Commentary: THE TRANSFUSION INDICATION THRESHOLD (TITRe) STUDY
Murphy et al. N Engl J Med 2015; 372:997-1008
In the wake of the recently published TITRe study, SHG received numerous queries as to whether this trial casts doubt upon restrictive transfusion practices for cardiovascular surgery patients. The study’s conclusion suggests it does not. Moreover, it highlights the importance of transfusing patients for clinical indications.
The TITRe Study included adults undergoing non-emergent open heart surgery at 17 hospitals in the United Kingdom. Just over 2,000 patients were randomly assigned to be transfused at a Hb of 7.5 g/dL or 9 g/dL. Fifty-three percent of the restrictive group and 92% of the liberal group were transfused. Complications such as serious wound infection or ischemic events occurred in 35% of the restrictive group and 33% of the liberal group. Mortality rates at 30 days post-randomization were 2.6% and 1.9% (p=NS) and 4.2% and 2.6% at 90 days respectively. Finally, total costs did not differ significantly between the two groups. The authors concluded that a restrictive transfusion threshold after cardiac surgery was not superior to a liberal threshold with respect to morbidity or healthcare costs.
There are at least eight previously published RCTs comparing outcomes in transfused patients with restrictive vs. liberal strategies (see below). The TITRe study brings this to nine. If we look at these RCTs, the results all reflect either similar outcomes in the restrictive groups compared to the liberal, or worse outcomes with liberal transfusion in certain subpopulations.
Randomized Trials – all supporting Hb triggers of 7 or 8 g/dL compared to higher levels
- Hebert PC, et al: NEJM 1999 – Critically ill MICU patients
- Lacroix J, et al: NEJM 2007 – Critically ill PICU patients
- Hajjar LA, et al: JAMA 2010 – Cardiac surgery patients
- Carson JL, et al: NEJM 2011 – Elderly orthopedic surgery patients
- Villanueva C, et al: NEJM 2013 – Severe GI Bleeding
- Holst LB, et al: NEJM 2014 – Septic Shock
- Robertson CS. et al: JAMA 2014 – Traumatic Brain Injury
- Kirpalani H et al: J Pediatr 2006 – ELBW infants Threshold Hgb levels varied 11.5-7.7 in low threshold group and 13.5-9.0 in high threshold group (previously Bell, et al. found higher adverse neurologic events in the restrictive group).
The TITRe study, thus ADDS to the body of evidence that restrictive transfusion is not inferior in terms of patient outcomes.
Of note, several of these RCTs highlight the need for slightly higher Hgb “triggers” in patients with CV risk factors, active CV disease and those undergoing CV surgical procedures. Specifically, the TRICC trial suggested Hgb levels of >8.0 g/dL might be beneficial in patients with acute coronary syndromes, MI, etc. The TRACS and FOCUS trials both used an 8.0 vs. 10.0 g/dL paradigm for transfusion protocols. The results of these studies have been embraced by numerous professional societies, including ASH and ACP (www.choosingwisely.org). The most recent STS (2011) and ASA (2015) guidelines, utilizing the GRADE criteria, incorporate the evidence base for restrictive transfusion. Interestingly, the TITRe investigators chose LOWER Hgb triggers than these other RCTs that include cardiac patients, i.e. 7.5 and 9.0 respectively.
Several other points must be made:
- As presented in the accompanying editorial in the same issue of the Journal, there is some question as to the significance of the difference in 90-day mortality. If anemia were to be associated with or the cause of mortality, then why did the 30-day mortality rate not reflect this as well? I would agree with the author that this might represent chance alone or perhaps other confounding factors. I will also add that there are certainly therapies other than transfusion to prevent and treat anemia perioperatively.
- In addition, the primary outcome (serious infection or an ischemic event) occurred in >30% in both patient groups. This seems awfully high and there is no explanation provided in the discussion. I would hope that over one-third of patients would not have these cumulative serious complications post-operatively! Typical complication rates of which I am aware are between 1-5%, give or take. (Mediastinitis 0.1-2.3% per Ang LB et al. Heart & Lung 2012;41:25-263; Neurologic morbidity 0.37-2.4% not transfused vs transfused, respectively per Koch CG et al. Crit Care Med 2006;34:1-9).
- The overall transfusion rates were also quite high in both groups, roughly 53% and 92% respectively. A review of U.S. cardiac surgery practices for on-pump CABG showed transfusion rates from 8% to 93% after adjusting for risk factors (Bennett-Guerrero. JAMA 2010; 304:1568-1575). However, in a more recent study of transfusion in CVS, the rate of RBC transfusion was 39% PRIOR to even initiating any restrictive transfusion practices or other blood management strategies (Gross I et al. Transfus 2015; doi: 10.1111/trf.12946). The study design is somewhat unclear—3565 patients consented, but only 2007 were randomized. Also, 25.7% received transfusions prior to randomization.
In conclusion, there are several issues with the TITRe study that need to be carefully considered. However, this RCT still provides evidence that restrictive RBC transfusion is NOT associated with worse clinical outcomes. Again, this mirrors the other available studies. Of note, there is an additional trial being undertaken in this arena: the TRICS-III Trial (Transfusion Requirements In Cardiac Surgery). Patients will be randomized to a similar 7.5 vs. 9.5 strategy. Perhaps this will further our knowledge of transfusion needs and interventions in this complex patient population that is certainly at risk for ischemic events.
Of course, patient blood management is more far-reaching than merely transfusion “triggers”. The authors suggest that many of the patients receiving transfusions were dependent on oxygen supplementation in the immediate post-operative period, perhaps at the limit of cardiac reserve. As always, transfusion strategies should be incorporated into robust programs that encompass bleeding risk assessment, optimization of patients prior to procedures, meticulous surgical techniques, cell salvage, and pharmaceuticals as applicable. Avoidance of unnecessary transfusions reduces the risk of potential acute and long-term adverse events for patients and preserves component inventory for those who can truly benefit from life- or limb-saving transfusions.
Carolyn Burns, M.D.
Acknowledgement: I would like to thank the following people for their clinical and editorial remarks during the development of this commentary.
Sarah Daccarett, M.D.
Peter Mazolewski, M.D.
Jay Menitove, M.D.
Susann Nienhaus, R.N., J.D.