Transfusion strategy in gastrointestinal bleeding: Less is best?
Authors: Marika Rudler, Dominique Thabut
Journal: Journal of Hepatology (2013)

COMMENTARY ON: Transfusion strategies for acute upper gastrointestinal bleeding. Villanueva C, Colomo A, Bosch A, Concepción M, Hernandez-Gea V, Aracil C, Graupera I, Poca M, Alvarez-Urturi C, Gordillo J, Guarner-Argente C, Santaló M, Muñiz E, Guarner C. N Engl J Med. 2013 Jan 3;368(1):11–21. doi: 10.1056/NEJMoa1211801. Copyright (2013). Abstract reprinted with permission from the Massachusetts Medical Society. http://www.ncbi.nlm.nih.gov/pubmed/23281973 Abstract: Background: The hemoglobin threshold for transfusion of red cells in patients with acute gastrointestinal bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy. Methods: We enrolled 921 patients with severe acute upper gastrointestinal bleeding and randomly assigned 461 of them to a restrictive strategy (transfusion when the hemoglobin level fell below 7gperdeciliter) and 460 to a liberal strategy (transfusion when the hemoglobin fell below 9gperdeciliter). Randomization was stratified according to the presence or absence of liver cirrhosis. Results: A total of 225 patients assigned to the restrictive strategy (51%), as compared with 61 assigned to the liberal strategy (14%), did not receive transfusions (P<0.001) [corrected]. The probability of survival at 6 weeks was higher in the restrictive-strategy group than in the liberal-strategy group (95% vs. 91%; hazard ratio for death with restrictive strategy, 0.55; 95% confidence interval [CI], 0.33–0.92; P=0.02). Further bleeding occurred in 10% of the patients in the restrictive-strategy group as compared with 16% of the patients in the liberal-strategy group (P=0.01), and adverse events occurred in 40% as compared with 48% (P=0.02). The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer (hazard ratio, 0.70; 95% CI, 0.26–1.25) and was significantly higher in the subgroup of patients with cirrhosis and Child-Pugh class A or B disease (hazard ratio, 0.30; 95% CI, 0.11–0.85), but not in those with cirrhosis and Child-Pugh class C disease (hazard ratio, 1.04; 95% CI, 0.45–2.37). Within the first 5 days, the portal-pressure gradient increased significantly in patients assigned to the liberal strategy (P=0.03) but not in those assigned to the restrictive strategy. Conclusions: As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding. (Funded by Fundació Investigació Sant Pau; ClinicalTrials.gov number, NCT00414713.) Severe gastrointestinal bleeding often requires red blood transfusions. Recommendations on when to transfuse have been based on results of meta-analyses of randomized trials comparing restrictive and liberal transfusion strategies and included very few patients with gastrointestinal bleeding [1Barkun A.N. Bardou M. Kuipers E.J. Sung J. Hunt R.H. Martel M. et al.International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding.Ann Intern Med. 2010; 152: 101-113Crossref PubMed Scopus (868) Google Scholar, 2de Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension.J Hepatol. 2005; 43: 167-176Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar]. However, in an open-label trial conducted by Villanueva et al. [[3]Villanueva C. Colomo A. Bosch A. Concepción M. Hernandez-Gea V. Aracil C. et al.Transfusion strategies for acute upper gastrointestinal bleeding.N Engl J Med. 2013; 368: 11-21Crossref PubMed Scopus (862) Google Scholar], 921 patients with upper gastrointestinal bleeding were randomized to receive a restrictive transfusion strategy (when the haemoglobin level was <7 g/dl) or a liberal strategy (when the haemoglobin was <9 g/dl). All causes of bleeding were considered. Patients were stratified by presence of cirrhosis (inclusion of 277 cirrhotic patients). The primary outcome was mortality at day 45 and was significantly lower in the restrictive than liberal strategy group (5% vs. 9%, p = 0.02). Moreover, the risk of further bleeding, length of hospital stay, need for rescue therapy, overall rate of complications and rate of serious adverse events were all significantly reduced with the restrictive vs. liberal strategy. These data strongly suggest that the restrictive strategy is the best and should be used for upper gastrointestinal bleeding. The benefit of a restrictive strategy seemed particularly strong in patients with Child-Pugh A/B cirrhosis. Whether these results should be generalized to all patients with gastrointestinal bleeding is matter of debate. Indeed, in the Villanueva et al. study, patients were partly selected: (1) 2372 patients were admitted for gastrointestinal bleeding during the study period, but only 1610 were screened and (2) patients with the most severe condition (i.e., with massive exsanguination) at admission were excluded, as were patients at low risk of re-bleeding. However, this study remains the first in the field and provides data for recommendations for transfusion policy in this setting. The haemoglobin threshold for transfusion in cirrhotic patients is controversial. The rationale for the restrictive strategy is to prevent rebound increase in portal pressure [[4]Hochain P. Merle V. Tuil S. Michel P. Ducrotte P. Lerebours E. et al.Transfusion for variceal bleeding in cirrhotic patients.Gut. 1996; 38: 154Crossref PubMed Scopus (5) Google Scholar]. Nevertheless, hypovolemia can lead to functional renal failure, a strong predictor of mortality in patients with cirrhosis [[5]Cárdenas A. Ginès P. Uriz J. Bessa X. Salmerón J.M. Mas A. et al.Renal failure after upper gastrointestinal bleeding in cirrhosis: incidence, clinical course, predictive factors, and short-term prognosis.Hepatology. 2001; 34: 671-676Crossref PubMed Scopus (270) Google Scholar]. Cirrhotic patients at risk of death from gastrointestinal bleeding are Child-Pugh C patients or patients with active bleeding at endoscopy [[6]Bosch J. Thabut D. Bendtsen F. D'Amico G. Albillos A. González Abraldes J. et al.Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: a randomized, double-blind trial.Gastroenterology. 2004; 127: 1123-1130Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar], that is, patients with high hepatic venous pressure gradient (HVPG). In the Villanueva et al. trial, data for patients with active bleeding at endoscopy are lacking. The restrictive strategy had no effect on survival in Child-Pugh C patients. This result might be due to the small sample size of Child-Pugh C patients (55 patients). For about half of the cirrhotic patients (n = 151), HVPG measurements were repeated, with no mention of their Child-Pugh score. However, the mean HVGP was 20.1 ± 0.1 mmHg and 20.6 ± 5.2 mmHg respectively in the restrictive and liberal strategy, highlighting the severity of portal hypertension. Therefore, restrictive strategy seems to have a beneficial effect on survival in severe patients. Of note, in the restrictive-strategy group, HVPG did not decrease, despite somatostatin treatment. This finding is not in accordance with results from another study conducted by the same group, in which patients received the same dose of somatostatin [[7]Villanueva C. Ortiz J. Miñana J. Soriano G. Sàbat M. Boadas J. et al.Somatostatin treatment and risk stratification by continuous portal pressure monitoring during acute variceal bleeding.Gastroenterology. 2001; 121: 110-117Abstract Full Text PDF PubMed Scopus (108) Google Scholar] and in which units of red cells were administered to maintain haemoglobin level at approximately 9 g/dl. The liberal strategy could have a deleterious effect in patients with less severe liver disease, and the reason remains unsolved. The liberal strategy may lead to cardiac decompensation because patients with cirrhosis often present diastolic dysfunction [[8]Rabie R.N. Cazzaniga M. Salerno F. Wong F. The use of E/A ratio as a predictor of outcome in cirrhotic patients treated with transjugular intrahepatic portosystemic shunt.Am J Gastroenterol. 2009; 104: 2458-2466Crossref PubMed Scopus (148) Google Scholar]. Still, no data is available to evaluate the frequency of cardiac decompensation related to a liberal transfusion strategy. Early transjugular intrahepatic portosystemic shunt (TIPS) placement should considerably modify the prognosis of variceal bleeders with severe cirrhosis (Child-Pugh C or B with active bleeding) [9García-Pagán J.C. Caca K. Bureau C. Laleman W. Appenrodt B. Luca A. et al.Early use of TIPS in patients with cirrhosis and variceal bleeding.N Engl J Med. 2010; 362: 2370-2379Crossref PubMed Scopus (808) Google Scholar, 10Rudler M. Cluzel P. Saqué V. Le Corvec T. Benosman H. Poynard T. et al.Early TIPS in patients with variceal bleeding: an external validation.Hepatology. 2012; 56: 274AGoogle Scholar]. The rationale for this therapy is to stop bleeding rapidly and prevent renal failure and other classical complications. In the present study, no patients underwent an early TIPS strategy. Further studies regarding transfusion policy and fluid resuscitation are mandatory for patients who will benefit from early TIPS placement. Interestingly, in our prospective pilot study of 35 consecutive non-selected patients with variceal bleeding who underwent early TIPS, we observed more than 20% acute cardiac failure after TIPS [[10]Rudler M. Cluzel P. Saqué V. Le Corvec T. Benosman H. Poynard T. et al.Early TIPS in patients with variceal bleeding: an external validation.Hepatology. 2012; 56: 274AGoogle Scholar]. However, data regarding transfusion policy have still to be analysed. In conclusion, the restrictive transfusion strategy seems to be significantly superior to the liberal strategy in patients with gastrointestinal bleeding, especially in patients with Child-Pugh A/B cirrhosis. However, insufficient data are available regarding transfusion thresholds for high-risk patients, such as Child-Pugh C patients or those patients who undergo early TIPS placement after variceal bleeding. Further studies of these patients are warranted. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.