Walter Alexander

Intestinal decontamination with rifaximin prevents spontaneous bacterial peritonitis and improves transplant-free survival in cirrhotic patients with ascites.

Intestinal decontamination with rifaximin effectively prevents spontaneous bacterial peritonitis (SBP) and improves transplant-free survival in cirrhotic patients with ascites, according to a presentation at Digestive Disease Week 2011.

SBP, said Ibrahim A. Hanouneh, MD, gastroenterology fellow at Cleveland Clinic, Cleveland OH, occurs in 8-25% of cirrhotic patients with ascites. The in-hospital mortality rate among these patients ranges from 10-30%, and SBP recurs within a year in 70% of those who survive an episode.

AASLD (American Association for the Study of Liver Disease) practice guidelines recommend the use of antibiotics such as norfloxacin or trimethoprim/sulfamethoxazole for primary prophylaxis of SBP in high-risk cirrhotic with ascites.

There is, however, no current consensus on whether prophylactic antibiotics provide a long-term survival benefit. In addition, there is a concern that prophylactic antibiotics can lead to the emergence of resistant gut flora which can subsequently cause spontaneous infection.

Rifaximin is a poorly absorbed, well-tolerated antibiotic with low bacterial resistance risk. It is broad spectrum and covers Gram-positive and Gram-negative organisms, aerobes as well as anaerobes, Hanouneh said.

To determine whether rifaximin prevents SBP in cirrhotic patients with ascites, and to determine whether rifaximin provides survival benefit for cirrhotic patients with ascites, Hanouneh reviewed all patients seen at the Cleveland Clinic liver transplant unit between 2003 and 2007 (N=664). Among these, 434 with ascites clinically significant enough to justify paracentesis were included in the evaluation. They were stratified by use of rifaximin (rifaximin=49; no rifaximin=355), which had been given primarily for hepatic encephalopathy at a dose of 400 mg TID. Those who had received primary SBP prophylaxis with norfloxacin or trimethoprim/sulfamethoxazole (N=8), with histories of SBP (N=14), SBP in the setting of a GI bleed (N-=2) or prior transplantation (N=6) were excluded. Patients were followed until organ transplant or death.

Mean patient age was ~54 years (~60% male, ~83% Caucasian). Encephalopathy was more common in the rifaximin group (100% versus 32%, P<0.001), as was elevated Child’s Pugh (a cirrhosis severity scale) (11.5% versus 10.4%, P<0.001).

After about 60 months of follow-up, 118 (29%) of patients had developed SBP, 5 in the rifaximin group and 113 in the no rifaximin group (p=0.001). Based on that, the NNT (number needed to treat) to prevent 1 SBP with rifaximin treatment is 5, Hanouneh said.

A multivariable analysis of factors associated with SBP revealed rifaximin (hazard ratio [HR]=0.28, P=0.007) and MELD score (Mayo End-Stage Liver Disease score)(HR=1.06, P<0.001), another marker of disease severity and mortality in persons with chronic alcoholic liver disease, as significant factors,

After adjusting for MELD score, Child’s Pugh score, serium sodium and ascetic fluid total protein, there was a 72 percent reduction in the rate of SBP in the rifaximin group. Analysis showed also greater transplant-free survival in the rifaximin group (72% versus 57%, p=0.04). Multivariable analysis of transplant-free survival factors showed significance for rifaximin (HR=0.54; P=0.039) and for MELD score (HR= 1.09; P<0.001).

Hanouneh concluded, “Intestinal decontamination with rifaximin is an effective measure to prevent SBP and improve transplant-free survival in cirrhotic patients with ascites.” Hanouneh commented at the DDW press conference, “I would not make recommendations based on this study now because it was retrospective. If the findings are confirmed prospectively, I would.”

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DDW 2011: Rifaximin Reduces SBP Risk, Improves Transplant-Free Survival

Cardiovascular risks associated with discontinuing clopidogrel before elective colonoscopy exceed the risks of post-polypectomy bleeding.

“We speculate that the cardiovascular risks of routinely discontinuing clopidogrel may well exceed any excess risk of post-polypectomy bleeding,” stated Fatema Uddin, MD, a fellow in the division of digestive and liver diseases at University of Texas Southwestern Medical Center, Dallas, TX. Her statement, given in an oral presentation at Digestive Disease Week 2011, was based on findings from a retrospective study of all patients undergoing colonoscopy with polypectomy at the Dallas VA Hospital between July 2008 and December 2009.

Uddin noted that the majority of adults age 60 years and older have one or more type of cardiovascular disease, with 20% requiring anticoagulation or antiplatelet agents (ie, aspirin, warfarin, clopidogrel). ASGE (American Society for Gastrointestinal Endoscopy) guidelines recommend considering withholding clopidogrel for 7-10 days prior to high-risk procedures like polypectomy. Stopping these agents, however, entails risk for myocardial infarction, cerebrovascular accidents, thromboembolic events, and stent thrombosis. Stent thrombosis among patients who have received a drug-eluting stent, in particular, has been shown to carry a high mortality risk. Data are lacking, however, on the risk of bleeding if clopidogrel is continued during polypectomy.

Uddin noted that because physicians at the Dallas VA Hospital have judged the cardiovascular risks of discontinuing clopidogrel prior to elective colonoscopy to exceed the risks of post-polypectomy bleeding, the procedure there is to not routinely discontinue clopidogrel. Uddin and colleagues evaluated the safety of continuing clopidogrel during colonoscopy when polypectomy is performed.

In the study, colonoscopy with polyp removal was performed in 118 patients on clopidogrel and 1,849 patients not on clopidogrel. A logistic regression analysis revealed no significant difference in the frequency of delayed post-polypectomy bleeding (PPB) between clopidogrel users and non-users (0.8% versus 0.3%, p=0.37, unadjusted OR=2.63, 95% CI:0.31-22). There were significant differences between clopidogrel users and non-users in the frequency of coronary artery disease (94.1% vs. 24.2%), aspirin use (78% vs. 27.9%), age (64.9 vs. 62.4), and lung disease (24.6% vs. 13.4%). Matched analysis taking these into account also revealed no significant difference in PPB rates between clopidogrel users and non-users (0.9% vs. 0%, p=0.99). Importantly, the outcomes among patients who did have bleeding were without major consequences.

Uddin concluded, “The delayed PPB rate for our patients taking clopidogrel was less than 1% (1 PPB). PPB rates did not differ significantly between the clopidogrel users and non-users, even after controlling for potential confounders by propensity scoring. We speculate that the cardiovascular risks of routinely discontinuing clopidogrel before elective colonoscopy may well exceed any excess risk of PPB.”

Lead investigator on the study, Linda A. Feagins, MD, assistant professor of medicine at UT Southwestern Medical Center, speaking at a DDW press conference, noted that the study was limited in that it was retrospective and in that most of the polyps removed were small (<1 cm).

Press conference moderator Nicholas J. Talley, MD, PhD, University of Newcastle, Callaghan, Australia, said that the study had made him more convinced that continuing clopidogrel with removal of small polyps is the most sensible approach. He expressed apprehension, however, about removing larger polyps with clopidogrel discontinued, and said when colonoscopy revealed a large polyp, he would ask patients to return for a second procedure.

Feagins responded, “All procedures have complications. The risk is small, but when we have to treat PPB, we are good at it.” The largest polyp removed in the study was 8 mm. “We use hemoclips. That makes us feel better,” she said.

DDW 2011: Study Examines Colonoscopy Bleeding Risk with Clopidogrel vs. CV Risk Without

GLP-2 analog teduglutide reduces the need for parenteral support in patients with short bowel syndrome-intestinal failure.

In patients with short bowel syndrome-intestinal failure (SBS/IF), teduglutide (TDG), a dipeptidyl peptidase-IV degradation-resistant, recombinant analog of human GLP-2, reduces the need for parenteral support, according to findings from STEPS (Study of Teduglutide Effectiveness in Parenteral Support-dependent Short Bowel Syndrome) in an oral session and press conference at Digestive Disease Week 2011.

STEPS investigator Palle B. Jeppesen, MD, associate professor of gastroenterology at Rigshospitalet, University Hospital of Denmark, said GLP-2 repairs and restores functional integrity of the intestinal mucosa, improving fluid and nutrient balance by enhancing absorption. Enhanced absorption ensues from GLP-2-induced increases in villus height/diameter and crypt depth, dilatation and thickening of mucosa and increases in RNA/DNA content. It has been shown also in some SBS/IF patients to promote rapid gastric emptying and gastric acid hypersecretion, intestinal blood flow, and adaptation. TDG has been show further to increase wet weight absorption (equivalent to 750 ml/d) and urine sodium excretion, and to reduce fecal weight and energy excretion in SBS patients.

SBS/IF, Jeppesen noted, is generally the result of surgical resection, congenital defect, or disease-related loss of absorption. SBS/IF patients are characterized by an inability to maintain protein, energy, fluid and electrolyte levels and micronutrient balance. Compensatory fluid or nutritional support for this malabsorption is accomplished through hyperphagia (additional oral intake) and intravenous parenteral support (PN/IV). Intestinal rehabilitation may be addressed through intestinal growth factors, anti-secretory agents, anti-diarrheals, rehydration solutions and dietary modifications.

Among the medical needs of SBS/IF patients, Dr. Jeppesen listed decreasing dependence on PN/IV, and reducing the morbidity and life-threatening complications associated with parenteral support, which include catheter-related blood stream infections, venous thrombosis and intestinal failure-associated liver disease. There is further need, he added, to improve quality of life and to seek novel treatment options.

In order to evaluate TDG’s ability to reduce the volume of parenteral support (intravenous fluids, nutrients, or both), 86 SBS-IF subjects, dependent on parenteral support for ≥1 year were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, multinational, multicenter study. After an initial optimization/stabilization period of parenteral support volume (ensuring stable urine output), subjects were randomized to subcutaneous TDG (0.05 mg/kg/d) or placebo, once daily, for 24 weeks. Parenteral support volumes were reduced at scheduled visits if urine volumes exceeded baseline by ≥10%. Response was defined as a 20% to 100% reduction from baseline in weekly parenteral support volume at weeks 20 and 24. The primary efficacy endpoint was a comparison of the percentage of responders in the teduglutide and placebo groups.

Among 78 study completers, 39 received TDG and 39 received placebo. In the intention-to-treat (ITT) population, responses were reported in  63% (27/43) of SBS-IF subjects receiving TDG and in 30% (13/43) receiving placebo (p=0.002). At week 24, TDG reduced mean weekly parenteral support volume by 4.4 L/wk (12.9 L/wk at baseline), as compared with 2.3 L/wk (13.2 L/wk at baseline; p≤0.001) volume reduction with placebo. Significantly more TDG-treated subjects than placebo treated were able to reduce the number of infusion days by 1 or more days (54% versus 23%; p=0.0047). Despite the significant parenteral support volume reduction, however, body weight remained constant.

TDG was well tolerated. Of the eight dropouts, three of four in the placebo group and two of four in the teduglutide group were due to adverse events (AEs). AEs were found in 83% (35/42) treated with teduglutide versus 79% (34/43) for placebo. The most common AEs were abdominal pain, nausea, gastrointestinal stoma complications, and abdominal distension.

Jeppesen pointed out that more than 97% of the subjects who completed this study elected to enroll in an open-label 24-month continuation study.

At the DDW press conference, Jeppesen emphasized the debilitating nature of SBS/IF, saying that while the normal absorptive surface area of the gut is like that of a tennis court, in these patients it is closer to that of a table tennis surface. “Their treatment is isolating; with their nightly infusions they alternate between dehydration and fluid overload and have quality of life comparable to those on dialysis,” he said. Jeppesen added that in actual practice, the 30% reduction in parenteral support volume with TGD treatment might allow an additional two days off from parenteral support. “They cherish days off so they can lead a more normal life.”

DDW 2011: STEPS Study Shows Promising Results for Patients with Short Bowel Syndrome

Results from the REALIZE study indicate that combination treatment with telaprevir is superior to standard treatment for patients with hepatitis C virus infection.

Adding telaprevir, an investigational oral protease inhibitor recently recommended for approval by an FDA advisory panel, to pegylated-interferon alfa-2a (P) and ribavirin (R) (P/R) substantially increases rates of the sustained viral responses (SVRs) considered to represent cure for hepatitis C virus (HCV) infection. In approximately 60% of patients with genotype 1 chronic HCV infection, said Paul Pockros, MD, Scripps Research Institute, La Jolla, CA, combination treatment fails with R/B, the current standard of care.

Pockros presented SVR findings from the REALIZE trial, a Phase 3 evaluation of telaprevir in 662 patients whose responses to prior P/R had been null or partial, or who relapsed after initial response. The REALIZE primary objective was to evaluate the proportion of these patients achieving SVR, defined as undetectable plasma HCV RNA at 24 weeks after the last planned intake of study medication. A secondary objective was evaluation of the effect of a 4-week P/R lead-in on efficacy in one of the trial’s three study arms.

Patients in the international, multicenter, double-blind, placebo-controlled trial were randomized 2:2:1, to one of two telaprevir-containing regimens or to one P/R+placebo group. The telaprevir-containing regimens included 12 weeks of telaprevir (750 mg q8h) + P (180 µg/w) + R (1000-1200 mg/d), one with the 4-week P/R+placebo lead-in (LI12/PR48), and one followed by 4 weeks of P/R+placebo (telaprevir 12/PR48). Both were followed by P/R in weeks 16-48. Patients in the third arm (Pbo/PR48) received P/R+placebo for 16 weeks followed by P/R in weeks 16-48. Follow-up continued for all arms until SVR assessment at week 72.

Null responders, partial responders and relapsers constituted 27%/18%/and 55%, respectively, of the cohort, and nearly 50% of patients were in advanced stages of disease. Median age was ~51 years (~70% males).

The SVR rates among prior relapsers were 83% for telaprevir 12/PR48 (p<0.001 vs. placebo/PR48P), 88% for LIT12/PR48 (p<0.001 vs. placebo/PR48P) and 24% for placebo/PR48. Among prior non-responders (partial or null responders), SVR rates were 41% for both telaprevir arms (p<0.001 vs. placebo/PR48P) and 9% for placebo/PR48. Looking at the non-responders more closely, Pockros pointed out that SVR rates were higher for prior partial responders than for prior null responders. He said further that the use of the 4-week lead-in phase with P+R led to no reductions in virologic failure or relapse rates and no improvements in SVR rates.

Relapse rates were 10% each for the two telaprevir-containing arms and 23% for the placebo/PR48 arm.

During treatment phases, the most common adverse events were fatigue, pruritus and anorectal symptoms. Fatigue occurred in 55% (T12/PR48), 50% (LIT12/PR46) and 40% (placebo/PR48), and pruritus in 52% (T12/PR48), 50% (LIT12/PR46) and 427% (placebo/PR48). Anorectal symptoms (anal pruritus, anorectal discomfort, hemorrhoids) were reported in 28% (T12/PR48), 22% (LIT12/PR46) and 8% (placebo/PR48). For each of these adverse events, and for anemia, rash, nausea and diarrhea, incidence was >10% greater in the T12/PR48 arm than in the placebo/PR48 arm. Discontinuations of any study drug during T treatment occurred in 29% of patients, and were most common for rash (5% (T12/PR48), 4% (LIT12/PR46) and 0% (placebo/PR48), and anemia 2% (T12/PR48), 3% (LIT12/PR46) and 0% (placebo/PR48).

Commenting on the adverse events with telaprevir in a DDW press conference, REALIZE co-investigator Zobair. M. Younossi, MD, vice president of Inova Health System, Falls Church, VA, said, “Generally speaking, these safety rates are consistent with previously reported data.”

Pockros concluded, “Telaprevir with P/R was superior to P/R alone in treatment-experienced populations including prior relapsers, partial responders, and null responders.”

Results from the REALIZE study show that combination treatment with telaprevir is superior to standard treatment for patients with hepatitis C virus infection.