Up to 50% of patients with cirrhosis have esophageal varices at initial endoscopy, and nearly all patients with varices have a high portal pressure, that is, an hepatic venous pressure gradient (HVPG) of 12 mmHg or higher (normal, 3–5). In patients without varices, esophageal varices develop and grow in size at a rate of about 7% per year as a result of ongoing portal hypertension. It has been shown that varices develop at a significantly higher rate in patients with a baseline HVPG above 10 mmHg and in patients in whom the HVPG increases by more than 10% in the first year. Without treatment, varices rupture in about one third of patients, with the highest rates observed in patients with large varices, red wale marks. and/or in Child C patients. In the past, and before the use of drugs, bands, and/or shunts, 4 of 10 patients with acute variceal hemorrhage (AVH) died at 6 weeks, one third rebled at 6 weeks, and only about one third survived beyond 1 year.
This article updates the current use of drugs, bands, and shunts in the different settings—primary prophylaxis, secondary prophylaxis, and the treatment of AVH—and shows how they have altered the natural history of varices and variceal hemorrhage.
Drugs
Most currently used drugs to treat varices and/or variceal hemorrhage cause splanchnic vasoconstriction leading to a reduction in portal venous inflow and consequently to a decrease in portal pressure. Drugs in this category include nonselective β-blockers (NSBB), vasopressin and its analog terlipressin, and somatostatin and its analogs, octreotide and vapreotide. Vasodilators are another type of drugs that can reduce portal pressure through intrahepatic vasodilatation. However, most of the vasodilators currently available, specifically nitrates (which have been the most widely investigated), act not only on the intrahepatic circulation, but also have a potentially deleterious systemic vasodilating effect and seem to reduce portal pressure through reflex splanchnic vasoconstriction that results from hypotension rather than by causing intrahepatic vasodilatation. In fact, a randomized, controlled trial (RCT) of isosorbide mononitrate (ISMN) versus placebo in the prevention of first variceal hemorrhage showed a higher variceal hemorrhage rate in the ISMN group. Therefore, vasodilators used alone are not recommended in the management of portal hypertension, but are used in combination with NSBB when they have a synergistic portal pressure-reducing effect.
NSBB
Propranolol and nadolol are the most commonly used NSBB for the chronic outpatient management of varices/variceal hemorrhage. NSBB act through β-1 and β-2 adrenergic receptor blockade. β-1 Blockade leads to a decrease in portal flow by decreasing cardiac output, whereas β-2 blockade leads to a decrease in portal flow directly by inducing splanchnic vasoconstriction. The latter effect is the most important effect and explains the lack of correlation between the decrease in heart rate induced by NSBB (a β-1 effect) and the decrease in portal pressure. More recently, a role for angiogenesis in the development of portal hypertension in cirrhosis has been described and, interestingly, there is evidence that propranolol has an antiangiogenic effect.
NSBBs lead to a median reduction in HVPG of approximately 15%, with 37% of the patients being hemodynamic “responders”; that is, their HVPG decreases to levels below 12 mmHg and/or is reduced by more than 20% from baseline. Hemodynamic responders have been shown to have a significantly lower incidence of variceal hemorrhage and a significantly better survival. This incidence seems to be similar to that reported for patients treated with shunt therapies [either surgical or transjugular intrahepatic portosystemic shunt (TIPS); Fig. 1 ]. Although it would seem rational to monitor the HVPG response to NSBB and adjust their dose accordingly during the therapy of varices/variceal hemorrhage, HVPG measurements are not standardized or widely used. Therefore, the currently recommended dose of NSBB is the dose that is maximally tolerated by the patient with an ideal heart rate goal of 50 to 55 bpm ( Table 1 ). It has recently been shown that NSBB dose titration performed in a nurse-led clinic results in higher maintenance doses of NSBB and a very low discontinuation rate (5%), lower than that observed in a RCT setting (∼15%).
| Therapy | Starting Dose | Therapy Goals | Maintenance/Follow-up | Comments |
|---|---|---|---|---|
| Propranolol | 20 mg orally twice a day. Adjust every 2–3 days until treatment goal is achieved. Maximal daily dose should not exceed 320 mg. | Maximum tolerated dose. Aim for resting heart rate of 50–55 bpm | At every outpatient visit, make sure that patient is appropriately β-blocked Continue indefinitely. If for primary prophylaxis, no need for follow-up EGD If for secondary prophylaxis, make sure that endoscopic procedures are scheduled. | If for secondary prophylaxis, start in hospital as soon as acute vasoconstrictor (eg, octreotide) is discontinued. |
| Nadolol | 40 mg orally once a day. Adjust every 2–3 days until treatment goal is achieved. Maximal daily dose should not exceed 160 mg. | As for propranolol. | As for propranolol. | As for propranolol. |
| Isosorbide-5-mononitrate | Only to be used in conjunction with propranolol or nadolol. 10 mg orally at night every day. Adjust every 2–3 days by adding 10 mg in the am and then in the pm. Maximal dose is 20 mg twice a day. | Maximal tolerated dose. Systolic blood pressure >95 mmHg. | Continue indefinitely. | Started after patients are on a stable maintenance dose of NSBB. Recommended only for secondary prophylaxis. |
The most common side effects related to NSBB are lightheadedness, fatigue, and shortness of breath and the prospect of experiencing these side effects detract many patients from electing to take NSBB. Additionally, up to 15% of the patients may have relative contraindications (eg, sinus bradycardia, insulin-dependent diabetes) or absolute contraindications (eg, obstructive pulmonary disease, heart failure, aortic valve disease, heart block, peripheral arterial insufficiency) to NSBB.
A recent study suggests that NSBB are associated with a poorer survival in patients with refractory ascites and that NSBB should be contraindicated in this setting. However, the study is retrospective and the groups were disparate at baseline, with patients on NSBB having more advanced disease as shown by a higher prevalence of varices and variceal hemorrhage. Contrary to this finding, in a meta-analysis of NSBB versus placebo for recurrent variceal hemorrhage, sensitivity analysis showed that NSBB were associated with a significant survival benefit in patients with the most severe liver disease. This survival benefit could be explained, at least partially, by the finding that NSBB may lower the risk of spontaneous bacterial peritonitis in patients with cirrhosis and ascites. At this time, and unless stronger evidence arises, the use of NSBB in patients with refractory ascites should not be contraindicated.
NSBB in the prevention of varices
A large, multicenter, double-blind RCT of timolol, an NSBB, versus placebo in patients with cirrhosis and portal hypertension but without varices showed a similar rate of development of varices in both treatment groups with a higher rate of adverse events in the timolol group. Therefore, NSBB are not recommended for the prevention of varices.
Notably, in this very compensated group of patients, treatment of the underlying cause of cirrhosis (alcohol abstention, antiviral therapy) is the mainstay of therapy, because treating the etiology can potentially reduce portal pressure, thereby reducing variceal development.
NSBB in the prevention of first variceal hemorrhage
Overall, NSBB compared with placebo or no active drug decreases the risk of the first episode of variceal hemorrhage (over 2 years) by about 50%. In patients with medium/large varices, who are at the greatest risk of first variceal hemorrhage, propranolol or nadolol significantly reduce the risk of first variceal hemorrhage, from 30% to 14% at a median follow-up of 2 years. Only 11 patients need to be treated to prevent 1 bleeding episode.
Meta-analyses of trials comparing NSBB versus endoscopic variceal ligation (EVL) show that EVL is more effective in preventing first variceal hemorrhage, without differences in mortality. However, meta-analyses restricted to trials with an adequate design or with a sample size greater than 100 show no differences in the rate of first variceal hemorrhage between NSBB and EVL. Therefore, because both therapies seem equal, it has been recommended that the choice should depend on local resources, patient preferences, and presence of contraindications to either therapy.
NSBB have advantages that go beyond the prevention of first variceal hemorrhage. In this setting, reductions in HVPG of only less than 10% to 12% from baseline have been associated with a decrease in the development of ascites, spontaneous bacterial peritonitis, and death. This is not surprising; as these complications result at least partially from portal hypertension. Therefore, it is reasonable to start with NSBB and switch to EVL in cases of intolerance to NSBB.
Patients with small varices with red wale marks or that are present in a Child C patient have the same (or an even greater) risk of hemorrhage than patients with large varices and are therefore considered “high risk.” Because EVL is not feasible in many of these cases, NSBB are the currently recommended therapy. In other patients with small varices, nadolol was shown to significantly decrease progression to large varices and in these patients NSBB could be administered, although this is considered optional. Once patients are started on NSBB, there is no need to perform follow-up endoscopies.
NSBB in the prevention of recurrent variceal hemorrhage
If patients who have recovered from an episode of AVH receive no therapy, the risk of recurrent variceal hemorrhage is very high at around 65% in 1 to 2 years. NSBB significantly reduce the risk of rebleeding, and prolong survival. Only 5 patients need to be treated with a NSBB to prevent 1 rebleeding episode.
The efficacy of NSBB has been shown to correlate with hemodynamic response. In this setting, a reduction in HVPG of more than 20% from the baseline value, or to values of 12 mmHg or lower, is associated with a very low rebleeding rate of approximately 11%, a rate comparable to that associated with shunting therapies ( Fig. 1 ). HVPG-guided therapy cannot yet be recommended in daily practice, not only owing to the lack of standardization of HVPG measurements, but also because of uncertain issues such as the best timing (or need) for repeat HVPG measurement and the best treatment for hemodynamic nonresponders.
The combination of pharmacologic therapy (NSBB with or without ISMN) plus EVL seems to be more effective than either therapy alone ( Fig. 1 ). NSBB plus EVL remains the recommended first-line treatment to prevent recurrent variceal hemorrhage.
As a rule, NSBB should be initiated once variceal hemorrhage is controlled and acute intravenous vasoactive drugs have been discontinued; that is, between 2 and 5 days after the initiation of intravenous therapy.
NSBB Plus Nitrates
In hemodynamic studies, the association of vasodilators such as ISMN or prazosin with NSBB leads to a greater reduction in HVPG (20%–24%) compared with the reduction observed with NSBB alone. However, complications, mainly ascites and/or symptomatic hypotension, occur more frequently with combination therapy. The rate of HVPG responders with NSBB plus ISMN is 44%, a rate that is significantly higher than that observed with NSBB alone (37%). In RCT, a meta-analysis has confirmed a significantly higher number of side effects for NSBB plus ISMN (38%) compared with NSBB alone (23%), with a higher discontinuation rate (15% vs 6%, respectively). Recommended doses of ISMN are shown in Table 1 .
NSBB plus ISMN in the prevention of first variceal hemorrhage
The largest, double-blind RCT comparing propranolol plus placebo versus propranolol plus ISMN showed no differences in the rate of first variceal hemorrhage or mortality between groups. These findings have been confirmed in a recent Cochrane meta-analysis. Therefore, the combination of NSBB plus nitrates is not recommended in the primary prophylaxis of variceal hemorrhage.
NSBB plus nitrates in the prevention of recurrent variceal hemorrhage
A single RCT fully published in English compared propranolol alone versus propranolol plus ISMN and showed, at the end of the study, a borderline significant difference in favor of combination therapy regarding prevention of recurrent variceal hemorrhage ( P = .05). This difference became significant after an additional year of follow-up ( P = .03), without differences in the incidence of overall rebleeding. A recent Cochrane meta-analysis confirms no differences in the rate of overall bleeding or mortality between these therapies, but a borderline lower rate of recurrent variceal hemorrhage in patients on combination NSBB plus nitrates (relative risk, 0.71; 95% confidence interval, 0.52–0.96) and with a higher rate of side effects.
Compared with endoscopic therapy (sclerotherapy or EVL), NSBB plus ISMN show no differences regarding recurrent hemorrhage, but seem to reduce mortality, although this effect was not confirmed in trial sequential analysis. This effect on mortality is consistent with results from one of the studies included in the meta-analysis that shows that, in the long term (82-month follow-up) propranolol plus ISMN is associated with a better survival compared with EVL.
The combination of NSBB with ISMN has similar rates of recurrent hemorrhage compared with EVL alone, whereas the combination of pharmacologic (NSBB alone or NSBB with ISMN) plus EVL has lower rebleeding rates than either therapy alone, consistent with results of a recent meta-analysis and a recent summary of trials. Therefore, the recommended therapy for prevention of recurrent variceal hemorrhage is EVL plus pharmacologic therapy. Because the combination of NSBB and ISMN has more adverse events than NSBB alone and, until a survival advantage of NSBB and ISMN can be confirmed, the recommended pharmacologic therapy to be associated to EVL is NSBB alone.
Parenteral Vasoconstrictors in the Treatment of Acute Variceal Hemorrhage
In the setting of AVH, NSBB are not indicated and have not been tested given their slow action and a potentially deleterious effect blocking the heart rate response to hypovolemia. Intravenously administered splanchnic vasoconstrictors that lower portal pressure acutely are vasopressin (and its analog terlipressin) and somatostatin (and its analogs octreotide and vapreotide). Parenteral vasoconstrictors, particularly if safe, are generally applicable and can be initiated as soon as a diagnosis of variceal hemorrhage is suspected, even before diagnostic esophagogastroduodenoscopy (EGD).
Vasopressin is the most potent splanchnic vasoconstrictor. It reduces blood flow to all splanchnic organs, leading to a decrease in portal venous inflow and a decrease in portal pressure. Unfortunately, the clinical usefulness of vasopressin is limited by its multiple side effects that are related to splanchnic vasoconstriction (eg, bowel ischemia) and to systemic vasoconstriction (eg, hypertension, myocardial ischemia). Combining vasopressin with transdermal glyceryl trinitrate has been shown to reduce some of these side effects. However, because other much safer drugs are now available, vasopressin plus nitroglycerin is only recommended when these are unavailable.
Terlipressin is a synthetic analog of vasopressin that has a longer biological activity and significantly fewer side effects than vasopressin. It is the only vasoconstrictor that has shown a survival benefit when compared with placebo.
Somatostatin and analogs such as octreotide and vapreotide also cause splanchnic vasoconstriction at pharmacologic doses, both through an inhibition of the release of vasodilatory peptides (mainly glucagon) and a local vasoconstrictive effect. Bolus injections of both somatostatin and octreotide cause a marked reduction in portal pressure but, with continuous infusion, only somatostatin seems to maintain a portal hypotensive effect. Somatostatin and its analogs may have an added benefit of decreasing the postprandial (including blood in stomach) elevation in portal pressure. The near absence of side effects of somatostatin and analogs represents a major advantage over other vasoconstrictive agents, allowing them to be administered for a longer period of time.
RCTs comparing different pharmacologic agents demonstrate no differences among them regarding control of hemorrhage and early rebleeding, although vasopressin is associated with more adverse events. In practice, the choice of pharmacologic agent is usually based on availability and cost. Octreotide, a somatostatin analog, is the only safe vasoactive drug available in the United States. Doses and schedules for the different vasoconstrictors are shown in Table 2 .
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