CRD summary

This review concluded that heparin prophylaxis had little or no net benefit and mechanical prophylaxis provided no benefit and resulted in harm to patients with stroke. The authors' conclusions should be interpreted with some caution due to the acknowledged publication bias and the pooling of clinically heterogeneous and poor-quality studies.

Authors' objectives

To assess the benefits and harms of venous thromboembolism prophylaxis in hospitalised adult medical patients and those with acute stroke.

Searching

MEDLINE was searched from 1950 to April 2011 for studies in English; search terms were reported. The Cochrane Library was searched. Reference lists of relevant randomised trials and systematic reviews were screened.

Study selection

Randomised controlled trials (RCTs) that evaluated treatments (such as heparin, mechanical compression)commonly recommended and used to prevent venous thromboembolism compared to placebo, no treatment or active prophylaxis were eligible for inclusion. Trials had to report data specifically for hospitalised medical patients or those with stroke in acute or intermediate care facilities. RCTs of patients that were routinely treated with an anticoagulant or thrombolytic agent were excluded. Studies of heparin prophylaxis in patients with acute myocardial infarction were excluded.

The indication for prophylaxis varied considerably across studies; where reported, the most common reasons in the general medical patients were cancer, heart failure and respiratory disorders. Selection criteria and the resulting population varied considerably across studies. Where reported, mean age of participants ranged from 61 to 84 years, the proportion of males ranged from 15% to 78% and studies specified UK recruiting. The most commonly used prophylaxes were dalteparin, nadroparin, enoxaparin and unfractionated heparin with various dosing regimens, and compression stockings. The primary outcome was total mortality.

[A: Three reviewers divided the search results between them to check abstracts for studies of interest. All authors discussed the selected full-text papers.]

Assessment of study quality

RCTs that used an appropriate method of randomisation were included if they evaluated heparin. Two reviewers independently assessed study quality in terms of allocation concealment, blinding, intention-to-treat (ITT) analysis, reporting of study withdrawals and drop-outs and source of funding; disagreements were resolved by discussion with all authors. Evidence strength was evaluated on the basis of risk for bias, consistency, directness of the link between intervention and outcome, and precision.

Data extraction

Two reviewers independently extracted data to calculate odds ratios (OR) or risk ratios (RR) with 95% confidence intervals (CI) for: total mortality, symptomatic deep vein thrombosis (DVT), pulmonary embolism; and fatal pulmonary embolism, all bleeding, major bleeding and skin damage up to 120 days after randomisation. Disagreements were resolved by discussion with all authors. Additional information was requested from the original authors when required.

Methods of synthesis

Where event rates were less than 1%, Peto odds ratios with 95% CI were calculated. Where event rates were more than 1%, pooled relative risks with 95% CI were calculated using a random-effects model. Absolute reductions and increases in events per 1,000 patients were presented. Heterogeneity was assessed using X² and I² (I²>50% was considered high). Sensitivity analyses were conducted to assess the impact of double-blinding, use of heparin dosages no longer recommended for prophylaxis and for follow-up less than 90 days. Publication bias was investigated using funnel plots and the Egger intercept test.

Results of the review

Forty RCTs met the inclusion criteria (62,480 participants, range 20 to 14,578): 21 conducted in medical patients and 19 in patients with acute stroke. Seventeen trials reported adequate allocation concealment, 22 were reported as double blind (six also blinded outcome assessors), six blinded outcome assessors only, 19 used ITT analysis in at least some outcomes and 28 adequately described withdrawals and drop-outs.

Medical patients: Compared to no heparin, heparin reduced the incidence of pulmonary embolism (OR 0.69, 95% CI 0.52 to 0.90; 10 RCTs) and increased the incidence of bleeding (OR 1.34, 95% CI 1.08 to 1.66; eight RCTs), but had no significant impact on mortality (10 RCTs), symptomatic DVT (five RCTs), fatal pulmonary embolism (five RCTs) and major bleeds (nine RCTs). There was no significant difference between unfractionated heparin and low molecular weight heparin (LMWH) in terms of mortality (nine RCTs), pulmonary embolism (nine RCTs), bleeding (eight RCTs), symptomatic DVT (three RCTs), fatal pulmonary embolism (three RCTs) and major bleeds (nine RCTs).

Acute stroke: Compared to no heparin, heparin increased the incidence of major bleeding (OR 1.66, 95% CI 1.20 to 2.28; eight RCTs), but had no significant impact on mortality (eight RCTs), symptomatic DVT (one RCT), pulmonary embolism (five RCTs), fatal pulmonary embolism (two RCTs) and all bleeding (six RCTs). There was no significant difference between unfractionated heparin and LMWH in terms of mortality (five RCTs), pulmonary embolism (four RCTs), bleeding (five RCTs), symptomatic DVT (two RCTs), fatal pulmonary embolism (four RCTs) and major bleeds (five RCTs). There was no significant impact of mechanical prophylaxis on mortality (three RCTs), symptomatic DVT (one RCT), pulmonary embolism (two RCTs). Mechanical prophylaxis increased skin damage (RR 4.02, 95% CI 2.34 to 6.91; one RCT).

Results were presented for medical and stroke patients combined and for sensitivity analyses. Results were tabulated for comparisons evaluated in single RCTs. Data from two RCTs that compared different durations of LMWH were reported. The authors reported evidence of publication bias in the analyses of heparin versus no heparin.

Authors' conclusions

Heparin prophylaxis had no significant effect on mortality, may have reduced pulmonary embolism in medical patients and all patients combined, and led to more bleeding and major bleeding events, thus it resulted in little or no net benefit. Mechanical prophylaxis provided no benefit and resulted in clinically important harm to patients with stroke.

CRD commentary

The review addressed a clear research question supported by appropriate inclusion criteria. Relevant sources were searched. Language bias may have been present and the authors reported evidence for the presence of publication bias. Data extraction and the quality assessment were conducted by two independent reviewers. Study quality was assessed using appropriate criteria and the results were reported in full. Many of the included studies had methodological limitations; double-blinding was the only quality criterion investigated in sensitivity analyses. Although statistical heterogeneity was generally low, clinical heterogeneity was substantial across the studies and so the generalisability of the pooled results to any specific population in clinical practice was uncertain.

The authors' conclusions should be interpreted with some caution due to the acknowledged publication bias and the pooling of clinically heterogeneous and poor-quality studies.

Implications of the review for practice and research

Practice: The authors stated that where heparin prophylaxis was to be used in hospitalised nonsurgical patients, the choice of agent would probably depend on factors such as convenience and cost rather than comparative effectiveness and harms.

Research: The authors did not give any recommendations for research.

Funding

American College of Physicians.

Bibliographic details

Lederle FA, Zylla D, MacDonald R, Wilt TJ. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American college of physicians clinical practice guideline. Annals of Internal Medicine 2011; 155(9): 602-615. [PubMed: 22041949]

Original Paper URL

http://www.annals.org/content/155/9/602.abstract

Indexing Status

Subject indexing assigned by NLM

MeSH

Anticoagulants /administration & dosage /adverse effects /therapeutic use; Comparative Effectiveness Research; Hemorrhage /chemically induced; Heparin /administration & dosage /adverse effects /therapeutic use; Hospital Mortality; Hospitalization; Humans; Odds Ratio; Publication Bias; Pulmonary Embolism /mortality /prevention & control; Randomized Controlled Trials as Topic; Risk Assessment; Stockings, Compression; Stroke /complications; Venous Thromboembolism /prevention & control

AccessionNumber

12011006520

Database entry date

09/11/2011

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.