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Quality Improvement

Review: Interventions to increase thromboprophylaxis do not benefit inpatients at risk for VTE

Kahn SR, Morrison DR, Cohen JM, et al. Interventions for implementation of thromboprophylaxis in hospitalized medical and surgical patients at risk for venous thromboembolism. Cochrane Database Syst Rev. 2013;(7):CD008201.

Clinical impact ratings: h ★★★★★★✩ H ★★★★★✩✩ c ★★★★★✩✩ p ★★★★★✩✩ Question What is the effectiveness of interventions intended to increase thromboprophylaxis and reduce venous thromboembolism (VTE) in at-risk hospitalized adult medical and surgical patients?

Review scope Included studies compared individual- or cluster-targeted strategies (alerts, education, or multifaceted) intended to increase prescription of thromboprophylaxis and/or reduce VTE with no intervention, a policy, or another intervention in medical or surgical inpatients at risk for VTE. Studies in which the interventions were not clearly described were excluded. Outcomes were implementation of prophylaxis (pharmacologic or mechanical), symptomatic VTE, asymptomatic VTE, and safety outcomes.

Review methods MEDLINE, EMBASE/Excerpta Medica, SCOPUS (all to Apr 2010), Cochrane CENTRAL (2010, Issue 3), and Cochrane Peripheral Vascular Diseases Group’s Specialised Register ( Jul 2010) (which includes studies identified from MEDLINE, EMBASE/ Interventions to increase thromboprophylaxis vs control in hospitalized adults at risk for VTE* Outcomes VTE

Intervention type

Effect of intervention


Reduction (1 RCT, n = 2506) No difference (1 RCT, n = 2493)

Symptomatic deep venous thrombosis


No difference (1 RCT, n = 2493)

Asymptomatic deep venous thrombosis


No difference (1 RCT, n = 812)


Reduction (1 RCT, n = 2506)

Symptomatic pulmonary embolism

No difference (1 RCT, n = 2493)

Excerpta Medica, CINAHL, AMED, and hand searches of relevant journals) were searched for randomized controlled trials (RCTs), cluster RCTs, quasi-RCTs, and nonrandomized studies. Reference lists were reviewed. Studies that simply delivered published guidelines were excluded. 55 studies met the inclusion criteria; 54 (n = 78 343) had data available for analysis. RCTs and non-RCTs were analyzed separately; only analyses of RCTs are reported here. Of the 8 RCTs (n = 20 294), which included 1 cluster RCT and 1 quasi-RCT, none clearly had adequate allocation concealment, 1 clearly reported adequate randomization sequence generation, and 3 reported adequate blinding of patients and outcome assessors.

Main results No RCTs assessed educational interventions. Meta-analysis of 4 RCTs showed that alert interventions increased the proportion of patients who received prophylaxis (risk difference 13%, 95% CI 1% to 25%); heterogeneity across studies was high (I2 = 95%). 1 RCT found that multifaceted interventions increased prophylaxis from 27% to 55%, and 1 trial found that they did not but was marginally nonsignificant. Results for other main outcomes are in the Table. No trial found that the intervention increased risk for safety outcomes.

Conclusion Interventions to increase thromboprophylaxis in at-risk hospitalized patients increase prescription of thromboprophylaxis, but there is inconsistent evidence for an effect on clinical outcomes. Source of funding: Canadian Institutes for Health Research Knowledge Synthesis Grant. For correspondence: S.R. Kahn, McGill University, Montreal, QC, Canada. E-mail [email protected]

*RCT = randomized controlled trial; VTE = venous thromboembolism. Analysis includes randomized controlled trials only.

Commentary Establishing mechanisms to ensure physician adherence with evidenced-based guidelines is essential to improve quality of patient care and comply with requirements from accrediting organizations. The systematic review by Kahn and colleagues showed that providerdirected alerts double prophylaxis rates; however, < 40% of inpatients receive prophylaxis, even when alerts are used. Combining education and alerts in a multifaceted approach improves prophylaxis rates in nonrandomized studies and has mixed results in RCTs. Despite the increase in VTE prophylaxis, neither alerts nor multifaceted approaches decrease risk for VTE events. 2 randomized studies of the effect of alert systems on VTE outcomes found differing results. Therefore, although alerts and multifaceted approaches may improve prophylaxis rates, the evidence considered in the present meta-analysis does not establish that these systems will improve patient-important outcomes. JC10

Piazza and colleagues investigated an effort-intensive intervention of physician phone call alerts in high-risk patients considered eligible for VTE prophylaxis at hospital discharge. This study was initiated before completion of the EXCLAIM (1), MAGELLAN (2), and ADOPT (3) trials, which highlight questions about the net clinical benefit of postdischarge VTE prophylaxis in patients admitted for medical illness. Piazza and colleagues found that physician alerts improved prophylaxis rates by 12% (unweighted). If these data had been included in the systematic review by Kahn and colleagues, the unweighted risk difference for alerts would have decreased from 19% to 17%. Like the trials in the metaanalysis by Kahn and colleagues, alerts did not affect symptomatic VTE in the study by Piazza and colleagues, but the study was underpowered for that outcome. The Kaplan–Meier curves for both the alert and control groups nearly overlap and depict a steady

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(continued on page 11) 19 November 2013 | ACP Journal Club | Volume 159 • Number 10

Quality Improvement

Thromboprophylaxis alerts for physicians did not reduce VTE in at-risk patients after discharge

Piazza G, Anderson FA, Ortel T, et al. Randomized trial of physician alerts for thromboprophylaxis after discharge. Am J Med. 2013;126: 435-42.

Clinical impact ratings: h ★★★★★★✩ H ★★★★★✩✩ Question Do thromboprophylaxis alerts for physicians before discharge of hospitalized patients at high risk for venous thromboembolism (VTE) reduce VTE after discharge?

Methods Design: Randomized controlled trial. NCT00853463. Allocation: Concealed.* Blinding: Blinded* (outcome assessors, {data collectors, data analysts, and safety committee}†). Follow-up period: 90 days. Patients: 2513 adults ≥ 18 years of age (mean age 69 y, 53% women, 63% received inpatient prophylaxis) who were about to be discharged from hospital and were at high risk for VTE. Exclusion criteria included hospitalization on surgical or rehabilitation units, existing orders for postdischarge mechanical or pharmacologic prophylaxis, or plans for postdischarge anticoagulation therapy. Thromboprophylaxis alerts vs no alerts for physicians before discharge of patients at high risk for VTE‡

Symptomatic DVT only Mortality Major bleeding (30 d)

Alerts 2.4% 19% 1.0%

No alerts At 90 d unless otherwise indicated RRR (95% CI) NNT (CI) 2.5% 1.1%

Main results Physician alerts increased prescription of thromboprophylaxis (22% vs 9.7%, relative benefit increase 130%, 95% CI 89 to 180) but did not reduce clinical outcomes (Table).

Conclusion Thromboprophylaxis alerts for physicians before discharge of patients at high risk for venous thromboembolism (VTE) did not reduce VTE after discharge. *See Glossary.


†Information provided by author.

8% (−7 to 22)


Source of funding: Not stated.

6% (−100 to 56)


6% (−54 to 43)


Outcomes: Symptomatic deep venous thrombosis (DVT) or pulmonary embolism (PE) confirmed by diagnostic imaging at 90 days. Secondary outcomes included prescription of prophylaxis. Safety endpoints included mortality and major bleeding at 30 and 90 days. Patient follow-up: 99.9% (intention-to-treat analysis).

Setting: 18 clinical centers in the USA.


Intervention: Physician alert (n = 1252) or no alert (n = 1261). In the alert group, attending physicians were alerted via page and informed by telephone by a hospital staff member that their patient was at high risk for VTE at discharge, that there was no order for postdischarge thromboprophylaxis, and that an order should be considered. Recommendations did not specify the type or duration of prophylaxis that should be implemented.



Symptomatic VTE



12% (−26 to 67)


Symptomatic PE only



116% (−17 to 466)


Symptomatic DVT and PE 0.4%


151% (−51 to 1181)


For correspondence: Dr. S.Z. Goldhaber, Brigham & Women’s Hospital, Boston, MA, USA. E-mail [email protected]

‡DVT = deep venous thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism; other abbreviations defined in Glossary. RRR, RRI, NNT, NNH, and CI calculated from control event rates and hazard ratios in article.

Commentary (continued from page 10) rate of symptomatic VTE throughout the follow-up period. This suggests that, although these patients are at risk for VTE, the rate of prophylaxis and/or the anticoagulant dose was insufficient. When viewed together, these studies show that alert systems increase VTE prophylaxis rates but do not sufficiently impact VTE events. Future research will need to better define ways to alter physician behavior, assess the extent to which patient adherence is a modifiable factor, and determine the cost-effectiveness of those interventions before VTE prophylaxis alert systems are widely adopted by hospitals or mandated by regulatory agencies.

References 1. Hull RD, Schellong SM, Tapson VF, et al; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010;153: 8-18. 2. Cohen AT, Spiro TE, Büller HR, et al; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368:513-23. 3. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011;365:2167-77.

Lisa M. Baumann Kreuziger, MD, MS Blood Center of Wisconsin Milwaukee, Wisconsin, USA 19 November 2013 | ACP Journal Club | Volume 159 • Number 10 Downloaded From: by a Universite Laval Biblioteque User on 08/06/2017

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ACP Journal Club. Review: interventions to increase thromboprophylaxis do not benefit inpatients at risk for VTE.

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