 51 or to another type of intervention (combination of educational session, dissemination of educational material, audit and feedback).52 Of these trials, only one included an alert component.51 This study evaluated a computer alert (computer‐based clinical decision support system and computerised reminders) along with educational lectures, posters and pocket cards compared with no intervention. However, the computer alert component of the intervention was implemented in only 2 of the 14 intervention group centres. Thus, the overall effect of this multifaceted intervention might have been smaller than expected.

  • One trial evaluated a preprinted orders intervention using predefined anticoagulant prescription forms as a passive reminder to use thromboprophylaxis, compared with the standard of care.53

  • One trial reported a head-to-head comparison among interventions. This trial evaluated an educational intervention that used a hospital-administered course with self-assessment examinations compared with the standard of care and with a multifaceted intervention.39

Two of the 13 trials were not included in meta-analyses (one because of missing raw data on study outcomes,42 and one was the only RCT to study a preprinted orders intervention).53 One type of comparison (educational intervention compared with the standard of care) was not included in meta-analyses due to a lack of studies assessing this intervention.39

Methodological quality of included studies

The methodological quality of the included studies was variable (figure 2). The overall ROB was high in two trials due to the existence of potential selection, performance, attrition, reporting and other sources of bias.42 48 These two trials were excluded from meta-analyses. The assessment of the certainty of the evidence for improvement in outcomes was limited by the incomplete reporting of study design features that did not allow proper scoring of relevant study design features such as sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other potential sources of bias. While we were able to account for clustering using the reported ICC where available,43 50–52 in many cases the ICC was not provided,39 41 42 46 48 53 leading to CIs that may be narrower than if clustering had been adequately accounted for. The units of clusters were intensive care units (1/10 CRTs),43 medical teams (2/10 CRTs),41 48 medical wards/departments (3/10 CRTs)46 52 53 and hospitals (4/10 CRTs).39 42 50 51

Figure 2

Methodological quality graph: review authors’ judgements about each methodological quality item for each included study.

Effects of interventions

Table 3 summarises the results from the meta-analyses conducted for the primary and secondary outcomes, and figure 3 and figure 4 depict the forest plots for the meta-analyses. Funnel plots are shown in online supplementary figure S1, S2 and S3. There was a near symmetrical distribution of individual trials around the pooled estimate of effect in each meta‐analysis, particularly for the alerts interventions (outcome RAP) and the multifaceted interventions (outcome RP).

Table 3

Summary of main findings

Figure 3

Forest plot and risk of bias assessment—comparison of alerts intervention with no intervention (standard care). Risk of bias: (A) random sequence generation (selection bias); (B) allocation concealment (selection bias); (C) blinding of participants and personnel (performance bias); (D) blinding of outcome assessment (detection bias); (E) incomplete outcome data (attrition bias); (F) selective reporting (reporting bias) and (G) other bias.

Figure 4

Forest plot and risk of bias assessment—comparison of multifaceted intervention with no intervention (standard care) or another intervention for the primary outcome ’Proportion of patients who received prophylaxis': (1) intraclass correlation coefficient not reported. Risk of bias: (A) random sequence generation (selection bias); (B) allocation concealment (selection bias); (C) blinding of participants and personnel (performance bias); (D) blinding of outcome assessment (detection bias); (E) incomplete outcome data (attrition bias); (F) selective reporting (reporting bias) and (G) other bias.

Comparison of alerts with standard care

Alerts interventions were associated with three types of changes:

  • A 21% absolute increase in the proportion of patients who received prophylaxis (RD 0.21, 95% CI 0.15 to 0.27; three studies; 5057 participants; I²=75%; low-certainty evidence).

  • A 16% absolute increase in the proportion of patients who received appropriate prophylaxis (RD 0.16, 95% CI 0.12 to 0.20; three studies; 1820 participants; I²=0; moderate-certainty evidence).

  • A 36% relative risk decrease in the risk of symptomatic VTE at 3 months post intervention (RR 0.64, 95% CI 0.47 to 0.86; three studies; 5353 participants; I²=15%; low-certainty evidence) (figure 3).

Subgroup analyses to address statistical heterogeneity were not feasible as there were not enough studies to pool subgroup results and distinguish chance from subgroup differences.

Comparison of multifaceted interventions with standard care or another intervention

Multifaceted interventions were associated with a small increase in the proportion of patients who received prophylaxis in the intervention groups, with no heterogeneity between individual studies when cluster design effect adjustment was performed (RD 0.04, 95% CI 0.02 to 0.06; five studies; 9198 participants; I²=0%; moderate-certainty evidence) (figure 4).

Comparison of educational interventions with standard care

One study that compared the effectiveness of using educational and multifaceted interventions to control, reported that educational interventions were associated with a non-significant decrease in the proportion of patients who received prophylaxis (RD −0.02, 95% CI −0.09 to 0.05; one study; 1311 participants), but were less effective than a multifaceted intervention.39

Comparison of preprinted orders with standard care

One study reported the use of written thromboprophylaxis prescription aids, which was associated with a non-significant decrease in the proportion of patients who received prophylaxis compared with the group that did not receive preprinted orders (RD −0.05, 95% CI −0.12 to 0.02; one study; 719 participants).53

Head-to-head comparisons

One study reported comparisons between an educational intervention (continuing medical education) and a multifaceted intervention (continuing medical education in association with a quality assurance programme), each compared with a control group (standard of care). The educational intervention was associated with a 2% decrease in the proportion of patients who received prophylaxis (RD −0.02, 95% CI −0.09 to 0.05) and the multifaceted intervention was associated with a 4% increase in the proportion of patients who received prophylaxis (RD 0.04, 95% CI −0.03 to 0.11).39

Additional analyses

A sensitivity analysis removing the high ROB trial in the meta-analysis of studies with alerts interventions48 did not substantially impact the point estimate. A sensitivity analysis for the estimation of missing ICCs in the meta-analysis of studies with multifaceted interventions showed similar point estimates and similar variance. A sensitivity analysis was done removing the multifaceted intervention study that included an alert component, and was associated with a decrease in the pooled RD (RD 0.02, 95% CI ‐0.02 to 0.06) with the result no longer statistically significant, indicating that alerts might play a role in the estimate effect of multifaceted interventions. A sensitivity analysis to ensure there was no contamination between intervention groups where the one multifaceted intervention including an alert51 was added to the alerts (RP) analysis did not substantially change the significance of the result (RD of 0.15 [0.02,0.27]). The sensitivity analyses using a fixed-effect approach did not change our point estimates.

Planned analyses without sufficient data for meta-analysis

Mortality and safety outcomes such as major and minor bleeding did not appear to differ in frequency between interventions and control groups. However, we were unable to provide pooled effect estimates on the relative effectiveness of each type of intervention for all primary and secondary outcomes.

While not directly compared with each other, computer alerts seemed to be more effective than human alerts in increasing the proportion of patients who received appropriate prophylaxis and reducing the risk of symptomatic VTE at 3 months post intervention. Multifaceted interventions that included an alert component also appeared to be more effective than those without an alert component in increasing the proportion of patients who received prophylaxis and appropriate prophylaxis, although there were not enough studies to conduct a pooled analysis.

All outcomes and interventions subgroup categories without sufficient data for meta-analysis are reported in detail in the full Cochrane review.36

Discussion

Summary of main results

The main new finding from our updated review which was focused on RCTs only was that alerts interventions, whether computer alerts or human alerts, increased the absolute proportion of patients who received thromboprophylaxis by 21%, increased the absolute proportion of patients who received appropriate thromboprophylaxis by 16% and decreased the relative risk of symptomatic VTE at 3 months post treatment by 36%. Multifaceted interventions were associated with a modest 4% absolute increase in the prescription of thromboprophylaxis.

Quality of evidence and study limitations

This updated review improves on prior meta-analyses conducted in this area as it was restricted to RCTs only, thus providing a higher level of evidence, less widely differing estimates (ie, heterogeneity in results) across studies, more appropriate comparisons (ie, narrower confidence intervals) of pooled effects due to the reduced between-study variance, lower ROB of included studies and better quality of evidence for improvement in outcomes. Even if meta-analyses in our updated review were based on relatively small numbers of studies, we included a large number of patients (n=33 207 participants). We were able to account for clustering in one meta-analysis. The certainty of evidence for the improvement in outcomes was low or moderate in this updated review, as compared with very low in our previous review. The level of certainty of the evidence was downgraded from high to moderate or low because of methodological limitations in the included RCTs, and/or unexplained statistical heterogeneity in the pooled result and/or imprecision of pooled results related to the small number of VTE events (<300). Despite the fact that we could not assess for the presence of publication bias because all analyses were underpowered to distinguish chance from real asymmetry, there was a nearly symmetrical distribution of individual trials around the pooled estimate of effect in each meta-analysis. A number of factors could contribute to the perfect symmetry of the funnel plots, including selective outcome reporting, differences in methodological quality among studies, poor methodological quality leading to spuriously inflated effects in smaller studies, true heterogeneity, artefact and chance.38

Due to the lack of published trials, we were unable to provide quantitative estimates of the effects of the different types of system-wide interventions on the prescription of thromboprophylaxis and on key outcomes such as appropriate thromboprophylaxis, mortality and safety outcomes.

Agreements and disagreements with other reviews

Our findings are in agreement with other previous systematic reviews.34 35 54–61 Only two of the previous reviews performed a meta-analysis.35 57 In our previous review, multifaceted interventions were found to be the most effective system-wide intervention in observational studies.35 In the most recent systematic review and meta-analysis, the use of computer-based clinical decision support system in observational studies was associated with an increased rate of ordering appropriate thromboprophylaxis and a reduced rate of VTE in hospitalised surgical patients.57 The additional findings from our updated review compared with other reviews are most likely due to the inclusion of the largest number of RCTs involving a large number of hospitalised medical and surgical patients at risk of VTE.

Implications for practice

Our findings provide low-to-moderate certainty evidence to support the use of system-wide interventions to improve the prescription of thromboprophylaxis and decrease the incidence of symptomatic VTE in hospitalised adult medical and surgical patients at risk of VTE. Our results suggest that alerts interventions are associated with significant improvements in the prescription of prophylaxis. We also found that in individual studies that reported the outcome symptomatic VTE, the risk of symptomatic VTE was significantly reduced with alerts interventions, particularly with computer alerts. Multifaceted interventions were less effective overall than alerts interventions. Due to a lack of studies, we were not able to assess if multifaceted interventions that include an alert component were more effective than multifaceted interventions that did not include an alert.

Implications for research

The effect of system-wide interventions on important clinical outcomes such as VTE, mortality and safety outcomes should be assessed in well-designed multicentre RCTs that ideally include university-affiliated and community hospitals of various sizes. In addition, rates of prescription of appropriate prophylaxis should also be reported. Future research should also evaluate costs related to the implementation of various system-wide interventions. Finally, research should be conducted to better understand why such interventions do not have a larger effect on prescribing behaviours.

Conclusion

This systematic review assessed the effectiveness of various system-wide interventions aimed to increase the use of VTE prophylaxis and decrease the incidence of VTE in hospitalised patients. Alerts interventions (eg, computer alerts or human alerts) increased the prescription of appropriate thromboprophylaxis and decreased the incidence of symptomatic VTE in hospitalised medical and surgical patients at risk of VTE. This updated systematic review helps to identify the most effective system-wide interventions that could help healthcare providers to improve the use of appropriate VTE prophylaxis and thereby reduce the morbidity and the mortality associated with VTE in hospital.

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View Abstract

Footnotes

  • Contributors All authors contributed to the original Cochrane review and have approved this abridged Cochrane review article. SRK, GD and DRM: article reviewing, drafting the manuscript and resolving disputes; AP and KBF: statistical expertise; SRK, KBF, JDD, JE, AR, VT and WG: content expertise; GD: administrative coordination; DRM, AJK-D and MM: literature searches; all authors: revising the manuscript.

  • Funding This review was funded by a Canadian Institutes for Health Research Knowledge Synthesis Grant (# 141001) and a Canadian Institutes for Health Research Foundation Grant to SRK (# 143346). SRK holds a Tier 1 Canada Research Chair in venous thromboembolism. SRK, VT, AR and WG are investigators of the CanVECTOR Network (CIHR funding reference CDT-142654). AJK-D is supported by a CanVECTOR fellowship award. KBF is supported by a Junior II salary support award from the Fonds de recherche du Québec - Santé (Quebec Foundation for Health Research).

  • Competing interests The authors of this review have not received any funding to undertake this review other than the peer-reviewed grant noted above. The authors report the following declarations of interest: SRK has received grant support from public granting agencies (CIHR) for research on the treatment of venous thrombosis. She participated in industry-sponsored advisory board meetings (Boehringer-Ingelheim, Servier Canada, one meeting for each entity) on the treatment of venous thrombosis and provided expert testimony for the Canadian Medical Protective Association. SRK also reports that Sanofi Aventis has partnered with her institution to help create a center of excellence in thrombosis and anticoagulation. AJK-D’s institution has received funds from the Young Investigator Award from the American Society of Clinical Oncology Conquer Cancer Foundation. AJK-D reports receiving payments from Bristol Myers Squibb for lectures. JDD reports receiving funds from board memberships of Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi-Sankyo, Pfizer and Sanofi; consultancy fees from Actelion, Janssen Research and Development; funds for speaking at educational activities; royalties from the Merck Manual, Up-to-Date; JDD’s institution has received a grant from Boehringer-Ingelheim. JE received an honorarium for participation in a single meeting (focus group) with LEO Pharma for work unrelated to the submitted review. AR reports board membership and consultancy activities for BMS, BI, Pfizer and Bayer, and received payment for lectures from BMS, BI, Bayer and Pfizer not related to this review. AR also reports that his institution has received a CIHR grant for AIDS vascular research, and payment for development of educational presentations from BI, Bayer, BMS and Pfizer for the preparation of university-accredited symposiums and slide kits. VT has received, and currently holds grant support from the CIHR for research in venous thrombosis; has engaged in lectures sponsored by companies that manufacture anticoagulants (Leo Pharma, Bristol Myer Squibb and Pfizer); has received a grant from a manufacturer of an anticoagulant (Sanofi Aventis). MM reports receiving funds from American Academy of Clinical Toxicology for creation of search strategies for systematic reviews, and from International Team for Implantology for peer reviewing of search strategy. WG reports consultancy (Bayer Healthcare, Pfizer and Sanofi) and payment for lectures (Bayer Healthcare, Leo Pharma and Sanofi). Other support has been received by his institution from Sanofi for clinical and quality of care initiatives in thromboembolism within and outside of his institution. WG reports that these relationships in no way impacted his involvement with this Cochrane review. SRK, JDD, JE, AR, VT and WG are investigators and AJK-D is a fellow of the CanVECTOR Network; the Network receives grant funding from the Canadian Institutes of Health Research (Funding Reference: CDT-142654).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional data are available.

  • Patient consent for publication Not required.

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