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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials

CC Hsia, IH Chin-Yee, and VC McAlister.

Review published: 2008.

CRD summary

This review evaluated the benefits and harms of treatment with recombinant activated factor VII in non-haemophilia patients. The authors concluded that treatment reduced the need for blood transfusion and may reduce mortality. Therapeutic doses limited to 90υg/kg may be the most appropriate treatment regimen. The authors' conclusion reflected the evidence presented and appears reliable.

Authors' objectives

To evaluate the benefits and harms of treatment with recombinant activated factor VII (rFVIIa) in non-haemophilia patients.

Searching

MEDLINE, EMBASE, BIOSIS Previews, CINAHL, Science Citation Index Expanded, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched up to November 2007. There were no publication or language restrictions. Bibliographies of identified material presented at major scientific meetings were scanned for additional studies. Trial investigators and Novo Nordisk (manufacturer of rFVIIa) were consulted.

Study selection

Placebo-controlled randomised controlled trials (RCTs) of rFVIIa in patients without haemophilia were eligible for inclusion in the review.

Patients with a variety of clinical conditions were included. Most patients were adults; some trials included children. Treatment was administered therapeutically in slightly more than half of the included trials. The dosing schedule of rFVIIa ranged from 5ug/kg to 200ug/kg given one or more times. Total dose of rFVIIa ranged from 5υg/kg to 1,120υg/kg. Outcomes measured were all-cause mortality, thromboembolic adverse events (TAE) classified as arterial (stroke, myocardial infarction, arterial embolism) and venous (deep vein thrombosis, pulmonary embolism) and the need for additional red blood cell transfusions (patients previously received eight units of blood and an additional 20 units or more). Patients with acquired inhibitors, rare congenital coagulation factor deficiencies and inherited platelet disorders were excluded. Healthy recipients of the treatment were not included in the primary analysis, but were used in the sensitivity analysis and in the evaluation of adverse events.

The authors did not state how many reviewers carried out study selection.

Assessment of study quality

Trial quality was assessed in terms of adequacy of randomisation, allocation concealment and follow-up.

Three reviewers independently carried out the quality assessment. Disagreements were resolved by consensus.

Data extraction

Data were extracted on the number of events and number of patients to enable the calculation of odds ratios (OR) and 95% confidence intervals (CI).

Three reviewers independently carried out data extraction. Disagreements were resolved by consensus.

Methods of synthesis

Odds ratios were weighted according to their 95% CI in a random-effects meta-analysis (DerSimonian and Laird). Statistical heterogeneity was assessed by the Mantel-Haenszel method and I2 statistic. Subgroup analysis was carried out according aetiology of the disease: intracranial haemorrhage (ICH) or not; prophylactic or therapeutic administration of rFVIIa; single or multiple doses; and total dose. Sensitivity analysis included addition of trials of healthy volunteers and trauma trials in the additional transfusion data set.

Results of the review

Twenty-two RCTs were included in the review (n=3,184). All trials were reported to have adequate randomisation and allocation concealment. Follow-up ranged from six hours to 90 days.

The requirement for additional red blood cell transfusion was significantly lower in the rFVIIa group than the placebo group (OR 0.54, 95% CI 0.34 to 0.86, I2=49.5%; 11 trials). Mortality was lower in the rFVIIa group, but this did not reach statistical significance. Thromboembolic events were higher in the treatment group compared to placebo, but this was not statistically significant. A statistically significant increase in myocardial infarction rate was reported in the treatment group compared to placebo (2.8% versus 1%; p<0.01).

Subgroup analyses revealed that transfusion requirements were significantly reduced if rFVIIa dose was ≤90υg/kg (OR 0.42, 95% CI 0.19 to 0.93), treatment was administered once (OR 0.33, 95% CI 0.11 to 0.96) and administered therapeutically (OR 0.54, 95% CI 0.34 to 0.86) or prophylactically (OR 0.50, 95% CI 0.25 to 0.99).

Sensitivity analyses did not materially alter the main findings.

Authors' conclusions

Use of rFVIIa reduces the need for blood transfusion and it may reduce mortality. Therapeutic doses limited to 90υg/kg may be the most appropriate treatment regimen. There is no increased risk of venous thrombosis, but arterial thrombosis is a possibility.

CRD commentary

This review addressed a clear question and appeared to be supported by detailed inclusion criteria for all aspects, although it was unclear whether the reported outcomes were preselected. The search strategy included several relevant sources. Sufficient steps were taken to minimise publication and language biases. Selection bias in the inclusion of studies was a possibility, but the rest of the review process was conducted with attempts to minimise error and other biases. Appropriate quality assessment criteria were applied and the results indicated that the included trials were methodologically robust. Study details were clearly presented. The chosen method of synthesis appeared to be appropriate in light of the reported statistically heterogeneity.

The authors' conclusion reflected the evidence presented and (with a caveat for selection bias) is likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that there was insufficient evidence to endorse unrestricted use of rFVIIa in non-haemophilic patients.

Research: The authors stated that further trials should continue to test the single therapeutic dose of rFVIIa at conventional doses in patients at high risk of persistent haemorrhage despite receipt of standard care. Trials should stratify patients according to their premorbid risk of stroke or myocardial infarction, seek a relative reduction in mortality of 10% to 15%, and contain a sample size of at least 4,000 patients.

Funding

Not stated.

Bibliographic details

Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials. Annals of Surgery 2008; 248(1): 61-68. [PubMed: 18580208]

Indexing Status

Subject indexing assigned by NLM

MeSH

Erythrocyte Transfusion /statistics & numerical data; Factor VIIa /administration & dosage /pharmacology /therapeutic use; Hemorrhage /drug therapy /prevention & control; Hemostasis /drug effects; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins /administration & dosage /pharmacology /therapeutic use; Thromboembolism /chemically induced /epidemiology

AccessionNumber

12008105601

Database entry date

12/01/2011

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.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 18580208

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