The TRICC Trial

Author: Kent Lavery
Reviewer: Chris Nickson

Journal Club 015

Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999 Feb 11;340(6):409-17. Erratum in: N Engl J Med 1999 Apr
1;340(13):1056. PubMed PMID: 9971864. [Free Full Text]

THE QUESTION

  • In patients with a critical illness does a restrictive transfusion strategy (to a target of 70 – 90 g/L, transfusion trigger <70 g/L) produce equivalent mortality outcomes to a liberal transfusion strategy (target of 100 – 120 g/L, transfusion trigger <100 g/L)?

STUDY DESIGN

TYPE OF STUDY

  • Multi centre randomised controlled trial (22 tertiary level and 3 ‘community’ ICUs in Canada)
  • Computer randomised using permuted blocks of 4 or 6, and stratified by center APACHE score of >15 and 15 or less
  • Non-blinded
  • See CONSORT diagram

POPULATION

  • Inclusion criteria:
    • Expected to stay in ICU > 24 hours
    • Hb concentration of 90 g/L or less within 72 hours of admission to ICU
    • Considered to be euvolaemic following initial treatment by ICU team
  • Exclusion criteria:
    • Age < 16 years
    • Inability to receive blood products
    • Active bleeding at time of enrolment (evidence of ongoing blood loss and a decrease in Hb concentration of 30 g/L in the preceding 12 hours OR a requirement for at least 3 units of packed RBCs in the same period)
    • Chronic anaemia
    • Pregnancy
    • Brain death
    • Imminent death (<24 hours)
    • Consideration of withdrawal of treatment/DNR order
    • Admission for a routine cardiac surgical procedure
    • Previous transfusion
    • Enrolment in other study

INTERVENTIONS/ COMPARISONS

  • Restrictive transfusion strategy (to a target of Hb 70 – 90 g/L, transfusion trigger Hb <70 g/L); n = 418
  • Liberal transfusion strategy (to target of Hb 100 – 120 g/L, transfusion trigger Hb <100 g/L); n = 420

OUTCOMES

  • Average daily Hb concentrations differed significantly
    • Restrictive 85 +/- 7 g/L, Liberal 107 +/- 7 g/L
    • Number of units of RBCs transfused was significantly reduced (RRR 0.54) in the restrictive group (2.6 +/- 4.1 units) compared with the liberal group (5.6 +/- 5.3 units) (p < 0.01)
  • Primary outcome
    • rate of death from all causes at 30 days
      • No significant difference
      • Restrictive 18.7%, Liberal 23.3% (95%CI -0.84 – 10.2%, p = 0.11)
  • Secondary outcomes
    • Mortality rates during hospitalisation were lower in the restrictive group, but there was no difference in ICU mortality or 60 day mortality
      • inpatient mortality: 22.2% vs. 28.1% (ARR 5.8%; P=0.05)
      • ICU mortality: 13.9% vs. 16.2% (ARR 2.3%; P=0.29)
      • 60-day mortality: 22.7% vs. 26.5% (ARR 3.7%; P=0.23)
    • There were slightly lower adjusted multiple-organ dsyfunction scores in the restrictive group (10.7 +/- 7.5 vs 11.8 +/- 7.7; p=0.03)
  • Subgroup analyses
    • When analysed by sub-group baseline characteristics remained similar between treatment arms
    • No differences in survival when adjusted for:
      • trauma
      • cardiac disease
      • severe infections or septic shock
    • There was lower mortality in the restrictive group for these a priori determined subgroups:
      • APACHE II ≤20: 8.7% vs 16.1% (95% CI 1.0% – 13.6%, p = 0.03)
      • Age <55 years: Restrictive 5.7%, Liberal 13.0% (95% CI 1.1% – 13.5%, p = 0.02)

Adjusted multiple-organ dysfunction scores were statistically significantly lower in the restrictive group. compared with the liberal group, in the APACHE <20 and age < 55 subgroups

  • Adverse cardiac events (e.g. cardiac ischaemia, pulmonary oedema, cardiac arrest) were more common in the liberal group: 13.2% vs. 21% (ARR 7.8%; P<0.01)
  • All of the liberal group received blood transfusion, whereas 33% of the restrictive group did not receive transfusion

CRITICISMS AND COMMENTARY

Commentary

  • This is a landmark practice-changing classic of ICU research, but it is not without its flaws.
  • The study raised concerns about the harms of blood transfusion and questioned the presumed benefit of increasing oxygen delivery – at least by transfusion – in the critically ill.
  • Practice guidelines today generally support a transfusion trigger of Hb 70 g/L in critically ill patients as a result, except for selected patient subgroups (e.g. cardiac patients)
  • Subsequent studies have supported similar targets in patients with upper GI haemorrhage and septic shock
  • There is considerable controversy about the optimal Hb target in individual ICU patients and there are concerns over the external validity and power of the TRICC trial

Strengths

  • Randomised, multicentre controlled trial
  • Appropriately chosen primary/secondary outcomes
  • Power calculation performed, but…
    • calculated to detect a 5% difference in 30d mortality
    • target sample size of 1620 patients was determined by an interim analysis suggesting a higher than expected mortality rate
    • see criticisms below
  • used intention to treat analysis
  • Relevant population group (i.e. APACHEII scores consistent with critical illness)
  • Comparable healthcare setting to the Australian setting
  • Highlighted how a simple, inexpensive to institute intervention could significantly reduce costs and lead to apparently superior patient outcomes

Criticisms

  • The total number of patients enrolled (n=838) resulted in the study being underpowered and thus prone to type II error
  • Only ~12.9% of total assessed patients were enrolled in the trial, with a large number of them being excluded due to physician refusal (selection bias)
  • APACHE II score subgroup stratification was altered after the fact (<15 changed to <20) – would a significant difference favouring restrictive blood transfusion in the less severely ill group have been found otherwise?
  • This study may have been subject to practice misalignment
    • a survey by Hebert et al (1998) showed that standard practice was not to transfuse patients to Hb >100 g/L and most clinicians would use a target higher than 70 g/L in patients with ischaemic heart disease. Allocation of these patients to the corresponding treatment arms might have been expected to cause harm.
  • External validity is limited by the following:
    • Exclusion of patients following cardiac surgery removed a large population of critically ill patients that may require significant volumes of blood and blood products – this is markedly different to the Alfred ICU population
    • The study not include long-stay ICU patients who required transfusion later (i.e. onset of anaemia had to occur within 72 hours)
    • There was a significant difference in the percentage of patients with cardiovascular disease between those excluded from the trial and those enrolled (20% vs 26% respectively) – excluded pateints also tended to be older – decreasing ability to apply results across a broader population
    • 297 patients were excluded for having had a transfusion prior to ICU that increased their Hb to >90 g/L – may reduce applicability to certain patient groups who may receive frequent or be at high likelihood of transfusion
    • Study conducted prior to routine use of leucodepleted PRBCs in Canada – would repeating the trial with leucodepleted PRBCs diminish the significant differences?

FINAL WORDS

  • The TRICC study is a landmark trial that supports the use of a restrictive transfusion strategy targeting Hb> 70 g/L in ICU patients. However, the optimal Hb target in different patient subgroups (e.g. cardiac disease) remains uncertain.
  • Concerns remain over the external validity of the study and the fact that it was underpowered.

References and links

  • Deans KJ, Minneci PC, Danner RL, Eichacker PQ, Natanson C. Practice misalignments in randomized controlled trials: Identification, impact, and potential solutions. Anesth Analg. 2010 Aug;111(2):444-50. doi: 10.1213/ane.0b013e3181aa8903. Review. PubMed PMID: 19820238; PubMed Central PMCID: PMC2888723.
  • Hébert PC, Wells G, Martin C, Tweeddale M, Marshall J, Blajchman M, Pagliarello G, Schweitzer I, Calder L. A Canadian survey of transfusion practices in critically ill patients. Transfusion Requirements in Critical Care Investigators and the Canadian Critical Care Trials Group. Crit Care Med. 1998 Mar;26(3):482-7. PubMed PMID: 9504576.  [Free Full Text]
  • Nickson CP. Practice misalignment. Lifeinthefastlane.com. [Cited 4 Dec 2014] Availble at URL: http://lifeinthefastlane.com/ccc/practice-misalignment/

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