Results of the CONTROL Trial: Efficacy and Safety of Recombinant

Activated Factor VII in the Management of Refractory Traumatic

Hemorrhage

(J Trauma. 2010;69:489–500)

Background• Traumatic coagulopathy contributes to early death by

exsanguination and late death in multiple organ failure• Blood products aimed at restoring “normal” coagulation test results

may be inadequate in major injuries• Recombinant Factor VIIa is a procoagulant that might limit bleeding

and improve trauma outcomes• Factor VII acts physiologically by enhancing clot formation in the

presence of tissue factor expressed on injured or ischaemic vascular subendothelium

• It also acts pharmacologically, binding to activated platelets, increasing thrombin burst, and promoting the formation of a stable haemostatic plug

• In a large prospective phase II trauma trial, rVIIa decreased blood loss in patients surviving the first 48 hours without increasing thrombotic events

• rVIIa is widely used anecdotally as an adjunct to the management of traumatic coagulation

• rVIIa is expensive

Objectives

• To evaluate the safety and efficacy of rFVIIa as an adjunct to direct haemostasis in major trauma

Methods

• Prospective, randomised, double blind, multi-centre placebo controlled trial

• 150 hospitals (including Liverpool Hosp)• 26 countries• Aug 2005 to Sept 2008• Enrolment target 1502 (1267 blunt)• Efficacy was assessed through 30 days• Safety was assessed through 90 days

Eligibility• Inclusion criteria

– ≥ 18 years of age– Received ≥ 4 units RBC– Continuing torso and/or proximal lower extremity bleeding

despite standard haemostatic interventions• SBP ≤ 90mmHg or • lactate > 6 mmol/L or base deficit ≥ 5 mEq/L or• IV fluid of ≥ 1 L/hr

• Exclusion criteria– > 70 years of age– Moribund– Severe brain injury (AIS ≥ 4 or GSC ≤ 5)– Injured > 12 hours before randomisation– Injured > 4 hours before hospital arrival– Received > 8 units RBC

Randomisation

• Randomisation was conducted in random permuted blocks, with the allocation of every randomisation block to a specific centre

• Eligible patients were randomised and assigned the lowest available randomisation number

• Randomisation was confirmed through an interactive voice response system set up by the Sponsor who was accessible by telephone or the internet

• Data management and data entry were performed by the Sponsor

Trial schematic

Endpoints

• The primary efficacy endpoint was tiered– 1st tier superiority in all cause 30-day mortality in blunt trauma– 2nd tier non-inferiority on 30-day mortality and superiority on 30-

day morbidity (pulmonary and/or renal dysfunction at day 30)

• Secondary endpoints included– transfused units of RBC, fresh frozen plasma (FFP), platelets,

cryoprecipitate, fibrinogen concentrate, and all allogeneic blood products at 24 hours and 48 hours after dosing and number of patients requiring transfusion of 10 units or more of RBC at 24 hr

• Other endpoints– number of patients with multiple organ failure (MOF) or single

organ failure (SOF) and days alive and free from MOF, SOF, intensive care unit (ICU), hospital or ventilator, and/or renal replacement therapy, through day 30

Statistical Analysis

• Sample size based on comparisons of mortality for the intent-to-treat population using the one-sided X2 test (α=2.5%) and 16.7% mortality reduction with rFVIIa, assuming 30% mortality for placebo

• N=1276 blunt trauma patients• Treatment differences in 30-day mortality

assessed by 2-sided superiority test and a (1-sided) non-inferiority test, α=5%

• All other analyses were assessed using two-sided superiority tests, α=5%

Statistical Analysis cont

• 30 day Mortality, MOF, SOF by logistic regression – adj for age, ISS, GCS, INR (see Table 1), PaO2/FIO2 ratio<300

• Days alive and free of MOF, SOF, ventilator, renal replacement therapy, ICU, hospitalization thru day 30 by similarly adj ANCOVA

• RBC, FFP, platelets, cryoprecipitate /fibrinogen concentrates, total allogeneic units transfused in 24 & 48 hr by Wilcoxon-Mann-Whitney

• AEs by 2-sided X2 / Fisher’s

Statistical Analysis cont

• If the first-tier endpoint, superiority in all-cause 30-day mortality in blunt trauma, was not met, the second-tier primary conditional endpoint of noninferiority on mortality and superiority on durable morbidity was applied

What is a noninferiority test?

Subject disposition

Demographics and baseline characteristics ITT population

Clinical outcomes 30 dayITT analysis

Transfusion requirementsITT population

AEs through day 90Safety population

Results• Lower than expected mortality in the placebo group• Study terminated at 573 patients (481 blunt, 92

penetrating) as demonstration of superiority deemed to be “futile”

• 30 day mortality– 11.0% (rFVIIa) vs 10.7% (Placebo) ps=0.93, pn=0.37, blunt– 18.2% (rFVIIa) vs 13.2% (Placebo) ps=0.40, penetrating

• RBC units through 48 hours (rFVIIa vs Placebo)– 7.8 (rFVIIa) vs 9.1 (Placebo) ps=0.04, blunt

• Total allogeneic units through 48 hours– 19.0 (rFVIIa) vs 23.5 (Placebo) ps=0.04, blunt

• Thrombotic AEs– 36 (rFVIIa) vs 33 (Placebo) ps=0.38– 2 (rFVIIa) vs 4 (Placebo) ps=0.41

Post-hoc questions

• Did rFVIIa reduce the need for blood products in bleeding trauma patients?

• Is rFVIIa safe?

• In the aggregate, does rFVIIa help patients?

Did rFVIIa reduce the need for blood products in bleeding trauma patients?

Did rFVIIa reduce the need for blood products in bleeding trauma patients?

“….the current study….unequivocally demonstrate(s) the hemostatic effect of rFVIIa in injured patients.”

based on – RBC 7.8 (rFVIIa) vs 9.1 (Placebo) p=0.04– total allogeneic 19.0 (rFVIIa) vs 23.5 (Placebo)

p=0.04

Did rFVIIa reduce the need for blood products in bleeding trauma patients?

“….the current study….unequivocally demonstrate(s) the hemostatic effect of rFVIIa in injured patients.”

based on – RBC 7.8 (rFVIIa) vs 9.1 (Placebo) p=0.04– total allogeneic 19.0 (rFVIIa) vs 23.5 (Placebo)

p=0.04

But…

What about adjusting for multiple hypothesis testing?

“No corrections were made for multiple comparisons, primarily because the transfusion parameters were highly correlated.”

What about adjusting for multiple hypothesis testing?

“No corrections were made for multiple comparisons, primarily because the transfusion parameters were highly correlated.”

Interim analysis?

Is rFVIIa safe?

Is rFVIIa safe?

“…although not powered for safety, two large, randomized, controlled trauma trials (the current trial and the trial by Boffard et al.; a total of 837 subjects) have demonstrated no increases in thrombotic events where patients received rFVIIa rather than placebo”.

Is rFVIIa safe?

“…although not powered for safety, two large, randomized, controlled trauma trials (the current trial and the trial by Boffard et al.; a total of 837 subjects) have demonstrated no increases in thrombotic events where patients received rFVIIa rather than placebo”.

However….

Absence of evidence is not evidence of absence

A nonsignificant result obtained from a superiority test does not indicate that the two treatment options are similar!

In other words, the lack of evidence of superiority does not guarantee a lack of difference in the performance shown by the therapies

In the aggregate, does rFVIIa help patients?

In the aggregate, does rFVIIa help patients?

“No prevention of death and only a trend toward less-frequent MOF (p = 0.06) could be identified in the population studied at the current trial size.”

Why was the mortality rate so much lower than expected?

• Could suboptimal inclusion / exclusion criteria result in enrolment of a patient population at lower than expected risk?– As evidenced by the need for massive

transfusion occurred in only 30% of rFVIIa-treated patients with penetrating trauma and 50% with blunt trauma

• Could rigorous adherence to “best-practice” have produced this result?

PICOP Patients with blunt and penetrating trauma who bled 4 to 8 red blood cell units within 12 hours of injury and were still bleeding despite strict damage control resuscitation and operative managementI rFVIIa (200 μg/kg initially; 100 μ g/kg at 1 hour and 3 hours)C Placebo O 30-day mortality/30-day morbidity

Research question:In patients with blunt and penetrating trauma who bled 4 to 8 red blood cell units within 12 hours of injury and continued to bleed despite strict damage control resuscitation and operative management does administration of rFVIIa result in reduced 30 day mortality compared with placebo?

1a. R- Was the assignment of patients to treatments randomised?

1b. R- Were the groups similar at the start of the trial?

2a. A – Aside from the allocated treatment, were groups treated equally?

2b. A – Were all patients who entered the trial accounted for? – and were they analysed in the groups to which they were randomised?

3. M - Were measures objective or were the patients and clinicians kept “blind” to

which treatment was being received?

How large was the treatment effect?

How precise was the estimate of the treatment effect?

Will the results help me in caring for my patient? (ExternalValidity/Applicability)

The questions that you should ask before you decide to apply the results of the study to your patient are: – Is my patient so different to those in the study that the

results cannot apply?– Is the treatment feasible in my setting?

• Will the potential benefits of treatment outweigh the potential harms of treatment for my patient?

Criticisms

• Non-inferiority margin neither reported nor justified

• Unclear in which population the non-inferiority test was applied

• Inadequate explanation for no adjustment for multiple hypothesis testing

• Quoting mean ± SD for non-normal data

• Randomisation process poorly described

Bottom line

A well conducted study with some dodgy reporting that has found no 30-day mortality advantage for rFVIIa

As a result of this study all trauma units should undertake an audit of adherence to patient management guidelines