Preventing a first episode of esophageal variceal hemorrhage
ABSTRACTIn patients with esophageal varices, hemorrhage is common and often lethal, so we need to take a proactive approach to preventing a first episode of bleeding. All patients with cirrhosis should undergo endoscopy to look for varices. Depending on the size and appearance of the varices and the patient’s Child-Pugh grade, prophylactic treatment may be indicated.
KEY POINTS
- The hepatic vein pressure gradient (HVPG) correlates well with the portal pressure and is easier to measure. However, whether it is cost-effective to measure the HVPG in clinical practice is controversial.
- Nonselective beta-blockers are the mainstay of treatment; selective beta-blockers do not reduce portal pressure to the same degree and are not recommended for preventing variceal bleeding.
- Endoscopic variceal ligation is an acceptable alternative to beta-blocker therapy for patients who cannot tolerate these drugs and for patients with varices at high risk of bleeding.
- Nitrates are no longer used as monotherapy for preventing variceal hemorrhage, and their use in combination with beta-blockers is controversial. Surgical portal decompression, transjugular intrahepatic portosystemic shunting, and endoscopic sclerotherapy are not recommended.
How to tell if beta-blocker treatment is ‘working’
An HVPG ≤ 12 mm Hg? Studies have shown that the most important predictor of efficacy of prophylaxis for variceal bleeding is a decrease in the HVPG to 12 mm Hg or less or a decrease in the initial HVPG of more than 20%.9 Although measuring the HVPG is invasive, expensive, and not routinely done in clinical practice, several studies have investigated the role of measuring hemodynamic response to medication.
Merkel et al16 measured the HVPG in 49 cirrhotic patients with previously nonbleeding varices before starting therapy with beta-blockers with or without nitrates and after 1 to 3 months of treatment. They followed the patients for up to 5 years. The mean HVPG value at baseline was 18.8 mm Hg. At 3 years of follow-up, 7% of those who had responded well to therapy (defined as achieving an HVPG less than 13 mm Hg or a decrease of more than 20%) had experienced a bleeding episode, which was significantly less than the rate (41%) in those who did not meet those hemodynamic end points. No patient reaching an HVPG of 12 mm Hg or less during treatment had variceal bleeding during follow-up.
Groszmann et al17 also prospectively measured the HVPG in patients with cirrhosis and varices, but their patients received either propranolol or placebo. Variceal hemorrhage occurred in 13 patients (11 of 51 in the placebo group and 2 of 51 in the propranolol group), all of whom had an HVPG greater than 12 mm Hg. Again, none of the patients whose HVPG was decreased to 12 mm Hg or less bled from esophageal varices.
Unfortunately, routine HVPG measurement to guide primary prophylaxis is an expensive strategy. Data suggest that measuring the HVPG is cost-effective only when the cost of measuring the HVPG is very low, the risk of variceal bleeding is very high, or the patient is expected to survive at least 3 to 5 years.18
A heart rate of 55 to 60? An alternative to HVPG measurement to monitor the effectiveness of beta-blocker therapy is to follow the heart rate. A 25% reduction from baseline or a heart rate of 55 to 60 beats per minute is the standard goal19,20; yet, at least 40% of patients treated with enough propranolol to decrease the heart rate by 25% do not respond with significant HVPG reductions.14,21
So, although beta-blockade is effective peripherally, it may not reduce HVPG to less than 12 mm Hg or 20% from baseline, and direct HVPG measurement is still the gold standard.
Treatment should be lifelong
Once a patient is started on a beta-blocker to prevent variceal hemorrhage, the treatment should be lifelong.
In 2001, a group of patients (most of them in Child-Pugh class A or B) completing a prospective randomized controlled trial of propranolol for primary prevention of variceal hemorrhage were tapered off propranolol or placebo.22 Of the 49 patients, 9 experienced variceal hemorrhage (6 of 25 former propranolol recipients and 3 of 24 former placebo recipients), and 17 patients died (12 former propranolol and 5 former placebo recipients), suggesting that treatment should be maintained for life.
Therefore, when beta-blocker therapy is discontinued, the risk of variceal hemorrhage returns to what would be expected in an untreated population.
Beta-blockers may not prevent varices
Although many trials have shown that beta-blockers are effective as prophylaxis against a first variceal hemorrhage, there is no evidence that these drugs prevent varices from forming in cirrhotic patients.
Groszmann et al23 treated more than 200 patients who had biopsy-proven cirrhosis and portal hypertension (HVPG > 6 mm Hg) but no varices with timolol (Blocadren), a nonselective beta-blocker, or placebo. At a median follow-up of about 55 months, the groups did not differ significantly in the incidence of primary events (development of varices or variceal hemorrhage) or treatment failures (transplantation or death). Varices developed less frequently among patients with a baseline HVPG of less than 10 mm Hg and among those whose HVPG had decreased by more than 10% at 1 year. In patients whose HVPG increased by more than 10%, varices developed more frequently.
Contraindications, side effects
The major drawbacks to therapy with beta-blockers are their contraindications and side effects.
Contraindications include chronic obstructive lung disease, psychosis, atrioventricular heart blocks, and aortic-valve disease.
Side effects are reported in 15% of patients but severe events are rare.24 Still, an estimated 10% to 20% of patients discontinue treatment because they cannot tolerate it.25 The more common complaints include fatigue, shortness of breath, sexual dysfunction, and sleep disorders.
Dosage
No specific starting dose of beta-blockers is agreed upon, but nadolol 20 to 40 mg once daily or long-acting propranolol 60 mg once daily can be used as initial therapy.25 Once-daily dosing increases the likelihood of compliance.
Since portal pressure progressively declines from 12 noon to 7 PM and then increases throughout the night and back to baseline by 9 AM,26 we recommend that the medication be taken in the evening to counteract increases in portal pressure that occur in the middle of the night.
