A multi-center randomized controlled study of primary prevention of esophageal variceal bleeding in cirrhotic patients treated with HVPG-guided beta- blocker therapy or standard heart rate-guided beta-blocker therapy.

About 50% of cirrhotic patients who use nonselective beta-blockers (NSBB) for
primary prevention of variceal bleeding do not reach target hemodynamic
response, defined as HVPG < 12 mmHg or a > 10% decrease in HVPG from baseline.
These so-called hemodynamic nonresponding patients have significantly higher
rate of first esophageal variceal hemorrhage as compared to patients who do
respond to NSBB.
Although the efficacy of HVPG monitoring in the primary prevention of variceal
hemorrhage is not an issue, international institutions that publish guidelines
differ in their recommendations concerning HVPG monitoring. As a result,
practice currently varies widely.
We hypothesize that HVPG-directed primary prophylaxis leads to a reduction in
first variceal bleeding episodes and is cost-effective in the long term.

To determine cost-effectiveness of hepatic venous pressure gradient
(HVPG)-guided nonselective beta-blocker therapy as compared to standard heart
rate-guided beta-blocker therapy in the primary prevention of esophageal
variceal bleeding in cirrhotic patients.

A multi-center randomized controlled study comparing nonselective beta-blocker
therapy guided by the hemodynamic response as determined by the difference in
HVPG before and after starting oral nonselective beta-blockers, to standard
heart rate-guided nonselective beta-blocker therapy in patients with esophageal
varices due to liver cirrhosis.

-In HVPG-group: Perform baseline HVPG measurement, then start propranonlol 20
mg orally twice daily (BID), increase the dose stepwise with 3 days interval to
decrease the heart rate to maximum tolerated dose. After 4 weeks a second HVPG
is performed.
In hemodynamic responders (HVPG second measurement< 12 mmHg or >10% reduction
in HVPG compared to baseline) beta-blockers are continued until end of
follow-up.
In hemodynamic nonresponders ( who do not reach target decrease in HVPG),
beta-blockers are continued and repeated endocopic band ligation is performed
with 2-4 weeks interval until complete obliteration of large varices.
-In control group: Start propranolol 20 mg BID, increase the dose stepwise with
3 days interval to maximum heart rate-guided tolerated dose.

In the control group standard of care is given.
In the study arm two extra admissions in day-care setting (for 3 h) for HVPG
measurements are required for the study protocol. Hepatic venous pressure
gradient measurement is performed via catheterisation of the internal jugular
vein. Complications due to HVPG measurement are very rare and include
hemorrhage near the insertion place or cardiac arrhythmia during progression of
the catheter through the heart.
In hemodynamic nonresponders from the study arm, repeated endoscopic band
ligation is performed in daycare setting with intervals of 2-4 weeks.
Endoscopic band ligation is standard of care in primary prohylaxis of variceal
hemorrhage in patients who do not tolerate betablockers and is always performed
as secondary prophylaxis. Complication rate of endoscopic bandligation is
approximately 2%, with the most frequent complication hemorrhage from a banding
ulcer or varix.
Patients will visit the outpatient clinic during dose escalation on a weekly
basis until a stable dose is reached. Then a 3 monthly outpatient clinic visit
including physical examination scheme will be followed. The site visits
required for dose escalation and outpatient clinic follow-up are standard of
care.
Patients are requested to complete biannual questionnares, and health VAS.
During the study a total of 200 cc blood will be taken in 9 sessions.