November 23, 2010

Management of Ascites Caused by Cirrhosis - CME

Author: Atif Zaman, MD, MPH
Associate Professor of Medicine
Section Chief, Division of Gastroenterology and Hepatology
Director of Clinical Hepatology
Oregon Health & Science University
Disclosure: None

Last Updated: September 10, 2010

LEARNING OBJECTIVES

1. Discuss appropriate use of sodium restriction and diuretic therapy for the management of ascites.

2. Summarize the approach to patients with refractory ascites.

A 57-year-old woman with chronic hepatitis C infection has cirrhosis that has been complicated by ascites and encephalopathy. She has had a history of hospitalizations for encephalopathy, but currently, her encephalopathy is well controlled on lactulose. Her laboratory studies 4 weeks prior showed a serum total bilirubin of 4.7 mg/dL, albumin 2.3 g/dL, international normalized ratio (INR) 2.0, and creatinine 1.0 mg/dL. Her ascites has been well controlled on furosemide 120 mg daily and spironolactone 300 mg daily, but recently the ascites has become more difficult to control and her furosemide is increased to 160 mg daily and spironolactone to 400 mg daily. Follow-up laboratory studies a week later notably shows that serum sodium has dropped from 132 to 120 mEq/L, serum potassium from 3.6 to 3.0 mEq/L, and creatinine has increased from 1.0 to 1.4 mg/dL. The patient's ascites has not improved. She is classified as Child-Pugh-Turcotte Class C and she has a calculated Model for End-Stage Liver Disease (MELD) score of 23.

What would you recommend as the next step in managing this patient’s ascites?

A. Slowly increase diuretics further with close laboratory monitoring.

B. Restrict the patient’s fluid intake to 1 liter a day to correct hyponatremia and continue current diuretic doses for another week to see if ascites improves.

C. Stop diuretics, perform large volume paracentesis as needed to control ascites, and refer for evaluation of possible liver transplantation.  (Correct Answer)

D. Proceed with a transjugular intrahepatic portosystemic shunt (TIPS) procedure to manage the refractory ascites.

DISCUSSION
 
Introduction

In patients who have underlying liver disease, development of fluid retention is a hallmark of liver decompensation and is associated with significant morbidity and mortality in cirrhotic patients[1]. Successful treatment of ascites depends on identifying the correct cause, since some nonhepatic causes of ascites do not respond to sodium restriction and diuretic therapy. The following discussion will address the management of patients with ascites, including patients with refractory ascites. The initial evaluation of patients with new onset ascites is discussed in the case Evaluation of New Onset Ascites in a Patient with Chronic Hepatitis C.

Estimating Prognosis

As part of the initial plan for managing the patient's ascites, especially refractory ascites, the clinician should determine the patient's Child-Pugh-Turcotte score (Figure 1) and a Model for End-Stage Liver Disease (MELD) score[2,3]. The MELD score incorporates the patient's age, total bilirubin serum creatinine, and international normalized ratio (INR) for persons age 12 and older (Figure 2), but the actual calculation of the score is complex and requires log scale. Accordingly, several online resources, such as on the HRSA Organ Procurement and Transplantation Network MELD calculator, are available to provide an easy on-line method for calculating the MELD score. The MELD score and, to a lesser extent the Child-Pugh-Turcotte score, serve as strong predictors of 3-month mortality (Figure 3)[3].

General Approach to the Treatment of Ascites

As part of the evaluation of the patient with ascites, the clinician should determine (or should have already determined) the serum-ascites albumin gradient (SAAG); the SAAG is calculated as the difference between the serum and ascitic fluid albumin values and helps guide the appropriate management of ascites. In essentially all cases, if the SAAG is less than 1.1, sodium restriction and diuretics are ineffective. On the other hand, in cases where the SAAG is 1.1 or greater, sodium restriction and diuretics are the primary treatment modalities, since these patients generally have portal hypertension-related ascites[1]. Patients with ascites should avoid taking prostaglandin inhibitors, such as nonsteroidal anti-inflammatory drugs, since they can precipitate renal failure in the setting of diuretic use for ascites.

Sodium Restriction

For patients with ascites caused by portal hypertension, the ascites results from avid renal retention of sodium and water. In this setting, the most critical aspect of ascites management is sodium (salt) restriction. All patients with ascites should receive thorough education on sodium restriction and many will benefit from dietary counseling. It is important to note that diuretics are less effective in patients who do not also restrict sodium intake. Patients should restrict their dietary sodium to approximately 2000 mg/day (88 meq/day)[1]. The more strict the sodium restriction, the quicker the ascites will respond, but dietary restrictions more stringent than 2000 mg/day can be very difficult for patients to tolerate and maintain. The general goal with ascites treatment is to restrict sodium intake and maintain a urinary sodium excretion greater than 78 mmol/day; only the 10 to 15% of patients who have spontaneous urinary excretion of sodium greater than 78 mmol/day will achieve this goal without the addition of a diuretic[1].

In order to precisely calculate the urinary sodium excretion, a 24-hour urine collection is necessary, which is cumbersome and in many cases impractical. Instead, a spot urine sodium that is greater than a spot urine potassium concentration correlates well with a sodium urinary excretion greater than 78 mmol/day[1]. Patients who have a urine sodium/potassium ratio greater than 1 and are not losing weight, are likely consuming too much sodium in their diet and should undergo dietary counseling. There is a common misconception that fluid restriction is an important treatment modality in managing ascites. Fluid restriction, however, is not generally a necessary part of the initial management of ascites. Indiscriminately applied fluid restriction can lead to dehydration and renal failure in cirrhotic patients who have intravascular volume depletion. Sodium restriction and diuretic use is much more effective in managing ascites than fluid restriction. Careful fluid restriction can be applied when the serum sodium is less than 120 to 125 mmol/L.

Diuretics

Sodium restriction alone may be adequate for the select group of patients who have a spontaneous urinary Na excretion greater than 75mmol/L, but most patients with ascites need sodium restriction and diuretic therapy. The recommended diuretic therapy consists of the combination of a loop diuretic and a potassium sparing diuretic[1,4]. Combination therapy is more effective than sequential therapy[5] and can better maintain serum potassium levels (since furosemide wastes potassium and spironolactone spares potassium).

The recommended initial regimen is furosemide 40 mg plus spironolactone 100 mg daily, both given as once daily doses in the morning. The doses can be increased simultaneously every 3 to 5 days, while maintaining the 40:100 mg ratio in a once-daily fashion. The maximum dose for furosemide is 160 mg daily and for spironolactone 400 mg daily. At the higher doses the total diuretic dose can be given once daily or divided as twice daily dosing, depending on patient preference. As dose adjustments are made, serum electrolytes and renal function tests should be carefully monitored. Once the discomfort from the tense ascites has resolved with initial diuresis, a maximal weight loss of about 0.5 kg per day due to fluid loss is a good target, ideally continuing at this rate until the patient has an abdomen without clinically apparent fluid. If there is a concern for inadequate diuresis, checking a spot urine sodium and potassium concentration can be helpful.

Some experts recommend use of spironolactone monotherapy initially for patients with first episode ascites that is mild to moderate, with addition of furosemide if the patient has an inadequate response to full dose spironolactone, or develops hyperkalemia[1,6]. For patients intolerant or allergic to furosemide, bumetanide can be used as an alternative; the recommended dose of bumetanide ranges from 0.5 mg to 2 mg once daily. To convert furosemide to a bumetanide, divide the furosemide dose by 40 to give you the equivalent bumetanide dose. Triamterene and amiloride are potassium-sparing diuretics that can be used as an alternative to spironolactone, particularly if gynecomastia develops with spironolactone. The patient should discontinue diuretic therapy if the serum sodium decreases to less than 120 mmol/L (despite fluid restriction), uncontrolled or recurrent encephalopathy develops, or the serum creatinine exceeds 2.0 mg/dL[1].

Refractory Ascites

Refractory ascites is commonly understood as ascites that is not successfully managed by medical therapy[7]. Refractory ascites can further be divided into two categories: (1) ascites unresponsive to sodium-restricted diet and high-dose diuretic treatment (400 mg/day of spironolactone and 160 mg/day of furosemide) or (2) ascites that recurs rapidly after a therapeutic paracentesis and high-dose diuretic treatment[8]. Randomized trials involving patients with cirrhosis and ascites have shown that with standard medical therapy fewer than 10% of patients have refractory ascites[9,10]. The development of refractory ascites portends a very poor prognosis, with 21% of these patients dying within 6 months and approximately 70% dying within 2 year [1,7,11]. Options for patients refractory to routine medical therapy include serial therapeutic paracentesis, transjugular intrahepatic portasystemic shunt (TIPS), or liver transplantation. Placement of a peritoneovenous shunt, such as the Leveen or Denver Shunt, is no longer recommended as a routine initial approach, primarily because of the poor long-term patency, high complication rate, and lack of proven survival benefit in this setting[1]. The use of peritoneovenous shunt has been relegated to an option for patients who are not candidates for serial therapeutic paracentesis, liver transplantation, or TIPS procedure.

Serial Therapeutic Paracentesis

Serial therapeutic paracentesis is generally a safe and effective option for patients with refractory ascites. For patients with advanced liver disease who do not have an option for liver transplantation, serial therapeutic paracentesis may provide the only option for managing refractory ascites. Although one might expect therapeutic paracentesis to have a higher complication rate than diagnostic paracentesis, prospective studies have not borne this out[12]. Controversy has existed regarding the necessity for post-paracentesis volume replacement (with colloid solution) to prevent electrolyte and renal abnormalities. A prospective study has demonstrated that patients with diuretic-resistant, tense ascites can undergo a single 5-liter paracentesis without post-paracentesis colloid infusion, as long as baseline renal dysfunction is not present[13]. In addition, removal of volumes of fluid exceeding 5 liters has also been shown to be safe with the administration of intravenous albumin[14]. Based on available data, many experts do not recommend the use of albumin or other colloid expanders with removal of less than 5 liters of ascitic fluid, but would give albumin when ascitic fluid removal exceeds 5 liters (at a dose of 6.25 grams of 25% albumin for every 1 liter removed above the initial 5 liters).

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

In recent years, placement of a TIPS has emerged as an alternative treatment for refractory ascites. The TIPS is an artificial connection (stent) in the liver made between the lower pressure hepatic vein (which transports blood from the liver back to the heart) and the higher pressure portal vein (transports blood from the gastrointestinal tract) (Figure 4); the TIPS procedure creates a shunt that so that blood flows from the higher pressure portal vein directly into the lower pressure hepatic vein (Figure 5), thereby reducing the vascular resistance of the liver, decreasing portal venous pressure, and reducing the formation of ascites[15]. The TIPS procedure is usually performed by an interventional radiologist under conscious sedation, although sometimes general anesthesia is used[15]. Several meta-analyses have compared TIPS with large volume paracentesis and have found TIPS more effective in controlling ascites, but more likely to cause severe encephalopathy[15,16,17,18,19]. Overall, about a third of patients who receive a TIPS develop encephalopathy, with a minority of them developing severe encephalopathy that requires a TIPS revision, which is performed by narrowing or occluding the shunt. Although most studies report no difference in overall survival when comparing TIPS and repeated large volume paracentesis, a recent meta-analysis reported significant improved transplant-free survival with TIPS[17]. Patients who receive a TIPS may require diruretics following the procedure.

For patients who have advanced liver dysfunction and high predicted 30-day mortality, as determined by a Child Class C or MELD score greater than 19, should be informed of their overall poor prognosis and a health professional should discuss the potential need for liver transplantation with them; in this setting, the patient should undergo placement of TIPS only if no other options exist7[15]. In addition, placement of TIPS in patients with advanced liver dysfunction has significant risk of causing hepatic dysfunction and liver failure (because the TIPS shunts portal blood flow away from the liver). Further, post-TIPS heart failure has also been described and most experts recommend not performing a TIPS in patients with an ejection fraction less than 60% or who have diastolic dysfunction. The ejection fraction cut-off of 60% may seem unreasonably high, but patients with cirrhosis typically have hyperdynamic circulation and usually have an ejection fraction greater than 65%[20]. Considering the significant risks associated with TIPS, this procedure should only be performed at centers with significant experience in performing the procedure and with risk stratification of patients with refractory ascites. The AASLD has published guidelines on the role of TIPS in the Management of Portal Hypertension, including a list of absolute and relative contraindications to placement of a TIPS (Figure 6)[15].

Liver Transplantation

Finally, since approximately 20% of patients with refractory ascites die within 6 months, liver transplantation should be considered as one of the treatment options of patients with refractory ascites [1,11]. Therefore, liver transplantation evaluation should be considered a part of the management of patients with refractory ascites. Calculating a MELD score, as outlined above, is an essential component of the transplantation evaluation.

REFERENCES

1. Runyon BA; AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology. 2009;49:2087-107.
2. D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217-31.
3. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:91-6.
4. Runyon BA. Care of patients with ascites. N Engl J Med. 1994;330:337-42.
5. Angeli P, Fasolato S, Mazza E, et al. Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial. Gut. 2010;59:98-104.
6. European Association for the Study of the Liver, Ginès P, Angeli P, et al. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010;53:397-417.
7. Salerno F, Guevara M, Bernardi M, et al. Refractory ascites: pathogenesis, definition and therapy of a severe complication in patients with cirrhosis. Liver Int. 2010;30:937-47.
8. Arroyo V, GinèsP, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996;23:164-76.
9. Pérez -Ayuso RM, Arroyo V, Planas R, et al. Randomized comparative study of efficacy of furosemide versus spironolactone in nonazotemic cirrhosis with ascites. Relationship between the diuretic response and the activity of the rennin-aldosterone system. Gastroenterology. 1983;84:961-8.
10. Stanley MM, Ochi S, Lee KK, et al. Peritoneovenous shunting as compared with medical treatment in patients with alcoholic cirrhosis and massive ascites. Veterans Administration Cooperative Study on Treatment of Alcoholic Cirrhosis with Ascites. N Engl J Med. 1989;321:1632-8.
11. Heuman DM, Abou-Assi SG, Habib A, et al. Persistent ascites and low serum sodium to identify patients with cirrhosis and low MELD scores who are high risk for early death. Hepatology. 2004;40:802-10.
12. Grabau CM, Crago SF, Hoff LK, Simon JA, Melton CA, Ott BJ, Kamath PS. Performance standards for therapeutic abdominal paracentesis. Hepatology. 2004;40:484-8.
13. Peltekian KM, Wong F, Liu PP, Logan AG, Sherman M, Blendis LM. Cardiovascular, renal and neurohumoral responses to single large-volume paracentesis patients with cirrhosis and diuretic-resistant ascites. Am J Gastroenterol. 1997;92:394-9.
14. Titó L, Ginès P, Arroyo V, et al. Total paracentesis associated with intravenous albumin management of patients with cirrhosis and ascites. Gastroenterology. 1990;98:146-51.
15. Boyer TD, Haskal ZJ; American Association for the Study of Liver Diseases. The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009. Hepatology. 2010;51:1-16.
16. Saab S, Nieto JM, Ky D, Runyon BA. TIPS versus paracentesis for cirrhotic patients with refractory ascites. Cochrane Database Syst Rev. 2004;3:CD004889.
17. Deltenre P, Mathurin P, Dharancy S, et al. Transjugular intrahepatic portosystemic shunt in refractory ascites: a meta-analysis. Liver Int. 2005;25:349-56.
18. D'Amico G, Luca A, Morabito A, Miraglia R, D'Amico M. Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis. Gastroenterology. 2005;129:1282-93.
19. Salerno F, Cammà C, Enea M, Rössle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology. 2007;133:825-34.
20. Pozzi M, Carugo S, Boari G, et al. Evidence of functional and structural cardiac abnormalities in cirrhotic patients with and without ascites. Hepatology. 1997;26:1131-7.
Source

Journal experts prefer 'splashy' findings

By Frederik Joelving
NEW YORK
Mon Nov 22, 2010 5:19pm EST

NEW YORK (Reuters Health) - The 'man bites dog' principle doesn't just apply to news-hungry journalists, researchers said Monday.

Experts who keep the gates at medical journals also have a penchant for reports that show one treatment works better than another, they found, potentially impacting patient care.

Given similar, fabricated reports that compared two treatments, reviewers from a pair of top-line orthopedic journals recommended publishing the fake results in 97 percent of cases when there was a difference between treatments, but only in 80 percent of cases when there was no difference.

"No-difference studies affect practice just as much as positive ones, but they aren't as sexy," said Dr. Seth Leopold of the University of Washington in Seattle, who led the new research. "Something splashy, something new, is more exciting to everybody."

The problem is that favoring studies that identify, say, a new drug as superior to an older one will make the newer drug seem better than it really is.

As a consequence, when doctors scour the scientific literature about a given treatment, they don't see the whole picture.

"The literature should be a fair representation of all the high-quality studies out there, so a practicing physician can make good treatment decisions," said Leopold.

"We felt that these results really confirm beyond any reasonable doubt that positive bias occurs at the level of peer review. That is critically important for the integrity of the medical literature," he added.

Earlier research has shown so-called publication bias is much more common when drugmakers fund studies of their own products than when the government picks up the bill.

But it hadn't been clear if academics - who don't stand to gain financially from a given report - would also favor positive outcomes.

To investigate that, Leopold and colleagues fabricated a pair of fake study reports on whether giving antibiotics after a surgery would help prevent infections.

The reports were nearly identical, but one showed the treatment worked and the other showed it didn't.

More than 200 regular reviewers from The Journal of Bone and Joint Surgery and Clinical Orthopedics and Related Research received one of the two studies.

During peer review, such experts make recommendations to a journal's editors as to whether or not they should publish a given paper.

Apart from being partial to the positive report, reviewers were also twice as likely to pick up errors in the no-difference study and generally rated the research quality lower - despite the fact that the two reports had the same intentional errors and the same methods.

Leopold said the findings suggest reviewers were looking for reasons to endorse positive findings and reject negative ones.

The editors-in-chief of both journals told Reuters Health they were concerned, but not surprised, by the results.

"For practicing orthopedic surgeons, if you see something that has the potential to change your practice, you're more likely to want to recommend that it go into print," said Dr. Vernon Tolo of The Journal of Bone and Joint Surgery.

He said he would circulate the new study among his reviewers to raise awareness about the issue.

Dr. Richard Brand, of Clinical Orthopedics and Related Research, said he pays special attention to publication bias when considering the recommendations from reviewers.

"Realizing the potential for positive outcome bias," he said, "I carefully consider the comments on any recommendation to reject a well-designed study that shows no difference when I receive other recommendations to accept."

SOURCE: link.reuters.com/fev96m Archives of Internal Medicine, November 22, 2010.

Source

Less invasive surgery works for liver, too

By Alison McCook
NEW YORK
Thu Nov 18, 2010 1:44pm EST

NEW YORK (Reuters Health) - People who undergo surgery to remove benign or cancerous tumors in their liver appear to fare better when they receive a newer type of surgery that makes only small incisions, two new reports show.

More than 24,000 Americans are expected to get liver cancer in 2010, and nearly 19,000 will die from the disease, according to the National Cancer Institute.

While there are several treatments available, such as radiation and chemotherapy, surgery is a common option.

In the new studies, two research teams tried to gauge how laparoscopy, an increasingly popular type of surgery in which doctors make a few small incisions, compared with traditional surgery, in which they make one long cut to enter the body.

Reviewing earlier published reports, they found patients who underwent laparoscopic surgery had less blood loss, needed less pain medication, and were able leave the hospital earlier.

One of the research teams, based in Canada, also found that people receiving laparoscopic surgery had a 60 percent lower chance of complications after surgery. And those with cancer tumors were 36 percent less likely to have died two to five years after surgery.

The other research team, from the University of Pittsburgh in Pennsylvania, found no differences in survival after the two types of surgery. Both teams were limited in their conclusions, however, because none of the studies they reviewed was optimally designed, with patients randomly assigned to each surgery.

Doctors now use laparoscopy during surgery in many organs -- including the gall bladder, spleen and colon -- and this research should help add another organ to that list, said Dr. Joseph Buell of Tulane University, who was not involved in the studies.

"This is something that benefits patients, and it works," Buell told Reuters Health. "I think that people should have an option."

The reason laparoscopic liver surgery likely benefits patients, said Dr. David Geller, who led the University of Pittsburgh team, is that it's less invasive than the traditional technique.

Many surgeons continue to rely on larger incisions that enable them to visualize the liver directly, but that is often because they aren't trained in laparoscopy, Geller told Reuters Health.

There have also been concerns that doctors who use smaller incisions may inadvertently spill cancer cells as they pull tumors out of the tiny opening. But there was "not a single report" of this occurring, Geller said.

According to Buell, doctors have also reasoned that controlling an accidental bleed would be easier with a larger incision, where "everything is right in front of you."

However, these reports, based on published results as well as new data from almost 1,300 patients at the University of Pittsburgh Medical Center, showed there was less blood loss with the newer technique, not more.

Both studies appear in the November issue of the Archives of Surgery.

Although laparoscopy costs more in the operating room, patients who received it spent two to three days less recovering in the hospital, Geller and colleagues found.

Recently, the team reported that hospital costs for laparoscopy totaled $15,000 on average, versus $18,000 for the traditional technique. During laparoscopy, doctors make a few incisions between one-quarter and one-half inch in size, whereas the incision in traditional surgery is several inches long.

Still, laparoscopy is not an option for everybody. People with multiple liver tumors, for instance, or tumors that are too large or too close to blood vessels will need a large incision, Geller noted.

Buell said he travels the world teaching doctors to use the laparoscope -- a telescope-like tube inserted through one of the incisions to guide the surgery -- and has himself performed 400 of these procedures.

Patients should seek out experienced surgeons, he cautioned, since it can take 50 or so liver surgeries before most doctors feel comfortable using a laparoscope.

What's encouraging, Geller noted, is that people with liver cancer now have one more tool at their disposal.

"When people and their loved ones are diagnosed with liver cancer, in the old days that would be a death sentence," he said. "There's hope, and there are treatment options for liver cancer."

SOURCE: link.reuters.com/zuk26q and link.reuters.com/xuk26q Archives of Surgery, November 15, 2010.

Source

Also See: Laparoscopic Liver Resection May Beat Open Surgery
Alice Goodman

November 22, 2010 (New York, New York) — Although cross-sectional imaging is recommended by several well-respected societies as the standard of care for the diagnosis of hepatocellular carcinoma (HCC), many physicians still rely on a liver biopsy for diagnosis.

"This problem is not well recognized. More publicity and education are needed to promote appropriate use of cross-sectional imaging to diagnose HCC," said Matthew S. Johnson, MD, an interventional radiologist at Indiana University in Indianapolis, here at the 37th Annual VEITH Symposium.

Dr. Johnson discussed the importance of cross-sectional imaging as the diagnostic standard. HCC is currently responsible for more than 650,000 deaths each year worldwide, and is the third most common cause of cancer-related death.

"The incidence of HCC is increasing exponentially in the United States because of the increasing prevalence of risk factors such as alcohol consumption, hepatitis B and C, and obesity," he continued.

In 2001, the European Association for the Study of Liver guidelines validated imaging as the preferred method of diagnosis of HCC; this recommendation was strengthened by the American Association for the Study of Liver Disease in 2005. "Still, the vast majority of oncologists do biopsies, driven primarily by the demand from medical oncologists," Dr. Johnson said.

Biopsies are no more sensitive or specific than imaging, he continued, and biopsy carries about a 3% risk for tumor seeding. Although this is a relatively low risk, when seeding occurs and cancer is found outside the liver, the patient is no longer eligible for transplant.

In addition, a needle biopsy can miss a tumor, and pathologists are often unable to differentiate between a high-grade dysplastic nodule and a cancer, Dr. Johnson continued. "Stromal invasion is hard to detect," he emphasized.

"At Indiana University, we consider biopsy potentially dangerous, and we avoid biopsy. . . . [A] biopsy can render a patient transplant-ineligible," he explained.

Three different imaging methods are suitable for the diagnosis of HCC: contrast-enhanced ultrasound, which is not used much in the United States because of the widespread availability of the other 2, more sophisticated, methods — computed tomography scanning and magnetic resonance imaging, which is most commonly used. Both of the latter methods are excellent at detecting cancers larger than 2 cm.

"According to societal guidelines, a lesion larger than 2 cm with hypervascularity and washout on imaging is diagnostic for HCC," Dr. Johnson explained.

"Imaging should be used instead of biopsy to diagnose HCC. There are no downsides to imaging. There is a lot of ignorance out there, and this issue needs to be brought to the attention of the medical community," he stated.

"This is an important topic," agreed Jean-Francois Geschwind, MD, professor of oncology, radiology, and surgery at Johns Hopkins Medical Center, in Baltimore, Maryland. "Biopsies are overutilized in the United States, and decreasing the number of biopsies would lead to fewer procedures and less risk of tumor seeding."

Biopsy should be reserved for the few cases in which a positive result would change management, Dr. Geschwind stated. "Biopsy is useless for early-stage HCC. It can miss the target or not obtain enough tissue to make an accurate diagnosis," he continued.

At Johns Hopkins, a combination of alfa fetoprotein, imaging, and background cirrhosis is used to make the diagnosis of HCC. More than 90% of patients with HCC have cirrhosis. "A hypervascular tumor with background cirrhosis should be considered HCC until proven otherwise," Dr. Geschwind stated.

Dr. Johnson reports serving as consultant to Angiotech, Cook, Boston Scientific, MDS Nordion, and Sirtex. Dr. Geschwind has disclosed no relevant financial relationships.

37th Annual VEITH Symposium: Presented November 18, 2010.

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Boost for liver research

23 Nov, 2010 01:00 AM

THE Westmead Millennium Institute is celebrating a major success following the announcement of National Health and Medical Research Council grants for 2011.

The institute's research team at the Storr Liver Unit secured four project grants for work focused on treatments for liver disease, including liver cancer and hepatitis C.

One of these projects will study the role of cannabis-like hormones in hepatitis C and other chronic liver diseases.

Working on the project will be Mark Douglas, a specialist who runs the viral hepatitis service at Blacktown Hospital.

"This is a very interesting project because we have known for some time that in people with hepatitis C, smoking cannabis can cause fatty liver and accelerate liver fibrosis," Dr Douglas said.

"What we discovered recently was that hepatitis C actually makes the liver more sensitive to cannabis and to cannabis-like hormones produced normally in the body.

"We believe the hepatitis C virus uses these hormones to its advantage, helping it to replicate better.

"The aim of our project is to understand how this works, so we can turn it to our advantage and improve treatments.

"We hope that by blocking endocannabinoids in people with hepatitis C, we can improve current cure rates."

In other projects, led by Dr Lionel Hebbard, Dr Jianhua Wang and Associate Professor David Booth, researchers will investigate the underlying mechanisms for the development of liver cancer, liver scarring and liver disease in hepatitis C.

Source
- Submission based on results from Phase 3 studies that showed high SVR (viral cure) rates with telaprevir-based combination therapy compared to approved medicines -

- Six-Month Priority Review Requested -

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) announced today that it has completed the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval for telaprevir, Vertex’s investigational treatment for people with hepatitis C. The NDA submission is supported by results from three Phase 3 studies, ADVANCE, ILLUMINATE and REALIZE, which evaluated telaprevir in people chronically infected with genotype 1 hepatitis C virus (HCV) who were new to treatment as well as those who were treated before but did not achieve a sustained viral response (SVR, or viral cure). The submission includes a request for Priority Review, which would reduce the FDA’s review time from 10 months to six months. The FDA grants Priority Review status for several reasons, including if the medicine is considered a major advance in treatment.

“This submission is a milestone in our more than 15-year effort to change the way hepatitis C is treated,” said Matthew Emmens, Chairman, President and Chief Executive Officer of Vertex. “We are committed to working closely with the FDA to make telaprevir available as quickly as possible to the millions of people with hepatitis C who need new medicines to increase their chances for a viral cure.”


Highlights of the Telaprevir Phase 3 Data Included in the Submission

All Phase 3 studies met their primary endpoints and results below are from the treatment arms where telaprevir was started immediately in combination with pegylated-interferon and ribavirin for the first 12 weeks of treatment.

In people with hepatitis C who were new to treatment (treatment-naïve):

• Up to 75% achieved a viral cure with telaprevir-based combination therapy, compared to 44% of people who received pegylated-interferon and ribavirin alone;

• A majority (58% in ADVANCE and 65% in ILLUMINATE) were eligible to reduce their treatment time by half – from 48 weeks to 24 weeks; and

• Data showed there was no benefit to extending total treatment from 24 weeks to 48 weeks in people whose virus was undetectable at weeks 4 and 12 with telaprevir-based therapy.

In the three major subgroups of people with hepatitis C who had not achieved a viral cure with a prior course of treatment (treatment-experienced):

• 83% of prior relapsers, 59% of prior partial responders and 29% of prior null responders achieved a viral cure with telaprevir-based combination therapy compared to 24%, 15%, and 5% of people in these subgroups, respectively, who received pegylated-interferon and ribavirin alone. These results were achieved with a simultaneous start of all three drugs for the first 12 weeks followed by pegylated-interferon and ribavirin alone for an additional 36 weeks.

The safety and tolerability results of telaprevir-based combination therapy were consistent across the Phase 3 studies. The most common adverse events regardless of treatment arm were rash, fatigue, pruritis, headache, nausea, anemia, insomnia, diarrhea, flu-like symptoms and pyrexia, with the majority being mild or moderate in severity.

More Effective Therapies Needed to Improve Viral Cure Rates

Hepatitis C is a serious disease, typically without symptoms, which affects up to 3.9 million people in the United States. Hepatitis C can lead to scarring of the liver (cirrhosis), resulting in liver failure, liver cancer and the need for liver transplantation. Approved medicines for people with genotype 1 hepatitis C are given for a year, and less than half of people treated with these therapies achieve a viral cure.4,5,6 Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with genotype 1 hepatitis C have received telaprevir in Phase 2 and Phase 3 studies.

“In our trials, starting patients with 12 weeks of telaprevir-based combination therapy significantly improved viral cure rates compared to treatment with currently approved medicines, even in groups of people considered the most difficult to treat,” said Peter Mueller, Ph.D., Chief Scientific Officer and Executive Vice President of Global Research and Development at Vertex. “We’re also encouraged by telaprevir data that showed most patients new to therapy were able to achieve high viral cure rates and reduce their total treatment time by half.”

Vertex is developing telaprevir in collaboration with Tibotec Pharmaceuticals and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America and Tibotec has rights in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.

Vertex was granted Fast Track designation by the FDA for telaprevir in 2005. In mid-2010, as part of the Fast Track designation, Vertex began to submit completed sections of the NDA for review by the FDA on a rolling basis rather than wait until every section of the application was complete.

Data from Phase 3 Studies in All Major Patient Types, Including the Most Difficult-to-Treat

The Phase 3 studies evaluated people with genotype 1 hepatitis C who were new to treatment as well as those who had previously received treatment but did not achieve a cure, including people who have traditionally responded poorly to approved medicines. In Phase 3 studies, telaprevir was given to people three times a day in combination with pegylated-interferon and ribavirin for the first 12 weeks of therapy followed by either 12 weeks or 36 weeks of Pegasys® (pegylated-interferon alfa-2a) and Copegus® (ribavirin) alone for a total treatment time of either 24 weeks or 48 weeks. The ability to shorten treatment time from 48 weeks to 24 weeks for people new to treatment was based on their response to therapy at weeks 4 and 12. People who did not achieve a viral cure with a prior course of therapy received a total of 48 weeks of treatment. In October 2010, Vertex announced the start of a Phase 3 study to evaluate twice-daily (BID) dosing of a telaprevir-based combination regimen.

ADVANCE: Pivotal study in 1,095 people who were new to treatment

The primary endpoint of ADVANCE was SVR, defined as the proportion of people who had undetectable viral load (HCV RNA) both at the end of treatment and 24 weeks after the end of treatment. The secondary endpoint was to evaluate the safety of telaprevir when dosed in combination with pegylated-interferon and ribavirin. ADVANCE also evaluated the ability to reduce total treatment time by half – from 48 weeks to 24 weeks, which was guided by a patient’s response to therapy (undetectable viral load at weeks 4 and 12).

ILLUMINATE: Supplemental study in 540 people to evaluate shorter treatment durations in people who were new to treatment

The primary endpoint of the study was SVR in two telaprevir-based treatment arms of people whose virus was undetectable at week 4 and week 12 of treatment (eRVR, extended rapid viral response). These patients were randomized to either 24 weeks or 48 weeks of total therapy. ILLUMINATE was designed to evaluate whether there was any benefit to extending therapy from 24 weeks to 48 weeks in people who met these criteria. There was no control arm of pegylated-interferon and ribavirin alone in the study.

In both the ADVANCE and ILLUMINATE studies, telaprevir-based combination therapy also resulted in improved SVR rates in various subgroups of people with characteristics known to limit response to approved medicines such as race/ethnicity or stage of liver fibrosis. Data from these studies were presented in November 2010 at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

REALIZE: Pivotal study in 662 people who did not achieve a viral cure with previous therapy

The primary endpoint of the study was SVR in each of the two telaprevir treatment arms compared to the control arm, and for the three subgroups of people included in the study. REALIZE is the only Phase 3 study to date of a direct-acting antiviral medicine to include all three major subgroups of people with hepatitis C who did not achieve a viral cure with a previous course of therapy:

• Relapser: defined as a person whose hepatitis C virus was undetectable at the completion of at least 42 weeks of a prior course of therapy but whose virus became detectable during the follow-up period;

• Partial Responder: defined as a person who achieved at least a 2 log10 (100 times) reduction in viral load (HCV RNA) at week 12, but whose hepatitis C virus never became undetectable by week 24 of a prior course of therapy; and

• Null Responder: defined as a person who experienced a less than 2 log10 drop in viral load at week 12 of a prior course of therapy.

In REALIZE, people received 48 weeks of total therapy, which included 12 weeks of telaprevir combined with pegylated-interferon and ribavirin. One of the telaprevir treatment arms was designed to evaluate, for the first time, whether viral cure rates could be further improved by starting pegylated-interferon and ribavirin alone for the first four weeks of treatment (delayed start) compared to a simultaneous start of telaprevir in combination with these medicines. There was no clinical benefit observed with the telaprevir delayed-start treatment arm in any of the subgroups of patients compared to the simultaneous-start arm. Final results from REALIZE, including safety and efficacy data, will be presented at an upcoming medical meeting.

Safety and Tolerability Information for ADVANCE, ILLUMINATE and REALIZE

The safety and tolerability results of telaprevir-based combination regimens were consistent across the Phase 3 studies. The most common adverse events (AEs) were rash, fatigue, pruritis, headache, nausea, anemia, insomnia, diarrhea, flu-like symptoms and pyrexia with the majority being mild or moderate in severity. Rash and anemia occurred more frequently in the telaprevir treatment arms compared to the control arms.

Rash was primarily characterized as eczema-like, manageable and resolved upon stopping telaprevir. More than 90% of rash was mild to moderate and was primarily managed with the use of topical corticosteroids and antihistamines. Anemia was primarily managed by reducing the dose of ribavirin. Erythropoiesis-stimulating agents (ESAs) were used in only 1% of people in the Phase 2 and Phase 3 studies. Discontinuation of all drugs due to either rash or anemia during the telaprevir/placebo treatment phase was 1% to 3% in the telaprevir treatment arms.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.2 Up to 3.9 million people in the United States have chronic hepatitis C and 75% of those infected are unaware of their infection.3 The majority of people with hepatitis C were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.11 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.2 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.2

Approximately 60 percent of genotype 1 patients who undergo an initial 48-week regimen with pegylated-interferon and ribavirin, the currently approved medicines, do not achieve SVR, 4,5,6 or viral cure.1 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8,9,10,11 In the United States, hepatitis C is the leading cause of liver transplantations and is reported to contribute to 4,600 to 12,000 deaths annually.8 By 2029, total annual medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.11

Additional resources for media are available at: http://investors.vrtx.com/press.cfm.

About Vertex

Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with other pharmaceutical companies. Vertex's product pipeline is focused on viral diseases, cystic fibrosis, inflammation, autoimmune diseases, epilepsy, cancer and pain.

Vertex co-discovered the HIV protease inhibitor, Lexiva, with GlaxoSmithKline.

Lexiva is a registered trademark of the GlaxoSmithKline group of companies.

PEGASYS® and COPEGUS® are a registered trademarks of Hoffman-La Roche.

References:

1 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

2 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed May 25, 2010.

3 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed May 25, 2010.

4 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

5 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

6 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

8 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.

9 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

10 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

11 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. This report was commissioned by Vertex Pharmaceuticals, Inc.

12 Picchio G, et al. Discrepancies between definitions of null response to treatment with peginterferon alfa-2a and ribavirin: Implications for new HCV drug development. [poster 289]. In: Program and Abstracts of the 2010 International Liver Conference by the European Association for the Study of Liver Disease. . Athens, Greece: April 2010.

13 United States Food and Drug Administration. Chronic hepatitis C virus infection: developing direct-acting antiviral agents for treatment. http://www.federalregister.gov/articles/2010/09/14/2010-22806/draft-guidance-for-industry-on-chronic-hepatitis-c-virus-infection-developing-directacting-antiviral. Updated September 14, 2010. Accessed September 14, 2010.

Special Note Regarding Forward-looking Statements

This press release contains forward-looking statements, including statements regarding (i) the potential that the FDA’s review time for the telaprevir NDA will be reduced from 10 months to six months; (ii) Vertex’s commitment to working closely with the FDA to make telaprevir available as quickly as possible; (iii) Vertex being encouraged by telaprevir data that showed most patients new to therapy were able to achieve high viral cure rates and reduce their total treatment time by half and (iv) the expectation that final results from REALIZE will be presented at an upcoming medical meeting. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that Vertex could experience unforeseen delays in obtaining approval to market telaprevir; that there may be varying interpretations of the data from the telaprevir clinical trials; that future outcomes from clinical trials of telaprevir may not be favorable; that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir-based therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

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Vertex Pharmaceuticals Incorporated
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