EBQ:PROPPR Trial

Complete Journal Club Article

Holcomb JB, Tilley BC, Baraniuk S, et al.. "Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma". JAMA. 2015. 313(5):471-482.
PubMed Full text

Clinical Question

• Compare 1:1:1 vs 1:1:2 in safety and efficacy in trauma rescus

Conclusion

• No significant differences in mortality at 24 hours or at 30 days between two groups
• More patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours (86% vs 78%; p=0.006)
• Exsanguination in first 24 hours decreased in the 1:1:1 group (9.2% vs 14.6%; p=0.03)
• No other safety differences were identified between the two groups

Major Points

• This was a negative trial - the 1:1:1 was as safe as 1:1:2
• They did not meet the 10% mortality advantage which the study was powered to but found 4.2% improvement in the 1:1:1 group at 24hr and 3.7% at 30d

Study Design

• Randomized clinical trial
• Blood product protocol
  • 1:1:1 = 6 plt, (1 RBC, 1 FFP) x 6, 6 plt...
  • 1:1:2 = (2 RBC, 1 FFP) x 3, 6 plt, (2 RBC, 1 FFP) x 3, 6 plt...

Population

• 680 patients from of 12 participating level I trauma centers in North America

Patient Demographics

No differences were detected between treatment groups in baseline characteristics

Characteristics	1:1:1	1:1:2
Age	34.5 (25-51)	34 (24-50)
Male	263 (77.8%)	283 (82.7%)
Race - White	210 (62.1%)	224 (65.5%)
Race - Black	94 (27.8%)	93 (27.2%)
Race - Other	35 (10.4%)	25 (7.3%)

Inclusion Criteria

• Highest trauma level activation
• ≥15 yo or weight ≥50 kg if age unknown
• Received directly from the injury scene
• Transfusion initiated with at least 1 U of blood component within the first hour of arrival
• Predicted to receive a massive transfusion

Exclusion Criteria

• Received a lifesaving intervention from OSH
• Terminal injuries and expected to die within 1 hour of admission (eg, lethal traumatic brain injury)
• Directly admitted from a correctional facility
• Required a thoracotomy prior to randomization
• <15 yo or <50 kg if age unknown
• Pregnant
• Burns >20% total BSA
• Suspected inhalation injury
• >5 mins of CPR
• DNR
• Enrolled in a concurrent, ongoing, interventional, randomized clinical trial
• >3 U of pRBC given before randomization

Interventions

• Two cohorts received blood product ratios of 1:1:1 (n=338) vs 1:1:2 (n=342) during active resuscitation

Outcomes

Primary Outcome

• Absolute percentage group differences for 24-hour and 30-day mortality

Time Period	1:1:1 n=338	1:1:2 n=342	Difference	Adjusted RR	p value
24h mortality	43 (12.7%)	58 (17.0%)	−4.2 (−9.6-1.1)	0.75 (0.52-1.08)	0.12
30d mortality	75 (22.4%)	89 (26.1%)	−3.7 (−10.2-2.7)	0.86 (0.65-1.12)	0.26

Secondary Outcomes

1. Time to hemostasis
   • 1:1:1 - 291 (86.1%)
   • 1:1:2 - 267 (78.1%)
   • p=0.006
2. Exsanguination within first 24h
   • 1:1:1 - 9.2%
   • 1:1:2 - 14.6%
   • p=0.03
3. Exsanguination within 30d
   • 1:1:1 - 10.7%
   • 1:1:2 - 14.7%
   • p value no reported
4. Number and type of blood products used from randomization until hemostasis was achieved
   • 1:1:1 - 25.5 units (pRBC 9u, FFP 7u, Plt 12u)
   • 1:1:2 - 19 units (pRBC 9u, FFP 5u, Plt 6u)
   • p=0.001 for units of platelets
5. Number and type of blood products used after hemostasis was achieved up to 24 hours postadmission
   • 1:1:1 group received fewer blood products during the postintervention period than the 1:1:2 group (median of 1 U vs 2 U, respectively)
6. Analysis of 23 complications
   • Differences were not detected in any of the 23 complications at 30 days
7. Incidence of major surgical procedures
   • 1:1:1 - 290 (85.8%)
   • 1:1:2 - 284 (83.0%)
8. Functional status at hospital discharge or 30 days (median , whichever occurred first
   • 1:1:1 - 4 (3-6)
   • 1:1:2 - 4.5 (3.5-7.0)
   • p=0.11
9. Hospital-free days, ventilator-free days, and ICU-free days

	1:1:1	1:1:2	p value
Hospital-free days	1 (0-17)	0 (0-16)	0.83
Ventilator-free days	8 (0-16)	7 (0-14)	0.14
ICU-free days	5 (0-11)	4 (0-10)	0.10

Criticisms & Further Discussion

• This was ultimately an unblinded and was a negative primary outcome due to the powering to detect only an absolute difference of 10% in mortality. To reach statistical significance for a small effect, 2968 patients would have been required to detect the observed difference of 4.2% (24 hour mortality) with 90% power. Regardless this is the best evidence to date the 1:1:1 ratio is a safe and effective treatment.
• The 1:1:1 group received platelets first (six units) followed by alternating RBCs and plasma. However, the 1:1:2 group received two unis RBCs first followed by 1 unt of plasma. Patients were not given until the patient received 9 units of other blood products. This makes interpretation of the results unclear since the platelets not the ratio may have been responsible for the early hemostasis achieved.
• Study design was randomized, multi-centre, and pragmatic, with minimal loss to 30 day followup, and allocation concealed during trial duration.
• Transfusion complications may be more likely related to the increased use of platelets in the treatment arm.
• This trial did not truly compare 1:1:1 vs 1:1:2 resuscitative strategies. Rather Holcomb et al examined a protocol intending to give 1:1:1 vs 1:1:2. In reality, neither group truly reached their proportional expectations. The 1:1:1 group in actuality was given products closer to a 2:1:2 ratio, while the 1:1:2 group only received products in a 2:1:4 ratio.
• Lab guided strategies in smaller sample sizes have not demonstrated 1:1:1 to be superior

External Links

• Podcast 144 – The PROPPR trial with John Holcomb
• EM Nerd - The Adventure of the Blanched Soldier

Funding

• US National Heart, Lung, and Blood Institute grant U01HL077863
• Department of Defense
• The Defence Research and Development Canada in partnership with the Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health (grant CRR-120612)

References

Authors

Neil Young, Daniel Ostermayer, Daniel Eggeman