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Mishra SR, Sharma BC, Kumar A, Sarin SK. Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and beta-blockers: a randomized controlled trial. J Hepatol 2011;54:1161–1167.

Abstract

  1. Top of page
  2. Abstract
  3. Comment
  4. References

In this randomized single center trial, 89 cirrhotic patients with GOV2 (eradicated esophageal varices) or IGV1 (both at least 10 mm size) not previously bled were selected for randomization over a 3 year period. Patients were randomized to: (1) Cyanoacrylate (n=30); (2) Propranolol (n=29); or (3) No treatment. There was complete obturation of GV in all patients after a mean of 1.6 ± 0.4 sessions. Propranolol was commenced at 20mg BD and titrated to aim for a heart rate of 55/min (mean dose 140 mg). There was no discontinuation of propranolol due to side effects. Hepatic venous pressure gradient (HVPG) measurements were performed at baseline and after 1 year in all groups and within 24h of bleeding. Most patients had alcoholic or cryptogenic cirrhosis and GOV2 (85%) of 20mm median size. The median follow up time was 26 (3-34) months. There was significantly lower gastric variceal bleeding with cyanoacrylate in (10% versus 38% and 53% for propranolol and no treatment respectively). There was no difference in bleeding between propranolol and no treatment. There was a significant reduction in HVPG in the propranolol group (35% had HVPG response) and an increase in the other groups. HVPG at baseline and HVPG response did not predict bleeding. There was a significant difference in overall and bleeding related mortality in favor of the cyanoacrylate group compared with no treatment (7 versus 26%). No difference in mortality was seen between propranolol and the other groups.

Comment

  1. Top of page
  2. Abstract
  3. Comment
  4. References

Gastric variceal bleeding (GVB) remains an important clinical problem. The management of gastric varices is controversial, with a lack of consensus regarding therapies for the primary prevention of gastric variceal hemorrhage. Risk factors for GVB are similar to those of esophageal varices and include size of fundal varices, child's class, and red spots.1 The risk of bleeding is lower than with esophageal varices, yet the transfusion requirements and mortality associated with a bleeding episode are both higher [reference]. Gastric varices are supplied by the short left gastric and polar veins, and unlike esophageal varices, they lie deep within the submucosa.2 The widely used classification described by Sarin et al.3 defines four types of gastric varices according to site and risk of bleeding. The most common types are gastro-esophageal varices types 1 and 2 (GOV1 and GOV1), which are continuations of esophageal varices along the lesser and greater curve, respectively. Isolated gastric varices (IGV) type 1 occur in isolation in the fundus, are less common, and bleed less frequently (albeit more severely).3 GOV1 are treated like esophageal varices, and GOV2 and IGV1 require specific therapy. The 2-year bleeding risk for larger gastric varices can be as much as 65%.3 Therefore, it would seem appropriate to concentrate on therapies to prevent bleeding in patients with GOV2 and IGV1 (Fig. 1).

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Figure 1. High-risk gastric varices based on the classification of Sarin et al.3 GOV2, gastro-esophageal varices type 2; IGV1, isolated gastric varices type 1.

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Clinical trials investigating primary prophylaxis of GVB are lacking, perhaps because gastric varices are less common than esophageal varices. The recruitment of patients sufficient for studies of primary prophylaxis of moderate to large esophageal varices has proved difficult.4 Uncontrolled studies have demonstrated the efficacy of endoscopic therapies in eradicating gastric varices.5, 6 There has been some interest in balloon-occluded retrograde obliteration (B-RTO) of gastric varices, wherein large gastric varices are obliterated by injection of a sclerosant through gastro-renal shunts under fluoroscopic guidance. A small prospective study comparing B-RTO with no treatment revealed reduced bleeding and mortality with B-RTO. These findings must be interpreted with caution, because the study was not randomized, and other investigators have found that B-RTO can increase the long-term risk of bleeding in patients with coexisting esophageal varices.7 Both the American Association for the Study of Liver Diseases guidelines8 and the latest Baveno V9 consensus do not provide definitive guidance, although nonselective beta-blockers (NSBBs) are suggested by Baveno V.9

The work by Mishra et al.10 is the first randomized controlled trial comparing therapies in the primary prevention of GVB, and as such makes an important contribution to the literature and merits closer review. More than 90% of screened patients (n = 1,050) were excluded because they failed to meet the strict inclusion criteria. Therefore, the investigators carefully selected patients who had the highest risk of bleeding. Perhaps this explains the relatively small sample size required to show differences between cyanoacrylate, NSBBs, and no treatment. There were significant differences in favor of cyanoacrylate for bleeding and survival when compared with no treatment (P = 0.046), and only for prevention of bleeding when compared with propranolol. The latter observation is interesting, because there was a significant reduction in the hepatic venous pressure gradient (HVPG) with propranolol and a rise in HVPG in the other groups. The lack of HVPG response in predicting bleeding is in contrast to that for esophageal variceal bleeding, where HVPG response to NSBBs has been shown to predict both bleeding and the formation of varices.11 This finding perhaps reinforces our understanding of the risk factors for GVB. It has been shown that gastric varices can bleed at lower pressures compared with esophageal varices, suggesting that reduction in portal pressure will have less influence in bleeding risk or that a greater magnitude in pressure reduction is necessary to protect against bleeding.12 Other risk factors (in particular the size of gastric varices) that in turn influence wall tension may also be important. The median size of gastric varices in the study was 20 mm and obturation of varices was achieved in all patients. Patients treated with cyanoacrylate all had a reduction in the size of gastric varices, in contrast to over a third of patients in the other arms having an increase in size of gastric varices. There was no difference in the appearance of esophageal varices or appearance/worsening of portal hypertensive gastropathy during follow-up in the two groups.

Certain aspects of the Mishra et al.10 findings must be considered carefully. It is not clear from the three-arm study whether a Bonferroni multiple comparison correction was used. Therefore, the findings may not withstand close statistical scrutiny. In practice, particularly outside of large specialized units, many patients may be ineligible for treatment given the strict inclusion criteria. Although no complications from cyanoacrylate were observed, in less expert hands this may not always be the case. It may be difficult to convince patients or clinicians to accept prophylactic cyanoacrylate if it has not been shown to be more effective than propranolol in improving survival. This brings into question the choice of NSBBs. The recent demonstration that carvedilol was more effective than band ligation in preventing bleeding from esophageal varices makes one wonder how this drug would compare with cyanoacrylate.13 Only one-third of patients in the Mishra et al. study responded to propranolol, and because carvedilol has been shown to be more effective at lowering portal pressure in a greater proportion of patients,14 the results could have been different. NSBBs would also treat esophageal varices and portal hypertensive gastropathy. The caveat is that NSBBs should be used with caution in patients with advanced cirrhosis, in particular those with refractory ascites.15

In conclusion, it is clear that carefully selected patients with large gastric varices should receive prophylactic treatment to prevent bleeding. Despite the promise shown by cyanoacrylate, further controlled trials comparing cyanoacrylate with beta-blockers such as carvedilol or even thrombin injection16 are necessary. The latter therapy shows promise and, due to ease of use and lack of complications compared with cyanoacrylate, may be a more attractive option; however, it has yet to be studied in a controlled clinical trial.

References

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  2. Abstract
  3. Comment
  4. References
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