Aiden McCormick

A predictive model for failure to control bleeding during acute variceal haemorrhage

BACKGROUND/AIMS Variceal bleeding is a frequent complication of cirrhosis and is associated with a high risk of early rebleeding. In patients with peptic ulcers, continued bleeding or early rebleeding are risk factors for mortality and can be predicted by statistical models; however, no such models exist for acute variceal bleeding. METHODS We prospectively evaluated failure to control bleeding in 695 consecutive patients with cirrhosis, admitted for haematemesis and/or melaena. Criteria were defined for failure to control bleeding, which comprised both continued bleeding or early rebleeding within 5 days of admission. There were 2 sequential groups of patients: (i) those with variceal bleeding initially treated with blood transfusion and vasoactive drugs, and if these failed followed by sclerotherapy (n = 385); (ii) those with variceal bleeding treated with injection sclerotherapy at diagnostic endoscopy (n = 144). The third group was those with bleeding from other sources related to portal hypertension (n = 166). RESULTS Failure to control bleeding was noted in 169 (44%) patients in group 1, 55 (38%) in group 2 and 44 (25%) in group 3. Twenty variables that were evaluable within 6 h of admission, pertaining to severity of bleeding, severity of type of liver disease, mode of admission, and time of diagnostic endoscopy, were entered into a multivariate Cox model. Independent predictors of early rebleeding in group 1 were: active bleeding at endoscopy (irrespective of interval from admission) (p<0.0001), encephalopathy (p = 0.007), platelet count (p = 0.002), history of alcoholism (p = 0.002), presentation with haematemesis (p = 0.02), log urea (p = 0.03) and (shorter) interval to admission (p = 0.007). The variables predictive of 30-day mortality were: early bleeding (p<0.0007), bilirubin (p = 0.0006), encephalopathy (p<0.0001), (shorter) interval to admission (p<0.0001), and log urea (p = 0.004); a model based on these variables was also a good predictor of mortality in the other 2 groups. However, the model derived from group 1 for failure to control variceal bleeding was different in group 2, despite similar patient characteristics and a similar failure rate (following a single injection). This could suggest that sclerotherapy may induce bleeding in some patients independently of the baseline risk for failure to control bleeding. CONCLUSIONS In cirrhotic patients who present with haematemesis or melaena, active variceal bleeding at diagnostic endoscopy is predictive of failure to control bleeding (continued bleeding or early rebleeding within 5 days of admission), and this failure is predictive of 30-day mortality.

Factors related to early mortality after transjugular intrahepatic portosystemic shunt for failed endoscopic therapy in acute variceal bleeding

BACKGROUND Uncontrolled variceal haemorrhage is the main indication for transjugular intrahepatic portosystemic shunt. However, mortality is 50% for this high-risk group. We have evaluated clinical and laboratory variables prior to transjugular intrahepatic portosystemic shunt in order to establish predictors of mortality, validated prospectively. METHOD Over a 4-year period, 367 patients were admitted with variceal bleeding. In 54 patients endoscopic therapy for acute variceal bleeding failed and they had emergency transjugular intrahepatic portosystemic shunt. Failure of therapy was defined as continued bleeding after 2 endoscopy sessions (n=39) or vasoconstrictor-resistant bleeding from gastric/ectopic varices (n=15). Thirty-three variables were analysed from data available immediately prior to transjugular intrahepatic portosystemic shunt. RESULTS Twenty-six patients died within 6 weeks. In a multivariate analysis, 6 factors had independent prognostic value: moderate/severe ascites, requirement for ventilation, white cell blood count (WBC), platelet count (PLT), partial thromboplastin time with kaolin (PTTK) and creatinine. A prognostic index (PI) score was derived, in which presence of moderate/severe ascites, or need for ventilation, scored 1: PI=1.54 (Ascites)+1.27 (Ventilation)+1.38 Ln (WBC)+2.48 ln (PTTK)+1.55 Ln (Creat)-1.05 Ln (PLT). Using this equation, 42% (n=10) of deaths occurred in the fifth quintile (PI > or = 18.52), where the mortality was 100%. The score was prospectively validated in a further 31 patients, giving 100% positive predictive value. Eleven further patients died, including all seven with a PI >18.5. No survivors had a PI >18.3. CONCLUSION Despite immediate control of bleeding by transjugular intrahepatic portosystemic shunt, patients with uncontrolled variceal haemorrhage have a high mortality, particularly when associated with markers of advanced liver disease, sepsis and multi-organ failure. The use of transjugular intrahepatic portosystemic shunt is probably not justified in this subgroup. Our prognostic index can help identify such patients, and, if validated elsewhere, will help in deciding when to use transjugular intrahepatic portosystemic shunt.

Outcome of recurrent hepatitis C virus after liver transplantation in a randomized trial of tacrolimus monotherapy versus triple therapy

Less potent immunosuppression is considered to reduce the severity of hepatitis C virus (HCV) recurrence after liver transplantation. An optimal regimen is unknown. We evaluated tacrolimus monotherapy versus triple therapy in a randomized trial of 103 first transplants for HCV cirrhosis. One hundred three patients who underwent transplantation for HCV were randomized to tacrolimus monotherapy (n = 54) or triple therapy with tacrolimus, azathioprine, and steroids (n = 49), which were tapered to zero by 3 to 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. The time to reach Ishak stage 4 was the predetermined endpoint. All factors documented in the literature as being associated with HCV recurrence and the allocated treatment were evaluated for reaching stage 4 and HVPG ≥ 10 mm Hg. No significant preoperative, perioperative, or postoperative differences, including the frequency of biopsies between groups, were found. During a mean follow‐up of 53.5 months, 9 monotherapy patients and 6 triple therapy patients died, and 5 monotherapy patients and 4 triple therapy patients underwent retransplantation. Stage 4 fibrosis was reached in 17 monotherapy patients and 10 triple therapy patients (P = 0.04), with slower fibrosis progression in the triple therapy patients (P = 0.048). Allocated therapy and histological acute hepatitis were independently associated with stage 4 fibrosis. HVPG increased to ≥10 mm Hg more rapidly in monotherapy patients versus triple therapy patients (P = 0.038). In conclusion, long‐term maintenance immunosuppression with azathioprine and shorter term prednisolone with tacrolimus in HCV cirrhosis recipients resulted in a slower onset of histologically proven severe fibrosis and portal hypertension in comparison with tacrolimus alone, and this was independent of known factors affecting fibrosis. Liver Transpl 15:1783–1791, 2009.

Randomized Trial of Micafungin for the Prevention of Invasive Fungal Infection in High-Risk Liver Transplant Recipients

In this randomized clinical trial comparing micafungin 100 mg with standard-care antifungal prophylaxis (fluconazole, liposomal amphotericin B, or caspofungin) in high-risk liver transplant patients, micafungin 100 mg was noninferior and had a better kidney safety profile.

Altered prostacyclin synthesis by aortae from hepatic portal vein-constricted rats : evidence for effects on protein kinase C and calcium

To investigate the mechanisms causing reduced systemic vascular reactivity to vasoconstrictor agents in portal hypertension, we studied receptor- and signal-transduction-linked PGI2 (a vasodilator) synthesis (measured as 6-oxo-PGF1 alpha by radioimmunoassay) in the aorta (ex vivo) of portal vein-constricted rats. PGI2 synthesis was stimulated by adrenaline (via heterogeneous alpha-adrenoceptors), phorbol ester dibutyrate (a protein kinase C activator), arachidonic acid (the substrate for PGI2 synthesis) and the Ca2+ ionophore A23187 (A23187) and thapsigargin (both of which elevate intracellular Ca2+, which in turn elicits the release of arachidonic acid). The release of PGI2 by the aortae of rats with portal hypertension in comparison to sham-operated controls was: 1) enhanced in response to adrenaline, 2) reduced in response to phorbol ester dibutyrate, A23187 and thapsigargin and 3) unchanged in response to arichidonic acid. These data indicate that in aortae from rats with experimental portal hypertension: i) there are no changes in the enzymes involved in PGI2 synthesis (cyclooxygenase, PGI2 synthase), ii) there is a specific increase in adrenoceptor-linked PGI2 synthesis in aortae which may contribute to arterial vasodilation in this experimental model and 3) the diminished response of PGI2 synthesis to A23187, phorbol ester dibutyrate and thapsigargin indicates that there is a generalised attenuation of protein kinase C activator activity and of Ca2+. Since Ca2+ is a key component of excitation-contraction coupling and protein kinase C activator has been implicated in mediating this event, attenuation of these systems may also explain, at least in part, the known reduced vasoactivity of aortae from rats with portal hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

High mortality during direct acting antiviral therapy for hepatitis C patients with Child’s C cirrhosis: Results of the Irish Early Access Programme

Please cite this article as: Gray, E., O’Leary, A., Stewart, S., Bergin, C., Cannon, M., Courtney, G., Crosbie, O., De Gascun, C.F., Feeney, E., Houlihan, D.D., Kelleher, B., Lambert, J.S., Lee, J., Mallon, P., McConkey, S., McCormick, A., McKiernan, S., McNally, C., Murray, F., Sheehan, G., Norris, S., Fanning, L.J., on behalf of the Irish Hepatitis C Outcomes and Research Network (ICORN), High mortality during direct acting antiviral therapy for hepatitis C patients with Child’s C cirrhosis: Results of the Irish Early Access Programme, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.03.022

Effectiveness of interferon-free therapy for the treatment of HCV-patients with compensated cirrhosis treated through the Irish early access program

ABSTRACT Background: We investigated the real-world effectiveness of interferon-free regimens for the treatment of patients with compensated cirrhosis infected with hepatitis C virus (HCV). Method: Using the Irish national HCV treatment registry, the effectiveness and safety of interferon-free regimens for HCV-infected patients treated between April 2015 and August 2016, was determined. Results: A SVR12 was achieved in 86% of subjects treated with sofosbuvir/ledipasvir ± ribavirin (SOF/LDV±RBV), 93% treated with paritaprevir, ombitasvir and ritonavir combined with dasabuvir ± ribavirin (3D±RBV) and 89% treated with sofosbuvir/daclatasvir ± ribavirin (SOF/DCV±RBV). The discontinuation rate was 5% and the on-treatment mortality rate was 1%. Conclusion: The availability of interferon-free regimens represents a significant breakthrough for the treatment of HCV infection. Treatments options, with high SVR12 rates, are now available for patients with compensated cirrhosis who were unsuitable for treatment with interferon-based regimens. Data obtained from studies conducted in real world practice provide robust information fundamental for input into future economic evaluations for agents used for the treatment of HCV infection.