- Email: [email protected]
207 SAFETY OF RIFAXIMIN IN PATIENTS WITH HEPATIC ENCEPHALOPATHY: RESULTS OF A RANDOMIZED, PHASE 3, PLACEBO-CONTROLLED CLINICAL TRIAL
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Poster Session − Thursday, April 23
extremity edema, pulmonary, weight gain during the last weeks) and signs of congestion on the chest radiograph and in echocardiography prior and after recompensation mostly by diuretics treatment. Body weight, vena cava diameter in inspiration and expiration, circulating pro-NT-BNP levels and liver stiffness (kPa) were correlated before and after treatment of congestive heart failure. Results: Initially elevated liver stiffness decreased in 19 out of 20 patients, in 16 of them markedly. In 14 patients liver stiffness was elevated to a degree that suggested liver cirrhosis (mean 22.6 kPa). Successful diuretic therapy and antiarrhythmic therapy if necessary with a mean weight loss of 5 kg over 8 days led to a significant drop in liver stiffness (mean decrease 14.4 kPa). In all patients decrease of liver stiffness correlated highly with weight loss (Spearman) and decreased pro-NT-BNP levels. Patients who did not reach normal stiffness values despite adequate diuretic therapy and weight loss had a long history of right heart failure and two of them even showed signs of cirrhose cardiaque with esophageal varices. To further prove that increased venous pressure has a strong impact on liver stiffness we evaluated 24 healthy individuals before and during a Valsalva maneuver. Stiffness values increased significantly from a median of 4.4 kPa to 6.6 kPa (p = 0.008). Single individuals were able to increase their liver stiffness from normal values up to values suggesting cirrhosis (>12 kPa). Conclusion: Increased venous pressure by congestive heart failure of a Valsalva maneuver strongly interferes with liver fibrosis assessment using transient elastography (Fibroscan). Therefore, fibrosis assessment by Fibroscan should included standard measuring positions and the exclusion of right congestive heart failure. 205 RELATION BETWEEN BAROREFLEX SENSITIVITY AND PULMONARY DYSFUNCTION IN CIRRHOSIS: EFFECT OF HYPEROXIA S. Moeller1 , J.S. Iversen2 , A. Krag3 , F. Bendtsen3 . 1 Department of Clinical Physiology 239, Hvidovre Hospital, University of Copenhagen, Hvidovre, 2 Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, 3 Department of Medical Gastroenterology 439, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark E-mail: [email protected] Background and Aims: Patients with cirrhosis exhibit cardiopulmonary complications that affect the course of the disease. These include a hyperdynamic circulation with impaired regulation of the arterial blood pressure. Moreover, a considerable number of the patients exhibit a pulmonary dysfunction with hypoxaemia and impaired lung diffusing capacity (DLCO). A fraction of these patients present with a hepatopulmonary syndrome (HPS) defined as an alveolar-arterial oxygen gradient (AaPO2 ) > 2 kPa, and extrapulmonary shunting. The baroreflex sensitivity (BRS) is reduced in patients with cirrhosis, which may further impair cardiovascular adaptation. Moreover, BRS is reduced at exposure to chronic hypoxia such as during sojourn in high altitudes. The present study was therefore undertaken to assess the relation of the reduced BRS to pulmonary dysfunction and to assess the effects of hyperoxia in patients with cirrhosis. Methods: Forty-three patients with cirrhosis and 12 healthy controls were included in the study. All underwent haemodynamic and pulmonary investigations including assessment of DLCO and CEE for the identification of HPS. Standard lung function tests were performed. BRS was assessed by cross-spectral analysis of variabilities between blood pressure and heart rate time series. A 100% oxygen test was performed with the assessment of arterial oxygen tensions (PaO2 ) and AaPO2 . Results: DLCO was significantly reduced in more than 70% of the patients. Baseline BRS was significantly reduced in the cirrhotic patients compared with the controls (4.7±0.8 vs 10.3±2.0 ms/mmHg (p < 0.001). The frequency of HPS in the patient population was 10%. There was no significant difference in BRS according to presence of HPS or ChildTurcotte score. There were no significant correlations between baseline BRS and PaO2 , AaPO2 , or DLCO. After 100% oxygen inhalation, BRS was unchanged in the cirrhotic patients and BRS remained significantly lower in the cirrhotic patients (p > 0.005).
Conclusions: BRS is significantly reduced in patients with cirrhosis compared with matched controls but is unrelated to the degree of pulmonary dysfunction. Acute hyperoxia does not significantly improve baroreceptor sensitivity in cirrhotic patients and may not be of use for improvement of cardiovascular baroreflex control in these patients. 206 HEPATO-ADRENAL SYNDROME: DOES CORTISOL SAMPLE TIME MATTER? S. Montagnese1 , B. Middleton2 , A.R. Mani1 , D.J. Skene2 , M.Y. Morgan1 . 1 Centre for Hepatology, Royal Free Campus, University College London Medical School, University College London, London, 2 Centre for Chronobiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK E-mail: [email protected] Background and Aims: The prevalence of relative adrenal insufficiency is high in patients with end-stage liver disease; the term hepato-adrenal syndrome has been proposed to describe this condition (Marik et al., 2005). In addition, liver transplant recipients are prone to functional adrenal gland atrophy, secondary to prolonged corticosteroid treatment (Toniutto et al., 2008). The diagnosis of adrenal insufficiency is based, in the first instances, on measurement of the cortisol concentration at 08:00, although stimulating tests are needed for confirmation. The aim of this study was to determine whether the 08:00 cortisol concentration provides an accurate ‘snap-shot’ of adrenal function in patients with cirrhosis. Methods: The study population comprised 20 patients with cirrhosis [mean (range) age 59 (39−77) yr] and nine healthy volunteers [age 60 (38−84) yr]. Hourly blood samples for measurement of plasma cortisol were obtained, under light and posture-controlled conditions, over 24 hours; plasma cortisol concentrations were measured by RIA (Read et al., 1977). The 24-hour profiles were evaluated by cosinor analysis and standard circadian indices were obtained. Results: There were no significant differences in the average 24-hour plasma cortisol concentration or in the amplitude of the 24-hour rhythm between patients and healthy volunteers. However, the mean (±1SD) time of the cortisol rhythm onset and peak concentration were considerably delayed in the patients compared to the healthy volunteers (05:24±02:06 vs. 03:54±01:00, p = 0.02; 10:18±02:54 vs. 08:54±01:24, p = 0.06). No significant differences were observed in the time of the rhythm offset but the duration of the peak was significantly shorter in the 13 patients compared to the seven healthy volunteers in whom the parameter was available (7.0±3.8 vs. 10.6±2.3 hours, p = 0.03). A significant correlation was observed between the plasma cortisol peak time and the Pugh’s score (R = 0.49, p < 0.05). Conclusions: Significant abnormalities were observed in plasma cortisol profiles in patients with cirrhosis, most likely reflecting central circadian dysfunction (Montagnese et al., 2005). The observed delays in the cortisol 24-hour rhythm might result in erroneously low estimates of 08:00 plasma cortisol and, consequently, in unnecessary cortisol release stimulating tests. Samples are probably best obtained around 09:30. 207 SAFETY OF RIFAXIMIN IN PATIENTS WITH HEPATIC ENCEPHALOPATHY: RESULTS OF A RANDOMIZED, PHASE 3, PLACEBO-CONTROLLED CLINICAL TRIAL K. Mullen1 , S. Sigal2 , M. Sheikh3 , N. Bass4 , F. Poordad5 , K. Merchant6 , S. Huang6 , A. Shaw6 , E. Bortey6 , W. Forbes6 . 1 Case Western Reserve University, Cleveland, OH, 2 Weill Medical College of Cornell University, New York, New York, 3 University of California San Francisco, Fresno, CA, 4 University of California San Francisco, San Francisco, CA, 5 CedarsSinai Medical Center, Los Angeles, CA, 6 Salix Pharmaceuticals, Inc, Morrisville, NC, USA E-mail: [email protected] Background and Aims: Rifaximin, a minimally absorbed gut-selective antibiotic, significantly reduced the risk of breakthrough hepatic encephalopathy (HE) in patients with HE by 58% (hazard ratio, 0.421;
02b: CIRRHOSIS AND COMPLICATIONS − b) CLINICAL ASPECTS p < 0.0001) versus placebo in a large multinational trial. This analysis evaluated the safety of rifaximin in the study population. Methods: Rifaximin (550 mg twice daily) was compared with placebo in a randomized, double-blind, placebo-controlled trial for 6 months in patients with a history of HE. Continued therapy with lactulose was permitted. Patients with cirrhosis and documented episodic HE (Conn score 2) were enrolled while in remission (Conn score = 0 or 1). The primary endpoint was time to first breakthrough HE episode. Safety evaluations, including physical examination, laboratory values, and adverse events, were assessed at study visits. Results: The safety population included 299 patients who received 1 dose of either rifaximin (n = 140) or placebo (n = 159). Mean exposure was greater for rifaximin (130 d) versus placebo (106 d), primarily due to breakthrough HE in the placebo group resulting in early discontinuation. Overall, 80% of patients experienced at least one treatment-emergent adverse event (TEAE), the majority being mild to moderate in intensity. The most common TEAEs (10%) that occurred more frequently for rifaximin than placebo were ascites (11% vs 9%), dizziness (13% vs 8%), fatigue (12% vs 11%), and peripheral edema (15% vs 8%) for rifaximin versus placebo, respectively. Severe TEAEs (26% vs 31%) and drugrelated TEAEs (19% vs 21%) were similar in rifaximin versus placebo groups, respectively. A similar percentage of patients reported infection in the rifaximin and placebo groups (33% vs 31%, respectively), with the most common being urinary tract infections (6% vs 9%, respectively). The percentage of patients who experienced serious adverse events was similar in the rifaximin (36%) versus placebo group (40%). Additionally, 7% of patients died in each group. No significant differences were noted between groups in other safety assessments. Conclusions: These findings indicate that rifaximin 550 mg taken twice daily has a favorable safety profile, comparable to placebo in patients with HE treated for up to 6 months.
208 LONG-TERM OUTCOME OF CIRRHOTIC PATIENTS AFTER AN EPISODE OF VARICEAL BLEEDING: ANALYSIS OF PROGNOSTIC FACTORS L. Muntaner1 , J.T. Altamirano1 , S. Augustin1 , A. Gonz´alez1 , E. Saperas2 , J. Genesc`a1 . 1 Internal Medicine- Liver Unit, 2 Digestive Department, Vall d’Hebron Hospital General, Barcelona, Spain E-mail: [email protected] Background and Aim: Few trials have evaluated the long-term prognosis of cirrhotic patients surviving a variceal bleeding episode. We analyzed the prognostic factors that influence variceal rebleeding and long-term mortality in cirrhotic patients who have survived the 6-week period after an acute variceal bleeding. Methods: Prospective cohort study of cirrhotic patients with esophageal variceal bleeding admitted to our Bleeding Unit from 2001 to 2007. Basal clinical and biochemical data, as well as subsequent rebleeding episodes, were registered. Follow-up extended from 6-weeks after index bleeding to the latest visit, death or liver transplantation. During follow-up special attention was paid to the type of therapy received, patient compliance and whether the patient was included or not in a prospective study of prevention of rebleeding. Stepwise Cox regression model was applied to identify the long-term independent prognostic factors associated to rebleeding and death/transplantation. Results: 210 patients were admitted for variceal bleeding, 54 (25.7%) died during the first 6 weeks. 138 patients (95 males and 53 females) with a mean age of 58±14 years were followed-up. The initial Child–Pugh class was: A 41 (34.8%), B 65 (44.2%) and C 36 (26.1%), with a mean score of 7.9. 63 (45.6%) were enrolled in a prospective clinical trial of prevention of variceal rebleeding. The mean follow-up was 27 months (range 1−74). 45 (32.6%) patients had a rebleeding episode, 42 (93.3%) of them caused by esophageal varices. Independent prognostic factors related to rebleeding were: mean dose of betablockers (HR 0.99, 95% CI: 0.98−0.99, p = 0.037), alcoholic abstinence (HR 3.4, 95% CI: 1.6−7.1, p = 0.002) and being in a prospective clinical trial (HR 2.6, 95% CI: 1.3−5.4, p = 0.010). During follow-up, 39 (28.3%) patients died and 8 (13%) were transplanted.
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Mortality or liver transplantation were independently associated to Child– Pugh score (HR 1.2, 95% CI: 1.1−1.4, p = 0.004), basal creatinine level (HR 1.6, 95% CI: 1.2−2.3, p = 0.004) and the presence of hepatocellular carcinoma (HR 2.8, 95% CI: 1.6−4.9, p < 0.001). Conclusions: After an episode of variceal bleeding the optimization of pharmacological therapy and a good compliance reduce the rebleeding rate. However, the long-term prognosis of these patients depends mainly on the degree of liver function. 209 CARDIOMYOPATHY IN PATIENTS WITH CIRRHOSIS. FREQUENCY, CHARACTERISTICS AND RELATIONSHIP WITH CIRCULATORY DYSFUNCTION AND PROGNOSIS A. Nazar1,2,3 , M. Sitges4 , M. Guevara1,2,3 , C. Terra1,2,3 , M. Marinelli1,2,3 , F. Villa4 , M. Mart´ın-Llahi1,2,3 , M.E. Baccaro1,2,3 , J. Bosch1,2,3 , M. Pavesi1,2,3 , S. Poyatos4 , V. Arroyo1,2,3 , P. Gines1,2,3 . 1 Liver Unit, Hospital Cl´ınic/University of Barcelona, 2 IDIBAPS, 3 CIBERehd, Ciber de Enfermedades Hep´ aticas y Digestivas, 4 Cardiology Unit, Hospital Cl´ınic/University of Barcelona, Barcelona, Spain, Barcelona, Spain E-mail: [email protected] Background: Recent studies have described a cardiomyopathy characteristic of cirrhosis which causes diastolic dysfunction. However, its frequency as well as its clinical relevance in the natural history of cirrhosis is still unknown. Patients: 102 consecutive patients (71 men; 56±11 years) with cirrhosis (Child–Pugh A 26, B 39 and C 37) without clinical signs of cardiac disease were prospectively evaluated. Methods: A conventional Doppler echocardiography with tissue Doppler was used to assess the dimensions of cardiac cavities and ventricular systolic and diastolic function. The diastolic dysfunction was classified from 0 to 4 based on well-established criteria (American Society of Echocardiography). In 85 patients the plasma levels of vasoactive hormones were determined, and in 54 patients a right cardiac and hepatic catheterization was performed. Patients were followed up for 6 months. Results: The dimensions and the ejection fraction (63±8%) of the left ventricle were normal. Diastolic dysfunction was observed in 57% of patients (41% grade 1 and 16% grade 2). There was a relationship between diastolic dysfunction and pulmonary capillary pressure (no dysfunction: 8±3 mmHg; dysfunction grade 1: 10±3 mmHg; dysfunction grade 2: 14±6 mmHg; p < 0.001). Compared to patients without diastolic dysfunction or with diastolic dysfunction grade 1, patients with diastolic dysfunction grade 2 had more severe liver failure (Child–Pugh 8±2 vs 10±2 and MELD 14±6 vs 20±11, respectively, p < 0.05), more intense circulatory dysfunction (systemic vascular resistance: 877±330 vs 626±151dyn/seg/cm-5, p < 0.05; cardiac index: 9±3 vs 10±2, p = 0.07; plasma noradrenalin: 338±233 vs 620±646pg/ml, respectively, p < 0.0001) and higher plasma levels of atrial natriuretic factor (42±32 vs 64±49 fmol/ml, p < 0.01) and brain natriuretic peptide (54±76 vs 91±94 pg/ml, p < 0.07). Diastolic dysfunction grade 2 was observed in 8, 11 and 28% of patients in groups A, B and C of Child– Pugh, respectively (p < 0.05). The 6 month transplant-free survival was lower in patients with diastolic dysfunction grade 2 compared to that of the remaining patients (25% vs 61%, p < 0.01). Conclusions: A cardiomyopathy characterized by diastolic dysfunction is frequent in non-selected patients with cirrhosis, particularly in those with advanced disease. The presence of diastolic dysfunction grade 2 is associated with more severe liver failure, greater circulatory dysfunction, and worse prognosis.
Poster Session − Thursday, April 23
extremity edema, pulmonary, weight gain during the last weeks) and signs of congestion on the chest radiograph and in echocardiography prior and after recompensation mostly by diuretics treatment. Body weight, vena cava diameter in inspiration and expiration, circulating pro-NT-BNP levels and liver stiffness (kPa) were correlated before and after treatment of congestive heart failure. Results: Initially elevated liver stiffness decreased in 19 out of 20 patients, in 16 of them markedly. In 14 patients liver stiffness was elevated to a degree that suggested liver cirrhosis (mean 22.6 kPa). Successful diuretic therapy and antiarrhythmic therapy if necessary with a mean weight loss of 5 kg over 8 days led to a significant drop in liver stiffness (mean decrease 14.4 kPa). In all patients decrease of liver stiffness correlated highly with weight loss (Spearman) and decreased pro-NT-BNP levels. Patients who did not reach normal stiffness values despite adequate diuretic therapy and weight loss had a long history of right heart failure and two of them even showed signs of cirrhose cardiaque with esophageal varices. To further prove that increased venous pressure has a strong impact on liver stiffness we evaluated 24 healthy individuals before and during a Valsalva maneuver. Stiffness values increased significantly from a median of 4.4 kPa to 6.6 kPa (p = 0.008). Single individuals were able to increase their liver stiffness from normal values up to values suggesting cirrhosis (>12 kPa). Conclusion: Increased venous pressure by congestive heart failure of a Valsalva maneuver strongly interferes with liver fibrosis assessment using transient elastography (Fibroscan). Therefore, fibrosis assessment by Fibroscan should included standard measuring positions and the exclusion of right congestive heart failure. 205 RELATION BETWEEN BAROREFLEX SENSITIVITY AND PULMONARY DYSFUNCTION IN CIRRHOSIS: EFFECT OF HYPEROXIA S. Moeller1 , J.S. Iversen2 , A. Krag3 , F. Bendtsen3 . 1 Department of Clinical Physiology 239, Hvidovre Hospital, University of Copenhagen, Hvidovre, 2 Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, 3 Department of Medical Gastroenterology 439, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark E-mail: [email protected] Background and Aims: Patients with cirrhosis exhibit cardiopulmonary complications that affect the course of the disease. These include a hyperdynamic circulation with impaired regulation of the arterial blood pressure. Moreover, a considerable number of the patients exhibit a pulmonary dysfunction with hypoxaemia and impaired lung diffusing capacity (DLCO). A fraction of these patients present with a hepatopulmonary syndrome (HPS) defined as an alveolar-arterial oxygen gradient (AaPO2 ) > 2 kPa, and extrapulmonary shunting. The baroreflex sensitivity (BRS) is reduced in patients with cirrhosis, which may further impair cardiovascular adaptation. Moreover, BRS is reduced at exposure to chronic hypoxia such as during sojourn in high altitudes. The present study was therefore undertaken to assess the relation of the reduced BRS to pulmonary dysfunction and to assess the effects of hyperoxia in patients with cirrhosis. Methods: Forty-three patients with cirrhosis and 12 healthy controls were included in the study. All underwent haemodynamic and pulmonary investigations including assessment of DLCO and CEE for the identification of HPS. Standard lung function tests were performed. BRS was assessed by cross-spectral analysis of variabilities between blood pressure and heart rate time series. A 100% oxygen test was performed with the assessment of arterial oxygen tensions (PaO2 ) and AaPO2 . Results: DLCO was significantly reduced in more than 70% of the patients. Baseline BRS was significantly reduced in the cirrhotic patients compared with the controls (4.7±0.8 vs 10.3±2.0 ms/mmHg (p < 0.001). The frequency of HPS in the patient population was 10%. There was no significant difference in BRS according to presence of HPS or ChildTurcotte score. There were no significant correlations between baseline BRS and PaO2 , AaPO2 , or DLCO. After 100% oxygen inhalation, BRS was unchanged in the cirrhotic patients and BRS remained significantly lower in the cirrhotic patients (p > 0.005).
Conclusions: BRS is significantly reduced in patients with cirrhosis compared with matched controls but is unrelated to the degree of pulmonary dysfunction. Acute hyperoxia does not significantly improve baroreceptor sensitivity in cirrhotic patients and may not be of use for improvement of cardiovascular baroreflex control in these patients. 206 HEPATO-ADRENAL SYNDROME: DOES CORTISOL SAMPLE TIME MATTER? S. Montagnese1 , B. Middleton2 , A.R. Mani1 , D.J. Skene2 , M.Y. Morgan1 . 1 Centre for Hepatology, Royal Free Campus, University College London Medical School, University College London, London, 2 Centre for Chronobiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK E-mail: [email protected] Background and Aims: The prevalence of relative adrenal insufficiency is high in patients with end-stage liver disease; the term hepato-adrenal syndrome has been proposed to describe this condition (Marik et al., 2005). In addition, liver transplant recipients are prone to functional adrenal gland atrophy, secondary to prolonged corticosteroid treatment (Toniutto et al., 2008). The diagnosis of adrenal insufficiency is based, in the first instances, on measurement of the cortisol concentration at 08:00, although stimulating tests are needed for confirmation. The aim of this study was to determine whether the 08:00 cortisol concentration provides an accurate ‘snap-shot’ of adrenal function in patients with cirrhosis. Methods: The study population comprised 20 patients with cirrhosis [mean (range) age 59 (39−77) yr] and nine healthy volunteers [age 60 (38−84) yr]. Hourly blood samples for measurement of plasma cortisol were obtained, under light and posture-controlled conditions, over 24 hours; plasma cortisol concentrations were measured by RIA (Read et al., 1977). The 24-hour profiles were evaluated by cosinor analysis and standard circadian indices were obtained. Results: There were no significant differences in the average 24-hour plasma cortisol concentration or in the amplitude of the 24-hour rhythm between patients and healthy volunteers. However, the mean (±1SD) time of the cortisol rhythm onset and peak concentration were considerably delayed in the patients compared to the healthy volunteers (05:24±02:06 vs. 03:54±01:00, p = 0.02; 10:18±02:54 vs. 08:54±01:24, p = 0.06). No significant differences were observed in the time of the rhythm offset but the duration of the peak was significantly shorter in the 13 patients compared to the seven healthy volunteers in whom the parameter was available (7.0±3.8 vs. 10.6±2.3 hours, p = 0.03). A significant correlation was observed between the plasma cortisol peak time and the Pugh’s score (R = 0.49, p < 0.05). Conclusions: Significant abnormalities were observed in plasma cortisol profiles in patients with cirrhosis, most likely reflecting central circadian dysfunction (Montagnese et al., 2005). The observed delays in the cortisol 24-hour rhythm might result in erroneously low estimates of 08:00 plasma cortisol and, consequently, in unnecessary cortisol release stimulating tests. Samples are probably best obtained around 09:30. 207 SAFETY OF RIFAXIMIN IN PATIENTS WITH HEPATIC ENCEPHALOPATHY: RESULTS OF A RANDOMIZED, PHASE 3, PLACEBO-CONTROLLED CLINICAL TRIAL K. Mullen1 , S. Sigal2 , M. Sheikh3 , N. Bass4 , F. Poordad5 , K. Merchant6 , S. Huang6 , A. Shaw6 , E. Bortey6 , W. Forbes6 . 1 Case Western Reserve University, Cleveland, OH, 2 Weill Medical College of Cornell University, New York, New York, 3 University of California San Francisco, Fresno, CA, 4 University of California San Francisco, San Francisco, CA, 5 CedarsSinai Medical Center, Los Angeles, CA, 6 Salix Pharmaceuticals, Inc, Morrisville, NC, USA E-mail: [email protected] Background and Aims: Rifaximin, a minimally absorbed gut-selective antibiotic, significantly reduced the risk of breakthrough hepatic encephalopathy (HE) in patients with HE by 58% (hazard ratio, 0.421;
02b: CIRRHOSIS AND COMPLICATIONS − b) CLINICAL ASPECTS p < 0.0001) versus placebo in a large multinational trial. This analysis evaluated the safety of rifaximin in the study population. Methods: Rifaximin (550 mg twice daily) was compared with placebo in a randomized, double-blind, placebo-controlled trial for 6 months in patients with a history of HE. Continued therapy with lactulose was permitted. Patients with cirrhosis and documented episodic HE (Conn score 2) were enrolled while in remission (Conn score = 0 or 1). The primary endpoint was time to first breakthrough HE episode. Safety evaluations, including physical examination, laboratory values, and adverse events, were assessed at study visits. Results: The safety population included 299 patients who received 1 dose of either rifaximin (n = 140) or placebo (n = 159). Mean exposure was greater for rifaximin (130 d) versus placebo (106 d), primarily due to breakthrough HE in the placebo group resulting in early discontinuation. Overall, 80% of patients experienced at least one treatment-emergent adverse event (TEAE), the majority being mild to moderate in intensity. The most common TEAEs (10%) that occurred more frequently for rifaximin than placebo were ascites (11% vs 9%), dizziness (13% vs 8%), fatigue (12% vs 11%), and peripheral edema (15% vs 8%) for rifaximin versus placebo, respectively. Severe TEAEs (26% vs 31%) and drugrelated TEAEs (19% vs 21%) were similar in rifaximin versus placebo groups, respectively. A similar percentage of patients reported infection in the rifaximin and placebo groups (33% vs 31%, respectively), with the most common being urinary tract infections (6% vs 9%, respectively). The percentage of patients who experienced serious adverse events was similar in the rifaximin (36%) versus placebo group (40%). Additionally, 7% of patients died in each group. No significant differences were noted between groups in other safety assessments. Conclusions: These findings indicate that rifaximin 550 mg taken twice daily has a favorable safety profile, comparable to placebo in patients with HE treated for up to 6 months.
208 LONG-TERM OUTCOME OF CIRRHOTIC PATIENTS AFTER AN EPISODE OF VARICEAL BLEEDING: ANALYSIS OF PROGNOSTIC FACTORS L. Muntaner1 , J.T. Altamirano1 , S. Augustin1 , A. Gonz´alez1 , E. Saperas2 , J. Genesc`a1 . 1 Internal Medicine- Liver Unit, 2 Digestive Department, Vall d’Hebron Hospital General, Barcelona, Spain E-mail: [email protected] Background and Aim: Few trials have evaluated the long-term prognosis of cirrhotic patients surviving a variceal bleeding episode. We analyzed the prognostic factors that influence variceal rebleeding and long-term mortality in cirrhotic patients who have survived the 6-week period after an acute variceal bleeding. Methods: Prospective cohort study of cirrhotic patients with esophageal variceal bleeding admitted to our Bleeding Unit from 2001 to 2007. Basal clinical and biochemical data, as well as subsequent rebleeding episodes, were registered. Follow-up extended from 6-weeks after index bleeding to the latest visit, death or liver transplantation. During follow-up special attention was paid to the type of therapy received, patient compliance and whether the patient was included or not in a prospective study of prevention of rebleeding. Stepwise Cox regression model was applied to identify the long-term independent prognostic factors associated to rebleeding and death/transplantation. Results: 210 patients were admitted for variceal bleeding, 54 (25.7%) died during the first 6 weeks. 138 patients (95 males and 53 females) with a mean age of 58±14 years were followed-up. The initial Child–Pugh class was: A 41 (34.8%), B 65 (44.2%) and C 36 (26.1%), with a mean score of 7.9. 63 (45.6%) were enrolled in a prospective clinical trial of prevention of variceal rebleeding. The mean follow-up was 27 months (range 1−74). 45 (32.6%) patients had a rebleeding episode, 42 (93.3%) of them caused by esophageal varices. Independent prognostic factors related to rebleeding were: mean dose of betablockers (HR 0.99, 95% CI: 0.98−0.99, p = 0.037), alcoholic abstinence (HR 3.4, 95% CI: 1.6−7.1, p = 0.002) and being in a prospective clinical trial (HR 2.6, 95% CI: 1.3−5.4, p = 0.010). During follow-up, 39 (28.3%) patients died and 8 (13%) were transplanted.
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Mortality or liver transplantation were independently associated to Child– Pugh score (HR 1.2, 95% CI: 1.1−1.4, p = 0.004), basal creatinine level (HR 1.6, 95% CI: 1.2−2.3, p = 0.004) and the presence of hepatocellular carcinoma (HR 2.8, 95% CI: 1.6−4.9, p < 0.001). Conclusions: After an episode of variceal bleeding the optimization of pharmacological therapy and a good compliance reduce the rebleeding rate. However, the long-term prognosis of these patients depends mainly on the degree of liver function. 209 CARDIOMYOPATHY IN PATIENTS WITH CIRRHOSIS. FREQUENCY, CHARACTERISTICS AND RELATIONSHIP WITH CIRCULATORY DYSFUNCTION AND PROGNOSIS A. Nazar1,2,3 , M. Sitges4 , M. Guevara1,2,3 , C. Terra1,2,3 , M. Marinelli1,2,3 , F. Villa4 , M. Mart´ın-Llahi1,2,3 , M.E. Baccaro1,2,3 , J. Bosch1,2,3 , M. Pavesi1,2,3 , S. Poyatos4 , V. Arroyo1,2,3 , P. Gines1,2,3 . 1 Liver Unit, Hospital Cl´ınic/University of Barcelona, 2 IDIBAPS, 3 CIBERehd, Ciber de Enfermedades Hep´ aticas y Digestivas, 4 Cardiology Unit, Hospital Cl´ınic/University of Barcelona, Barcelona, Spain, Barcelona, Spain E-mail: [email protected] Background: Recent studies have described a cardiomyopathy characteristic of cirrhosis which causes diastolic dysfunction. However, its frequency as well as its clinical relevance in the natural history of cirrhosis is still unknown. Patients: 102 consecutive patients (71 men; 56±11 years) with cirrhosis (Child–Pugh A 26, B 39 and C 37) without clinical signs of cardiac disease were prospectively evaluated. Methods: A conventional Doppler echocardiography with tissue Doppler was used to assess the dimensions of cardiac cavities and ventricular systolic and diastolic function. The diastolic dysfunction was classified from 0 to 4 based on well-established criteria (American Society of Echocardiography). In 85 patients the plasma levels of vasoactive hormones were determined, and in 54 patients a right cardiac and hepatic catheterization was performed. Patients were followed up for 6 months. Results: The dimensions and the ejection fraction (63±8%) of the left ventricle were normal. Diastolic dysfunction was observed in 57% of patients (41% grade 1 and 16% grade 2). There was a relationship between diastolic dysfunction and pulmonary capillary pressure (no dysfunction: 8±3 mmHg; dysfunction grade 1: 10±3 mmHg; dysfunction grade 2: 14±6 mmHg; p < 0.001). Compared to patients without diastolic dysfunction or with diastolic dysfunction grade 1, patients with diastolic dysfunction grade 2 had more severe liver failure (Child–Pugh 8±2 vs 10±2 and MELD 14±6 vs 20±11, respectively, p < 0.05), more intense circulatory dysfunction (systemic vascular resistance: 877±330 vs 626±151dyn/seg/cm-5, p < 0.05; cardiac index: 9±3 vs 10±2, p = 0.07; plasma noradrenalin: 338±233 vs 620±646pg/ml, respectively, p < 0.0001) and higher plasma levels of atrial natriuretic factor (42±32 vs 64±49 fmol/ml, p < 0.01) and brain natriuretic peptide (54±76 vs 91±94 pg/ml, p < 0.07). Diastolic dysfunction grade 2 was observed in 8, 11 and 28% of patients in groups A, B and C of Child– Pugh, respectively (p < 0.05). The 6 month transplant-free survival was lower in patients with diastolic dysfunction grade 2 compared to that of the remaining patients (25% vs 61%, p < 0.01). Conclusions: A cardiomyopathy characterized by diastolic dysfunction is frequent in non-selected patients with cirrhosis, particularly in those with advanced disease. The presence of diastolic dysfunction grade 2 is associated with more severe liver failure, greater circulatory dysfunction, and worse prognosis.