A DE L B OU E I Z
In these patients with cirrhosis who were hospitalized for acute variceal bleeding and at high risk for treatment failure, the early use of tIPS was associated with significant reductions in treatment failure and in mortality . . . [However], because of [previous] findings, tIPS is [still]
currently recommended only as a rescue therapy.
—García-Pagán et al.1
Research Question: For high-risk patients with cirrhosis and acute variceal bleeding, is early treatment with transjugular intrahepatic portosystemic shunts (tIPS) better than drug therapy plus endoscopic band ligation?1
Funding: W. l. Gore and associates, the maker of the extended polytetrafluo-roethylene (e-PtFe)-covered stents used in the study, as well as several gov-ernment and academic institutions in Spain and France.
Year Study Began: 2004 Year Study Published: 2010
Study Location: nine centers in europe.
Who Was Studied: adults with Child-Pugh class B or C cirrhosis admitted in the previous 12 hours with acute variceal bleeding who were being treated with endoscopic therapy, prophylactic antibiotics, and vasoactive medications. to be eligible for inclusion, patients were required to have either Child-Pugh class C cirrhosis (a score of 10 to 13) or class B cirrhosis (a score of 7 to 9) accompanied by “active bleeding at diagnostic endoscopy.”
Who Was Excluded: Patients with severe cirrhosis (Child-Pugh score >13) were excluded as were patients with previous treatment with combined phar-macologic and endoscopic therapy or tIPS to prevent variceal rebleeding. In addition, patients were excluded if they were >75 years old, had hepatocellular carcinoma not amenable to transplantation, had a serum creatinine >3 mg/dl, or had “bleeding from isolated gastric or ectopic varices.”
How Many Patients: 63
Study Overview: See Figure 21.1 for a summary of the study design.
Study Intervention: all patients in both groups were treated initially with vasoactive medications, prophylactic antibiotics, and endoscopic therapy (band ligation or sclerotherapy).
Patients randomized to drug therapy plus endoscopic band ligation were managed with vasoactive drugs until they were “free of bleeding for a minimum of 24 hours” and ideally for up to 5 days, at which point they were transitioned to therapy with nonselective beta blockers and isosorbide-5-mononitrate. Patients
Drug Therapy Plus
Endoscopic Band Ligation Early Transjugular Intrahepatic Portosystemic Shunts (TIPS) Randomized
Patients with Child-Pugh Class B or C Cirrhosis and Acute Variceal Bleeding
Figure 21.1 Summary of the Study Design.
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in this group also received elective endoscopic band ligation at 7–14 days fol-lowing initial endoscopic treatment and then “every 10–14 days thereafter until variceal eradication was achieved.” Surveillance endoscopy was performed 1, 6, and 12 months after eradication with endoscopic band ligation for recurrent varices. Patients who experienced a single rebleeding episode requiring trans-fusion with two or more units of blood or multiple less-severe rebleeding epi-sodes were eligible for tIPS as “rescue therapy.”
Patients randomized to early tIPS received tIPS with placement of an e-PTFE-covered stent within 72 hours of the initial diagnostic endoscopy. The stent was initially dilated to 8 mm but if the portal pressure gradient (pres-sure difference between the portal vein and inferior vena cava) did not fall to
<12 mm Hg, the stent was dilated to 10 mm. tIPS revision with angioplasty or stent replacement was performed if there was “clinical recurrence of portal hypertension or evidence of tIPS dysfunction on ultrasound.”
Follow-Up: Median follow-up was 10.6 months in the endoscopic therapy group and 14.6 months in the tIPS group.
Endpoints: Primary outcome: a composite of bleeding episodes (“failure to control acute bleeding or failure to prevent recurrent clinically significant vari-ceal rebleeding within 1 year”). Secondary outcomes: Mortality and time spent in the intensive care unit or hospital.
RESULTS
• Of 359 patients admitted for acute variceal bleeding during the enrollment period, only 63 underwent randomization; many were excluded based on their Child-Pugh score (72 were class A, 40 were class B without active bleeding, and 18 had scores >13).
• Baseline characteristics were similar between the two groups with an average age of 50 years; 67% of patients were male.
• In the endoscopy therapy group, variceal eradication was achieved in 52% of patients.
• In the TIPS group, the procedure was carried out without major complications in all but one patient who withdrew consent, and in all but two patients portal-pressure gradient dropped below 12 mm Hg following the procedure.
• Early use of TIPS was associated with reduced risk of bleeding events and mortality compared with endoscopic therapy (table 21.1).
• Of 14 patients in the endoscopic therapy group experiencing bleeding events, 7 received TIPS with e-PTFE-covered stents as “rescue therapy”; 4 of these 7 died within 36 days.
• There were no between-group differences in the occurrence of hepatic encephalopathy, ascites, spontaneous bacterial peritonitis, or hepatorenal syndrome.
Criticisms and Limitations: only a small percentage of very high risk patients admitted with acute variceal bleeding were eligible for the trial. Thus these results only apply to a small subset of very high risk patients (i.e. those with Child-Pugh class C cirrhosis or class B cirrhosis with active bleeding).
Other Relevant Studies:
• A meta-analysis of 11 trials and 801 patients concluded that, for patients with acute variceal bleeding, tIPS was associated with a reduced rate of rebleeding, an increased rate of hepatic encephalopathy, and no difference in mortality compared to endoscopic therapy.2 However, most prior studies used bare stents (rather than the e-PtFe-covered stents used in this trial), and many trials excluded high-risk patients who were included in this study.
• Guidelines from the American Association for the Study of Liver Disease recommend tIPS only as salvage therapy in patients with uncontrolled variceal bleeding that does not respond to endoscopic therapy.3 These guidelines were issued prior to the publication of this trial, however.
Summary and Implications: This study demonstrates the benefits of tIPS among a subset of very high-risk patients with acute variceal bleeding and Child-Pugh class B or C cirrhosis. Unlike prior studies that focused on a broad
Table 21.1. Summary of Key Findings
Outcome TIPS Endoscopic
Therapy P Value Failure to Control acute
Bleeding or Prevent Rebleeding 3% 45% 0.001
Mortality 13% 39% 0.01
Hepatic encephalopathy 25% 39% nonsignificant
Percentage of Follow-Up in the
Hospital 4% 15% 0.014
Days in the ICU 3.6 8.6 0.01
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population of patients with variceal bleeding, this study was limited to a very high-risk group (those with Child-Pugh class C cirrhosis or class B cirrhosis with active bleeding). Based on prior research, current guidelines still recom-mend tIPS only as salvage therapy for variceal bleeding not responsive to endo-scopic therapy. However, this study suggests a benefit of early tIPS among a subset of high-risk patients and underscores the need for more research.
References
1. García-Pagán JC et al. early use of tIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010 June 24;362(25):2370–2379.
2. Papatheodoridis GV et al. transjugular intrahepatic portosystemic shunt compared with endoscopic treatment for prevention of variceal rebleeding: a meta-analysis. Hepatology 1999;30:612.
3. Garcia-tsao G et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46(3):922–938.
CLINICAL CASE: MANAGEMENT OF ACUTE VARICEAL BLEEDING
Case History:
a 68-year-old man hospitalized for advanced cirrhosis complicated by ascites and encephalopathy is evaluated for massive hematemesis and hypotension.
The patient’s medications are spironolactone, furosemide, and lactulose. His stool is black and positive for blood. laboratory studies show hemoglobin of 9 g/dl, a platelet count of 60,000/µl, and an international normalized ratio (InR) of 2.2. His calculated Child-Pugh score is 13. Upper endoscopy reveals actively bleeding esophageal varices.
In addition to rapid volume resuscitation and antibiotics, what treatment would you recommend for this patient?
Suggested Answer:
This study found that early tIPS reduced bleeding episodes and mortality among high-risk patients like the one in this vignette with active variceal bleeding. although current guidelines recommend tIPS only as a salvage therapy, it would be reasonable to consider early tIPS in this patient because he is similar to the high-risk patients included in this study. on the other hand, because this patient suffers from hepatic encephalopathy, an initial endoscopic approach would also be reasonable because tIPS has been impli-cated as a cause of worsening encephalopathy in prior research.