Does pharmacological thromboprophylaxis decrease the incidence of venous thromboembolism (VTE) events and increase the incidence of major bleeding events of hospitalized cancer patients in randomized controlled trials?

A search strategy will be done through OVID, of MEDLINE (1950 to present), EMBASE (1980 to present), the Cochrane Central Register of Controlled Trials (CENTRAL), and all EBM Reviews. We plan to adapt our search to each database's preferred subject headings. Publications will also be sought through a hand-search of journals and of the America Society of Hematology (ASH) and International Society of Thrombosis and Haemostasis (ISTH) conference proceedings for the past 5 years (2007-2012). The references lists of identified trials will be reviewed to identify additional articles. There will be no restriction on language.

We will include randomized controlled trials assessing pharmacological thromboprophylaxis in hospitalized acute medically ill cancer patients

VTE and major bleeding episodes.

Hospitalized cancer patients.

Main intervention: Pharmacological thromboprophylaxis.

1) Low-molecular-weight-heparin (LMWH): Prophylactic doses of dalteparin, enoxaparin, tinzaparin, nadroparin, bemiparin, certoparin.

2) Unfractionated heparin (UFH) (Prophylactic doses of 5000 IU BID or TID).

3) Fondaparinux: prophylactic doses.

Comparison: Placebo. All other co-interventions (e.g. mechanical thromboprophylaxis) should be similar among the compared groups

Inclusion Criteria

1. Hospitalized acute medically ill adults including patients with cancer.

2. The intervention will be any pharmacological thromboprophylaxis .

3. Randomized controlled trials.

4. One or more primary or secondary outcome measures will be reported.

Exclusion Criteria:

1. Children.

2. Studies specifically conducted in surgical patients.

3. Non-randomized controlled trial.

4.Study conducted specifically in patients with central venous catheters.

Primary outcomes

• Rates of VTE (Symptomatic and screening deep vein thrombosis (DVT) or pulmonary embolism (PE)).

• Major bleeding episodes.

VTE events will need to be objectively confirmed by radiological studies including compressive ultrasonography, contrast venography, ventilation/perfusion (V/Q) scan, pulmonary angiogram or computed tomographic pulmonary angiography.

Major bleeding episodes will be defined as per the individual study definitions.

Secondary outcomes

• Arterial events.

• Major bleeding as per the ISTH definition.

• Minor bleeding episodes (not “major” episodes by above definition).

• All-cause mortality.

• Cancer-related mortality.

Reviewers (MC and PM) will independently assess citations retrieved from the literature search for relevant trials with the aim of minimizing bias.

Following the first preliminary screening of abstracts, the reviewers will acquire copies of all potentially relevant original publications for closer review and final study selection.

Decisions about study citations retrieved from the search and inclusion will be made independently, and a consensus will be achieved to resolve any discrepancies.

Both reviewers will obtain the data from the selected studies. The data will be compared, and the differences will be resolved by consensus. If we need further information on a specific paper, we intend to communicate with the authors.

Both authors will independently assess the quality of all included trials and we will use the Risk of Bias Assessment Tool from the Cochrane Handbook for randomized trials including the assessment of:

• Masking of randomization.

• Masking of intervention.

• Completeness of follow-up.

• Masking of outcome measurements.

Statistical methods will include calculation of relative risk, number to treat and weighted mean difference where appropriate. 95% confidence intervals for these estimates will be calculated. We will use a random-effect model for meta-analyses and apply tests for between-study heterogeneity including the I-squared test to assess the appropriateness of combining studies.

The impact of publication bias, explored using funnel plots, will be performed and reported if a minimum of 8 trials are included in the analyses.

If heterogeneity exists, we will examine potential sources using the following steps: subgroup analysis (trial quality, dosing regiments, etc), meta-regression (if feasible), and sensitivity analyses (e.g. LMWH Vs. UFH).

Publication into a peered-reviewed medical journal.

Marc Carrier

Ottawa Hospital - General Campius

501 Smyth Road - Box 201 A

Ottawa, ON,Canada K1N 8L6

mcarrier@toh.on.ca

None

Dr Marc Carrier, Ottawa Hospital Research Institute
Dr Jeffrey Zwicker, Beth Israel Deaconess Medical Center
Dr Patricia Moretto, Ottawa Hospital Research Institute
Dr Alok Khorana, University of Rochester

23 August 2012

28 February 2013

None

None known

English

Canada, United States of America

Subject indexing assigned by CRD

Drug Therapy; Humans; Hospitalization; Neoplasms; Venous Thromboembolism

23 August 2012

23 January 2013