Villa E, Cammà C, Marietta M, Luongo M, Critelli R, Colopi S, et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012;143:1253–1260. (Reprinted with permission.)
Background & Aims: We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis. Methods: In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n = 34) or no treatment (controls, n = 36). Ultrasonography (every 3 months) and computed tomography (every 6 months) were performed to check the portal vein axis. The primary outcome was prevention of PVT. Radiologists and hepatologists that assessed outcomes were blinded to group assignments. Analysis was by intention to treat. Results: At 48 weeks, none of the patients in the enoxaparin group had developed PVT, compared with 6 of 36 (16.6%) controls (P = 0.025). At 96 weeks, no patient developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P = 0.001). At the end of the follow-up period, 8.8% of patients in the enoxaparin group and 27.7% of controls developed PVT (P = 0.048). The actuarial probability of PVT was lower in the enoxaparin group (P = 0.006). Liver decompensation was less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P = 0.0001); overall values were 38.2% vs 83.0%, respectively (P = 0.0001). The actuarial probability of liver decompensation was lower in the enoxaparin group (P = 0.0001). Eight patients in the enoxaparin group and 13 controls died. The actuarial probability of survival was higher in the enoxaparin group (P = 0.020). No relevant side effects or hemorrhagic events were reported. Conclusions: In a small randomized controlled trial, a 12-month course of enoxaparin was safe and effective in preventing PVT in patients with cirrhosis and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival.
Portal vein thrombosis (PVT) is a frequent event in cirrhosis with a prevalence up to 26%[1-3] and an annual incidence up to 19%[2, 4] (in patients without hepatocellular carcinoma). It is noteworthy that the prevalence of PVT increases with the severity of the liver disease (1% in comensated cirrhosis versus 8%-25% in liver transplant candidates). Development of PVT is usually associated with a more severe liver dysfunction, more severe degree of portal hypertension, and more frequent portal hypertension-related complications such as ascites or variceal bleeding.[3, 5] Since almost all studies are retrospective there are not enough data to establish whether the association of PVT with liver decompensations is causal or only a further consequence of it. In addition to the possible consequences of PVT, recent data have shown a close relationship between coagulation activation and a more rapid progression of liver fibrosis. Thrombin generation, as a result of the activation of the coagulation cascade, has been involved in liver fibrogenesis[7-9] and two possible pathogenic mechanisms have been described: thrombus formation in the microvasculature causing parenchymal extinction and fibrosis; and activation of hepatic stellate cells by thrombin through protease activated receptors. All these findings suggest a possible role of coagulation activation, and hence anticoagulation therapy, in cirrhosis. Up to now only a few studies, mainly retrospective, have evaluated its use in patients with cirrhosis and PVT, showing an acceptable recanalization rate and safety profile.[2, 10-12] Moreover, recent studies have shown that low-molecular-weight heparin (LMWH) reduces the extent of fibrosis in experimental models of liver fibrosis.[13-16] This last observation provides a rationale to suggest that anticoagulation in patients with cirrhosis may have beneficial effects on liver function and portal hemodynamics beyond its beneficial effect on portal vein recanalization.
This randomized control trial by Villa et al., evaluating the role of LMWH in the prevention of PVT in patients with cirrhosis, sheds more light on the role of anticoagulation in cirrhosis. Villa et al. randomized 70 patients with cirrhosis, moderate liver failure (Child B7-C10), and no PVT to receive prophylactic doses of enoxaparin or no treatment during 48 weeks. The results of this interesting and innovative study were very provocative. Indeed, patients treated with enoxaparin had a significantly lower incidence of PVT. Beyond this effect, patients receiving enoxaparin also had a significantly lower incidence of liver decompensation (mainly ascites) and of mortality than controls. A drop in circulating biomarkers of intestinal integrity and immune activation in response to bacterial products was also observed in the enoxaparin group in association with a reduction in the incidence of bacterial infections. The authors suggested that these changes may be responsible for the observed additional benefits of enoxaparin besides preventing PVT. In any case, as stated by the authors, the study was not designed to clarify the ultimate mechanism of enoxaparin action. It is important to note that the prophylactic doses of enoxaparin used in the study showed a good safety profile, as no differences in bleeding complications were observed between groups, and only one patient needed to stop enoxaparin because of a reversible heparin-induced thrombocytopenia.
Thus, the study by Villa et al. shows that the use of prophylactic doses of enoxaparin in patients with cirrhosis is safe and improves prognosis. So, are we ready to introduce enoxaparin in the treatment of our patients with cirrhosis? Or, are we just facing the first steps of a long road? Before answering this pivotal question we should discuss some points. Absence of a blinded control group and the small sample size of the study are important issues to consider. In addition, a careful review of fig. 1 of the article shows that only 22/34 (65%) of patients in the enoxaparin arm and 17/36 (47%) in the control arm were at risk of developing PVT at 1 year of treatment, suggesting that there were a significant number of patients who were lost to follow-up without reaching 1 year of treatment. In addition, the investigators do not state whether patients who developed PVT were anticoagulated; therefore, it is not possible to assess whether the significant benefit of treating all patients with enoxaparin remains if the strategy to use anticoagulation only in patients suffering from PVT is applied. All patients included in the study had a Child-Pugh score between 7 and 10 points and we do not know if the potential benefit of enoxaparin may be extrapolated to all patients with cirrhosis. Last, but not least, the study shows that most benefits of treatment are lost early after enoxaparin discontinuation. Thus, efficacy, safety, and tolerability of more long-term regimens deserve further investigation.
It is our view that many unanswered questions currently preclude the use of prophylactic enoxaparin in the treatment of patients with cirrhosis without PVT. However, this relevant study opens new therapeutic paths for the management of patients with cirrhosis, even though further evidence is still needed prior to recommending enoxaparin in routine clinical practice.
Susana Seijo, M.D.
Juan Carlos Garcia-Pagan, M.D., Ph.D.
Hepatic Hemodynamic Lab
Hospital Clínic, University of Barcelona
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