1) The ATTIRE trial investigated whether daily albumin infusions would reduce infections and organ dysfunction in hospitalized patients with cirrhosis compared to standard care. 2) Over 700 patients with cirrhosis were randomly assigned to either daily albumin infusions or standard care without explicit albumin therapy for up to 14 days. 3) The trial found no benefit of albumin therapy over standard care on the composite primary outcome of infections, organ dysfunction and mortality.
efficacy and safety of Sulfad tablets in the management of NASH
patients: A randomized ,prospective, open label, multi-center,
controlled, phase III clinical trial.
efficacy and safety of Sulfad tablets in the management of NASH
patients: A randomized ,prospective, open label, multi-center,
controlled, phase III clinical trial.
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In addition to sorafenib and lenvatinib, other targeted therapies have shown promising results in the treatment of advanced HCC. Regorafenib, for instance, is a multi-kinase inhibitor that targets several pathways involved in tumor angiogenesis, cell proliferation, and survival. Cabozantinib is another multi-kinase inhibitor that has been approved as a second-line treatment option for patients who have progressed on or are intolerant to prior systemic therapy. These targeted therapies have demonstrated efficacy in improving overall survival and delaying disease progression in patients with advanced HCC.
Another significant advancement in systemic treatment for advanced HCC is the use of immune checkpoint inhibitors. Immunotherapy has revolutionized cancer treatment in recent years, including for HCC. Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, work by blocking proteins that act as checkpoints on immune cells, such as programmed cell death protein 1 (PD-1) or its ligand (PD-L1). By doing so, these drugs help restore and enhance the immune system's ability to recognize and eliminate cancer cells. Checkpoint inhibitors have shown promising results, with some patients experiencing durable responses and improved overall survival.
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1Oncology Unit, Beaujon University Hospital, Clichy, France; 2Service d’hépato-gastroentérologie et d’oncologie digestive, Groupe Hospitalier Saint André, Bordeaux, France; 3Service d'Hépato-Gastro-Entérologie, Hôpital de la Croix Rousse, Lyon, France; 4Dipartimento di Oncologia Medica, Ospedale San Raffaele IRCSS, Milan, Italy; 5Servizio di Endoscopia Digestiva, Ospedale Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo, Italy; 6Service Hépatologie, Hôpital Jean-Verdier, Bondy, France; 7Service d'hepato-gastro-enterologie, CHU de Grenoble - Hôpital Nord, Grenoble, France; 8Gastrointestinal Oncology, Goethe University Hospital, Frankfurt, Germany; 9Policlinico di Modena, Modena, Italy; 10Merck KGaA, Darmstadt, Germany
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Charlie Tomson, Consultant Nephrologist at theFreeman Hospital Newcastle upon Tyne and Chair of the Intervention Workstream, NHS England/UKRR Think Kidneys Programme
presented at a Measurement for Improvement event on 16th March.
Effect of hydrocortisone on development of shock amongDr fakhir Raza
effects of hydrocortisone on development of shock among patients with severe sepsis the HYPRESS Randomized Clinical Trial American Medical Association caring for the critically ill patients Surviving sepsis campaign, to determine weather hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock
Management of Acute Pancreatitis By Dr. Dhaval Mangukiya
https://drdhavalmangukiya.com/
http://www.youtube.com/c/DrDhavalMangukiyaGastrosurgeonSurat
https://gastrosurgerysurat.blogspot.com/
Systemic treatment in advanced hepatocellular carcinoma (HCC) refers to the use of medications or therapies that are administered throughout the body to target cancer cells beyond the liver. HCC is the most common type of liver cancer and often presents at an advanced stage, making systemic therapies crucial in managing the disease.
One of the main categories of systemic treatment for advanced HCC is targeted therapies. Targeted therapies are designed to selectively inhibit specific molecules or pathways involved in tumor growth, thereby blocking the signals that support cancer cell survival and proliferation. Sorafenib and lenvatinib are examples of targeted therapies that have been approved for the first-line treatment of advanced HCC. They target vascular endothelial growth factor (VEGF) receptors, which play a key role in promoting the growth of new blood vessels necessary for tumor growth. By inhibiting these receptors, these drugs can help slow down tumor growth and improve patient outcomes.
In addition to sorafenib and lenvatinib, other targeted therapies have shown promising results in the treatment of advanced HCC. Regorafenib, for instance, is a multi-kinase inhibitor that targets several pathways involved in tumor angiogenesis, cell proliferation, and survival. Cabozantinib is another multi-kinase inhibitor that has been approved as a second-line treatment option for patients who have progressed on or are intolerant to prior systemic therapy. These targeted therapies have demonstrated efficacy in improving overall survival and delaying disease progression in patients with advanced HCC.
Another significant advancement in systemic treatment for advanced HCC is the use of immune checkpoint inhibitors. Immunotherapy has revolutionized cancer treatment in recent years, including for HCC. Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, work by blocking proteins that act as checkpoints on immune cells, such as programmed cell death protein 1 (PD-1) or its ligand (PD-L1). By doing so, these drugs help restore and enhance the immune system's ability to recognize and eliminate cancer cells. Checkpoint inhibitors have shown promising results, with some patients experiencing durable responses and improved overall survival.
Poster presentation at the 2016 WORLD GASTROINTESTINAL SYMPOSIUM on tepotinib a selective inhibitor of c-MET by S. Faivre, J.-F. Blanc, P. Merle, A. Fasolo, A. Iacobellis, V. Grando, T. Decaens, J. Trojan, E. Villa, U. Stammberger, R. Bruns, E. Raymond
1Oncology Unit, Beaujon University Hospital, Clichy, France; 2Service d’hépato-gastroentérologie et d’oncologie digestive, Groupe Hospitalier Saint André, Bordeaux, France; 3Service d'Hépato-Gastro-Entérologie, Hôpital de la Croix Rousse, Lyon, France; 4Dipartimento di Oncologia Medica, Ospedale San Raffaele IRCSS, Milan, Italy; 5Servizio di Endoscopia Digestiva, Ospedale Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo, Italy; 6Service Hépatologie, Hôpital Jean-Verdier, Bondy, France; 7Service d'hepato-gastro-enterologie, CHU de Grenoble - Hôpital Nord, Grenoble, France; 8Gastrointestinal Oncology, Goethe University Hospital, Frankfurt, Germany; 9Policlinico di Modena, Modena, Italy; 10Merck KGaA, Darmstadt, Germany
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JC ATTIRE.pptx
1. A Randomised Trial of
Albumin Infusions in
Hospitalised Patients with
Cirrhosis
THE NEW ENGLAND JOURNAL OF MEDICINE
Dr. Riya Gautam
General Medicine
2. • Public title - A trial to investigate whether giving
albumin to patients with advanced liver cirrhosis
will reverse immune suppression and improve
outcome from infection.
• Scientific title- ATTIRE -Albumin To prevenT
Infection in chronic liveR failurE
• countries of recruitment- England, Wales, Scotland
• Duration -Jan, 15, 2016 to June, 28, 2019
3. Background
• Liver Cirrhosis - pathological definition
• Complications- ascites, jaundice, varices, Hepatic
encephalopathy
• Development of any of these complication is
termed decompensation.
4. Definitions
• Acute onset chronic liver failure - is a syndrome in
patients with chronic liver ds with or without
previously diagnosed cirrhosis which is
characterised by acute hepatic decompensation
resulting in liver failure (jaundice and prolongation
of the INR) and one or more extrahepaticorgan
failure ie. associated with increased mortality
within a period of 28days and upto 3months from
onset.
5.
6. • Systemic Inflammatory Response Syndrome (SIRS) is an
inflammatory process defined by presence of two or
more of the following: temperature >38°C (100.4°F) or <
36°C (96.8°F), heart rate > 90bpm, respiratory rate > 20
breaths per minute or PaCO2 < 32 mm Hg, WBC >
12,000/mm>, < 4,000/mm>, or > 10% bands.
• Sepsis is the body's response to infection and can be
defined as SIRS plus suspected or confirmed infection.
• Septic shock is currently defined as sepsis in the presence
of hypotension despite adequate fluid resuscitation
7. • Spontaneous bacteraemia: positive blood cultures
without a source of infection.
• SBP: ascitic fluid polymorphonuclear cells >250
cells/mm³.
• Prognostic scores - MELD, Child Pugh score, Chronic
Liver Failue Sequential Organ Failure Assesment
Score.
8.
9.
10.
11.
12. Albumin
• Most abundant protein in human blood plasma.
• Produced in the liver, soluble and monomeric.
• Albumin transports hormones, fatty acids, and
other compounds, buffers pH, and maintains
osmotic pressure, among other functions.
• present at reduced circulating levels in advanced
liver cirrhosis/chronic liver failure.
• N Levels -35 50 g/L.
• serum half-life - 20 days.
13. Central hypothesis
• Elevated circulating Prostaglandin E2 (PGE) levels underlie
immune suppression and vulnerability to infection in
decompensated liver cirrhosis.
• PGE, was more bioavailable and, consequently, more immune
suppressive because of decreased serum albumin levels, as
albumin binds and catalyses inactivation of PGE2
• Therefore in vivo administration of 20% HAS to these patients
will improve their leukocyte function thus enhancing their
ability to combat infection, reducing the incidence of
second/nosocomial infection. This will lead to fewer cases of
organ failure and improved mortality.
14. STUDY DESIGN-
• 2 Stages
• Stage 1- Feasibility study :-
a) Interventional
b) Single arm
c) Phase 2
d) Non blinded
Stage 2 - RCT :-
a) Interventional
b) RCT
c) Phase 3
d) Non blinded
15. Inclusion criteria
• All patients admitted to hospital with acute onset
or worsening of complications eg- alcoholic
hepatitis, HE, ascites, hepatic hydrothorax,
hyperbilirubinemia, any infection precipitating
acute decompensation/acute onset of chronic liver
failure
• over 18yrs of age
• predicted hospital admission >/= 5days (at trial
enrollment) which must be within 72hrs of
admission
16. • serum albumin <30g/l at screening
• documents informed consent to participate (or
consent given by a legal representative)
17. Exclusion criteria
• advanced hepatocellular carcinoma with expected life
expectancy of <8weeks
• patients who recieve palliative treatment only during
their hospital admission
• pregnancy
• known or suspected severe cardiac dysfunction
• any clinical condition which the investigator considers
would make the patient unsuitable for the trial
18. • the patient has been inolved in a clinical trial of
Investigatinal medicinal products(IMPs) within the
previous 30days (including re-randomisation into
the RCT)
• trial investigator unable to identify the patient (by
NHS no.)
19. Sample size
• Feasibility study - 80
• Success would be demonstrated if 60% of patients
treated were able to achieve and maintain serum
albumin levels above 30 g/l on at least 1/3 of days
where the level is recorded. With 72 evaluable patients
(allowing for 10% loss-to-follow-up/withdrawal), the
probability of achieving 44 or more 'successes' is
around 80%, assuming that each patient has a 65%
chance of attaining the required level. If 44 successes
are observed, then a single-sided 90% confidence
interval would suggest that the rate is higher than
50%..
20. 2. RCT
• They assumed that the "immune-restorative"
albumin treatment would reduce the rate of
nosocomial infection by 30% to a rate of 21%,
which would be considered clinically relevant. 389
patients per arm would be sufficient to detect such
a difference with 80% power at a significance level
of 0.05. Allowing for loss-to-follow-up/withdrawal
of 10% from the trial, they aim to recruit 433 to
each arm (866 in total).
• Recruited patients are 777.
21. METHODOLOGY
• Randomised, multicenter, open label, parallel-
group trial
• Randomisation - web based system(Sealed
envelope)
• Interventions-
1. Feasibility study - all patients will receive a daily
infusion of 20% HAS intravenously (at approx
100ml/hr) for a max of 14 days or discharge (if
<14 days). Vol. determined by patient's serum
albumin level on that day.
22. 2. RCT - patient are randomised to receive either
daily dose of 20% HAS iv (at approx 100ml/hr) or a
standard medical care (which may include 20% HAS
infusions) for a max. of 14 days or discharge ( <14
days).
23. ARM A ARM B
• Standard medical care -
which may iinclude 20%
HAS and can be given
for a no. of reasons BUT
not be given in order to
raise the serum
albumin level only.
24. Primary endpoint
• Feasibility Study:
Daily serum albumin level for the duration of the
treatment period (maximum of 14 day or when the
patient is considered fit for discharge if < 14 days)
• RCT:
A composite endpoint comprising incidence of
nosocomial infection, organ dysfunction and mortality
within the treatment period (for a maximum of 14 days
OR when the patient is considered fit for discharge if <
14 days).
25. Secondary endpoint
• Feasibility Study:
Daily Leukocyte Function assessed by our laboratory based leukocyte bioassay.
Information will also be collected on: Total volume of albumin infused; Safety; Rate of
nosocomial infections; in-hospital mortality; Total amount of fluid administered; ICU
admission; Organ dysfunction/prognostic score (UKELD, MELD, Child's Pugh, CLIF-SOFA
scores); Duration of hospital stay.
• RCT:
1. Mortality at 28 days post randomisation and 3 & 6 months post discharge
2. Time to outcome (first event of infection/organ dysfunction/death)
3. Transplant within six months of trial treatment
4. Total amount of HAS administered during the treatment period
5. Duration of hospital stay
6. Prognostic score (assessed by UKELD, MELD, CPS) at baseline and end of treatment
26. 7. Worst daily NEWS Score during treatment period
8. Incidence of Systemic Inflammatory Response Syndrome
(SIRS) during trial intervention period
9. Incidence of Septic Shock during trial treatment period
10. Days in ICU during trial treatment period
11. Incremental cost and cost-effectiveness for up to 6 month
post discharge
12. Impact on quality of life for up to 6 month post discharge
13. Safety and tolerability of HAS as indicated by Serious
Adverse Events (SAES)
14. Requirement for nutritional support (nasogastric feed,
nutritional supplements or total parenteral nutrition) during
the trial treatment period
27. Exploratory endpoint
• RCT:
1. Incidence, morbidity and mortality of the following infections:
a. Bacterial
i. Community acquired (diagnosed within 48 hours of admission)
ii. Nosocomial (e.g. MRSA, Norvovirus, VRE)
iii. Health care acquired (diagnosed within 48 hours of admission in patients
with hospitalisation for at least 2 days in previous 6 months)
iv. Drug resistant pathogens
v. Culture negative sepsis (patients treated with antibiotics in the absence of
microbiology evidence of infection)
vi. Clostridium Difficile infection
28. vii. Source of infection (e.g. bacteraemia, respiratory, peritonitis,
urine, skin etc)
b. Fungal
c. Viral
2. Incidence, morbidity and mortality according to aetiology of
Cirrhosis and whether patient presenting with decompensation
for the first time
3. Component of organ failure (comparing renal, cardiovascular
etc. according to treatment to determine whether treatment
has an organ-specific differential effect)
4. Requirement for ICU/organ support group.
37. DISCUSSION
• ATTIRE, a multicenter trial to assess the efficacy of
albumin to prevent infection, kidney dysfunction,
or death in patients with decompensated cirrhosis,
did not show a benefit of targeted albumin therapy
over the current standard care in the United
Kingdom.
38. • A Limitation of this trial was that it was not blinded,
reason being the patients in std care group who
were receiving non albumin fluid may not have had
increases in the serum albumin levels to set target
level and may have received harmful volumes of
fluid in a futile attempt to increase the albumin
level, and routine albumin testing would have
unblinded the trial.
39. • The use of a composite end point improved
statistical efficiency," and a consistent null effect
was observed in all components.
41. • Did the study ask a clearly-focused question?
• Yes
• Were the patients randomised?
• Yes.
• Was the randomisation concealed?
• Yes.
• Were the patients in study groups similar with
respect to known prognostic factors.
• Yes.
42. • To what extent was the study blinded?
• Not blinded
• Was the follow up complete?
• Follow up complete for 777 patients in efficacy analysis
• Were all of the participants who entered the trial accounted
for at its conclusion?
• Yes
• Did the new treatment make any difference?
• No