Randomised control trial
H. Decousus, P. Mismetti, R. Bauersachs, et al.Fondaparinux for the Treatment of Superficial-Vein Thrombosis in the Legs
The New England Journal of Medicine
September 23, 2010; 1222-1232
- Submitted by:Brian Adams - Medical Student
- Institution:Tulane University School of Medicine
- Date submitted:12th July 2011
1
Objectives and hypotheses
1.1
Are the objectives of the study clearly stated?
To establish the efficacy and safety of prophylactic anticoagulant treatment for patients with acute, symptomatic superficial-vein thrombosis in the legs but without concomitant deep-vein thrombosis or symptomatic pulmonary embolism at presentation.
2
Design
2.1
Is the study design suitable for the objectives
Yes, a treatment group was compared to a control group in terms of theoretically justifiable efficacy outcomes (including reduction in all-cause mortality, reduction in deep-vein thromboses or pulmonary embolism, and reduction in symptomatic extension of the original thromboses to the saphenofemoral junction,) as well as justifiable safety outcomes (including major bleeding, clinically relevant nonmajor and minor events, and arterial thromboembolic complications.)
2.2
Who / what was studied?
3002 consecutive hospitalized or nonhospitalized patients, 18 years of age or older, with acute, symptomatic lower-limb superficial-vein thrombosis at least 5 cm long (confirmed with compression ultrasonography) from 171 centers in 17 countries were randomized into the study's two cohorts.
2.3
Was this the right sample to answer the objectives?
Yes.
2.4
Is the study large enough to achieve its objectives? Have sample size estimates been performed?
The authors estimated that a sample of 2500 total patients would have at least 98% power to detect a 50% reduction in the rate of the primary efficacy outcome, assuming an incidence of the primary efficacy outcome of 8.0% in the placebo group. (A prior prospective, observational study cited by the authors determined the 3-month risk of such complications to be 8.3%.) However, perhaps due to the exclusion of high-risk patients such as those with cancer treated in the prior 6 months, or those with prior documented deep-vein thrombosis or pulmonary embolism in the prior 6 months, the initial rate of the primary efficacy outcome was only 3.1% as an overall event rate, as measured by an independent steering committee without knowledge of group assignments. The committee decided to increase the sample to 3000 patients in order to preserve at least 90% power to detect a 50% reduction in the rate of the primary efficacy outcome.
2.5
Were all subjects accounted for?
Yes.
2.6
Were all appropriate outcomes considered?
Yes. A primary composite based on death, pulmonary embolism, deep-vein thrombosis, extension of superficial-vein thrombosis to the saphenofemoral junction and recurrence of superficial-vein thrombosis. Also symptomatic deep-vein thrombosis or symptomatic pulmonary embolism were considered as secondary efficacy outcomes, as well as surgery for superficial-vein thrombosis.
2.7
Has ethical approval been obtained if appropriate?
The study was conducted according to the ethical principles stated in the Declaration of Helsinki and local regulations. The protocol was approved by an independent ethics committee, and written informed consent was obtained from all patients before they underwent randomization. The study was placebo-controlled,
since no standard treatment had been established in this clinical setting. This design was considered to be ethical, since all the patients benefited from close clinical monitoring, with adequate diagnostic procedures performed in the event of new or persistent symptoms, and since an independent data and safety monitoring committee carefully oversaw the study outcomes.
since no standard treatment had been established in this clinical setting. This design was considered to be ethical, since all the patients benefited from close clinical monitoring, with adequate diagnostic procedures performed in the event of new or persistent symptoms, and since an independent data and safety monitoring committee carefully oversaw the study outcomes.
2.8
Were the patients randomised between treatments?
Yes.
2.9
How was randomisation carried out?
With use of a central telephone system and a computer-generated randomization list, consecutive patients were randomly assigned in a 1:1 ratio to either receive fondaparinux at a daily dose of 2.5 mg or placebo. Randomization was performed in blocks of four without any stratification.
2.10
Are the outcomes clinically relevant?
Yes, in addition to mortality, deep-venous thromboses and pulmonary embolisms are significant indicators of morbidity with subsequent mobilization of healthcare resources.
3
Measurement and observation
3.1
Is it clear what was measured, how it was measured and what the outcomes were?
Yes, rates of death, deep-venous thromboses, pulmonary embolisms, surgical interventions, major bleeding events (fatal, symptomatic in a critical organ, or causing 2 g/dl fall in hemoglobin/necessitating transfusion of at least 2 units of packed red cells or whole blood,) clinically relevant nonmajor bleeding, minor bleeding, arterial thromboembolic complications, and all other adverse events.
3.2
Are the measurements valid?
Yes, the assignment of patients to treatment was randomized, all patients who entered the trial were accounted for, the patients and clinicians were blinded to treatment, the groups were similar at the start of the trial (including age, sex, body mass index, eleven relevant categories of prior medical conditions, and nine classes of relevant treatment regimens at inclusion) and the groups were monitored for supplemental treatments and rates of adherence.
3.3
Are the measurements reliable?
3.4
Are the measurements reproducible?
3.5
Were the patients and the investigators blinded?
Yes, Fondaparinux and placebo were packaged in identical boxes containing visually identical, prefilled 0.5-ml single-dose syringes. Each patient received one box containing 45 single-dose syringes (1 per day for 45 days) of either 2.5 mg of fondaparinux sodium (Arixtra, GlaxoSmithKline) or placebo (sodium chloride).
4
Presentation of results
4.1
Are the basic data adequately described?
Yes. Study populations and treatments are delineated. The primary efficacy outcome is presented as an absolute risk reduction, each component of the primary efficacy composite is also compared individually to the placebo arm, and all data is included in tabular format with both absolute risk reduction and relative risk values assigned to each line item. Finally, safety outcomes are adequately addressed with data included in tabular format.
4.2
Were groups comparable at baseline?
Yes, the most disparate variables at baseline were body mass index over 30 being more heavily represented in the treatment group (38.2% vs. 35.7% with a P Value of 0.16) and chronic heart failure being less heavily represented in the treatment group (4.7% vs. 5.9% with a P Value of 0.17.)
4.3
Are the results presented clearly, objectively and in sufficient detail to enable readers to make their own judgement?
Yes.
4.4
Are the results internally consistent, i.e. do the numbers add up properly?
Yes.
4.5
Were side effects reported?
Yes, including the rates of drug-related, nonfatal serious, those leading to discontinuation of study treatment, and those leading to withdrawal from the study.
5
Analysis
5.1
Are the data suitable for analysis?
Yes, driven by suitable power, non-biased, and medically justified endpoints that are easily defined.
5.2
Are the methods appropriate to the data?
Yes.
5.3
Are any statistics correctly performed and interpreted?
Yes. Two-sided Fisher's exact test at 5% significance level was performed for efficacy evaluations. Time-to event outcomes estimated by means of the Kaplan–Meier method were compared with the use of the log-rank test; a prespecified sensitivity analysis was performed in which patients with missing data on the primary efficacy outcome were excluded. And Zelen’s exact test was used to verify the consistency of the treatment effect across 16 prespecified sets of subgroups and 1 set of subgroups that was defined post hoc.
6
Discussion
6.1
Are the results discussed in relation to existing knowledge on the subject and study objectives?
Yes. The primary efficacy outcome event rate in the study's placebo group is referenced to a prospective observational study in which a similar composite outcome was evaluated.
6.2
Is the discussion biased?
No. The authors systematically present their results in a clear numerical fashion and also present a robust discussion of their study's potential limitations, including difficulty in applying the data to clinical practice, the use of a 45-day subcutaneous regimen, and the need for a cost analysis of the treatment and its impact on outcomes.
7
Interpretation
7.1
Are the authors' conclusions justified by the data?
Yes. The authors did not extend their conclusions beyond the population studied, nor the drug and dosage studied: patients with isolated, symptomatic superficial-vein thrombosis in the legs treated with 2.5 mg of fondaparinux once daily for 45 days.
7.2
What level of evidence has this paper presented? (using CEBM levels)
1b
7.3
Does this paper help me answer my problem?
Yes. It answers the question of how many cases of symptomatic superficial-vein thromboses need to be treated to prevent one case of deep-vein thrombosis or pulmonary embolism using a 45 day sub-cutaneous regimen of 2.5 mg fondaparinux. It also answers the question of the treatment protocol's safety in regards to all-cause mortality, and more narrow analyses of major/non-major bleeding, and a conglomerate rate of side-effects.
8
Implementation
8.1
Can any necessary change be implemented in practice?
Yes.
8.2
What aids to implementation exist?
8.3
What barriers to implementation exist?
Patient compliance with an extended subcutaneous regimen, although the authors note a compliance of over 90%.