Liver Disease

For patients with severe thrombocytopenia and chronic liver diseases, including hepatocellular carcinoma, treatment with lusutrombopag prior to invasive procedures significantly decreased the need for platelet transfusions without increasing the need for rescue treatment for bleeding or the rate of thromboembolic events.

In a post hoc analysis of data from 270 patients in two manufacturer-sponsored, multicenter, randomized, double-blind, placebo-controlled, phase 3 trials, significantly more lusutrombopag recipients met the primary efficacy endpoint, including patients with hepatocellular carcinoma (68.0% vs. 8.9% in the placebo group; P < .0001) and those without it (77.0% vs. 21.6%; P < .0001). Rates of treatment-emergent adverse events were similar between the lusutrombopag and placebo groups, and patients with hepatocellular carcinoma were not at increased risk for thrombosis, Naim Alkhouri, MD, of Texas Liver Institute in San Antonio, and associates wrote in Clinical Gastroenterology and Hepatology.

Platelet transfusion is the treatment mainstay for patients with thrombocytopenia related to cirrhosis who are undergoing invasive procedures, but its effects are short-lived, and at least one in five transfusions fails. Thrombopoietin agonists such as lusutrombopag are efficacious and approved in this setting, but they can be prothrombotic, particularly in patients with hepatocellular carcinoma, who already are at heightened risk for portal vein thrombosis.

Dr. Alkhouri and associates performed an integrated analysis of the PLUS 1 trial (Japan, October 2013–May 2014) and the L-PLUS 2 (global, June 2015–April 2017). Participants were adults with Child-Pugh Class A or B chronic liver disease and baseline platelet counts under 50 x 10⁹ per L who were scheduled for invasive procedures. Of the 270 patients, 95 had hepatocellular carcinoma. Patients were randomly assigned on a one-to-one basis to receive either lusutrombopag (3 mg) or placebo daily for up to 7 days before procedures. The primary endpoint was the percentage of patients in the per-protocol population who did not need a platelet transfusion before the invasive procedure or rescue therapy within 7 days afterward.

The treatment and placebo arms were similar except that patients with hepatocellular carcinoma were about 10 years older on average. In patients with hepatocellular carcinoma, 60.5% more lusutrombopag recipients than placebo recipients met the primary endpoint, and rates of bleeding-related adverse events were 9.1% and 15.7%, respectively. In patients with other chronic liver diseases, 52.6% more lusutrombopag recipients met the primary endpoint. Rates of bleeding-related adverse events were 5% and 10.6%.

“Approximately 88% of patients with hepatocellular carcinoma underwent a liver-related procedure, compared with approximately 10% of patients without hepatocellular carcinoma,” the investigators wrote. “This is significant because ablations or transcatheter arterial chemoembolizations can be associated with serious bleeding complications. It is clinically important that, given the greater number of liver-related procedures, the incidence of bleeding-related adverse events was lower in patients treated with lusutrombopag than placebo.”

Imaging after the procedures confirmed low rates of thromboses in both groups and subgroups. Four patients developed portal vein thromboses, including two lusutrombopag recipients (one of whom had hepatocellular carcinoma) and two placebo recipients without hepatocellular carcinoma.

These trials excluded patients undergoing major surgical procedures and those with decompensated cirrhosis; portal vein thrombosis; hematopoietic tumors; aplastic anemia; myelodysplastic syndrome; myelofibrosis; liver transplantation; splenectomy; and thrombocytopenia that was congenital, autoimmune, or drug induced. “A limitation of this study was the high rate of protocol violations related to platelet transfusions,” the researchers noted. “A number of patients [42 in all] were excluded from the per-protocol population owing to receipt of unnecessary platelet transfusions, or because they did not receive a needed platelet transfusion.”Shionogi makes lusutrombopag and sponsored the study. Dr. Alkhouri reported an advisory relationship with Shionogi and Dova Pharma. Two coinvestigators reported being employed by Shionogi. Three coinvestigators also disclosed ties to Shionogi and to several other pharmaceutical companies.

SOURCE: Alkhouri N et al. Clin Gastroenterol Hepatol. 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.032.

For patients with severe thrombocytopenia and chronic liver diseases, including hepatocellular carcinoma, treatment with lusutrombopag prior to invasive procedures significantly decreased the need for platelet transfusions without increasing the need for rescue treatment for bleeding or the rate of thromboembolic events.

In a post hoc analysis of data from 270 patients in two manufacturer-sponsored, multicenter, randomized, double-blind, placebo-controlled, phase 3 trials, significantly more lusutrombopag recipients met the primary efficacy endpoint, including patients with hepatocellular carcinoma (68.0% vs. 8.9% in the placebo group; P < .0001) and those without it (77.0% vs. 21.6%; P < .0001). Rates of treatment-emergent adverse events were similar between the lusutrombopag and placebo groups, and patients with hepatocellular carcinoma were not at increased risk for thrombosis, Naim Alkhouri, MD, of Texas Liver Institute in San Antonio, and associates wrote in Clinical Gastroenterology and Hepatology.

Platelet transfusion is the treatment mainstay for patients with thrombocytopenia related to cirrhosis who are undergoing invasive procedures, but its effects are short-lived, and at least one in five transfusions fails. Thrombopoietin agonists such as lusutrombopag are efficacious and approved in this setting, but they can be prothrombotic, particularly in patients with hepatocellular carcinoma, who already are at heightened risk for portal vein thrombosis.

Dr. Alkhouri and associates performed an integrated analysis of the PLUS 1 trial (Japan, October 2013–May 2014) and the L-PLUS 2 (global, June 2015–April 2017). Participants were adults with Child-Pugh Class A or B chronic liver disease and baseline platelet counts under 50 x 10⁹ per L who were scheduled for invasive procedures. Of the 270 patients, 95 had hepatocellular carcinoma. Patients were randomly assigned on a one-to-one basis to receive either lusutrombopag (3 mg) or placebo daily for up to 7 days before procedures. The primary endpoint was the percentage of patients in the per-protocol population who did not need a platelet transfusion before the invasive procedure or rescue therapy within 7 days afterward.

The treatment and placebo arms were similar except that patients with hepatocellular carcinoma were about 10 years older on average. In patients with hepatocellular carcinoma, 60.5% more lusutrombopag recipients than placebo recipients met the primary endpoint, and rates of bleeding-related adverse events were 9.1% and 15.7%, respectively. In patients with other chronic liver diseases, 52.6% more lusutrombopag recipients met the primary endpoint. Rates of bleeding-related adverse events were 5% and 10.6%.

“Approximately 88% of patients with hepatocellular carcinoma underwent a liver-related procedure, compared with approximately 10% of patients without hepatocellular carcinoma,” the investigators wrote. “This is significant because ablations or transcatheter arterial chemoembolizations can be associated with serious bleeding complications. It is clinically important that, given the greater number of liver-related procedures, the incidence of bleeding-related adverse events was lower in patients treated with lusutrombopag than placebo.”

Imaging after the procedures confirmed low rates of thromboses in both groups and subgroups. Four patients developed portal vein thromboses, including two lusutrombopag recipients (one of whom had hepatocellular carcinoma) and two placebo recipients without hepatocellular carcinoma.

These trials excluded patients undergoing major surgical procedures and those with decompensated cirrhosis; portal vein thrombosis; hematopoietic tumors; aplastic anemia; myelodysplastic syndrome; myelofibrosis; liver transplantation; splenectomy; and thrombocytopenia that was congenital, autoimmune, or drug induced. “A limitation of this study was the high rate of protocol violations related to platelet transfusions,” the researchers noted. “A number of patients [42 in all] were excluded from the per-protocol population owing to receipt of unnecessary platelet transfusions, or because they did not receive a needed platelet transfusion.”Shionogi makes lusutrombopag and sponsored the study. Dr. Alkhouri reported an advisory relationship with Shionogi and Dova Pharma. Two coinvestigators reported being employed by Shionogi. Three coinvestigators also disclosed ties to Shionogi and to several other pharmaceutical companies.

SOURCE: Alkhouri N et al. Clin Gastroenterol Hepatol. 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.032.

For patients with severe thrombocytopenia and chronic liver diseases, including hepatocellular carcinoma, treatment with lusutrombopag prior to invasive procedures significantly decreased the need for platelet transfusions without increasing the need for rescue treatment for bleeding or the rate of thromboembolic events.

In a post hoc analysis of data from 270 patients in two manufacturer-sponsored, multicenter, randomized, double-blind, placebo-controlled, phase 3 trials, significantly more lusutrombopag recipients met the primary efficacy endpoint, including patients with hepatocellular carcinoma (68.0% vs. 8.9% in the placebo group; P < .0001) and those without it (77.0% vs. 21.6%; P < .0001). Rates of treatment-emergent adverse events were similar between the lusutrombopag and placebo groups, and patients with hepatocellular carcinoma were not at increased risk for thrombosis, Naim Alkhouri, MD, of Texas Liver Institute in San Antonio, and associates wrote in Clinical Gastroenterology and Hepatology.

Platelet transfusion is the treatment mainstay for patients with thrombocytopenia related to cirrhosis who are undergoing invasive procedures, but its effects are short-lived, and at least one in five transfusions fails. Thrombopoietin agonists such as lusutrombopag are efficacious and approved in this setting, but they can be prothrombotic, particularly in patients with hepatocellular carcinoma, who already are at heightened risk for portal vein thrombosis.

Dr. Alkhouri and associates performed an integrated analysis of the PLUS 1 trial (Japan, October 2013–May 2014) and the L-PLUS 2 (global, June 2015–April 2017). Participants were adults with Child-Pugh Class A or B chronic liver disease and baseline platelet counts under 50 x 10⁹ per L who were scheduled for invasive procedures. Of the 270 patients, 95 had hepatocellular carcinoma. Patients were randomly assigned on a one-to-one basis to receive either lusutrombopag (3 mg) or placebo daily for up to 7 days before procedures. The primary endpoint was the percentage of patients in the per-protocol population who did not need a platelet transfusion before the invasive procedure or rescue therapy within 7 days afterward.

The treatment and placebo arms were similar except that patients with hepatocellular carcinoma were about 10 years older on average. In patients with hepatocellular carcinoma, 60.5% more lusutrombopag recipients than placebo recipients met the primary endpoint, and rates of bleeding-related adverse events were 9.1% and 15.7%, respectively. In patients with other chronic liver diseases, 52.6% more lusutrombopag recipients met the primary endpoint. Rates of bleeding-related adverse events were 5% and 10.6%.

“Approximately 88% of patients with hepatocellular carcinoma underwent a liver-related procedure, compared with approximately 10% of patients without hepatocellular carcinoma,” the investigators wrote. “This is significant because ablations or transcatheter arterial chemoembolizations can be associated with serious bleeding complications. It is clinically important that, given the greater number of liver-related procedures, the incidence of bleeding-related adverse events was lower in patients treated with lusutrombopag than placebo.”

Imaging after the procedures confirmed low rates of thromboses in both groups and subgroups. Four patients developed portal vein thromboses, including two lusutrombopag recipients (one of whom had hepatocellular carcinoma) and two placebo recipients without hepatocellular carcinoma.

These trials excluded patients undergoing major surgical procedures and those with decompensated cirrhosis; portal vein thrombosis; hematopoietic tumors; aplastic anemia; myelodysplastic syndrome; myelofibrosis; liver transplantation; splenectomy; and thrombocytopenia that was congenital, autoimmune, or drug induced. “A limitation of this study was the high rate of protocol violations related to platelet transfusions,” the researchers noted. “A number of patients [42 in all] were excluded from the per-protocol population owing to receipt of unnecessary platelet transfusions, or because they did not receive a needed platelet transfusion.”Shionogi makes lusutrombopag and sponsored the study. Dr. Alkhouri reported an advisory relationship with Shionogi and Dova Pharma. Two coinvestigators reported being employed by Shionogi. Three coinvestigators also disclosed ties to Shionogi and to several other pharmaceutical companies.

SOURCE: Alkhouri N et al. Clin Gastroenterol Hepatol. 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.032.

Bariatric surgery resolved nonalcoholic steatohepatitis (NASH) without worsening fibrosis in 84% of patients with evaluable biopsies, according to the findings of a prospective study.

The study included 180 severely or morbidly obese adults (body mass index >35 kg/m²) with NASH who underwent bariatric surgery at a center in France. Among 94 patients evaluated 5 years later, 68% had follow-up liver biopsies, of whom 84% (95% confidence interval, 73.1%-92.2%) met the primary endpoint of resolution of NASH without worsening of fibrosis. All histologic aspects of NASH had improved, median nonalcoholic fatty liver disease scores (NAS) fell from 5 (interquartile range, 4 to 5) to 1 (IQR, 0-2; P < .001), and 90% of patients achieved at least a 2-point NAS improvement. Hepatocellular ballooning also improved in 87.5% of patients. Baseline severity of NASH did not affect the chances of it resolving at 5 years. “The reduction of fibrosis [was] progressive, beginning during the first year and continuing through 5 years,” Guillaume Lassailly, MD, and associates wrote in Gastroenterology.

NASH is a priority for clinical research because of the substantial risk for subsequent cirrhosis, added Dr. Lassailly of CHU Lille (France). For NASH to resolve, most patients need to lose at least 7%-10% of their body weight, but “only 10% of patients reach this objective with lifestyle therapy at 1 year, and less than half maintain the weight loss 5 years later.” Despite ongoing drug development efforts, no medications have been approved for treating NASH. Although weight loss after bariatric surgery has been reported to resolve NASH in approximately 80% of patients at 1 year, longer-term data have been unavailable, and it has remained unclear whether bariatric surgery can slow or halt fibrosis progression.

All patients in this study had biopsy-confirmed NASH and at least a 5-year history of severe or morbid obesity as well as at least one comorbidity, such as diabetes mellitus or arterial hypertension. Patients were not heavy drinkers, and none had detectable markers of chronic liver disease.

Bariatric surgery produced a median 12-kg/m² drop in body mass index. At 5-year follow-up, 93% of patients meeting or exceeding this threshold who had biopsies performed showed resolution of NASH without worsening of fibrosis. Furthermore, 56% of patients (95% CI, 42.4%-69.3%) had no histologic evidence of fibrosis, including 45.5% of patients who had bridging fibrosis at baseline.

Participants in this study received intensive preoperative support, including evaluations by numerous specialists, a nutrition plan, and a 6- to 12-month therapeutic education program. Bariatric surgery techniques included Roux-en-Y gastric bypass, gastric banding, and sleeve gastrectomy. A subgroup analysis linked gastric bypass to a significantly higher probability of meeting the primary endpoint, compared with gastric banding. Refusal was the most common reason for not having a follow-up biopsy, the researchers said. “Patients without liver biopsy after bariatric surgery were not significantly different from those with a histological follow-up except for a lower BMI at 1 year. Baseline fibrosis did not influence the probability of undergoing histological reevaluation at 5 years.”

Two study participants died from surgical complications within 1 month after surgery, and one patient died from cardiac dysfunction 4 years later. No fatality was deemed liver related.

The study was funded by the French Ministry of Health, Conseil Régional Nord-Pas de Calais, National de la Recherche, and the European commission (FEDER). The researchers reported having no conflicts of interest.

SOURCE: Lassailly G et al. Gastroenterology. 2020 Jun 15. doi: 10.1053/j.gastro.2020.06.006.

Bariatric surgery resolved nonalcoholic steatohepatitis (NASH) without worsening fibrosis in 84% of patients with evaluable biopsies, according to the findings of a prospective study.

The study included 180 severely or morbidly obese adults (body mass index >35 kg/m²) with NASH who underwent bariatric surgery at a center in France. Among 94 patients evaluated 5 years later, 68% had follow-up liver biopsies, of whom 84% (95% confidence interval, 73.1%-92.2%) met the primary endpoint of resolution of NASH without worsening of fibrosis. All histologic aspects of NASH had improved, median nonalcoholic fatty liver disease scores (NAS) fell from 5 (interquartile range, 4 to 5) to 1 (IQR, 0-2; P < .001), and 90% of patients achieved at least a 2-point NAS improvement. Hepatocellular ballooning also improved in 87.5% of patients. Baseline severity of NASH did not affect the chances of it resolving at 5 years. “The reduction of fibrosis [was] progressive, beginning during the first year and continuing through 5 years,” Guillaume Lassailly, MD, and associates wrote in Gastroenterology.

NASH is a priority for clinical research because of the substantial risk for subsequent cirrhosis, added Dr. Lassailly of CHU Lille (France). For NASH to resolve, most patients need to lose at least 7%-10% of their body weight, but “only 10% of patients reach this objective with lifestyle therapy at 1 year, and less than half maintain the weight loss 5 years later.” Despite ongoing drug development efforts, no medications have been approved for treating NASH. Although weight loss after bariatric surgery has been reported to resolve NASH in approximately 80% of patients at 1 year, longer-term data have been unavailable, and it has remained unclear whether bariatric surgery can slow or halt fibrosis progression.

All patients in this study had biopsy-confirmed NASH and at least a 5-year history of severe or morbid obesity as well as at least one comorbidity, such as diabetes mellitus or arterial hypertension. Patients were not heavy drinkers, and none had detectable markers of chronic liver disease.

Bariatric surgery produced a median 12-kg/m² drop in body mass index. At 5-year follow-up, 93% of patients meeting or exceeding this threshold who had biopsies performed showed resolution of NASH without worsening of fibrosis. Furthermore, 56% of patients (95% CI, 42.4%-69.3%) had no histologic evidence of fibrosis, including 45.5% of patients who had bridging fibrosis at baseline.

Participants in this study received intensive preoperative support, including evaluations by numerous specialists, a nutrition plan, and a 6- to 12-month therapeutic education program. Bariatric surgery techniques included Roux-en-Y gastric bypass, gastric banding, and sleeve gastrectomy. A subgroup analysis linked gastric bypass to a significantly higher probability of meeting the primary endpoint, compared with gastric banding. Refusal was the most common reason for not having a follow-up biopsy, the researchers said. “Patients without liver biopsy after bariatric surgery were not significantly different from those with a histological follow-up except for a lower BMI at 1 year. Baseline fibrosis did not influence the probability of undergoing histological reevaluation at 5 years.”

Two study participants died from surgical complications within 1 month after surgery, and one patient died from cardiac dysfunction 4 years later. No fatality was deemed liver related.

The study was funded by the French Ministry of Health, Conseil Régional Nord-Pas de Calais, National de la Recherche, and the European commission (FEDER). The researchers reported having no conflicts of interest.

SOURCE: Lassailly G et al. Gastroenterology. 2020 Jun 15. doi: 10.1053/j.gastro.2020.06.006.

Bariatric surgery resolved nonalcoholic steatohepatitis (NASH) without worsening fibrosis in 84% of patients with evaluable biopsies, according to the findings of a prospective study.

The study included 180 severely or morbidly obese adults (body mass index >35 kg/m²) with NASH who underwent bariatric surgery at a center in France. Among 94 patients evaluated 5 years later, 68% had follow-up liver biopsies, of whom 84% (95% confidence interval, 73.1%-92.2%) met the primary endpoint of resolution of NASH without worsening of fibrosis. All histologic aspects of NASH had improved, median nonalcoholic fatty liver disease scores (NAS) fell from 5 (interquartile range, 4 to 5) to 1 (IQR, 0-2; P < .001), and 90% of patients achieved at least a 2-point NAS improvement. Hepatocellular ballooning also improved in 87.5% of patients. Baseline severity of NASH did not affect the chances of it resolving at 5 years. “The reduction of fibrosis [was] progressive, beginning during the first year and continuing through 5 years,” Guillaume Lassailly, MD, and associates wrote in Gastroenterology.

NASH is a priority for clinical research because of the substantial risk for subsequent cirrhosis, added Dr. Lassailly of CHU Lille (France). For NASH to resolve, most patients need to lose at least 7%-10% of their body weight, but “only 10% of patients reach this objective with lifestyle therapy at 1 year, and less than half maintain the weight loss 5 years later.” Despite ongoing drug development efforts, no medications have been approved for treating NASH. Although weight loss after bariatric surgery has been reported to resolve NASH in approximately 80% of patients at 1 year, longer-term data have been unavailable, and it has remained unclear whether bariatric surgery can slow or halt fibrosis progression.

All patients in this study had biopsy-confirmed NASH and at least a 5-year history of severe or morbid obesity as well as at least one comorbidity, such as diabetes mellitus or arterial hypertension. Patients were not heavy drinkers, and none had detectable markers of chronic liver disease.

Bariatric surgery produced a median 12-kg/m² drop in body mass index. At 5-year follow-up, 93% of patients meeting or exceeding this threshold who had biopsies performed showed resolution of NASH without worsening of fibrosis. Furthermore, 56% of patients (95% CI, 42.4%-69.3%) had no histologic evidence of fibrosis, including 45.5% of patients who had bridging fibrosis at baseline.

Participants in this study received intensive preoperative support, including evaluations by numerous specialists, a nutrition plan, and a 6- to 12-month therapeutic education program. Bariatric surgery techniques included Roux-en-Y gastric bypass, gastric banding, and sleeve gastrectomy. A subgroup analysis linked gastric bypass to a significantly higher probability of meeting the primary endpoint, compared with gastric banding. Refusal was the most common reason for not having a follow-up biopsy, the researchers said. “Patients without liver biopsy after bariatric surgery were not significantly different from those with a histological follow-up except for a lower BMI at 1 year. Baseline fibrosis did not influence the probability of undergoing histological reevaluation at 5 years.”

Two study participants died from surgical complications within 1 month after surgery, and one patient died from cardiac dysfunction 4 years later. No fatality was deemed liver related.

The study was funded by the French Ministry of Health, Conseil Régional Nord-Pas de Calais, National de la Recherche, and the European commission (FEDER). The researchers reported having no conflicts of interest.

SOURCE: Lassailly G et al. Gastroenterology. 2020 Jun 15. doi: 10.1053/j.gastro.2020.06.006.

Dear colleagues and friends,

Thank you for your continued support of the Perspectives debates. In this edition, Dr. Guadalupe Garcia-Tsao and Dr. Marwan Ghabril discuss the rationale for and against beta-blocker therapy in portal hypertension, and ultimately highlight the nuances required for appropriate decision-making. This topic invariably generates controversy and debate, and is broadly relevant to general GI and hepatology practices. I hope you will find it as informative as I did, and I welcome your comments and suggestions for future topics at [email protected].

Charles J. Kahi, MD, MS, AGAF, professor of medicine, Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.

Beta-blockers in portal hypertension – Yes!

BY GUADALUPE GARCIA-TSAO, MD

Portal hypertension is the main consequence of cirrhosis and is responsible for most of its complications. In compensated cirrhosis, a threshold portal pressure gradient, as determined by the hepatic venous pressure gradient (HVPG), of at least 10 mm Hg is the strongest predictor of clinical decompensation (ascites, variceal hemorrhage, or encephalopathy) which is, in turn, the main determinant of death in cirrhosis.

Portal hypertension is initially caused by an increase in intrahepatic resistance that leads to mild portal hypertension (HVPG, 5-10 mm Hg) but is then enhanced and maintained by an increase in portal venous inflow that leads to clinically significant portal hypertension (HVPG, at least 10 mm Hg).

Portal pressure can be reduced by either ameliorating intrahepatic resistance (which is mostly caused by structural changes that are difficult to reverse) and/or by decreasing portal vein blood inflow (the most modifiable pathogenic mechanism). For over 30 years, treatment of portal hypertension has been based on the use of nonselective beta-blockers (NSBB), drugs that decrease portal pressure through a reduction in splanchnic blood flow. Reduction in portal pressure is greater with NSBB (propranolol, nadolol) than with selective beta-blockers because, as demonstrated experimentally, the main portal pressure–reducing effect stems from splanchnic vasoconstriction because of beta2-adrenergic blockade. This has been confirmed in patients with cirrhosis, in whom the reduction in HVPG is greater with NSBB than with selective BB. On the other hand, carvedilol, an NSBB that also has a vasodilatory alpha1 adrenergic blocking effect, has a greater effect in reducing HVPG, compared with traditional NSBB.

A significant decrease in portal pressure has been associated with better outcomes in cirrhosis. A favorable portal pressure reduction (“response”) has been traditionally defined as a decrease in HVPG below 12 mm Hg or greater than 20% from baseline, although even decreases of 10% are associated with better outcomes. Initial studies had been focused on variceal hemorrhage, a complication that is clearly related to portal hypertension. In this setting, reducing portal pressure clearly leads to a decreased in the incidence of variceal hemorrhage and a decrease in mortality.¹ More recently, the focus has been on preventing decompensation (in compensated cirrhosis) and preventing further decompensation/death (in decompensated cirrhosis).

In compensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices (therefore with clinically significant portal hypertension) without ascites who were NSBB hemodynamic responders, had a reduced risk of developing not only variceal hemorrhage but also ascites and/or encephalopathy, and had lower mortality.² More importantly, a recent seminal randomized, double-blind, placebo-controlled trial performed in patients with compensated cirrhosis and clinically significant portal hypertension with no or small varices, showed that NSBB (propranolol or carvedilol) led to a significantly lower incidence of decompensation, with ascites being the single event that was significantly lower in the NSBB group.³ This study thereby demonstrates that NSBBs not only reduce the risk of variceal hemorrhage, as previously demonstrated, but also significantly reduces the probability of developing ascites, the most common complication of cirrhosis.

In decompensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices and ascites (decompensated) who were NSBB responders, had a reduced risk of developing not only variceal hemorrhage but also refractory ascites, spontaneous bacterial peritonitis and/or hepatorenal syndrome, and also had a lower mortality.² In patients with variceal hemorrhage, the recommended therapy to prevent recurrent variceal hemorrhage is the combination of NSBB plus variceal ligation but this is based on trials that combined compensated and decompensated patients. An individual patient data meta-analysis of these trials showed that, in the group of patients with decompensated Child-Pugh class B/C cirrhosis, rebleeding and mortality were higher with ligation alone, compared with combined therapy with NSBBs and ligation, underlining that NSBB is the key element of combination therapy in these patients.⁴

There is a fading controversy regarding the potential for increased mortality with the use of NSBBs in patients with refractory ascites and SBP, reported in two retrospective studies.5 These studies lacked information regarding the number of patients in whom NSBBs were withdrawn before the last observation and number of patients in whom NSBBs were started in the course of follow-up. Notably, a recent meta-analysis that included these and subsequent retrospective studies, encompassing a collective of over 1,300 patients, demonstrated that NSBB use in patients with ascites is not related to increased mortality.^1,4

Nevertheless, NSBBs should be used cautiously in patients with cirrhosis and ascites. Hemodynamic alterations typical of decompensated cirrhosis are maximal in patients with refractory ascites and spontaneous bacterial peritonitis and the use of NSBB in this setting could lead to worsening hemodynamics, with decreased mean arterial pressure and renal perfusion that could in turn lead to acute kidney injury and death. In studies showing a deleterious effect of NSBB, the mean arterial pressure was significantly lower in patients in the NSBB group.⁵ In a recent retrospective study, the beneficial effect of NSBBs in patients with refractory ascites, spontaneous bacterial peritonitis, and acute-on-chronic liver failure appeared to apply only to those with a mean arterial pressure of at least 65 mm Hg.⁶ This evidence has led to guideline recommendations that limit the dose of NSBB to a maximum of 160 mg/day for propranolol or 80 mg/day for nadolol in patients with ascites with close follow-up of arterial blood pressure. Carvedilol should preferably not be used. In the presence of a systolic blood pressure <90 mm Hg or acute kidney injury, NSBBs should be dose-reduced or discontinued. If a precipitant for hypotension is identified (e.g., spontaneous bacterial peritonitis), NSBB can be reinitiated once the precipitating event is resolved and hypotension/acute kidney injury has resolved.

In conclusion, NSBBs are a definite “yes” in the management of cirrhosis and portal hypertension as they prevent poor outcomes (including death) in patients with both compensated and decompensated cirrhosis. In patients with ascites and spontaneous bacterial peritonitis, NSBBs could have deleterious effects but these can be prevented by careful monitoring of blood pressure.
 

References

1. D’Amico G et al. Gastroenterology. 2006;131:1611-24.

2. Turco L et al. Clin Gastroenterol Hepatol. 2020;18:313-27.

3. Villanueva C et al. Lancet. 2019;393:1597-608.

4. Albillos A et al. Hepatology. 2017;66:1219-31.

5. Garcia-Tsao G. J Hepatol. 2016 Mar;64(3):532-4.

6. Tergast TL et al. Aliment Pharmacol. Ther 2019;50:696-706.

Dr. Garcia-Tsao is professor of medicine, digestive diseases; chief, digestive diseases, Veterans Affairs Connecticut Healthcare System; director, clinical and translational core, Yale Liver Center; program director, VA Connecticut Hepatitis C Resource Center, New Haven. She has no conflicts.

Can be a double-edged blade too dangerous to wield

BY MARWAN S. GHABRIL, MD, AGAF

Nonselective beta-blockers (NSBB) are a cornerstone in the primary and secondary prophylaxis of variceal bleeding in patients with cirrhosis and clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) of at least 10 mm Hg. In the absence of routine HVPG measurement in most clinical practices, NSBB therapy is targeted to a 25% heart rate reduction or target heart rate of 55-60 beats per minute. There is ample evidence supporting this indication for NSBB as summarized in the Baveno VI consensus recommendations in a wide range of liver disease severity, encompassing patients with low-risk small esophageal varices to those with large varices, stigmata, and advanced Child-Pugh class. Tasked with the contrarian perspective on NSBB use, the argument for caution hinges on observations that disease progression can shift the balance of risk and reward to NSBB minimization or avoidance. Understanding the hyperdynamic circulation in worsening portal hypertension of cirrhosis is paramount to these considerations.

The pathophysiology of portal hypertension

Portal hypertension arises as a result of both increased portal venous inflow and increased hepatic sinusoidal resistance and is characterized by splanchnic and systemic vasodilation and reduced effective systemic arterial volume. Compensatory mechanisms include systemic neurohormonal activation, increased heart rate and cardiac output, sodium and water retention (increased plasma volume), and vasoconstrictor system activation. These mechanisms suffice in restoring effective arterial volume initially but also contribute to increased splanchnic/portal inflow and portal hypertension. In advanced decompensation the cardiovascular reserve is overwhelmed with progressive systemic vasodilation, worsening sodium and water retention, vasoconstriction of vital organ vascular beds and an ineffective hyperdynamic state (tachycardia, inadequate cardiac output, and systemic hypotension). This pathophysiological state is heralded clinically by the development of worsening or refractory ascites, and belies the development of other complications of advanced cirrhosis including hyponatremia and hepatorenal syndrome.

The beneficial effects of NSBB in decreasing portal hypertension are mediated by inhibition of splanchnic vasodilation and cardiac effects (reduced heart rate and cardiac output) leading to reduced portal inflow. However, these cardiac effects can be deleterious to systemic hemodynamics in more advanced disease, particularly with acute insults that exacerbate arterial hypovolemia such as bleeding or infection. As such, blunting of sympathetic drive by NSBB carries different degrees of tolerance and risk depending on the hemodynamic reserve in the hyperdynamic state.
 

Reported clinical experiences

The controversy over NSBB use in advanced cirrhosis arises out of heterogeneous, commonly retrospective datasets and nonrandomized cohorts, with conflicting reports of positive, negative, or neutral effects on mortality and acute kidney injury. Not surprisingly, studies describing detrimental effects of NSBB are based on patients with strictly defined refractory ascites or those with spontaneous bacterial peritonitis.^1,2 Importantly, these studies also describe significantly lower blood pressure in at-risk NSBB treated patients, This baseline hemodynamic difference is either not observed,or not explicitly compared in studies/subcohorts with decreased or unaffected mortality with NSBB use in advanced cirrhosis.²

In the largest prospective study of NSBB in cirrhosis with ascites (which used data from three randomized satavaptan trials), NSBB users and nonusers were more closely matched for baseline mean arterial pressure.³ There was no effect of NSBB on mortality but there was a 29% rate of NSBB discontinuation (i.e., intolerance) during the year of follow-up. Predictors of NSBB discontinuation were hospitalization, variceal bleeding, infection, hepatorenal syndrome, Child-Pugh class C, and refractory ascites. Furthermore, NSBB discontinuation was associated with a notable increase in mortality. Similarly, clinically driven discontinuation of NSBB was observed in half of hospitalized patients with acute-on-chronic liver failure in the prospective CANONIC study, and was also associated with significantly higher short-term mortality.

It is possible that NSBB tolerance may select patients with adequate hemodynamic reserve despite the severity of other liver decompensations. Conversely, intolerance of therapeutic NSBB may signify evolving inadequacy of hemodynamic reserve, giving rise to two distinctly different risk/benefit profiles. This double-edged blade perspective is supported by findings of impaired cardiac output in patients with refractory ascites with impaired renal perfusion, and increased wait-list mortality with NSBB use in patients with compromised global cardiac function.^4,5

When is caution due?

Rather than a “therapeutic window” that is either wide open or suddenly shut, in nonhospitalized patients risk is on a continuum and there are no agreed upon liver-specific parameters that define strict barriers to NSBB treatment. Refractory ascites may not absolutely define the closure of this window but should put clinicians on notice for a patient’s vulnerability. The Baveno VI recommendations echo the need for caution, with NSBB in refractory ascites with close monitoring of blood pressure, serum sodium, and creatinine. Treatment cessation, reduction or temporary withholding, and careful reintroduction (with reversible insults) are advised in patients with systolic blood pressure <90 mm Hg, serum Na <130 mEq/L, or those with acute kidney injury.

In the absence of randomized trials that account for cirrhotic cardiomyopathy and cardiac reserve, the risks and putative nonvariceal benefits of NSBB (e.g., reducing gut bacterial translocation) are not truly defined in this patient population. We lack HVPG-based or surrogate assessments in routine practice to determine which patients are hemodynamically benefiting from NSBB therapy, or reliable indicators of imminent NSBB intolerance or risk. While the indications for NSBB may expand to prevention of decompensation, serious questions about their safety are being asked in advanced decompensation. Poor tolerance of therapeutic NSBB dosing and unquantified, but likely negative, impact on quality of life raise additional questions. In a shared decision-making partnership, the patient’s perspective on the utility, tolerance, and monitoring of NSBB therapy in preventing variceal bleeding is vital, particularly when there are endoscopic or earlier shunting alternatives. “Primum non nocere” is not a gladiatorial cry, and in the wrong patients NSBB can be a double-edged blade too dangerous to wield.
 

References

1. Serste T et al. Hepatology. 2010;52:1017-22.

2. Mandorfer M et al. Gastroenterology. 2014;146:1680-90 e1.

3. Bossen L et al. Hepatology. 2016;63:1968-76.

4. Giannelli V et al. J Hepatol. 2020;72:463-71.

5. Tellez L et al. J Hepatol. 2020 May 20. doi: 10.1016/j.jhep.2020.05.011.

Dr. Ghabril is a gastroenterologist with the Indiana University, Indianapolis. He has no conflicts.

Dear colleagues and friends,

Thank you for your continued support of the Perspectives debates. In this edition, Dr. Guadalupe Garcia-Tsao and Dr. Marwan Ghabril discuss the rationale for and against beta-blocker therapy in portal hypertension, and ultimately highlight the nuances required for appropriate decision-making. This topic invariably generates controversy and debate, and is broadly relevant to general GI and hepatology practices. I hope you will find it as informative as I did, and I welcome your comments and suggestions for future topics at [email protected].

Charles J. Kahi, MD, MS, AGAF, professor of medicine, Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.

Beta-blockers in portal hypertension – Yes!

BY GUADALUPE GARCIA-TSAO, MD

Portal hypertension is the main consequence of cirrhosis and is responsible for most of its complications. In compensated cirrhosis, a threshold portal pressure gradient, as determined by the hepatic venous pressure gradient (HVPG), of at least 10 mm Hg is the strongest predictor of clinical decompensation (ascites, variceal hemorrhage, or encephalopathy) which is, in turn, the main determinant of death in cirrhosis.

Portal hypertension is initially caused by an increase in intrahepatic resistance that leads to mild portal hypertension (HVPG, 5-10 mm Hg) but is then enhanced and maintained by an increase in portal venous inflow that leads to clinically significant portal hypertension (HVPG, at least 10 mm Hg).

Portal pressure can be reduced by either ameliorating intrahepatic resistance (which is mostly caused by structural changes that are difficult to reverse) and/or by decreasing portal vein blood inflow (the most modifiable pathogenic mechanism). For over 30 years, treatment of portal hypertension has been based on the use of nonselective beta-blockers (NSBB), drugs that decrease portal pressure through a reduction in splanchnic blood flow. Reduction in portal pressure is greater with NSBB (propranolol, nadolol) than with selective beta-blockers because, as demonstrated experimentally, the main portal pressure–reducing effect stems from splanchnic vasoconstriction because of beta2-adrenergic blockade. This has been confirmed in patients with cirrhosis, in whom the reduction in HVPG is greater with NSBB than with selective BB. On the other hand, carvedilol, an NSBB that also has a vasodilatory alpha1 adrenergic blocking effect, has a greater effect in reducing HVPG, compared with traditional NSBB.

A significant decrease in portal pressure has been associated with better outcomes in cirrhosis. A favorable portal pressure reduction (“response”) has been traditionally defined as a decrease in HVPG below 12 mm Hg or greater than 20% from baseline, although even decreases of 10% are associated with better outcomes. Initial studies had been focused on variceal hemorrhage, a complication that is clearly related to portal hypertension. In this setting, reducing portal pressure clearly leads to a decreased in the incidence of variceal hemorrhage and a decrease in mortality.¹ More recently, the focus has been on preventing decompensation (in compensated cirrhosis) and preventing further decompensation/death (in decompensated cirrhosis).

In compensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices (therefore with clinically significant portal hypertension) without ascites who were NSBB hemodynamic responders, had a reduced risk of developing not only variceal hemorrhage but also ascites and/or encephalopathy, and had lower mortality.² More importantly, a recent seminal randomized, double-blind, placebo-controlled trial performed in patients with compensated cirrhosis and clinically significant portal hypertension with no or small varices, showed that NSBB (propranolol or carvedilol) led to a significantly lower incidence of decompensation, with ascites being the single event that was significantly lower in the NSBB group.³ This study thereby demonstrates that NSBBs not only reduce the risk of variceal hemorrhage, as previously demonstrated, but also significantly reduces the probability of developing ascites, the most common complication of cirrhosis.

In decompensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices and ascites (decompensated) who were NSBB responders, had a reduced risk of developing not only variceal hemorrhage but also refractory ascites, spontaneous bacterial peritonitis and/or hepatorenal syndrome, and also had a lower mortality.² In patients with variceal hemorrhage, the recommended therapy to prevent recurrent variceal hemorrhage is the combination of NSBB plus variceal ligation but this is based on trials that combined compensated and decompensated patients. An individual patient data meta-analysis of these trials showed that, in the group of patients with decompensated Child-Pugh class B/C cirrhosis, rebleeding and mortality were higher with ligation alone, compared with combined therapy with NSBBs and ligation, underlining that NSBB is the key element of combination therapy in these patients.⁴

There is a fading controversy regarding the potential for increased mortality with the use of NSBBs in patients with refractory ascites and SBP, reported in two retrospective studies.5 These studies lacked information regarding the number of patients in whom NSBBs were withdrawn before the last observation and number of patients in whom NSBBs were started in the course of follow-up. Notably, a recent meta-analysis that included these and subsequent retrospective studies, encompassing a collective of over 1,300 patients, demonstrated that NSBB use in patients with ascites is not related to increased mortality.^1,4

Nevertheless, NSBBs should be used cautiously in patients with cirrhosis and ascites. Hemodynamic alterations typical of decompensated cirrhosis are maximal in patients with refractory ascites and spontaneous bacterial peritonitis and the use of NSBB in this setting could lead to worsening hemodynamics, with decreased mean arterial pressure and renal perfusion that could in turn lead to acute kidney injury and death. In studies showing a deleterious effect of NSBB, the mean arterial pressure was significantly lower in patients in the NSBB group.⁵ In a recent retrospective study, the beneficial effect of NSBBs in patients with refractory ascites, spontaneous bacterial peritonitis, and acute-on-chronic liver failure appeared to apply only to those with a mean arterial pressure of at least 65 mm Hg.⁶ This evidence has led to guideline recommendations that limit the dose of NSBB to a maximum of 160 mg/day for propranolol or 80 mg/day for nadolol in patients with ascites with close follow-up of arterial blood pressure. Carvedilol should preferably not be used. In the presence of a systolic blood pressure <90 mm Hg or acute kidney injury, NSBBs should be dose-reduced or discontinued. If a precipitant for hypotension is identified (e.g., spontaneous bacterial peritonitis), NSBB can be reinitiated once the precipitating event is resolved and hypotension/acute kidney injury has resolved.

In conclusion, NSBBs are a definite “yes” in the management of cirrhosis and portal hypertension as they prevent poor outcomes (including death) in patients with both compensated and decompensated cirrhosis. In patients with ascites and spontaneous bacterial peritonitis, NSBBs could have deleterious effects but these can be prevented by careful monitoring of blood pressure.
 

References

1. D’Amico G et al. Gastroenterology. 2006;131:1611-24.

2. Turco L et al. Clin Gastroenterol Hepatol. 2020;18:313-27.

3. Villanueva C et al. Lancet. 2019;393:1597-608.

4. Albillos A et al. Hepatology. 2017;66:1219-31.

5. Garcia-Tsao G. J Hepatol. 2016 Mar;64(3):532-4.

6. Tergast TL et al. Aliment Pharmacol. Ther 2019;50:696-706.

Dr. Garcia-Tsao is professor of medicine, digestive diseases; chief, digestive diseases, Veterans Affairs Connecticut Healthcare System; director, clinical and translational core, Yale Liver Center; program director, VA Connecticut Hepatitis C Resource Center, New Haven. She has no conflicts.

Can be a double-edged blade too dangerous to wield

BY MARWAN S. GHABRIL, MD, AGAF

Nonselective beta-blockers (NSBB) are a cornerstone in the primary and secondary prophylaxis of variceal bleeding in patients with cirrhosis and clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) of at least 10 mm Hg. In the absence of routine HVPG measurement in most clinical practices, NSBB therapy is targeted to a 25% heart rate reduction or target heart rate of 55-60 beats per minute. There is ample evidence supporting this indication for NSBB as summarized in the Baveno VI consensus recommendations in a wide range of liver disease severity, encompassing patients with low-risk small esophageal varices to those with large varices, stigmata, and advanced Child-Pugh class. Tasked with the contrarian perspective on NSBB use, the argument for caution hinges on observations that disease progression can shift the balance of risk and reward to NSBB minimization or avoidance. Understanding the hyperdynamic circulation in worsening portal hypertension of cirrhosis is paramount to these considerations.

The pathophysiology of portal hypertension

Portal hypertension arises as a result of both increased portal venous inflow and increased hepatic sinusoidal resistance and is characterized by splanchnic and systemic vasodilation and reduced effective systemic arterial volume. Compensatory mechanisms include systemic neurohormonal activation, increased heart rate and cardiac output, sodium and water retention (increased plasma volume), and vasoconstrictor system activation. These mechanisms suffice in restoring effective arterial volume initially but also contribute to increased splanchnic/portal inflow and portal hypertension. In advanced decompensation the cardiovascular reserve is overwhelmed with progressive systemic vasodilation, worsening sodium and water retention, vasoconstriction of vital organ vascular beds and an ineffective hyperdynamic state (tachycardia, inadequate cardiac output, and systemic hypotension). This pathophysiological state is heralded clinically by the development of worsening or refractory ascites, and belies the development of other complications of advanced cirrhosis including hyponatremia and hepatorenal syndrome.

The beneficial effects of NSBB in decreasing portal hypertension are mediated by inhibition of splanchnic vasodilation and cardiac effects (reduced heart rate and cardiac output) leading to reduced portal inflow. However, these cardiac effects can be deleterious to systemic hemodynamics in more advanced disease, particularly with acute insults that exacerbate arterial hypovolemia such as bleeding or infection. As such, blunting of sympathetic drive by NSBB carries different degrees of tolerance and risk depending on the hemodynamic reserve in the hyperdynamic state.
 

Reported clinical experiences

The controversy over NSBB use in advanced cirrhosis arises out of heterogeneous, commonly retrospective datasets and nonrandomized cohorts, with conflicting reports of positive, negative, or neutral effects on mortality and acute kidney injury. Not surprisingly, studies describing detrimental effects of NSBB are based on patients with strictly defined refractory ascites or those with spontaneous bacterial peritonitis.^1,2 Importantly, these studies also describe significantly lower blood pressure in at-risk NSBB treated patients, This baseline hemodynamic difference is either not observed,or not explicitly compared in studies/subcohorts with decreased or unaffected mortality with NSBB use in advanced cirrhosis.²

In the largest prospective study of NSBB in cirrhosis with ascites (which used data from three randomized satavaptan trials), NSBB users and nonusers were more closely matched for baseline mean arterial pressure.³ There was no effect of NSBB on mortality but there was a 29% rate of NSBB discontinuation (i.e., intolerance) during the year of follow-up. Predictors of NSBB discontinuation were hospitalization, variceal bleeding, infection, hepatorenal syndrome, Child-Pugh class C, and refractory ascites. Furthermore, NSBB discontinuation was associated with a notable increase in mortality. Similarly, clinically driven discontinuation of NSBB was observed in half of hospitalized patients with acute-on-chronic liver failure in the prospective CANONIC study, and was also associated with significantly higher short-term mortality.

It is possible that NSBB tolerance may select patients with adequate hemodynamic reserve despite the severity of other liver decompensations. Conversely, intolerance of therapeutic NSBB may signify evolving inadequacy of hemodynamic reserve, giving rise to two distinctly different risk/benefit profiles. This double-edged blade perspective is supported by findings of impaired cardiac output in patients with refractory ascites with impaired renal perfusion, and increased wait-list mortality with NSBB use in patients with compromised global cardiac function.^4,5

When is caution due?

Rather than a “therapeutic window” that is either wide open or suddenly shut, in nonhospitalized patients risk is on a continuum and there are no agreed upon liver-specific parameters that define strict barriers to NSBB treatment. Refractory ascites may not absolutely define the closure of this window but should put clinicians on notice for a patient’s vulnerability. The Baveno VI recommendations echo the need for caution, with NSBB in refractory ascites with close monitoring of blood pressure, serum sodium, and creatinine. Treatment cessation, reduction or temporary withholding, and careful reintroduction (with reversible insults) are advised in patients with systolic blood pressure <90 mm Hg, serum Na <130 mEq/L, or those with acute kidney injury.

In the absence of randomized trials that account for cirrhotic cardiomyopathy and cardiac reserve, the risks and putative nonvariceal benefits of NSBB (e.g., reducing gut bacterial translocation) are not truly defined in this patient population. We lack HVPG-based or surrogate assessments in routine practice to determine which patients are hemodynamically benefiting from NSBB therapy, or reliable indicators of imminent NSBB intolerance or risk. While the indications for NSBB may expand to prevention of decompensation, serious questions about their safety are being asked in advanced decompensation. Poor tolerance of therapeutic NSBB dosing and unquantified, but likely negative, impact on quality of life raise additional questions. In a shared decision-making partnership, the patient’s perspective on the utility, tolerance, and monitoring of NSBB therapy in preventing variceal bleeding is vital, particularly when there are endoscopic or earlier shunting alternatives. “Primum non nocere” is not a gladiatorial cry, and in the wrong patients NSBB can be a double-edged blade too dangerous to wield.
 

References

1. Serste T et al. Hepatology. 2010;52:1017-22.

2. Mandorfer M et al. Gastroenterology. 2014;146:1680-90 e1.

3. Bossen L et al. Hepatology. 2016;63:1968-76.

4. Giannelli V et al. J Hepatol. 2020;72:463-71.

5. Tellez L et al. J Hepatol. 2020 May 20. doi: 10.1016/j.jhep.2020.05.011.

Dr. Ghabril is a gastroenterologist with the Indiana University, Indianapolis. He has no conflicts.

Dear colleagues and friends,

Thank you for your continued support of the Perspectives debates. In this edition, Dr. Guadalupe Garcia-Tsao and Dr. Marwan Ghabril discuss the rationale for and against beta-blocker therapy in portal hypertension, and ultimately highlight the nuances required for appropriate decision-making. This topic invariably generates controversy and debate, and is broadly relevant to general GI and hepatology practices. I hope you will find it as informative as I did, and I welcome your comments and suggestions for future topics at [email protected].

Charles J. Kahi, MD, MS, AGAF, professor of medicine, Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.

Beta-blockers in portal hypertension – Yes!

BY GUADALUPE GARCIA-TSAO, MD

Portal hypertension is the main consequence of cirrhosis and is responsible for most of its complications. In compensated cirrhosis, a threshold portal pressure gradient, as determined by the hepatic venous pressure gradient (HVPG), of at least 10 mm Hg is the strongest predictor of clinical decompensation (ascites, variceal hemorrhage, or encephalopathy) which is, in turn, the main determinant of death in cirrhosis.

Portal hypertension is initially caused by an increase in intrahepatic resistance that leads to mild portal hypertension (HVPG, 5-10 mm Hg) but is then enhanced and maintained by an increase in portal venous inflow that leads to clinically significant portal hypertension (HVPG, at least 10 mm Hg).

Portal pressure can be reduced by either ameliorating intrahepatic resistance (which is mostly caused by structural changes that are difficult to reverse) and/or by decreasing portal vein blood inflow (the most modifiable pathogenic mechanism). For over 30 years, treatment of portal hypertension has been based on the use of nonselective beta-blockers (NSBB), drugs that decrease portal pressure through a reduction in splanchnic blood flow. Reduction in portal pressure is greater with NSBB (propranolol, nadolol) than with selective beta-blockers because, as demonstrated experimentally, the main portal pressure–reducing effect stems from splanchnic vasoconstriction because of beta2-adrenergic blockade. This has been confirmed in patients with cirrhosis, in whom the reduction in HVPG is greater with NSBB than with selective BB. On the other hand, carvedilol, an NSBB that also has a vasodilatory alpha1 adrenergic blocking effect, has a greater effect in reducing HVPG, compared with traditional NSBB.

A significant decrease in portal pressure has been associated with better outcomes in cirrhosis. A favorable portal pressure reduction (“response”) has been traditionally defined as a decrease in HVPG below 12 mm Hg or greater than 20% from baseline, although even decreases of 10% are associated with better outcomes. Initial studies had been focused on variceal hemorrhage, a complication that is clearly related to portal hypertension. In this setting, reducing portal pressure clearly leads to a decreased in the incidence of variceal hemorrhage and a decrease in mortality.¹ More recently, the focus has been on preventing decompensation (in compensated cirrhosis) and preventing further decompensation/death (in decompensated cirrhosis).

In compensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices (therefore with clinically significant portal hypertension) without ascites who were NSBB hemodynamic responders, had a reduced risk of developing not only variceal hemorrhage but also ascites and/or encephalopathy, and had lower mortality.² More importantly, a recent seminal randomized, double-blind, placebo-controlled trial performed in patients with compensated cirrhosis and clinically significant portal hypertension with no or small varices, showed that NSBB (propranolol or carvedilol) led to a significantly lower incidence of decompensation, with ascites being the single event that was significantly lower in the NSBB group.³ This study thereby demonstrates that NSBBs not only reduce the risk of variceal hemorrhage, as previously demonstrated, but also significantly reduces the probability of developing ascites, the most common complication of cirrhosis.

In decompensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices and ascites (decompensated) who were NSBB responders, had a reduced risk of developing not only variceal hemorrhage but also refractory ascites, spontaneous bacterial peritonitis and/or hepatorenal syndrome, and also had a lower mortality.² In patients with variceal hemorrhage, the recommended therapy to prevent recurrent variceal hemorrhage is the combination of NSBB plus variceal ligation but this is based on trials that combined compensated and decompensated patients. An individual patient data meta-analysis of these trials showed that, in the group of patients with decompensated Child-Pugh class B/C cirrhosis, rebleeding and mortality were higher with ligation alone, compared with combined therapy with NSBBs and ligation, underlining that NSBB is the key element of combination therapy in these patients.⁴

There is a fading controversy regarding the potential for increased mortality with the use of NSBBs in patients with refractory ascites and SBP, reported in two retrospective studies.5 These studies lacked information regarding the number of patients in whom NSBBs were withdrawn before the last observation and number of patients in whom NSBBs were started in the course of follow-up. Notably, a recent meta-analysis that included these and subsequent retrospective studies, encompassing a collective of over 1,300 patients, demonstrated that NSBB use in patients with ascites is not related to increased mortality.^1,4

Nevertheless, NSBBs should be used cautiously in patients with cirrhosis and ascites. Hemodynamic alterations typical of decompensated cirrhosis are maximal in patients with refractory ascites and spontaneous bacterial peritonitis and the use of NSBB in this setting could lead to worsening hemodynamics, with decreased mean arterial pressure and renal perfusion that could in turn lead to acute kidney injury and death. In studies showing a deleterious effect of NSBB, the mean arterial pressure was significantly lower in patients in the NSBB group.⁵ In a recent retrospective study, the beneficial effect of NSBBs in patients with refractory ascites, spontaneous bacterial peritonitis, and acute-on-chronic liver failure appeared to apply only to those with a mean arterial pressure of at least 65 mm Hg.⁶ This evidence has led to guideline recommendations that limit the dose of NSBB to a maximum of 160 mg/day for propranolol or 80 mg/day for nadolol in patients with ascites with close follow-up of arterial blood pressure. Carvedilol should preferably not be used. In the presence of a systolic blood pressure <90 mm Hg or acute kidney injury, NSBBs should be dose-reduced or discontinued. If a precipitant for hypotension is identified (e.g., spontaneous bacterial peritonitis), NSBB can be reinitiated once the precipitating event is resolved and hypotension/acute kidney injury has resolved.

In conclusion, NSBBs are a definite “yes” in the management of cirrhosis and portal hypertension as they prevent poor outcomes (including death) in patients with both compensated and decompensated cirrhosis. In patients with ascites and spontaneous bacterial peritonitis, NSBBs could have deleterious effects but these can be prevented by careful monitoring of blood pressure.
 

References

1. D’Amico G et al. Gastroenterology. 2006;131:1611-24.

2. Turco L et al. Clin Gastroenterol Hepatol. 2020;18:313-27.

3. Villanueva C et al. Lancet. 2019;393:1597-608.

4. Albillos A et al. Hepatology. 2017;66:1219-31.

5. Garcia-Tsao G. J Hepatol. 2016 Mar;64(3):532-4.

6. Tergast TL et al. Aliment Pharmacol. Ther 2019;50:696-706.

Dr. Garcia-Tsao is professor of medicine, digestive diseases; chief, digestive diseases, Veterans Affairs Connecticut Healthcare System; director, clinical and translational core, Yale Liver Center; program director, VA Connecticut Hepatitis C Resource Center, New Haven. She has no conflicts.

Can be a double-edged blade too dangerous to wield

BY MARWAN S. GHABRIL, MD, AGAF

Nonselective beta-blockers (NSBB) are a cornerstone in the primary and secondary prophylaxis of variceal bleeding in patients with cirrhosis and clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) of at least 10 mm Hg. In the absence of routine HVPG measurement in most clinical practices, NSBB therapy is targeted to a 25% heart rate reduction or target heart rate of 55-60 beats per minute. There is ample evidence supporting this indication for NSBB as summarized in the Baveno VI consensus recommendations in a wide range of liver disease severity, encompassing patients with low-risk small esophageal varices to those with large varices, stigmata, and advanced Child-Pugh class. Tasked with the contrarian perspective on NSBB use, the argument for caution hinges on observations that disease progression can shift the balance of risk and reward to NSBB minimization or avoidance. Understanding the hyperdynamic circulation in worsening portal hypertension of cirrhosis is paramount to these considerations.

The pathophysiology of portal hypertension

Portal hypertension arises as a result of both increased portal venous inflow and increased hepatic sinusoidal resistance and is characterized by splanchnic and systemic vasodilation and reduced effective systemic arterial volume. Compensatory mechanisms include systemic neurohormonal activation, increased heart rate and cardiac output, sodium and water retention (increased plasma volume), and vasoconstrictor system activation. These mechanisms suffice in restoring effective arterial volume initially but also contribute to increased splanchnic/portal inflow and portal hypertension. In advanced decompensation the cardiovascular reserve is overwhelmed with progressive systemic vasodilation, worsening sodium and water retention, vasoconstriction of vital organ vascular beds and an ineffective hyperdynamic state (tachycardia, inadequate cardiac output, and systemic hypotension). This pathophysiological state is heralded clinically by the development of worsening or refractory ascites, and belies the development of other complications of advanced cirrhosis including hyponatremia and hepatorenal syndrome.

The beneficial effects of NSBB in decreasing portal hypertension are mediated by inhibition of splanchnic vasodilation and cardiac effects (reduced heart rate and cardiac output) leading to reduced portal inflow. However, these cardiac effects can be deleterious to systemic hemodynamics in more advanced disease, particularly with acute insults that exacerbate arterial hypovolemia such as bleeding or infection. As such, blunting of sympathetic drive by NSBB carries different degrees of tolerance and risk depending on the hemodynamic reserve in the hyperdynamic state.
 

Reported clinical experiences

The controversy over NSBB use in advanced cirrhosis arises out of heterogeneous, commonly retrospective datasets and nonrandomized cohorts, with conflicting reports of positive, negative, or neutral effects on mortality and acute kidney injury. Not surprisingly, studies describing detrimental effects of NSBB are based on patients with strictly defined refractory ascites or those with spontaneous bacterial peritonitis.^1,2 Importantly, these studies also describe significantly lower blood pressure in at-risk NSBB treated patients, This baseline hemodynamic difference is either not observed,or not explicitly compared in studies/subcohorts with decreased or unaffected mortality with NSBB use in advanced cirrhosis.²

In the largest prospective study of NSBB in cirrhosis with ascites (which used data from three randomized satavaptan trials), NSBB users and nonusers were more closely matched for baseline mean arterial pressure.³ There was no effect of NSBB on mortality but there was a 29% rate of NSBB discontinuation (i.e., intolerance) during the year of follow-up. Predictors of NSBB discontinuation were hospitalization, variceal bleeding, infection, hepatorenal syndrome, Child-Pugh class C, and refractory ascites. Furthermore, NSBB discontinuation was associated with a notable increase in mortality. Similarly, clinically driven discontinuation of NSBB was observed in half of hospitalized patients with acute-on-chronic liver failure in the prospective CANONIC study, and was also associated with significantly higher short-term mortality.

It is possible that NSBB tolerance may select patients with adequate hemodynamic reserve despite the severity of other liver decompensations. Conversely, intolerance of therapeutic NSBB may signify evolving inadequacy of hemodynamic reserve, giving rise to two distinctly different risk/benefit profiles. This double-edged blade perspective is supported by findings of impaired cardiac output in patients with refractory ascites with impaired renal perfusion, and increased wait-list mortality with NSBB use in patients with compromised global cardiac function.^4,5

When is caution due?

Rather than a “therapeutic window” that is either wide open or suddenly shut, in nonhospitalized patients risk is on a continuum and there are no agreed upon liver-specific parameters that define strict barriers to NSBB treatment. Refractory ascites may not absolutely define the closure of this window but should put clinicians on notice for a patient’s vulnerability. The Baveno VI recommendations echo the need for caution, with NSBB in refractory ascites with close monitoring of blood pressure, serum sodium, and creatinine. Treatment cessation, reduction or temporary withholding, and careful reintroduction (with reversible insults) are advised in patients with systolic blood pressure <90 mm Hg, serum Na <130 mEq/L, or those with acute kidney injury.

In the absence of randomized trials that account for cirrhotic cardiomyopathy and cardiac reserve, the risks and putative nonvariceal benefits of NSBB (e.g., reducing gut bacterial translocation) are not truly defined in this patient population. We lack HVPG-based or surrogate assessments in routine practice to determine which patients are hemodynamically benefiting from NSBB therapy, or reliable indicators of imminent NSBB intolerance or risk. While the indications for NSBB may expand to prevention of decompensation, serious questions about their safety are being asked in advanced decompensation. Poor tolerance of therapeutic NSBB dosing and unquantified, but likely negative, impact on quality of life raise additional questions. In a shared decision-making partnership, the patient’s perspective on the utility, tolerance, and monitoring of NSBB therapy in preventing variceal bleeding is vital, particularly when there are endoscopic or earlier shunting alternatives. “Primum non nocere” is not a gladiatorial cry, and in the wrong patients NSBB can be a double-edged blade too dangerous to wield.
 

References

1. Serste T et al. Hepatology. 2010;52:1017-22.

2. Mandorfer M et al. Gastroenterology. 2014;146:1680-90 e1.

3. Bossen L et al. Hepatology. 2016;63:1968-76.

4. Giannelli V et al. J Hepatol. 2020;72:463-71.

5. Tellez L et al. J Hepatol. 2020 May 20. doi: 10.1016/j.jhep.2020.05.011.

Dr. Ghabril is a gastroenterologist with the Indiana University, Indianapolis. He has no conflicts.

Systemic inflammation and portal hypertension are key predictors of acute-on-chronic liver failure (ACLF) in the 3 months after a hospital stay for acute decompensated cirrhosis and also of death after 12 months, a preliminary analysis of data from the PREDICT study shows.

“Before this, we never had any patient signatures to identify ACLF,” said Jonel Trebicka, MD, PhD, from the JW Goethe University Hospital in Frankfurt, Germany.

Now, Dr. Trebicka’s team has “characterized the phenotypes in pre-ACLF that will progress within 3 months,” he said in an interview. “Those with high levels of inflammatory proteins, white blood cell count, are more likely to develop ACLF.”

ACLF is a highly complex disorder that can lead liver, cardiovascular, renal, cerebral, pulmonary, intestinal, adrenal, and immune systems to fail, Dr. Trebicka explained when he discussed the analysis – published online in the Journal of Hepatology – during the virtual International Liver Congress (ILC) 2020.

The chance of survival after the onset of ACLF is low – the 28-day survival rate is 30% – and “the only treatment we have is liver transplant,” he said.

For their prospective observational study, Dr. Trebicka and his colleagues assessed 1071 participants from 48 European hospitals in 14 countries who were admitted for an episode of acute decompensation, defined as the development of ascites, hepatic encephalopathy, gastrointestinal hemorrhage, infection, or a combination thereof.

The researchers identified three distinct clinical courses for a patient hospitalized with acute decompensated cirrhosis that will help clinicians predict the development of ACLF.

At study enrollment, more than half of the patients at highest risk for ACLF had pre-ACLF and high-grade systemic inflammation. The patients at intermediate risk had unstable decompensated cirrhosis with low-grade systemic inflammation and complications related to severe portal hypertension. And those at lowest risk for ACLF had stable decompensated cirrhosis and no severe systemic inflammation or portal hypertension complications, and did not develop ACLF or another episode of acute decompensation in the subsequent 3 months.

More tools emerging to help predict ACLF

The Albumin-functionality-test (AFT), which uses serum albumin levels to evaluate liver and kidney function, might also be useful in the prediction of ACLF and 12-month survival, according to a separate study an Italian group presented at the virtual ILC.

“Our main results are that parameters from albumin predict the development of ACLF in acute decompensated patients with the same diagnostic performance as the CLIF-AD score,” said Katja Waterstradt, PhD, from the University of Bologna in Italy.

And when the two tests are combined, diagnostic performance is increased, she added.

Dr. Trebicka has disclosed no relevant financial relationships. Dr. Waterstrand is a researcher for MedInnovation GmbH.
 

This article first appeared on Medscape.com.

Systemic inflammation and portal hypertension are key predictors of acute-on-chronic liver failure (ACLF) in the 3 months after a hospital stay for acute decompensated cirrhosis and also of death after 12 months, a preliminary analysis of data from the PREDICT study shows.

“Before this, we never had any patient signatures to identify ACLF,” said Jonel Trebicka, MD, PhD, from the JW Goethe University Hospital in Frankfurt, Germany.

Now, Dr. Trebicka’s team has “characterized the phenotypes in pre-ACLF that will progress within 3 months,” he said in an interview. “Those with high levels of inflammatory proteins, white blood cell count, are more likely to develop ACLF.”

ACLF is a highly complex disorder that can lead liver, cardiovascular, renal, cerebral, pulmonary, intestinal, adrenal, and immune systems to fail, Dr. Trebicka explained when he discussed the analysis – published online in the Journal of Hepatology – during the virtual International Liver Congress (ILC) 2020.

The chance of survival after the onset of ACLF is low – the 28-day survival rate is 30% – and “the only treatment we have is liver transplant,” he said.

For their prospective observational study, Dr. Trebicka and his colleagues assessed 1071 participants from 48 European hospitals in 14 countries who were admitted for an episode of acute decompensation, defined as the development of ascites, hepatic encephalopathy, gastrointestinal hemorrhage, infection, or a combination thereof.

The researchers identified three distinct clinical courses for a patient hospitalized with acute decompensated cirrhosis that will help clinicians predict the development of ACLF.

At study enrollment, more than half of the patients at highest risk for ACLF had pre-ACLF and high-grade systemic inflammation. The patients at intermediate risk had unstable decompensated cirrhosis with low-grade systemic inflammation and complications related to severe portal hypertension. And those at lowest risk for ACLF had stable decompensated cirrhosis and no severe systemic inflammation or portal hypertension complications, and did not develop ACLF or another episode of acute decompensation in the subsequent 3 months.

More tools emerging to help predict ACLF

The Albumin-functionality-test (AFT), which uses serum albumin levels to evaluate liver and kidney function, might also be useful in the prediction of ACLF and 12-month survival, according to a separate study an Italian group presented at the virtual ILC.

“Our main results are that parameters from albumin predict the development of ACLF in acute decompensated patients with the same diagnostic performance as the CLIF-AD score,” said Katja Waterstradt, PhD, from the University of Bologna in Italy.

And when the two tests are combined, diagnostic performance is increased, she added.

Dr. Trebicka has disclosed no relevant financial relationships. Dr. Waterstrand is a researcher for MedInnovation GmbH.
 

This article first appeared on Medscape.com.

Systemic inflammation and portal hypertension are key predictors of acute-on-chronic liver failure (ACLF) in the 3 months after a hospital stay for acute decompensated cirrhosis and also of death after 12 months, a preliminary analysis of data from the PREDICT study shows.

“Before this, we never had any patient signatures to identify ACLF,” said Jonel Trebicka, MD, PhD, from the JW Goethe University Hospital in Frankfurt, Germany.

Now, Dr. Trebicka’s team has “characterized the phenotypes in pre-ACLF that will progress within 3 months,” he said in an interview. “Those with high levels of inflammatory proteins, white blood cell count, are more likely to develop ACLF.”

ACLF is a highly complex disorder that can lead liver, cardiovascular, renal, cerebral, pulmonary, intestinal, adrenal, and immune systems to fail, Dr. Trebicka explained when he discussed the analysis – published online in the Journal of Hepatology – during the virtual International Liver Congress (ILC) 2020.

The chance of survival after the onset of ACLF is low – the 28-day survival rate is 30% – and “the only treatment we have is liver transplant,” he said.

For their prospective observational study, Dr. Trebicka and his colleagues assessed 1071 participants from 48 European hospitals in 14 countries who were admitted for an episode of acute decompensation, defined as the development of ascites, hepatic encephalopathy, gastrointestinal hemorrhage, infection, or a combination thereof.

The researchers identified three distinct clinical courses for a patient hospitalized with acute decompensated cirrhosis that will help clinicians predict the development of ACLF.

At study enrollment, more than half of the patients at highest risk for ACLF had pre-ACLF and high-grade systemic inflammation. The patients at intermediate risk had unstable decompensated cirrhosis with low-grade systemic inflammation and complications related to severe portal hypertension. And those at lowest risk for ACLF had stable decompensated cirrhosis and no severe systemic inflammation or portal hypertension complications, and did not develop ACLF or another episode of acute decompensation in the subsequent 3 months.

More tools emerging to help predict ACLF

The Albumin-functionality-test (AFT), which uses serum albumin levels to evaluate liver and kidney function, might also be useful in the prediction of ACLF and 12-month survival, according to a separate study an Italian group presented at the virtual ILC.

“Our main results are that parameters from albumin predict the development of ACLF in acute decompensated patients with the same diagnostic performance as the CLIF-AD score,” said Katja Waterstradt, PhD, from the University of Bologna in Italy.

And when the two tests are combined, diagnostic performance is increased, she added.

Dr. Trebicka has disclosed no relevant financial relationships. Dr. Waterstrand is a researcher for MedInnovation GmbH.
 

This article first appeared on Medscape.com.

Eleven high-income countries are on track to meet World Health Organization targets to eliminate hepatitis C infection by 2030, compared with 9 countries 2 years ago, researchers reported. But 28 countries, including the United States, are not expected to eliminate HCV until 2050.

“In the countries making progress, the common elements are political will, a clear national plan, and easing of restrictions on the cascade of care and testing,” Yuri Sanchez Gonzalez, PhD, director of health economics and outcomes research for biopharmaceutical company AbbVie said in an interview. That would include offering hepatitis C treatment to individuals who have liver fibrosis and those struggling with sobriety, he said. “We can’t overstate how much this is a massive driver of the hepatitis C epidemic.”

His research, presented at the digital edition of the International Liver Congress this week, showed more countries on target than in a study published 2 years ago in Liver International . “But it’s not enough,” Dr. Sanchez Gonzalez said. “We know that more than 80% of infections are in people who inject drugs. Stigmatization of drug use is still a very major issue.” Despite data clearly showing that countries who have harm-reduction programs make progress, “in many countries these programs are still illegal.”

To evaluate which countries are on target to eliminate hepatitis C by 2030, researchers performed Markov disease progression models of HCV infection in 45 high-income countries. The results showed that Australia, Canada, France, Germany, Iceland, Italy, Japan, Spain, Sweden, Switzerland, and the United Kingdom are “in the green” (on target for 2030).

Austria, Malta, the Netherlands, New Zealand, and South Korea are “in the yellow” (on target for 2040), and 28 remaining countries, including the United States, are “in the red,” with targets estimated to be met by 2050.

Compared with an analysis performed 2 years ago, South Korea moved from green to yellow, while Canada, Germany, and Sweden moved from red to green. 

Researchers say that the countries moving the needle are the ones addressing barriers to care.
 

EASL: Eliminate barriers to treatment

During this week’s Congress, the European Association for the Study of the Liver (EASL) launched a policy statement recommending breaking down all barriers that prevent people who inject drugs from getting access to hepatitis C treatment, including encouragement of laws and policies that “decriminalize drug use, drug possession and drug users themselves,” said statement coauthor Mojca Maticic, MD, PhD, University of Ljubljana, Slovenia.

“To reach the desired WHO goal, combining decriminalization of personal drug consumption and integrated interventions that include hepatitis C testing and treatment should be implemented,” she added. We need to adopt “an approach based on public health promotion, respect for human rights, and evidence.”

Although harm reduction is the top strategy for making 2030 targets, having precision data also helps a lot.

“High-quality data and harm-reduction innovation to curb the overdose crisis has moved us out of the red and into the green,” Canadian researcher Jordan Feld, MD, MPH, University of Toronto, said in an interview. He points to British Columbia, Canada’s third-most populous province, putting harm reduction programs in place as key to Canadian progress.

“Given the increasing opioid epidemic, you’re creating yourself a bigger problem if you don’t treat this population,” Dr. Feld said. When a person needs 6 months to get sober in order to be treated for HCV, that’s more potential time to pass the infection to others. His study, also presented at ILC this week, outlines anticipated timing of hepatitis C in Canada’s four most populous provinces (Ontario, Quebec, British Columbia, and Alberta), and shows British Columbia will reach targets by 2028.

Lifting all restrictions clearly helps, Dr. Sanchez Gonzalez reported. He pointed to Sweden as a good example, a country that recently lifted HCV treatment restrictions for individuals living with fibrosis. Sweden moved from a red to a green spot in this analysis and is now on target for 2030.

“As long as everyone who needs treatment gets treatment, you can make tremendous progress,” he said.

Keeping track is also essential to moving the needle. Since the WHO has no enforcement power, “these studies, which offer a report card of progress, really matter,” Dr. Sanchez Gonzalez explained. When a country knows where they stand, they are more likely to take action to change. “Nobody likes to be shown in the red.”

Still, “it’s not a shaming exercise,” he said. It’s about starting a conversation, showing who’s on track, and sharing how to get on track. “Knowing that there is something in your power to move the needle toward elimination by learning from your neighbors is powerful – often, it just takes political will.”

Dr. Feld has received consulting fees from AbbVie. Dr. Sanchez Gonzalez is on staff as the Director of Economics at AbbVie. Dr. Maticic has disclosed no relevant financial relationships.

Help your patients better understand the risks and treatment for hepatitis C by sharing AGA GI Patient Center education at http://ow.ly/xV2S30r8L29. 

A version of this article originally appeared on Medscape.com.

Eleven high-income countries are on track to meet World Health Organization targets to eliminate hepatitis C infection by 2030, compared with 9 countries 2 years ago, researchers reported. But 28 countries, including the United States, are not expected to eliminate HCV until 2050.

“In the countries making progress, the common elements are political will, a clear national plan, and easing of restrictions on the cascade of care and testing,” Yuri Sanchez Gonzalez, PhD, director of health economics and outcomes research for biopharmaceutical company AbbVie said in an interview. That would include offering hepatitis C treatment to individuals who have liver fibrosis and those struggling with sobriety, he said. “We can’t overstate how much this is a massive driver of the hepatitis C epidemic.”

His research, presented at the digital edition of the International Liver Congress this week, showed more countries on target than in a study published 2 years ago in Liver International . “But it’s not enough,” Dr. Sanchez Gonzalez said. “We know that more than 80% of infections are in people who inject drugs. Stigmatization of drug use is still a very major issue.” Despite data clearly showing that countries who have harm-reduction programs make progress, “in many countries these programs are still illegal.”

To evaluate which countries are on target to eliminate hepatitis C by 2030, researchers performed Markov disease progression models of HCV infection in 45 high-income countries. The results showed that Australia, Canada, France, Germany, Iceland, Italy, Japan, Spain, Sweden, Switzerland, and the United Kingdom are “in the green” (on target for 2030).

Austria, Malta, the Netherlands, New Zealand, and South Korea are “in the yellow” (on target for 2040), and 28 remaining countries, including the United States, are “in the red,” with targets estimated to be met by 2050.

Compared with an analysis performed 2 years ago, South Korea moved from green to yellow, while Canada, Germany, and Sweden moved from red to green. 

Researchers say that the countries moving the needle are the ones addressing barriers to care.
 

EASL: Eliminate barriers to treatment

During this week’s Congress, the European Association for the Study of the Liver (EASL) launched a policy statement recommending breaking down all barriers that prevent people who inject drugs from getting access to hepatitis C treatment, including encouragement of laws and policies that “decriminalize drug use, drug possession and drug users themselves,” said statement coauthor Mojca Maticic, MD, PhD, University of Ljubljana, Slovenia.

“To reach the desired WHO goal, combining decriminalization of personal drug consumption and integrated interventions that include hepatitis C testing and treatment should be implemented,” she added. We need to adopt “an approach based on public health promotion, respect for human rights, and evidence.”

Although harm reduction is the top strategy for making 2030 targets, having precision data also helps a lot.

“High-quality data and harm-reduction innovation to curb the overdose crisis has moved us out of the red and into the green,” Canadian researcher Jordan Feld, MD, MPH, University of Toronto, said in an interview. He points to British Columbia, Canada’s third-most populous province, putting harm reduction programs in place as key to Canadian progress.

“Given the increasing opioid epidemic, you’re creating yourself a bigger problem if you don’t treat this population,” Dr. Feld said. When a person needs 6 months to get sober in order to be treated for HCV, that’s more potential time to pass the infection to others. His study, also presented at ILC this week, outlines anticipated timing of hepatitis C in Canada’s four most populous provinces (Ontario, Quebec, British Columbia, and Alberta), and shows British Columbia will reach targets by 2028.

Lifting all restrictions clearly helps, Dr. Sanchez Gonzalez reported. He pointed to Sweden as a good example, a country that recently lifted HCV treatment restrictions for individuals living with fibrosis. Sweden moved from a red to a green spot in this analysis and is now on target for 2030.

“As long as everyone who needs treatment gets treatment, you can make tremendous progress,” he said.

Keeping track is also essential to moving the needle. Since the WHO has no enforcement power, “these studies, which offer a report card of progress, really matter,” Dr. Sanchez Gonzalez explained. When a country knows where they stand, they are more likely to take action to change. “Nobody likes to be shown in the red.”

Still, “it’s not a shaming exercise,” he said. It’s about starting a conversation, showing who’s on track, and sharing how to get on track. “Knowing that there is something in your power to move the needle toward elimination by learning from your neighbors is powerful – often, it just takes political will.”

Dr. Feld has received consulting fees from AbbVie. Dr. Sanchez Gonzalez is on staff as the Director of Economics at AbbVie. Dr. Maticic has disclosed no relevant financial relationships.

Help your patients better understand the risks and treatment for hepatitis C by sharing AGA GI Patient Center education at http://ow.ly/xV2S30r8L29. 

A version of this article originally appeared on Medscape.com.

Eleven high-income countries are on track to meet World Health Organization targets to eliminate hepatitis C infection by 2030, compared with 9 countries 2 years ago, researchers reported. But 28 countries, including the United States, are not expected to eliminate HCV until 2050.

“In the countries making progress, the common elements are political will, a clear national plan, and easing of restrictions on the cascade of care and testing,” Yuri Sanchez Gonzalez, PhD, director of health economics and outcomes research for biopharmaceutical company AbbVie said in an interview. That would include offering hepatitis C treatment to individuals who have liver fibrosis and those struggling with sobriety, he said. “We can’t overstate how much this is a massive driver of the hepatitis C epidemic.”

His research, presented at the digital edition of the International Liver Congress this week, showed more countries on target than in a study published 2 years ago in Liver International . “But it’s not enough,” Dr. Sanchez Gonzalez said. “We know that more than 80% of infections are in people who inject drugs. Stigmatization of drug use is still a very major issue.” Despite data clearly showing that countries who have harm-reduction programs make progress, “in many countries these programs are still illegal.”

To evaluate which countries are on target to eliminate hepatitis C by 2030, researchers performed Markov disease progression models of HCV infection in 45 high-income countries. The results showed that Australia, Canada, France, Germany, Iceland, Italy, Japan, Spain, Sweden, Switzerland, and the United Kingdom are “in the green” (on target for 2030).

Austria, Malta, the Netherlands, New Zealand, and South Korea are “in the yellow” (on target for 2040), and 28 remaining countries, including the United States, are “in the red,” with targets estimated to be met by 2050.

Compared with an analysis performed 2 years ago, South Korea moved from green to yellow, while Canada, Germany, and Sweden moved from red to green. 

Researchers say that the countries moving the needle are the ones addressing barriers to care.
 

EASL: Eliminate barriers to treatment

During this week’s Congress, the European Association for the Study of the Liver (EASL) launched a policy statement recommending breaking down all barriers that prevent people who inject drugs from getting access to hepatitis C treatment, including encouragement of laws and policies that “decriminalize drug use, drug possession and drug users themselves,” said statement coauthor Mojca Maticic, MD, PhD, University of Ljubljana, Slovenia.

“To reach the desired WHO goal, combining decriminalization of personal drug consumption and integrated interventions that include hepatitis C testing and treatment should be implemented,” she added. We need to adopt “an approach based on public health promotion, respect for human rights, and evidence.”

Although harm reduction is the top strategy for making 2030 targets, having precision data also helps a lot.

“High-quality data and harm-reduction innovation to curb the overdose crisis has moved us out of the red and into the green,” Canadian researcher Jordan Feld, MD, MPH, University of Toronto, said in an interview. He points to British Columbia, Canada’s third-most populous province, putting harm reduction programs in place as key to Canadian progress.

“Given the increasing opioid epidemic, you’re creating yourself a bigger problem if you don’t treat this population,” Dr. Feld said. When a person needs 6 months to get sober in order to be treated for HCV, that’s more potential time to pass the infection to others. His study, also presented at ILC this week, outlines anticipated timing of hepatitis C in Canada’s four most populous provinces (Ontario, Quebec, British Columbia, and Alberta), and shows British Columbia will reach targets by 2028.

Lifting all restrictions clearly helps, Dr. Sanchez Gonzalez reported. He pointed to Sweden as a good example, a country that recently lifted HCV treatment restrictions for individuals living with fibrosis. Sweden moved from a red to a green spot in this analysis and is now on target for 2030.

“As long as everyone who needs treatment gets treatment, you can make tremendous progress,” he said.

Keeping track is also essential to moving the needle. Since the WHO has no enforcement power, “these studies, which offer a report card of progress, really matter,” Dr. Sanchez Gonzalez explained. When a country knows where they stand, they are more likely to take action to change. “Nobody likes to be shown in the red.”

Still, “it’s not a shaming exercise,” he said. It’s about starting a conversation, showing who’s on track, and sharing how to get on track. “Knowing that there is something in your power to move the needle toward elimination by learning from your neighbors is powerful – often, it just takes political will.”

Dr. Feld has received consulting fees from AbbVie. Dr. Sanchez Gonzalez is on staff as the Director of Economics at AbbVie. Dr. Maticic has disclosed no relevant financial relationships.

Help your patients better understand the risks and treatment for hepatitis C by sharing AGA GI Patient Center education at http://ow.ly/xV2S30r8L29. 

A version of this article originally appeared on Medscape.com.

Repeat Fibrosis-4 (FIB-4) scores can be used to identify people at greatest risk for cirrhosis of the liver, new research shows.

“Done repeatedly, this test can improve prediction capacity to identify who will develop cirrhosis of the liver later in life,” said lead researcher Hannes Hagström, MD, from the Karolinska University Hospital in Stockholm.

A FIB-4 score that rises from one test to the next indicates that a person is at increased risk for severe liver disease, whereas a score that drops indicates a decreased risk, he told Medscape Medical News. The study results — published online July 1 in the Journal of Hepatology, was presented at the Digital International Liver Congress 2020.

The noninvasive, widely available, cheap FIB-4 test — which is calculated on the basis of age, transaminase level, and platelet count — is commonly used to identify the risk for advanced fibrosis in liver disease, but it has not been used to predict future risk.

To evaluate risk for cirrhosis, Hagström and his colleagues looked at 812,073 blood tests performed from 1985 to 1996 on people enrolled in the Swedish Apolipoprotein Mortality Risk (AMORIS) study.

They excluded people younger than 35 years and older than 79 years and anyone with a diagnosis of any liver disease at baseline.

The 40,729 people who had two FIB-4 measurements taken less than 5 years apart were included in the analysis. Test results were categorized into three risk groups: low (<1.30), intermediate (1.30 - 2.67), and high (>2.67).

After a median of 16.2 years, 11,929 people in the study cohort had died and 581 had a severe liver disease event.

Severe liver disease events were more common in people who had both tests categorized as high risk than in people who had both tests categorized as low risk (13.2% vs 1.0%; aHR, 17.04; 95% CI, 11.67 - 24.88).

The researchers found that a one-unit increase between the two test results was continuously predictive of a severe liver disease event (aHR, 1.81; 95% CI, 1.67 - 1.96).
 

One test not enough

The absolute risk for severe liver disease in the general population is 2%, but the FIB-4 score is elevated in about one-third of people in the general population.

“A lot of people who have increased levels of this biomarker will never develop cirrhosis,” Hagström told Medscape Medical News.

Although two FIB-4 scores might not identify everyone who will get cirrhosis, comparing scores provides insight into who is at greatest risk, he explained.

This information can be useful, particularly for primary care doctors. If you know that someone is at higher risk, “you can send that patient for a FibroScan, which is a much more sensitive measurement,” but also much more expensive. “Now we can better know who to send,” he said.

However, “the main problem is that these tests are not widely known” or used enough by primary care doctors, Hagström said.

A lack of knowledge about the utility of this test is a problem, agreed Jérôme Boursier, MD, PhD, from Angers University in France.

“The younger doctors are using these tests more often,” he told Medscape Medical News, but “the older doctors are not aware they exist.”

This study supports repeating the tests. “One test offers quite poor prediction,” Boursier said. But “when you have a higher score on a second one, this can help the conversation with the patient.”

Hagström and Boursier have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Repeat Fibrosis-4 (FIB-4) scores can be used to identify people at greatest risk for cirrhosis of the liver, new research shows.

“Done repeatedly, this test can improve prediction capacity to identify who will develop cirrhosis of the liver later in life,” said lead researcher Hannes Hagström, MD, from the Karolinska University Hospital in Stockholm.

A FIB-4 score that rises from one test to the next indicates that a person is at increased risk for severe liver disease, whereas a score that drops indicates a decreased risk, he told Medscape Medical News. The study results — published online July 1 in the Journal of Hepatology, was presented at the Digital International Liver Congress 2020.

The noninvasive, widely available, cheap FIB-4 test — which is calculated on the basis of age, transaminase level, and platelet count — is commonly used to identify the risk for advanced fibrosis in liver disease, but it has not been used to predict future risk.

To evaluate risk for cirrhosis, Hagström and his colleagues looked at 812,073 blood tests performed from 1985 to 1996 on people enrolled in the Swedish Apolipoprotein Mortality Risk (AMORIS) study.

They excluded people younger than 35 years and older than 79 years and anyone with a diagnosis of any liver disease at baseline.

The 40,729 people who had two FIB-4 measurements taken less than 5 years apart were included in the analysis. Test results were categorized into three risk groups: low (<1.30), intermediate (1.30 - 2.67), and high (>2.67).

After a median of 16.2 years, 11,929 people in the study cohort had died and 581 had a severe liver disease event.

Severe liver disease events were more common in people who had both tests categorized as high risk than in people who had both tests categorized as low risk (13.2% vs 1.0%; aHR, 17.04; 95% CI, 11.67 - 24.88).

The researchers found that a one-unit increase between the two test results was continuously predictive of a severe liver disease event (aHR, 1.81; 95% CI, 1.67 - 1.96).
 

One test not enough

The absolute risk for severe liver disease in the general population is 2%, but the FIB-4 score is elevated in about one-third of people in the general population.

“A lot of people who have increased levels of this biomarker will never develop cirrhosis,” Hagström told Medscape Medical News.

Although two FIB-4 scores might not identify everyone who will get cirrhosis, comparing scores provides insight into who is at greatest risk, he explained.

This information can be useful, particularly for primary care doctors. If you know that someone is at higher risk, “you can send that patient for a FibroScan, which is a much more sensitive measurement,” but also much more expensive. “Now we can better know who to send,” he said.

However, “the main problem is that these tests are not widely known” or used enough by primary care doctors, Hagström said.

A lack of knowledge about the utility of this test is a problem, agreed Jérôme Boursier, MD, PhD, from Angers University in France.

“The younger doctors are using these tests more often,” he told Medscape Medical News, but “the older doctors are not aware they exist.”

This study supports repeating the tests. “One test offers quite poor prediction,” Boursier said. But “when you have a higher score on a second one, this can help the conversation with the patient.”

Hagström and Boursier have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Repeat Fibrosis-4 (FIB-4) scores can be used to identify people at greatest risk for cirrhosis of the liver, new research shows.

“Done repeatedly, this test can improve prediction capacity to identify who will develop cirrhosis of the liver later in life,” said lead researcher Hannes Hagström, MD, from the Karolinska University Hospital in Stockholm.

A FIB-4 score that rises from one test to the next indicates that a person is at increased risk for severe liver disease, whereas a score that drops indicates a decreased risk, he told Medscape Medical News. The study results — published online July 1 in the Journal of Hepatology, was presented at the Digital International Liver Congress 2020.

The noninvasive, widely available, cheap FIB-4 test — which is calculated on the basis of age, transaminase level, and platelet count — is commonly used to identify the risk for advanced fibrosis in liver disease, but it has not been used to predict future risk.

To evaluate risk for cirrhosis, Hagström and his colleagues looked at 812,073 blood tests performed from 1985 to 1996 on people enrolled in the Swedish Apolipoprotein Mortality Risk (AMORIS) study.

They excluded people younger than 35 years and older than 79 years and anyone with a diagnosis of any liver disease at baseline.

The 40,729 people who had two FIB-4 measurements taken less than 5 years apart were included in the analysis. Test results were categorized into three risk groups: low (<1.30), intermediate (1.30 - 2.67), and high (>2.67).

After a median of 16.2 years, 11,929 people in the study cohort had died and 581 had a severe liver disease event.

Severe liver disease events were more common in people who had both tests categorized as high risk than in people who had both tests categorized as low risk (13.2% vs 1.0%; aHR, 17.04; 95% CI, 11.67 - 24.88).

The researchers found that a one-unit increase between the two test results was continuously predictive of a severe liver disease event (aHR, 1.81; 95% CI, 1.67 - 1.96).
 

One test not enough

The absolute risk for severe liver disease in the general population is 2%, but the FIB-4 score is elevated in about one-third of people in the general population.

“A lot of people who have increased levels of this biomarker will never develop cirrhosis,” Hagström told Medscape Medical News.

Although two FIB-4 scores might not identify everyone who will get cirrhosis, comparing scores provides insight into who is at greatest risk, he explained.

This information can be useful, particularly for primary care doctors. If you know that someone is at higher risk, “you can send that patient for a FibroScan, which is a much more sensitive measurement,” but also much more expensive. “Now we can better know who to send,” he said.

However, “the main problem is that these tests are not widely known” or used enough by primary care doctors, Hagström said.

A lack of knowledge about the utility of this test is a problem, agreed Jérôme Boursier, MD, PhD, from Angers University in France.

“The younger doctors are using these tests more often,” he told Medscape Medical News, but “the older doctors are not aware they exist.”

This study supports repeating the tests. “One test offers quite poor prediction,” Boursier said. But “when you have a higher score on a second one, this can help the conversation with the patient.”

Hagström and Boursier have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Fecal microbiota transplantation results in a short-term reduction in alcohol craving in patients with alcohol-induced cirrhosis who can’t stop drinking, results from a new study show.

And that reduction could lead to a better psychosocial quality of life for patients with cirrhosis and alcohol use disorder, said investigator Jasmohan Bajaj, MD, from Virginia Commonwealth University, Richmond.

“This is the most common addiction disorder worldwide, but we have nothing to treat these patients with,” he said.

Cirrhosis is associated with an altered gut-brain axis. It leads to organ damage in several parts of the body, including the brain, gut, pancreas, and liver. This makes changing the gut microbes “an attractive target,” Dr. Bajaj said at the Digital International Liver Congress 2020.

For their phase 1, double-blind study, he and his colleagues assessed 20 men from a Virginia veteran’s hospital with untreatable alcohol use disorder who were not eligible for liver transplantation.

All had failed behavioral or pharmacologic therapy and were unwilling to try again. “That’s what made them good candidates to try something new,” Dr. Bajaj said during a press briefing.

Mean age in the study cohort was 65 years, mean Model for End-Stage Liver disease score was 8.9, and demographic characteristics were similar between the 10 men randomly assigned to fecal transplantation and the 10 assigned to placebo. One man in each group dropped out of the study.

The investigators evaluated cravings, microbiota, and quality of life during the 30-day study period.

At day 15, significantly more men in the transplant group than in the placebo group experienced a reduction in alcohol cravings (90% vs. 30%).

At 30 days, levels of creatinine, serum interleukin-6, and lipopolysaccharide-binding protein were lower in the transplant group than in the placebo group. In addition, levels of butyrate and isobutyrate increased, as did cognition and quality of life scores.

There was also a decrease in urinary ethyl glucuronide in the transplant group, which “is the objective criteria for alcohol intake,” Dr. Bajaj reported, noting that there was no change in ethyl glucuronide in the placebo group.

The increase in microbiota diversity was significant in the transplant group but not in the placebo group. Alistipes, Odoribacter, and Roseburia were more abundant in the transplant group than in the placebo group.

During the 30-day study period, two men in the placebo group required medical attention, one for hyponatremia and the other for atrial fibrillation. However, no adverse events were seen in any men in the transplant group. “This was the No. 1 result,” Dr. Bajaj said.
 

Liver disease and the microbiome

“Understanding of interactions between the human and microbiome genome [metagenome] in health and disease has represented one of the major areas of progress in the last few years,” said Luca Valenti, MD, from the University of Milan, who is a member of the scientific committee of the European Association the Study of the Liver, which organized the congress.

“These studies lay the groundwork for the exploitation of this new knowledge for the treatment of liver disease,” he said.

“We are [now] diagnosing liver disease and the stages of liver disease based on microbiome changes,” said Jonel Trebicka, MD, PhD, from University Hospital Frankfurt (Germany), who chaired a session at the congress on the role of the microbiome in liver disease.

“This and other studies have shown us that the microbiome itself may influence liver disease,” he added.

Dr. Bajaj is considered one of the world’s experts on cirrhosis and the microbiome, Dr. Trebicka explained. Last year, Dr. Bajaj and his team demonstrated that fecal microbiota transplantation can reduce the incidence of recurrent hepatic encephalopathy, as reported by Medscape Medical News.

The current study also “shows clearly that the microbiome plays a role in craving. FMT reduces the desire for alcohol,” said Dr. Trebicka.

“The way to the brain is through the gut,” Dr. Bajaj said.

Dr. Bajaj, Dr. Trebicka, and Dr. Valenti disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Fecal microbiota transplantation results in a short-term reduction in alcohol craving in patients with alcohol-induced cirrhosis who can’t stop drinking, results from a new study show.

And that reduction could lead to a better psychosocial quality of life for patients with cirrhosis and alcohol use disorder, said investigator Jasmohan Bajaj, MD, from Virginia Commonwealth University, Richmond.

“This is the most common addiction disorder worldwide, but we have nothing to treat these patients with,” he said.

Cirrhosis is associated with an altered gut-brain axis. It leads to organ damage in several parts of the body, including the brain, gut, pancreas, and liver. This makes changing the gut microbes “an attractive target,” Dr. Bajaj said at the Digital International Liver Congress 2020.

For their phase 1, double-blind study, he and his colleagues assessed 20 men from a Virginia veteran’s hospital with untreatable alcohol use disorder who were not eligible for liver transplantation.

All had failed behavioral or pharmacologic therapy and were unwilling to try again. “That’s what made them good candidates to try something new,” Dr. Bajaj said during a press briefing.

Mean age in the study cohort was 65 years, mean Model for End-Stage Liver disease score was 8.9, and demographic characteristics were similar between the 10 men randomly assigned to fecal transplantation and the 10 assigned to placebo. One man in each group dropped out of the study.

The investigators evaluated cravings, microbiota, and quality of life during the 30-day study period.

At day 15, significantly more men in the transplant group than in the placebo group experienced a reduction in alcohol cravings (90% vs. 30%).

At 30 days, levels of creatinine, serum interleukin-6, and lipopolysaccharide-binding protein were lower in the transplant group than in the placebo group. In addition, levels of butyrate and isobutyrate increased, as did cognition and quality of life scores.

There was also a decrease in urinary ethyl glucuronide in the transplant group, which “is the objective criteria for alcohol intake,” Dr. Bajaj reported, noting that there was no change in ethyl glucuronide in the placebo group.

The increase in microbiota diversity was significant in the transplant group but not in the placebo group. Alistipes, Odoribacter, and Roseburia were more abundant in the transplant group than in the placebo group.

During the 30-day study period, two men in the placebo group required medical attention, one for hyponatremia and the other for atrial fibrillation. However, no adverse events were seen in any men in the transplant group. “This was the No. 1 result,” Dr. Bajaj said.
 

Liver disease and the microbiome

“Understanding of interactions between the human and microbiome genome [metagenome] in health and disease has represented one of the major areas of progress in the last few years,” said Luca Valenti, MD, from the University of Milan, who is a member of the scientific committee of the European Association the Study of the Liver, which organized the congress.

“These studies lay the groundwork for the exploitation of this new knowledge for the treatment of liver disease,” he said.

“We are [now] diagnosing liver disease and the stages of liver disease based on microbiome changes,” said Jonel Trebicka, MD, PhD, from University Hospital Frankfurt (Germany), who chaired a session at the congress on the role of the microbiome in liver disease.

“This and other studies have shown us that the microbiome itself may influence liver disease,” he added.

Dr. Bajaj is considered one of the world’s experts on cirrhosis and the microbiome, Dr. Trebicka explained. Last year, Dr. Bajaj and his team demonstrated that fecal microbiota transplantation can reduce the incidence of recurrent hepatic encephalopathy, as reported by Medscape Medical News.

The current study also “shows clearly that the microbiome plays a role in craving. FMT reduces the desire for alcohol,” said Dr. Trebicka.

“The way to the brain is through the gut,” Dr. Bajaj said.

Dr. Bajaj, Dr. Trebicka, and Dr. Valenti disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Fecal microbiota transplantation results in a short-term reduction in alcohol craving in patients with alcohol-induced cirrhosis who can’t stop drinking, results from a new study show.

And that reduction could lead to a better psychosocial quality of life for patients with cirrhosis and alcohol use disorder, said investigator Jasmohan Bajaj, MD, from Virginia Commonwealth University, Richmond.

“This is the most common addiction disorder worldwide, but we have nothing to treat these patients with,” he said.

Cirrhosis is associated with an altered gut-brain axis. It leads to organ damage in several parts of the body, including the brain, gut, pancreas, and liver. This makes changing the gut microbes “an attractive target,” Dr. Bajaj said at the Digital International Liver Congress 2020.

For their phase 1, double-blind study, he and his colleagues assessed 20 men from a Virginia veteran’s hospital with untreatable alcohol use disorder who were not eligible for liver transplantation.

All had failed behavioral or pharmacologic therapy and were unwilling to try again. “That’s what made them good candidates to try something new,” Dr. Bajaj said during a press briefing.

Mean age in the study cohort was 65 years, mean Model for End-Stage Liver disease score was 8.9, and demographic characteristics were similar between the 10 men randomly assigned to fecal transplantation and the 10 assigned to placebo. One man in each group dropped out of the study.

The investigators evaluated cravings, microbiota, and quality of life during the 30-day study period.

At day 15, significantly more men in the transplant group than in the placebo group experienced a reduction in alcohol cravings (90% vs. 30%).

At 30 days, levels of creatinine, serum interleukin-6, and lipopolysaccharide-binding protein were lower in the transplant group than in the placebo group. In addition, levels of butyrate and isobutyrate increased, as did cognition and quality of life scores.

There was also a decrease in urinary ethyl glucuronide in the transplant group, which “is the objective criteria for alcohol intake,” Dr. Bajaj reported, noting that there was no change in ethyl glucuronide in the placebo group.

The increase in microbiota diversity was significant in the transplant group but not in the placebo group. Alistipes, Odoribacter, and Roseburia were more abundant in the transplant group than in the placebo group.

During the 30-day study period, two men in the placebo group required medical attention, one for hyponatremia and the other for atrial fibrillation. However, no adverse events were seen in any men in the transplant group. “This was the No. 1 result,” Dr. Bajaj said.
 

Liver disease and the microbiome

“Understanding of interactions between the human and microbiome genome [metagenome] in health and disease has represented one of the major areas of progress in the last few years,” said Luca Valenti, MD, from the University of Milan, who is a member of the scientific committee of the European Association the Study of the Liver, which organized the congress.

“These studies lay the groundwork for the exploitation of this new knowledge for the treatment of liver disease,” he said.

“We are [now] diagnosing liver disease and the stages of liver disease based on microbiome changes,” said Jonel Trebicka, MD, PhD, from University Hospital Frankfurt (Germany), who chaired a session at the congress on the role of the microbiome in liver disease.

“This and other studies have shown us that the microbiome itself may influence liver disease,” he added.

Dr. Bajaj is considered one of the world’s experts on cirrhosis and the microbiome, Dr. Trebicka explained. Last year, Dr. Bajaj and his team demonstrated that fecal microbiota transplantation can reduce the incidence of recurrent hepatic encephalopathy, as reported by Medscape Medical News.

The current study also “shows clearly that the microbiome plays a role in craving. FMT reduces the desire for alcohol,” said Dr. Trebicka.

“The way to the brain is through the gut,” Dr. Bajaj said.

Dr. Bajaj, Dr. Trebicka, and Dr. Valenti disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Increasingly recognized as an independent risk factor for new-onset atrial fibrillation (AFib), new research suggests for the first time that nonalcoholic fatty liver disease (NAFLD) also confers a higher risk for arrhythmia recurrence after AFib ablation.

Over 29 months of postablation follow-up, 56% of patients with NAFLD suffered bouts of arrhythmia, compared with 31% of patients without NAFLD, matched on the basis of age, sex, body mass index (BMI), ejection fraction within 5%, and AFib type (P < .0001).

The presence of NAFLD was an independent predictor of arrhythmia recurrence in multivariable analyses adjusted for several confounders, including hemoglobin A1c, BMI, and AFib type (hazard ratio, 3.0; 95% confidence interval, 1.94-4.68).

The association is concerning given that one in four adults in the United States has NAFLD, and up to 6.1 million Americans are estimated to have Afib. Previous studies, such as ARREST-AF and LEGACY, however, have demonstrated the benefits of aggressive preablation cardiometabolic risk factor modification on long-term AFib ablation success.

Indeed, none of the NAFLD patients in the present study who lost at least 10% of their body weight had recurrent arrhythmia, compared with 31% who lost less than 10%, and 91% who gained weight prior to ablation (P < .0001).

All 22 patients whose A1c increased during the 12 months prior to ablation had recurrent arrhythmia, compared with 36% of patients whose A1c improved (P < .0001).

“I don’t think the findings of the study were particularly surprising, given what we know. It’s just further reinforcement of the essential role of risk-factor modification,” lead author Eoin Donnellan, MD, Cleveland Clinic, said in an interview.

The results were published Augus 12 in JACC Clinical Electrophysiology.

For the study, the researchers examined data from 267 consecutive patients with a mean BMI of 32.7 kg/m² who underwent radiofrequency ablation (98%) or cryoablation (2%) at the Cleveland Clinic between January 2013 and December 2017.

All patients were followed for at least 12 months after ablation and had scheduled clinic visits at 3, 6, and 12 months after pulmonary vein isolation, and annually thereafter.

NAFLD was diagnosed in 89 patients prior to ablation on the basis of CT imaging and abdominal ultrasound or MRI. On the basis of NAFLD-Fibrosis Score (NAFLD-FS), 13 patients had a low probability of liver fibrosis (F0-F2), 54 had an indeterminate probability, and 22 a high probability of fibrosis (F3-F4).

Compared with patients with no or early fibrosis (F0-F2), patients with advanced liver fibrosis (F3-F4) had almost a threefold increase in AFib recurrence (82% vs. 31%; P = .003).

“Cardiologists should make an effort to risk-stratify NAFLD patients either by NAFLD-FS or [an] alternative option, such as transient elastography or MR elastography, given these observations, rather than viewing it as either present or absence [sic] and involve expert multidisciplinary team care early in the clinical course of NAFLD patients with evidence of advanced fibrosis,” Dr. Donnellan and colleagues wrote.

Coauthor Thomas G. Cotter, MD, department of gastroenterology and hepatology, University of Chicago, said in an interview that cardiologists could use just the NAFLD-FS as part of an algorithm for an AFib.

“Because if it shows low risk, then it’s very, very likely the patient will be fine,” he said. “To use more advanced noninvasive testing, there are subtleties in the interpretation that would require referral to a liver doctor or a gastroenterologist and the cost of referring might bulk up the costs. But the NAFLD-FS is freely available and is a validated tool.”

Although it hasn’t specifically been validated in patients with AFib, the NAFLD-FS has been shown to correlate with the development of coronary artery disease  (CAD) and was recommended for clinical use in U.S. multisociety guidelines for NAFLD.

The score is calculated using six readily available clinical variables (age, BMI, hyperglycemia or diabetes, AST/ALT, platelets, and albumin). It does not include family history or alcohol consumption, which should be carefully detailed given the large overlap between NAFLD and alcohol-related liver disease, Dr. Cotter observed.

Of note, the study excluded patients with alcohol consumption of more than 30 g/day in men and more than 20 g/day in women, chronic viral hepatitis, Wilson’s disease, and hereditary hemochromatosis.

Finally, CT imaging revealed that epicardial fat volume (EFV) was greater in patients with NAFLD than in those without NAFLD (248 vs. 223 mL; P = .01).

Although increased amounts of epicardial fat have been associated with CAD, there was no significant difference in EFV between patients who did and did not develop recurrent arrhythmia (238 vs. 229 mL; P = .5). Nor was EFV associated with arrhythmia recurrence on Cox proportional hazards analysis (HR, 1.001; P = .17).

“We hypothesized that the increased risk of arrhythmia recurrence may be mediated in part by an increased epicardial fat volume,” Dr. Donnellan said. “The existing literature exploring the link between epicardial fat volume and A[Fib] burden and recurrence is conflicting. But in both this study and our bariatric surgery study, epicardial fat volume was not a significant predictor of arrhythmia recurrence on multivariable analysis.”

It’s likely that the increased recurrence risk is caused by several mechanisms, including NAFLD’s deleterious impact on cardiac structure and function, the bidirectional relationship between NAFLD and sleep apnea, and transcription of proinflammatory cytokines and low-grade systemic inflammation, he suggested.

“Patients with NAFLD represent a particularly high-risk population for arrhythmia recurrence. NAFLD is a reversible disease, and a multidisciplinary approach incorporating dietary and lifestyle interventions should by instituted prior to ablation,” Dr. Donnellan and colleagues concluded.

They noted that serial abdominal imaging to assess for preablation changes in NAFLD was limited in patients and that only 56% of control subjects underwent dedicated abdominal imaging to rule out hepatic steatosis. Also, the heterogeneity of imaging modalities used to diagnose NAFLD may have influenced the results and the study’s single-center, retrospective design limits their generalizability.

The authors reported having no relevant financial relationships.

Help your patients better understand their risk of NASH and NAFLD by sharing AGA patient education content at http://ow.ly/ZKi930r50am.  

A version of this article originally appeared on Medscape.com.

Increasingly recognized as an independent risk factor for new-onset atrial fibrillation (AFib), new research suggests for the first time that nonalcoholic fatty liver disease (NAFLD) also confers a higher risk for arrhythmia recurrence after AFib ablation.

Over 29 months of postablation follow-up, 56% of patients with NAFLD suffered bouts of arrhythmia, compared with 31% of patients without NAFLD, matched on the basis of age, sex, body mass index (BMI), ejection fraction within 5%, and AFib type (P < .0001).

The presence of NAFLD was an independent predictor of arrhythmia recurrence in multivariable analyses adjusted for several confounders, including hemoglobin A1c, BMI, and AFib type (hazard ratio, 3.0; 95% confidence interval, 1.94-4.68).

The association is concerning given that one in four adults in the United States has NAFLD, and up to 6.1 million Americans are estimated to have Afib. Previous studies, such as ARREST-AF and LEGACY, however, have demonstrated the benefits of aggressive preablation cardiometabolic risk factor modification on long-term AFib ablation success.

Indeed, none of the NAFLD patients in the present study who lost at least 10% of their body weight had recurrent arrhythmia, compared with 31% who lost less than 10%, and 91% who gained weight prior to ablation (P < .0001).

All 22 patients whose A1c increased during the 12 months prior to ablation had recurrent arrhythmia, compared with 36% of patients whose A1c improved (P < .0001).

“I don’t think the findings of the study were particularly surprising, given what we know. It’s just further reinforcement of the essential role of risk-factor modification,” lead author Eoin Donnellan, MD, Cleveland Clinic, said in an interview.

The results were published Augus 12 in JACC Clinical Electrophysiology.

For the study, the researchers examined data from 267 consecutive patients with a mean BMI of 32.7 kg/m² who underwent radiofrequency ablation (98%) or cryoablation (2%) at the Cleveland Clinic between January 2013 and December 2017.

All patients were followed for at least 12 months after ablation and had scheduled clinic visits at 3, 6, and 12 months after pulmonary vein isolation, and annually thereafter.

NAFLD was diagnosed in 89 patients prior to ablation on the basis of CT imaging and abdominal ultrasound or MRI. On the basis of NAFLD-Fibrosis Score (NAFLD-FS), 13 patients had a low probability of liver fibrosis (F0-F2), 54 had an indeterminate probability, and 22 a high probability of fibrosis (F3-F4).

Compared with patients with no or early fibrosis (F0-F2), patients with advanced liver fibrosis (F3-F4) had almost a threefold increase in AFib recurrence (82% vs. 31%; P = .003).

“Cardiologists should make an effort to risk-stratify NAFLD patients either by NAFLD-FS or [an] alternative option, such as transient elastography or MR elastography, given these observations, rather than viewing it as either present or absence [sic] and involve expert multidisciplinary team care early in the clinical course of NAFLD patients with evidence of advanced fibrosis,” Dr. Donnellan and colleagues wrote.

Coauthor Thomas G. Cotter, MD, department of gastroenterology and hepatology, University of Chicago, said in an interview that cardiologists could use just the NAFLD-FS as part of an algorithm for an AFib.

“Because if it shows low risk, then it’s very, very likely the patient will be fine,” he said. “To use more advanced noninvasive testing, there are subtleties in the interpretation that would require referral to a liver doctor or a gastroenterologist and the cost of referring might bulk up the costs. But the NAFLD-FS is freely available and is a validated tool.”

Although it hasn’t specifically been validated in patients with AFib, the NAFLD-FS has been shown to correlate with the development of coronary artery disease  (CAD) and was recommended for clinical use in U.S. multisociety guidelines for NAFLD.

The score is calculated using six readily available clinical variables (age, BMI, hyperglycemia or diabetes, AST/ALT, platelets, and albumin). It does not include family history or alcohol consumption, which should be carefully detailed given the large overlap between NAFLD and alcohol-related liver disease, Dr. Cotter observed.

Of note, the study excluded patients with alcohol consumption of more than 30 g/day in men and more than 20 g/day in women, chronic viral hepatitis, Wilson’s disease, and hereditary hemochromatosis.

Finally, CT imaging revealed that epicardial fat volume (EFV) was greater in patients with NAFLD than in those without NAFLD (248 vs. 223 mL; P = .01).

Although increased amounts of epicardial fat have been associated with CAD, there was no significant difference in EFV between patients who did and did not develop recurrent arrhythmia (238 vs. 229 mL; P = .5). Nor was EFV associated with arrhythmia recurrence on Cox proportional hazards analysis (HR, 1.001; P = .17).

“We hypothesized that the increased risk of arrhythmia recurrence may be mediated in part by an increased epicardial fat volume,” Dr. Donnellan said. “The existing literature exploring the link between epicardial fat volume and A[Fib] burden and recurrence is conflicting. But in both this study and our bariatric surgery study, epicardial fat volume was not a significant predictor of arrhythmia recurrence on multivariable analysis.”

It’s likely that the increased recurrence risk is caused by several mechanisms, including NAFLD’s deleterious impact on cardiac structure and function, the bidirectional relationship between NAFLD and sleep apnea, and transcription of proinflammatory cytokines and low-grade systemic inflammation, he suggested.

“Patients with NAFLD represent a particularly high-risk population for arrhythmia recurrence. NAFLD is a reversible disease, and a multidisciplinary approach incorporating dietary and lifestyle interventions should by instituted prior to ablation,” Dr. Donnellan and colleagues concluded.

They noted that serial abdominal imaging to assess for preablation changes in NAFLD was limited in patients and that only 56% of control subjects underwent dedicated abdominal imaging to rule out hepatic steatosis. Also, the heterogeneity of imaging modalities used to diagnose NAFLD may have influenced the results and the study’s single-center, retrospective design limits their generalizability.

The authors reported having no relevant financial relationships.

Help your patients better understand their risk of NASH and NAFLD by sharing AGA patient education content at http://ow.ly/ZKi930r50am.  

A version of this article originally appeared on Medscape.com.

Increasingly recognized as an independent risk factor for new-onset atrial fibrillation (AFib), new research suggests for the first time that nonalcoholic fatty liver disease (NAFLD) also confers a higher risk for arrhythmia recurrence after AFib ablation.

Over 29 months of postablation follow-up, 56% of patients with NAFLD suffered bouts of arrhythmia, compared with 31% of patients without NAFLD, matched on the basis of age, sex, body mass index (BMI), ejection fraction within 5%, and AFib type (P < .0001).

The presence of NAFLD was an independent predictor of arrhythmia recurrence in multivariable analyses adjusted for several confounders, including hemoglobin A1c, BMI, and AFib type (hazard ratio, 3.0; 95% confidence interval, 1.94-4.68).

The association is concerning given that one in four adults in the United States has NAFLD, and up to 6.1 million Americans are estimated to have Afib. Previous studies, such as ARREST-AF and LEGACY, however, have demonstrated the benefits of aggressive preablation cardiometabolic risk factor modification on long-term AFib ablation success.

Indeed, none of the NAFLD patients in the present study who lost at least 10% of their body weight had recurrent arrhythmia, compared with 31% who lost less than 10%, and 91% who gained weight prior to ablation (P < .0001).

All 22 patients whose A1c increased during the 12 months prior to ablation had recurrent arrhythmia, compared with 36% of patients whose A1c improved (P < .0001).

“I don’t think the findings of the study were particularly surprising, given what we know. It’s just further reinforcement of the essential role of risk-factor modification,” lead author Eoin Donnellan, MD, Cleveland Clinic, said in an interview.

The results were published Augus 12 in JACC Clinical Electrophysiology.

For the study, the researchers examined data from 267 consecutive patients with a mean BMI of 32.7 kg/m² who underwent radiofrequency ablation (98%) or cryoablation (2%) at the Cleveland Clinic between January 2013 and December 2017.

All patients were followed for at least 12 months after ablation and had scheduled clinic visits at 3, 6, and 12 months after pulmonary vein isolation, and annually thereafter.

NAFLD was diagnosed in 89 patients prior to ablation on the basis of CT imaging and abdominal ultrasound or MRI. On the basis of NAFLD-Fibrosis Score (NAFLD-FS), 13 patients had a low probability of liver fibrosis (F0-F2), 54 had an indeterminate probability, and 22 a high probability of fibrosis (F3-F4).

Compared with patients with no or early fibrosis (F0-F2), patients with advanced liver fibrosis (F3-F4) had almost a threefold increase in AFib recurrence (82% vs. 31%; P = .003).

“Cardiologists should make an effort to risk-stratify NAFLD patients either by NAFLD-FS or [an] alternative option, such as transient elastography or MR elastography, given these observations, rather than viewing it as either present or absence [sic] and involve expert multidisciplinary team care early in the clinical course of NAFLD patients with evidence of advanced fibrosis,” Dr. Donnellan and colleagues wrote.

Coauthor Thomas G. Cotter, MD, department of gastroenterology and hepatology, University of Chicago, said in an interview that cardiologists could use just the NAFLD-FS as part of an algorithm for an AFib.

“Because if it shows low risk, then it’s very, very likely the patient will be fine,” he said. “To use more advanced noninvasive testing, there are subtleties in the interpretation that would require referral to a liver doctor or a gastroenterologist and the cost of referring might bulk up the costs. But the NAFLD-FS is freely available and is a validated tool.”

Although it hasn’t specifically been validated in patients with AFib, the NAFLD-FS has been shown to correlate with the development of coronary artery disease  (CAD) and was recommended for clinical use in U.S. multisociety guidelines for NAFLD.

The score is calculated using six readily available clinical variables (age, BMI, hyperglycemia or diabetes, AST/ALT, platelets, and albumin). It does not include family history or alcohol consumption, which should be carefully detailed given the large overlap between NAFLD and alcohol-related liver disease, Dr. Cotter observed.

Of note, the study excluded patients with alcohol consumption of more than 30 g/day in men and more than 20 g/day in women, chronic viral hepatitis, Wilson’s disease, and hereditary hemochromatosis.

Finally, CT imaging revealed that epicardial fat volume (EFV) was greater in patients with NAFLD than in those without NAFLD (248 vs. 223 mL; P = .01).

Although increased amounts of epicardial fat have been associated with CAD, there was no significant difference in EFV between patients who did and did not develop recurrent arrhythmia (238 vs. 229 mL; P = .5). Nor was EFV associated with arrhythmia recurrence on Cox proportional hazards analysis (HR, 1.001; P = .17).

“We hypothesized that the increased risk of arrhythmia recurrence may be mediated in part by an increased epicardial fat volume,” Dr. Donnellan said. “The existing literature exploring the link between epicardial fat volume and A[Fib] burden and recurrence is conflicting. But in both this study and our bariatric surgery study, epicardial fat volume was not a significant predictor of arrhythmia recurrence on multivariable analysis.”

It’s likely that the increased recurrence risk is caused by several mechanisms, including NAFLD’s deleterious impact on cardiac structure and function, the bidirectional relationship between NAFLD and sleep apnea, and transcription of proinflammatory cytokines and low-grade systemic inflammation, he suggested.

“Patients with NAFLD represent a particularly high-risk population for arrhythmia recurrence. NAFLD is a reversible disease, and a multidisciplinary approach incorporating dietary and lifestyle interventions should by instituted prior to ablation,” Dr. Donnellan and colleagues concluded.

They noted that serial abdominal imaging to assess for preablation changes in NAFLD was limited in patients and that only 56% of control subjects underwent dedicated abdominal imaging to rule out hepatic steatosis. Also, the heterogeneity of imaging modalities used to diagnose NAFLD may have influenced the results and the study’s single-center, retrospective design limits their generalizability.

The authors reported having no relevant financial relationships.

Help your patients better understand their risk of NASH and NAFLD by sharing AGA patient education content at http://ow.ly/ZKi930r50am.  

A version of this article originally appeared on Medscape.com.

All patients with cancer who are candidates for systemic anticancer therapy should be screened for hepatitis B virus (HBV) infection prior to or at the start of therapy, according to an updated provisional clinical opinion (PCO) from the American Society of Clinical Oncology.

“This is a new approach [that] will actively take system changes ... but it will ultimately be safer for patients – and that is crucial,” commented Jessica P. Hwang, MD, MPH, cochair of the American Society of Clinical Oncology HBV Screening Expert Panel and the first author of the PCO.

Uptake of this universal screening approach would streamline testing protocols and identify more patients at risk for HBV reactivation who should receive prophylactic antiviral therapy, Dr. Hwang said in an interview.

The PCO calls for antiviral prophylaxis during and for at least 12 months after therapy for those with chronic HBV infection who are receiving any systemic anticancer treatment and for those with have had HBV in the past and are receiving any therapies that pose a risk for HBV reactivation.

“Hepatitis B reactivation can cause really terrible outcomes, like organ failure and even death,” Dr. Hwang, who is also a professor at the University of Texas MD Anderson Cancer Center, Houston, commented in an interview.

“This whole [issue of] reactivation and adverse outcomes with anticancer therapies is completely preventable with good planning, good communication, comanagement with specialists, and antiviral therapy and monitoring,” she added.

The updated opinion was published online July 27 in the Journal of Clinical Oncology.

It was developed in response to new data that call into question the previously recommended risk-adaptive approach to HBV screening of cancer patients, say the authors.

ASCO PCOs are developed “to provide timely clinical guidance” on the basis of emerging practice-changing information. This is the second update to follow the initial HBV screening PCO, published in 2010. In the absence of clear consensus because of limited data, the original PCO called for a risk-based approach to screening. A 2015 update extended the recommendation for screening to patients starting anti-CD20 therapy or who are to undergo stem cell transplant and to those with risk factors for HBV exposure.

The current update provides “a clinically pragmatic approach to HBV screening and management” that is based on the latest findings, say the authors. These include findings from a multicenter prospective cohort study of more than 3000 patients. In that study, 21% of patients with chronic HBV had no known risk factors for the infection. In another large prospective observational cohort study, led by Dr. Hwang, which included more than 2100 patients with cancer, 90% had one or more significant risk factors for HBV infection, making selective screening “inefficient and impractical,” she said.

“The results of these two studies suggest that a universal screening approach, its potential harms (e.g., patient and clinician anxiety about management, financial burden associated with antiviral therapy) notwithstanding, is the most efficient, clinically pragmatic approach to HBV screening in persons anticipating systemic anticancer treatment,” the authors comment.

The screening recommended in the PCO requires three tests: hepatitis B surface antigen (HBsAg), core antibody total immunoglobulin or IgG, and antibody to HBsAg tests.

Anticancer therapy should not be delayed pending the results, they write.

Planning for monitoring and long-term prophylaxis for chronic HBV infection should involve a clinician experienced in HBV management, the authors write. Management of those with past infection should be individualized. Alternatively, patients with past infection can be carefully monitored rather than given prophylactic treatment, as long as frequent and consistent follow-up is possible to allow for rapid initiation of antiviral therapy in the event of reactivation, they say.

Hormonal therapy without systemic anticancer therapy is not likely to lead to HBV reactivation in patients with chronic or past infection; antiviral therapy and management of these patients should follow relevant national HBV guidelines, they note.

Challenges in implementing universal HBV screening

The expert panel acknowledges the challenges associated with implementation of universal HBV screening as recommended in their report and notes that electronic health record–based approaches that use alerts to prompt screening have demonstrated success. In one study of high-risk primary care patients, an EHR alert system significantly increased testing rates (odds ratio, 2.64 in comparison with a control group without alerts), and another study that used a simple “sticky-note” alert system to promote referral of HBsAg patients to hepatologists increased referrals from 28% to 73%.

In a cancer population, a “comprehensive set of multimodal interventions,” including pharmacy staff checks for screening prior to anti-CD20 therapy administration and electronic medication order reviews to assess for appropriate testing and treatment before anti-CD20 therapy, increased testing rates to greater than 90% and antiviral prophylaxis rates to more than 80%.

A study of 965 patients in Taiwan showed that a computer-assisted reminder system that prompted for testing prior to ordering anticancer therapy increased screening from 8% to 86% but was less effective for improving the rates of antiviral prophylaxis for those who tested positive for HBV, particularly among physicians treating patients with nonhematologic malignancies.

“Future studies will be needed to make universal HBV screening and linkage to care efficient and systematic, likely based in EHR systems,” the panel says. The authors note that “[o]ngoing studies of HBV tests such as ultrasensitive HBsAg, HBV RNA, and hepatitis B core antigen are being studied and may be useful in predicting risk of HBV reactivation.”

The panel also identified a research gap related to HBV reactivation risks “for the growing list of agents that deplete or modulate B cells.” It notes a need for additional research on the cost-effectiveness of HBV screening. The results of prior cost analyses have been inconsistent and vary with respect to the population studied. For example, universal screening and antiviral prophylaxis approaches have been shown to be cost-effective for patients with hematologic malignancies and high HBV reactivation risk but are less so for patients with solid tumors and lower reactivation risk, they explain.

Dr. Hwang said that not one of the more than 2100 patients in her HBV screening cohort study encountered problems with receiving insurance payment for their HBV screening.

“That’s a really strong statement that insurance payers are accepting of this kind of preventative service,” she said.

Expert panel cochair Andrew Artz, MD, commented that there is now greater acceptance of the need for HBV screening across medical specialties.

“There’s growing consensus among hepatologists, infectious disease specialists, oncologists, and HBV specialists that we need to do a better job of finding patients with hepatitis B [who are] about to receive immunocompromising treatment,” Dr. Artz said in an interview.

Dr. Artz is director of the Program for Aging and Blood Cancers and deputy director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center, Duarte, California.

He suggested that the growing acceptance is due in part to the increasing number of anticancer therapies available and the resulting increase in the likelihood of patients receiving therapies that could cause reactivation.

More therapies – and more lines of therapy – could mean greater risk, he explained. He said that testing is easy and that universal screening is the simplest approach to determining who needs it. “There’s no question we will have to change practice,” Dr. Artz said in an interview. “But this is easier than the previous approach that essentially wasn’t being followed because it was too difficult to follow and patients were being missed.”

Most clinicians will appreciate having an approach that’s easier to follow, Dr. Artz predicted.

If there’s a challenge it will be in developing partnerships with HBV specialists, particularly in rural areas. In areas where there is a paucity of subspecialists, oncologists will have to “take some ownership of the issue,” as they often do in such settings, he said.

However, with support from pharmacists, administrators, and others in embracing this guidance, implementation can take place at a systems level rather than an individual clinician level, he added.

The recommendations in this updated PCO were all rated as “strong,” with the exception of the recommendation on hormonal therapy in the absence of systemic anticancer therapy, which was rated as “moderate.” All were based on “informal consensus,” with the exception of the key recommendation for universal HBV screening – use of three specific tests – which was “evidence based.”

The expert panel agreed that the benefits outweigh the harms for each recommendation in the update.

Dr. Hwang received research funding to her institution from Gilead Sciences and Merck Sharp & Dohme. She also has a relationship with the Asian Health Foundation. Dr. Artz received research funding from Miltenyi Biotec. All expert panel members’ disclosures are available in the PCO update.

This article first appeared on Medscape.com.

All patients with cancer who are candidates for systemic anticancer therapy should be screened for hepatitis B virus (HBV) infection prior to or at the start of therapy, according to an updated provisional clinical opinion (PCO) from the American Society of Clinical Oncology.

“This is a new approach [that] will actively take system changes ... but it will ultimately be safer for patients – and that is crucial,” commented Jessica P. Hwang, MD, MPH, cochair of the American Society of Clinical Oncology HBV Screening Expert Panel and the first author of the PCO.

Uptake of this universal screening approach would streamline testing protocols and identify more patients at risk for HBV reactivation who should receive prophylactic antiviral therapy, Dr. Hwang said in an interview.

The PCO calls for antiviral prophylaxis during and for at least 12 months after therapy for those with chronic HBV infection who are receiving any systemic anticancer treatment and for those with have had HBV in the past and are receiving any therapies that pose a risk for HBV reactivation.

“Hepatitis B reactivation can cause really terrible outcomes, like organ failure and even death,” Dr. Hwang, who is also a professor at the University of Texas MD Anderson Cancer Center, Houston, commented in an interview.

“This whole [issue of] reactivation and adverse outcomes with anticancer therapies is completely preventable with good planning, good communication, comanagement with specialists, and antiviral therapy and monitoring,” she added.

The updated opinion was published online July 27 in the Journal of Clinical Oncology.

It was developed in response to new data that call into question the previously recommended risk-adaptive approach to HBV screening of cancer patients, say the authors.

ASCO PCOs are developed “to provide timely clinical guidance” on the basis of emerging practice-changing information. This is the second update to follow the initial HBV screening PCO, published in 2010. In the absence of clear consensus because of limited data, the original PCO called for a risk-based approach to screening. A 2015 update extended the recommendation for screening to patients starting anti-CD20 therapy or who are to undergo stem cell transplant and to those with risk factors for HBV exposure.

The current update provides “a clinically pragmatic approach to HBV screening and management” that is based on the latest findings, say the authors. These include findings from a multicenter prospective cohort study of more than 3000 patients. In that study, 21% of patients with chronic HBV had no known risk factors for the infection. In another large prospective observational cohort study, led by Dr. Hwang, which included more than 2100 patients with cancer, 90% had one or more significant risk factors for HBV infection, making selective screening “inefficient and impractical,” she said.

“The results of these two studies suggest that a universal screening approach, its potential harms (e.g., patient and clinician anxiety about management, financial burden associated with antiviral therapy) notwithstanding, is the most efficient, clinically pragmatic approach to HBV screening in persons anticipating systemic anticancer treatment,” the authors comment.

The screening recommended in the PCO requires three tests: hepatitis B surface antigen (HBsAg), core antibody total immunoglobulin or IgG, and antibody to HBsAg tests.

Anticancer therapy should not be delayed pending the results, they write.

Planning for monitoring and long-term prophylaxis for chronic HBV infection should involve a clinician experienced in HBV management, the authors write. Management of those with past infection should be individualized. Alternatively, patients with past infection can be carefully monitored rather than given prophylactic treatment, as long as frequent and consistent follow-up is possible to allow for rapid initiation of antiviral therapy in the event of reactivation, they say.

Hormonal therapy without systemic anticancer therapy is not likely to lead to HBV reactivation in patients with chronic or past infection; antiviral therapy and management of these patients should follow relevant national HBV guidelines, they note.

Challenges in implementing universal HBV screening

The expert panel acknowledges the challenges associated with implementation of universal HBV screening as recommended in their report and notes that electronic health record–based approaches that use alerts to prompt screening have demonstrated success. In one study of high-risk primary care patients, an EHR alert system significantly increased testing rates (odds ratio, 2.64 in comparison with a control group without alerts), and another study that used a simple “sticky-note” alert system to promote referral of HBsAg patients to hepatologists increased referrals from 28% to 73%.

In a cancer population, a “comprehensive set of multimodal interventions,” including pharmacy staff checks for screening prior to anti-CD20 therapy administration and electronic medication order reviews to assess for appropriate testing and treatment before anti-CD20 therapy, increased testing rates to greater than 90% and antiviral prophylaxis rates to more than 80%.

A study of 965 patients in Taiwan showed that a computer-assisted reminder system that prompted for testing prior to ordering anticancer therapy increased screening from 8% to 86% but was less effective for improving the rates of antiviral prophylaxis for those who tested positive for HBV, particularly among physicians treating patients with nonhematologic malignancies.

“Future studies will be needed to make universal HBV screening and linkage to care efficient and systematic, likely based in EHR systems,” the panel says. The authors note that “[o]ngoing studies of HBV tests such as ultrasensitive HBsAg, HBV RNA, and hepatitis B core antigen are being studied and may be useful in predicting risk of HBV reactivation.”

The panel also identified a research gap related to HBV reactivation risks “for the growing list of agents that deplete or modulate B cells.” It notes a need for additional research on the cost-effectiveness of HBV screening. The results of prior cost analyses have been inconsistent and vary with respect to the population studied. For example, universal screening and antiviral prophylaxis approaches have been shown to be cost-effective for patients with hematologic malignancies and high HBV reactivation risk but are less so for patients with solid tumors and lower reactivation risk, they explain.

Dr. Hwang said that not one of the more than 2100 patients in her HBV screening cohort study encountered problems with receiving insurance payment for their HBV screening.

“That’s a really strong statement that insurance payers are accepting of this kind of preventative service,” she said.

Expert panel cochair Andrew Artz, MD, commented that there is now greater acceptance of the need for HBV screening across medical specialties.

“There’s growing consensus among hepatologists, infectious disease specialists, oncologists, and HBV specialists that we need to do a better job of finding patients with hepatitis B [who are] about to receive immunocompromising treatment,” Dr. Artz said in an interview.

Dr. Artz is director of the Program for Aging and Blood Cancers and deputy director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center, Duarte, California.

He suggested that the growing acceptance is due in part to the increasing number of anticancer therapies available and the resulting increase in the likelihood of patients receiving therapies that could cause reactivation.

More therapies – and more lines of therapy – could mean greater risk, he explained. He said that testing is easy and that universal screening is the simplest approach to determining who needs it. “There’s no question we will have to change practice,” Dr. Artz said in an interview. “But this is easier than the previous approach that essentially wasn’t being followed because it was too difficult to follow and patients were being missed.”

Most clinicians will appreciate having an approach that’s easier to follow, Dr. Artz predicted.

If there’s a challenge it will be in developing partnerships with HBV specialists, particularly in rural areas. In areas where there is a paucity of subspecialists, oncologists will have to “take some ownership of the issue,” as they often do in such settings, he said.

However, with support from pharmacists, administrators, and others in embracing this guidance, implementation can take place at a systems level rather than an individual clinician level, he added.

The recommendations in this updated PCO were all rated as “strong,” with the exception of the recommendation on hormonal therapy in the absence of systemic anticancer therapy, which was rated as “moderate.” All were based on “informal consensus,” with the exception of the key recommendation for universal HBV screening – use of three specific tests – which was “evidence based.”

The expert panel agreed that the benefits outweigh the harms for each recommendation in the update.

Dr. Hwang received research funding to her institution from Gilead Sciences and Merck Sharp & Dohme. She also has a relationship with the Asian Health Foundation. Dr. Artz received research funding from Miltenyi Biotec. All expert panel members’ disclosures are available in the PCO update.

This article first appeared on Medscape.com.

All patients with cancer who are candidates for systemic anticancer therapy should be screened for hepatitis B virus (HBV) infection prior to or at the start of therapy, according to an updated provisional clinical opinion (PCO) from the American Society of Clinical Oncology.

“This is a new approach [that] will actively take system changes ... but it will ultimately be safer for patients – and that is crucial,” commented Jessica P. Hwang, MD, MPH, cochair of the American Society of Clinical Oncology HBV Screening Expert Panel and the first author of the PCO.

Uptake of this universal screening approach would streamline testing protocols and identify more patients at risk for HBV reactivation who should receive prophylactic antiviral therapy, Dr. Hwang said in an interview.

The PCO calls for antiviral prophylaxis during and for at least 12 months after therapy for those with chronic HBV infection who are receiving any systemic anticancer treatment and for those with have had HBV in the past and are receiving any therapies that pose a risk for HBV reactivation.

“Hepatitis B reactivation can cause really terrible outcomes, like organ failure and even death,” Dr. Hwang, who is also a professor at the University of Texas MD Anderson Cancer Center, Houston, commented in an interview.

“This whole [issue of] reactivation and adverse outcomes with anticancer therapies is completely preventable with good planning, good communication, comanagement with specialists, and antiviral therapy and monitoring,” she added.

The updated opinion was published online July 27 in the Journal of Clinical Oncology.

It was developed in response to new data that call into question the previously recommended risk-adaptive approach to HBV screening of cancer patients, say the authors.

ASCO PCOs are developed “to provide timely clinical guidance” on the basis of emerging practice-changing information. This is the second update to follow the initial HBV screening PCO, published in 2010. In the absence of clear consensus because of limited data, the original PCO called for a risk-based approach to screening. A 2015 update extended the recommendation for screening to patients starting anti-CD20 therapy or who are to undergo stem cell transplant and to those with risk factors for HBV exposure.

The current update provides “a clinically pragmatic approach to HBV screening and management” that is based on the latest findings, say the authors. These include findings from a multicenter prospective cohort study of more than 3000 patients. In that study, 21% of patients with chronic HBV had no known risk factors for the infection. In another large prospective observational cohort study, led by Dr. Hwang, which included more than 2100 patients with cancer, 90% had one or more significant risk factors for HBV infection, making selective screening “inefficient and impractical,” she said.

“The results of these two studies suggest that a universal screening approach, its potential harms (e.g., patient and clinician anxiety about management, financial burden associated with antiviral therapy) notwithstanding, is the most efficient, clinically pragmatic approach to HBV screening in persons anticipating systemic anticancer treatment,” the authors comment.

The screening recommended in the PCO requires three tests: hepatitis B surface antigen (HBsAg), core antibody total immunoglobulin or IgG, and antibody to HBsAg tests.

Anticancer therapy should not be delayed pending the results, they write.

Planning for monitoring and long-term prophylaxis for chronic HBV infection should involve a clinician experienced in HBV management, the authors write. Management of those with past infection should be individualized. Alternatively, patients with past infection can be carefully monitored rather than given prophylactic treatment, as long as frequent and consistent follow-up is possible to allow for rapid initiation of antiviral therapy in the event of reactivation, they say.

Hormonal therapy without systemic anticancer therapy is not likely to lead to HBV reactivation in patients with chronic or past infection; antiviral therapy and management of these patients should follow relevant national HBV guidelines, they note.

Challenges in implementing universal HBV screening

The expert panel acknowledges the challenges associated with implementation of universal HBV screening as recommended in their report and notes that electronic health record–based approaches that use alerts to prompt screening have demonstrated success. In one study of high-risk primary care patients, an EHR alert system significantly increased testing rates (odds ratio, 2.64 in comparison with a control group without alerts), and another study that used a simple “sticky-note” alert system to promote referral of HBsAg patients to hepatologists increased referrals from 28% to 73%.

In a cancer population, a “comprehensive set of multimodal interventions,” including pharmacy staff checks for screening prior to anti-CD20 therapy administration and electronic medication order reviews to assess for appropriate testing and treatment before anti-CD20 therapy, increased testing rates to greater than 90% and antiviral prophylaxis rates to more than 80%.

A study of 965 patients in Taiwan showed that a computer-assisted reminder system that prompted for testing prior to ordering anticancer therapy increased screening from 8% to 86% but was less effective for improving the rates of antiviral prophylaxis for those who tested positive for HBV, particularly among physicians treating patients with nonhematologic malignancies.

“Future studies will be needed to make universal HBV screening and linkage to care efficient and systematic, likely based in EHR systems,” the panel says. The authors note that “[o]ngoing studies of HBV tests such as ultrasensitive HBsAg, HBV RNA, and hepatitis B core antigen are being studied and may be useful in predicting risk of HBV reactivation.”

The panel also identified a research gap related to HBV reactivation risks “for the growing list of agents that deplete or modulate B cells.” It notes a need for additional research on the cost-effectiveness of HBV screening. The results of prior cost analyses have been inconsistent and vary with respect to the population studied. For example, universal screening and antiviral prophylaxis approaches have been shown to be cost-effective for patients with hematologic malignancies and high HBV reactivation risk but are less so for patients with solid tumors and lower reactivation risk, they explain.

Dr. Hwang said that not one of the more than 2100 patients in her HBV screening cohort study encountered problems with receiving insurance payment for their HBV screening.

“That’s a really strong statement that insurance payers are accepting of this kind of preventative service,” she said.

Expert panel cochair Andrew Artz, MD, commented that there is now greater acceptance of the need for HBV screening across medical specialties.

“There’s growing consensus among hepatologists, infectious disease specialists, oncologists, and HBV specialists that we need to do a better job of finding patients with hepatitis B [who are] about to receive immunocompromising treatment,” Dr. Artz said in an interview.

Dr. Artz is director of the Program for Aging and Blood Cancers and deputy director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center, Duarte, California.

He suggested that the growing acceptance is due in part to the increasing number of anticancer therapies available and the resulting increase in the likelihood of patients receiving therapies that could cause reactivation.

More therapies – and more lines of therapy – could mean greater risk, he explained. He said that testing is easy and that universal screening is the simplest approach to determining who needs it. “There’s no question we will have to change practice,” Dr. Artz said in an interview. “But this is easier than the previous approach that essentially wasn’t being followed because it was too difficult to follow and patients were being missed.”

Most clinicians will appreciate having an approach that’s easier to follow, Dr. Artz predicted.

If there’s a challenge it will be in developing partnerships with HBV specialists, particularly in rural areas. In areas where there is a paucity of subspecialists, oncologists will have to “take some ownership of the issue,” as they often do in such settings, he said.

However, with support from pharmacists, administrators, and others in embracing this guidance, implementation can take place at a systems level rather than an individual clinician level, he added.

The recommendations in this updated PCO were all rated as “strong,” with the exception of the recommendation on hormonal therapy in the absence of systemic anticancer therapy, which was rated as “moderate.” All were based on “informal consensus,” with the exception of the key recommendation for universal HBV screening – use of three specific tests – which was “evidence based.”

The expert panel agreed that the benefits outweigh the harms for each recommendation in the update.

Dr. Hwang received research funding to her institution from Gilead Sciences and Merck Sharp & Dohme. She also has a relationship with the Asian Health Foundation. Dr. Artz received research funding from Miltenyi Biotec. All expert panel members’ disclosures are available in the PCO update.

This article first appeared on Medscape.com.

Perioperative bleeding risk was not associated with platelet count in a fairly large cohort of patients with liver cirrhosis, according to a review of cases, including some involving severe thrombocytopenia.

The findings raise questions about current recommendations that call for transfusing platelet concentrates to reduce bleeding risk during surgery in cirrhosis patients with extremely low platelet counts, Gian Marco Podda, MD, PhD, said at the International Society on Thrombosis and Haemostasis virtual congress.

The overall rate of perioperative bleeding was 8.9% in 996 patients who underwent excision of hepatocellular carcinoma by resection (42%) or radiofrequency ablation (58%) without platelet transfusion between 1998 and 2018. The rates were slightly higher among 65 patients with platelet count of fewer than 50 × 10⁹/L indicating severe thrombocytopenia, and in 292 patients with counts of 50-100 × 10⁹/L, indicating moderate thrombocytopenia (10.8% and 10.2%, respectively), compared with those with a platelet count of higher than 100 × 10⁹/L (8.1%), but the differences were not statistically significant, said Dr. Podda of the University of Milan (Italy).

The corresponding rates among those who underwent radiofrequency ablation were 8.6%, 5.9%, and 5%, and among those who underwent resection, they were 18.8%, 17.7%, and 15.9%.

On multivariate analysis, factors associated with an increased incidence of major bleeding were low hemoglobin level (odds ratio, 0.57), age over 65 years (OR, 1.19), aspartate aminotransferase level greater than twice the upper limit of normal (OR, 2.12), hepatitis B or C cirrhosis versus cryptogenic cirrhosis (OR, 0.08), and resection versus radiofrequency ablation (OR, 3.74), he noted. Logistic regression analysis showed no significant association between platelet count and major bleeding events.

Mortality, a secondary outcome measure, was significantly higher among those with moderate or severe thrombocytopenia (rate of 5.5% for each), compared with those with mild or no thrombocytopenia (2.4%), Dr. Podda said.

Factors associated with mortality on multivariate analysis were severe liver dysfunction as demonstrated by Model for End-Stage Liver Disease score of 10 or greater versus less than 10 (OR, 3.13) and Child-Pugh B and C score versus Child-Pugh A score (OR, 16.72), advanced tumor status as measured by Barcelona-Clínic Liver Cancer staging greater than A4 versus A1 (OR, 5.78), major bleeding (OR, 4.59), and resection versus radiofrequency ablation (OR, 3.31).

“Low platelet count was associated with an increased risk of mortality at 3 months. However, this association disappeared at the multivariate analysis, which took into account markers of severity of liver cirrhosis,” he said.

Dr. Podda and his colleagues conducted the study in light of a recommendation from a consensus conference of the Italian Association for the Study of Liver Disease and the Italian Society of Internal Medicine that called for increasing platelet count by platelet transfusions in patients with cirrhosis who undergo an invasive procedure and who have a platelet count lower than 50 × 10⁹/L.

“This recommendation mostly stemmed from consideration of biological plausibility prospects rather than being based on hard experimental evidence,” he explained, noting that such severe thrombocytopenia affects about 10% of patients with liver cirrhosis.

Based on the findings of this study, the practice is not supported, he concluded.

Dr. Podda reported honoraria from Sanofi, Boehringer Ingelheim.

[email protected]

SOURCE: Ronca V et al. ISTH 2020, Abstract OC 13.4.

Perioperative bleeding risk was not associated with platelet count in a fairly large cohort of patients with liver cirrhosis, according to a review of cases, including some involving severe thrombocytopenia.

The findings raise questions about current recommendations that call for transfusing platelet concentrates to reduce bleeding risk during surgery in cirrhosis patients with extremely low platelet counts, Gian Marco Podda, MD, PhD, said at the International Society on Thrombosis and Haemostasis virtual congress.

The overall rate of perioperative bleeding was 8.9% in 996 patients who underwent excision of hepatocellular carcinoma by resection (42%) or radiofrequency ablation (58%) without platelet transfusion between 1998 and 2018. The rates were slightly higher among 65 patients with platelet count of fewer than 50 × 10⁹/L indicating severe thrombocytopenia, and in 292 patients with counts of 50-100 × 10⁹/L, indicating moderate thrombocytopenia (10.8% and 10.2%, respectively), compared with those with a platelet count of higher than 100 × 10⁹/L (8.1%), but the differences were not statistically significant, said Dr. Podda of the University of Milan (Italy).

The corresponding rates among those who underwent radiofrequency ablation were 8.6%, 5.9%, and 5%, and among those who underwent resection, they were 18.8%, 17.7%, and 15.9%.

On multivariate analysis, factors associated with an increased incidence of major bleeding were low hemoglobin level (odds ratio, 0.57), age over 65 years (OR, 1.19), aspartate aminotransferase level greater than twice the upper limit of normal (OR, 2.12), hepatitis B or C cirrhosis versus cryptogenic cirrhosis (OR, 0.08), and resection versus radiofrequency ablation (OR, 3.74), he noted. Logistic regression analysis showed no significant association between platelet count and major bleeding events.

Mortality, a secondary outcome measure, was significantly higher among those with moderate or severe thrombocytopenia (rate of 5.5% for each), compared with those with mild or no thrombocytopenia (2.4%), Dr. Podda said.

Factors associated with mortality on multivariate analysis were severe liver dysfunction as demonstrated by Model for End-Stage Liver Disease score of 10 or greater versus less than 10 (OR, 3.13) and Child-Pugh B and C score versus Child-Pugh A score (OR, 16.72), advanced tumor status as measured by Barcelona-Clínic Liver Cancer staging greater than A4 versus A1 (OR, 5.78), major bleeding (OR, 4.59), and resection versus radiofrequency ablation (OR, 3.31).

“Low platelet count was associated with an increased risk of mortality at 3 months. However, this association disappeared at the multivariate analysis, which took into account markers of severity of liver cirrhosis,” he said.

Dr. Podda and his colleagues conducted the study in light of a recommendation from a consensus conference of the Italian Association for the Study of Liver Disease and the Italian Society of Internal Medicine that called for increasing platelet count by platelet transfusions in patients with cirrhosis who undergo an invasive procedure and who have a platelet count lower than 50 × 10⁹/L.

“This recommendation mostly stemmed from consideration of biological plausibility prospects rather than being based on hard experimental evidence,” he explained, noting that such severe thrombocytopenia affects about 10% of patients with liver cirrhosis.

Based on the findings of this study, the practice is not supported, he concluded.

Dr. Podda reported honoraria from Sanofi, Boehringer Ingelheim.

[email protected]

SOURCE: Ronca V et al. ISTH 2020, Abstract OC 13.4.

Perioperative bleeding risk was not associated with platelet count in a fairly large cohort of patients with liver cirrhosis, according to a review of cases, including some involving severe thrombocytopenia.

The findings raise questions about current recommendations that call for transfusing platelet concentrates to reduce bleeding risk during surgery in cirrhosis patients with extremely low platelet counts, Gian Marco Podda, MD, PhD, said at the International Society on Thrombosis and Haemostasis virtual congress.

The overall rate of perioperative bleeding was 8.9% in 996 patients who underwent excision of hepatocellular carcinoma by resection (42%) or radiofrequency ablation (58%) without platelet transfusion between 1998 and 2018. The rates were slightly higher among 65 patients with platelet count of fewer than 50 × 10⁹/L indicating severe thrombocytopenia, and in 292 patients with counts of 50-100 × 10⁹/L, indicating moderate thrombocytopenia (10.8% and 10.2%, respectively), compared with those with a platelet count of higher than 100 × 10⁹/L (8.1%), but the differences were not statistically significant, said Dr. Podda of the University of Milan (Italy).

The corresponding rates among those who underwent radiofrequency ablation were 8.6%, 5.9%, and 5%, and among those who underwent resection, they were 18.8%, 17.7%, and 15.9%.

On multivariate analysis, factors associated with an increased incidence of major bleeding were low hemoglobin level (odds ratio, 0.57), age over 65 years (OR, 1.19), aspartate aminotransferase level greater than twice the upper limit of normal (OR, 2.12), hepatitis B or C cirrhosis versus cryptogenic cirrhosis (OR, 0.08), and resection versus radiofrequency ablation (OR, 3.74), he noted. Logistic regression analysis showed no significant association between platelet count and major bleeding events.

Mortality, a secondary outcome measure, was significantly higher among those with moderate or severe thrombocytopenia (rate of 5.5% for each), compared with those with mild or no thrombocytopenia (2.4%), Dr. Podda said.

Factors associated with mortality on multivariate analysis were severe liver dysfunction as demonstrated by Model for End-Stage Liver Disease score of 10 or greater versus less than 10 (OR, 3.13) and Child-Pugh B and C score versus Child-Pugh A score (OR, 16.72), advanced tumor status as measured by Barcelona-Clínic Liver Cancer staging greater than A4 versus A1 (OR, 5.78), major bleeding (OR, 4.59), and resection versus radiofrequency ablation (OR, 3.31).

“Low platelet count was associated with an increased risk of mortality at 3 months. However, this association disappeared at the multivariate analysis, which took into account markers of severity of liver cirrhosis,” he said.

Dr. Podda and his colleagues conducted the study in light of a recommendation from a consensus conference of the Italian Association for the Study of Liver Disease and the Italian Society of Internal Medicine that called for increasing platelet count by platelet transfusions in patients with cirrhosis who undergo an invasive procedure and who have a platelet count lower than 50 × 10⁹/L.

“This recommendation mostly stemmed from consideration of biological plausibility prospects rather than being based on hard experimental evidence,” he explained, noting that such severe thrombocytopenia affects about 10% of patients with liver cirrhosis.

Based on the findings of this study, the practice is not supported, he concluded.

Dr. Podda reported honoraria from Sanofi, Boehringer Ingelheim.

[email protected]

SOURCE: Ronca V et al. ISTH 2020, Abstract OC 13.4.