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PHARMACOLOGIC THERAPY OF PORTAL HYPERTENSION AND VARICEAL HEMORRHAGE
1089-3261/97 $0.00
PORTAL HYPERTENSION
+ .20
PHARMACOLOGIC THERAPY OF PORTAL HYPERTENSION AND VARICEAL HEMORRHAGE Norman D. Grace, MD, FACP, FACG, and Kanishka Bhattacharya, MD
NATURAL HISTORY
Development of esophageal varices is a common and potentially life-threatening complication of portal hypertension. In a prospective study of patients with compensated cirrhosis, primarily of alcoholic origin, and no esophageal varices on initial endoscopic examination, 23% of patients developed esophageal varices at 1 year and 50% at 2 years.* Forty-two percent of patients with small varices at the onset of the study progressed to large varices during a mean follow-up of 16 months. In a similar study dealing primarily with patients who had hepatitis C as the cause of cirrhosis, 16% developed varices at 2 years and 30% at 6 years.37Once patients have developed varices, between 25% to 35% will experience an episode of variceal hemorrhage, with the highest risk occurring during the initial year after the diagnosis of v a r i c e ~In . ~patients ~ who survive the initial episode of variceal bleeding, the risk of recurrent bleeding is 30% at 6 weeks and nearly 70% at 1 year.26The mortality for each individual episode of variceal bleeding is between 30% and 50%, depending on the clinical status of the patient. Garceau et all7 reported that 34% of deaths in patients with cirrhosis and esophageal varices were attributable to upper gastrointestinal hemorrhage, with an additional 32% dying from liver failure. Between 10%
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From the Division of Gastroenterology, Faulkner Hospital (NDG, KB); and Tufts University School of Medicine (NDG), Boston, Massachusetts
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and 15% of patients succumb to variceal bleeding within 1 year of diagnosis of esophageal varices. These grim statistics have stimulated considerable interest in the development of therapies for the treatment and prevention of variceal hemorrhage. PHYSIOLOGIC BASIS FOR PHARMACOTHERAPY
Portal pressure is a product of portal venous blood flow and intrahepatic and portocollateral resistance. In patients with cirrhosis, portal hypertension is initiated by an increase in intrahepatic and portocollatera1 resistance, followed by an increase in portal venous blood flow. This increase in flow is initiated by a decrease in systemic vascular resistance as a result of vasodilatation. The increase in hepatic resistance is due to a combination of fixed architectural defects, dynamic effects of humoral factors on perivenular and perisinusoidal stellate cell-derived myofibroblasts, and changes in the smooth muscle component of the portocollateral vessels. Nitric oxide is the humoral agent primarily responsible for the development of this systemic vasodilatation, with glucagon, prostaglandins, tumor necrosis factor (TNF)-a, other cytokenes, and autonomic nervous system dysfunction also playing significant roles. The dynamic component of intrahepatic resistance seems to be modulated by elevated levels of endothelin, a decreased production of nitric oxide, and alterations in circulating levels of angiotensin 11, norepinephrine, and serotonin. The vasodilatation leads to an increase in plasma volume, cardiac output and portal venous blood flow. Pharmacologic therapy is based on the ability to alter the hemodynamics of portal hypertension, either by decreasing portal venous blood flow or decreasing intrahepatic and portocollateral resistance. Two classes of drugs, vasoconstrictors and vasodilators, have been evaluated in animal models and cirrhotic patients. Vasoconstricting agents include vasopressin, somatostatin, somatostatin analogs (octreotide), and nonselective P-adrenergic blockers that act by decreasing splanchnic blood flow. The vasodilating agents include nitroglycerin, long-acting nitrates, prazosin, and serotonin antagonists, ketanserin and ritanserin, which act primarily by altering hepatic and portocollateral resistance. A secondary and less significant mechanism of vasodilators is a reflex splanchnic vasoconstriction secondary to production of peripheral vasodilatation. WHY DO VARICES BLEED?
In patients with alcoholic cirrhosis, a hepatic venous pressure gradient (HVPG) of 12 mmHg or more is necessary for the development of variceal bleeding, although the absolute level of HVPG does not seem to be a significant factor.20Risk factors for initiation of variceal bleeding include the size of varices, the presence of endoscopic red color signs,
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Child's classification, and active alcohol consumption in patients with 13, 51 Prognostic indices using these criteria have alcoholic liver di~ease.~, been able to identify patients at higher risk for variceal hemorrhage, but still miss a significant number of patients who have a lower score but nevertheless experience variceal bleeding.45Estimating variceal wall tension has been evaluated in an attempt to better assess the relationship between variceal size and pressure.41,44, 46 A modification of Laplace's law states that: Variceal wall tension (T)
=
TP(TPl - TP,) X r X w-'
where, TP is the transmural pressure, TP, is the intraluminal pressure in the vessel, TP, is the esophageal intraluminal pressure, r is the radius of the vessel, and w is the wall thickness of the vessel. In portal hypertension, increasing portocollateral flow leads to an increase in TP,, resulting in progressive variceal dilatation with thinning of the variceal wall. When the maximal expanding capacity of the variceal wall is attained, further increases in the radius of the varix precipitate vessel rupture. PREVENTION OF FIRST VARICEAL HEMORRHAGE
Due to the high morbidity and mortality associated with variceal bleeding, therapy that would prevent the initial variceal hemorrhage might be expected to influence survival favorably. This concept prompted surgeons in the 1950s to perform portasystemic shunts to reduce portal pressure in patients with cirrhosis and esophageal varices. Although portacaval shunts were very effective in preventing variceal bleeding, randomized controlled trials (RCTs) demonstrated that they were associated with a high mortality due to an increase in hepatic failure and hepatic encephalopathy, and were therefore unsuitable for prophylactic therapy.'O, 25 In a meta-analysis of 19 RCTs evaluating prophylactic sclerotherapy to obliterate esophageal varices, Pagliaro et a13*used a scoring system to evaluate quality of the design and execution of the RCTs. There was an inverse correlation between the quality of design of the sclerotherapy trials and the reporting of favorable results. Although the meta-analysis showed sclerotherapy to be effective in preventing first variceal hemorrhage and in improving survival, the heterogeneity of the studies and issues of quality of design, especially in some of the more positive studies, have prompted investigators to abandon this technique for prevention of first variceal hemorrhage. PHARMACOLOGIC THERAPY
Although various agents have been shown to reduce portal pressure in animal models, only the effects of nonselective P-adrenergic blockers
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(propranolol, nadolol) and long-acting nitrates (isosorbide-5-mononitrate) have been evaluated in prospective RCTs. There are nine RCTs (seven published articles and two abstracts) comparing propranolol or nadolol to placebo for prevention of first variceal bleeding. A meta-analysis of the seven published studies shows a significant benefit of P-adrenergic blockers in the prevention of initial variceal bleeding ( P < 0.01) (Fig. 1) and a trend toward reduction of mortality ( P = 0.11) (Fig. 2).,, In the analysis of Pagliaro et a1,38all the RCTs received excellent scores for quality of design, and the results are homogeneous. Pooling data from the seven published trials, 16.3% of patients randomized to receive P-blockers developed upper gastrointestinal hemorrhage compared to 27.2% of control patients, a reduction of 40% in the risk of bleeding. Although five of the studies using P-blockers achieved a significant reduction in the incidence of initial variceal bleeding, only the trial by Pascal et a139reported a survival benefit. In a threeway randomization between propranolol, sclerotherapy, or placebo, propranolol was significantly better than either sclerotherapy or placebo in prevention of first variceal bleed, with no differences reported between the latter two groups'; there was a trend toward improved survival in the propranolol group. A four-way randomization between propranolol, sclerotherapy, the combination of propranolol and sclerotherapy, and a control group revealed a similar incidence of variceal bleeding in each
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Figure 1. Randomized, controlled trials of (A) nonselective beta-adrenergic blockers (propranolol and nadolol) versus (5)placebo for the prevention of first variceal hemorrhage. These results are for bleeding from all sites. Results for bleeding from esophageal varices alone are similar. The odds ratio for the group is 0.52; 95% confidence interval, 0.38-0.71 (p
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Pascal Italian
ldeo Lebrec Andreani Conn Prova
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Figure 2. Randomized, controlled trials of (A) nonselective beta-adrenergic blockers (propranolol and nadolol) versus (6)placebo for the prevention of first variceal hemorrhage. For prevention of mortality, odds ratio for the group is 0.75; 95% confidence interval, 0.57-1.03 (p = 0.1 12). (From Grace ND:Management of portal hypertension. Gastroenterologist 1:39,1993; with permission.)
of the four groups; however, survival was slightly better in the propran0101 and control groups when compared to patients treated with sclerotherapy.52Only one of the studies, which was published as an abstract, showed a higher incidence of bleeding in patients treated with propranolo1 when compared to placebo9; however, inclusion of these data in a meta-analysis does not alter the favorable outcome for patients on pblockers. Four of the trials found that patients classified as Child’s B benefited most from beta blocker therapy.l, 11, 28, 39 The study by the Italian Multicenter Project showed a significant benefit only in patients classified as Child’s A.50Lebrec et a131found no difference in the incidence of bleeding events in patients classified as Child’s A or B when compared to their control groups. The trial by the PROVA group did not present data correlating bleeding events with Child’s cla~sification.~~ Only 61 patients classified as Child’s C were included in these trials, a sample size too small to draw conclusions about the usefulness of @-blockersin patients with decompensated ~ i r r h o s i s . ~ ~ The presence of ascites is a well-established risk factor for variceal bleeding. Two of the trials showed @-blockersto be effective in patients with ascites at time of randomization,’l, 28 whereas another found propranolol to be more effective in patients without as cite^.^^ Poynard et a142analyzed four of the European studies and found that @-blockers were effective in preventing first variceal bleeding in patients with a~cites.~~
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Eighty-two percent of patients in these RCTs had large varices at time of entry to the trials. Only three of the trials included patients with small varices, a sample size inadequate to assess the effect of P-blocker therapy in this group of patients.24 Side effects of propranolol were severe enough to warrant discontinuation of therapy in 7%, 119'0, 14%, 17%, and 27% of patients respectively. In those treated with nadolol these figures were 3% and 4%, respectively. Unlike propranolol, nadolol is less lipophilic, is not metabolized by the liver, and does not cross the blood brain barrier. These differences may contribute to nadolol being better tolerated. In patients in whom P-blockers are contraindicated or patients who are unable to take @blockers because of significant side effects, longacting nitrates may be a reasonable alternative. Garcia-Pagan et all8 demonstrated that isosorbide-5-mononitrate given over a 3-month period produced a sustained reduction in HVPG. Angelic0 et a12compared isosorbide-5-mononitrate and propranolol in a controlled trial for prevention of first variceal bleeding and found that both drugs were equally efficacious in the prevention of first gastrointestinal hemorrhage; however, patients with isosorbide-5-mononitrate had less asthenia as a side effect. Another study comparing nadolol plus isosorbide-5-mononitrate with nadolol alone for the prevention of first variceal bleeding reported very few bleeding events in either group of ~atients.3~ There is emerging evidence that the risk of variceal bleeding is strongly related to HPVG. A reduction of HPVG by 20% and especially below 12 mmHg, is important in preventing bleedingz7Garcia-Pagan et all9 showed that the combination of propranolol and isosorbide-5mononitrate resulted in a greater reduction of HVPG than with propran0101 alone. Isosorbide-5-mononitrate achieved a reduction in HVPG in several patients who initially had not responded to propranolol. Vorobioff et a1- similarly demonstrated a greater reduction of HVPG in patients on propranolol and isosorbide dinitrate when compared to patients on propranolol alone. Combination therapy with a P-blocker and a longacting nitrate may benefit patients on P-blocker therapy who do not respond sufficiently to P-blockade, as evidenced by a significant lowering of HVPG. CONTROL OF ACUTE VARICEAL BLEEDING Initial management of acute variceal bleeding includes establishment of adequate venous access, replenishment of blood volume with packed red blood cells and fresh frozen plasma, and intubation to protect the airway in actively bleeding unstable patients. For actively bleeding patients, prophylactic antibiotic therapy may be of value. Pharmacologic treatment with vasoactive drugs may be started in the emergency room while the patient is awaiting endoscopy to determine the source of bleeding. RCTs have shown sclerotherapy to be superior to balloon tampon-
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ade or pharmacologic agents for the initial control of acute esophageal variceal bleeding, with a success rate of 75% to 90?0.~’In an RCT by Burroughs et a1,7 a single session of sclerotherapy controlled variceal bleeding in 62% of patients; two sessions successfully controlled bleeding in 78% of patients, but additional sessions of sclerotherapy were of minimal benefit. Because of the significant local and systemic complications associated with the use of sclerotherapy, pharmacologic treatment may be a reasonable alternative for stable patients with a relatively minor bleeding episode. Although the data are somewhat limited, endoscopic variceal ligation has a success rate similar to sclerotherapy, with far fewer complications. PHARMACOLOGICAGENTS Vasopressin Vasopressin has been used extensively for treatment of acute variceal bleeding. It acts by causing sphlanchnic vasoconstriction, a decrease in portal venous blood flow, and subsequently, a fall in portal venous pressure. RCTs have shown that vasopressin successfully controls acute variceal bleeding in 52% of patients compared to 18% for placebozz; however, its usage is associated with a high rate of recurrent bleeding and with significant complications, including myocardial and peripheral ischemia, bradycardia, hypertension, hyponatremia, and fluid retention. Moreover, the RCTs evaluating vasopressin did not demonstrate improvement in survival. Vasopressin Plus Nitroglycerin The addition of nitroglycerin to vasopressin has ameliorated many of the vasoconstrictive side effects of vasopressin. A meta-analysis of three controlled trials showed that vasopressin plus nitroglycerin was superior to vasopressin alone for the control of acute variceal bleeding12; however, Teres et a149reported better control of variceal bleeding with balloon tamponade compared to vasopressin and nitroglycerin. Nitroglycerin can be given sublingually, transdermally, or intravenously. Of these, the intravenous route is preferable as the dose can be titrated more easily. Somatostatin/Octreotide RCTs have demonstrated somatostatin to be superior to a placebo in one of two trials, superior to vasopressin, and comparable to glypressin, balloon tamponade, and sclerotherapy for control of acute variceal hemorrhage.” Although somatostatin was well tolerated with very few side
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effects, its use was not associated with any significant improvement in survival. Octreotide, a synthetic analogue of somatostatin, has a longer halflife (1.5 hours), but its effectiveness in reducing portal pressure remains in question. A recent study reported rapid tachyphylaxis developing after an initial bolus dose followed by intravenous infusion of octreotide, with failure to maintain an initial reduction in the HVPG."' Octreotide for the control of acute variceal bleeding has been found comparable to vasopressin, glypressin (triglycyl-lysine vasopressin) plus nitroglycerin, balloon tamponade, and sclerotherapy, but the sample size in most of these studies was ~ma11.l~ A recent six-center trial failed to find octreotide more effective than a placebo for the control of acute variceal bleeding and the prevention of rebleeding with or without the concomitant use of sclerotherapy?O Octreotide may have some benefit when used in combination with sclerotherapy for the control of acute variceal bleeding, although the results from RCTs are mixed.6,43 One trial found comparable control of acute variceal bleeding, but less rebleeding when octreotide was combined with endoscopic variceal ligation compared to variceal ligation alone>*Despite the equivocal data for the efficacy of octreotide, it has become the most widely used pharmacologic agent in the United States for the control of acute variceal bleeding. Glypressin (Terlipressin)
Glypressin is a long-acting, relatively inert analogue of vasopressin that can be given as a bolus. In vivo it is gradually activated with cleavage of its N-terminal glycyl residue. This slow release of the active component has been associated with lower blood levels and fewer side effects when compared to a continuous infusion of vasopressin. RCTs have shown glypressin to be superior to a placebo or vasopressin and comparable to somatostatin or balloon tamponade for the control of acute variceal hemorrhage.12In one use of glypressin was associated with a significant survival benefit. In a double-blind study that evaluated the prehospital use of glypressin combined with glyceral trinitrate initiated at the patient's home or during transfer to the emergency room, pharmacologic therapy showed a reduction in mortality.32 These promising results, coupled with the lower incidence of side effects, makes glypressin an attractive substitute for vasopressin. In Europe, it has become a widely used pharmacologic agent for control of acute variceal hemorrhage; however, its use in the United States has not yet been approved by the Food and Drug Administration. Miscellaneous Drugs
Metoclopramide, domperidone, and pentagastrin have been reported to decrease azygos blood flow and also reduce blood flow in the
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distal esophagus submucosal venous plexus. Hoskins et a1 demonstrated metoclopramide to be superior to placebo in a small controlled study;27a however, this beneficial effect is yet to be corroborated by large trials. Pharmacologic or endoscopic therapy is successful in controlling bleeding in 75% to 90% of patients; however, for patients who do not respond to either form of therapy, alternative treatment should be sought. The most commonly used rescue procedure is the transjugular intrahepatic portosystemic shunt (TIPS). Alternative therapies include esophageal staple transection, surgical shunts, and liver transplantation for appropriate candidates. PREVENTION OF RECURRENT VARICEAL BLEEDING The risk of recurrent variceal hemorrhage in patients successfully treated for acute variceal hemorrhage approaches 70%, making it essential that all patients receive therapy to prevent rebleeding. Nonselective P-adrenergic blockers, sclerotherapy and endoscopic variceal ligation have all been shown to be effective in reducing the risk of recurrent variceal hemorrhage. PHARMACOLOGIC THERAPY Eleven RCTs have compared propranolol or nadolol to a placebo or no treatment for prevention of variceal rebleeding. Meta-analyses of the trials have demonstrated that p-adrenergic blockers are highly effective in reducing the risk of recurrent variceal hemorrhage (Fig. 3).5Pooling the data from these trials reveals that the risk of recurrent variceal bleeding was reduced from 65.9% in controls to 44.7% in patients on padrenergic blocker therapy, a 32% reduction in the risk of bleeding. Although (3-adrenergic blockers significantly reduced the risk of rebleeding, their effect on mortality is more controversial. Using the Mantel-Haentzel-Pet0 method, D'Amico et all2 report an odds ratio of 0.70 (0.48-1.02 95% CI) in favor of nonselective p-blockers for mortality rate, which is not quite statistically significant. The odds ratio does not change when the two papers published in abstract only are excluded (Fig. 4); however, using different statistical methodology (Der Simonian stratified meta-analysis), Bernard et a15 found a significant survival advantage for patients treated with (3-blockers. They report a relative risk of death of 1.27 for patients not receiving (3-blocker therapy, and they estimate that 14 patients need to be treated to prevent one death. The meta-analysis by D'Amico et a1 included only the 11 RCTs whereas Bernard et a15 included a 12th studyI4 that was not clearly randomized. Regardless of the statistical methodology used, it is clear that P-blocker therapy decreases the risk of recurrent variceal bleeding and probably offers a modest survival benefit. As relatively few patients with decompensated (Child's C ) cirrhosis
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Figure 3. Randomized, controlled trials of patients treated with (A) nonselective betaadrenergic blockers (propranolol, nadolol) compared with a (6)placebo for the prevention of recurrent gastrointestinal bleeding related to portal hypertension (all sites). Odds ratio for the group is 0.40; 95% confidence interval, 0.29-to 0.57 (P
were included in these trials, p-blocker therapy should be reserved for patients classified as Child’s A or a stable Child’s B. The time interval between the index bleed and initiation of therapy in these trials ranged from 12 hours to 21 days. As shown by Graham et a1,2‘jthe highest risk for rebleeding occurs within the first 2 weeks after the index bleed. Therefore, a delay in initiation of therapy could miss the group of patients with the highest risk. Although p-blocker therapy has been associated with side effects, including dyspnea, asthma, depression, bradycardia, headaches, and impotence, use of p-blockers in these trials was reasonably well tolerated. Initial concerns about development of hepatic encephalopathy and renal failure did not materialize. For patients who cannot tolerate or have contraindications to p-blocker therapy, long-acting nitrates might be a reasonable alternative, although more studies are needed to verify their efficacy. SCLEROTHERAPY VERSUS @-ADRENERGIC BLOCKERS ALONE OR IN COMBINATION WITH NITRATES
Eight published RCTs have compared the efficacy of sclerotherapy and propranolol in preventing variceal rebleeding; six of the trials
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Odds Ratio Figure 4. Randomized, controlled trials of patients treated with (A) nonselective betaadrenergic blockers (propranolol, nadolol) compared with a (6)placebo for the prevention of mortality. The odds ratio is 0.74; 95% confidence interval, 0.50-1.09 (P=O.124). (From Grace ND: Nonsurgical therapy of hemorrhage from esophageal varices. In Conn HO, Palmaz JC, Rosch J, Rossle M (eds): TIPS: Transjugular lntrahepatic Portasystemic Shunts. New York, Igaku-Shoin 1996, p 28; with permission.)
showed comparable efficacy in the prevention of recurrent variceal bleeding, whereas two favored sclerotherapy. None of the trials demonstrates a significant survival advantage for either therapy. Although a meta-analysis of the RCTs favors sclerotherapy for the prevention of recurrent variceal bleeding,12the marked heterogeneity among the studies, the differences in patient population, severity of disease, and technical aspects make it difficult to recommend one therapy over the other. In general, P-blocker therapy may be preferable for patients with compensated cirrhosis whereas endoscopic therapy might be used in less compliant patients or patients with decompensated cirrhosis. As discussed in the article by Slosberg and Keefe, endoscopic variceal ligation has been shown to be superior to sclerotherapy for prevention of recurrent variceal bleeding. Villanueva et a153compared a combination of nadolol and isosorbide mononitrate to sclerotherapy for prevention of variceal rebleeding. Nadolol and isosorbide mononitrate significantly decreased the risk of rebleeding from esophageal varices when compared to sclerotherapy, and was associated with a survival benefit just short of statistical significance ( P = 0.07).
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COMBINED SCLEROTHERAPY AND P-ADRENERGIC BLOCKERS
In seven published RCTs a combination of propranolol (often given only until varices have been obliterated by sclerotherapy) and sclerotherapy was compared with sclerotherapy alone for the prevention of recurrent variceal bleeding.12 In three of these studies the combination was found to be more effective, whereas in the remaining four the results were similar. In none of these trials was an improvement in survival reported. In two RCTs the combination of propranolol and sclerotherapy was compared to propranolol given alone. One of the studies demonstrated a significant benefit for the combination of propranolol and sclerotherapy in reducing variceal rebleeding,36whereas the other study showed a favorable trend for combined therapy.29Although further trials, especially with longer follow-up periods, are necessary to properly assess the benefits of combination therapy, the data available so far seem to support the use of combination endoscopic and pharmacologic therapy. PORTAL GASTROPATHY AND GASTRIC VARICES Portal gastropathy and gastric varices remain less common but important causes of bleeding in patients with portal hypertension. There are very few RCTs evaluating treatment, and most of the current regimens used are derived from anecdotal evidence or are extrapolated from trials on the management of esophageal varices; however, as portal gastropathy and gastric varices are consequences of portal hypertension, drugs that reduce HVPG should have a beneficial effect. In a singleblind randomized trial propranolol has been shown to reduce bleeding in both acute and chronic portal g a ~ t r o p a t h yVasoactive .~~ drugs like somatostatin and glypressin have been found to be effective in acute gastric variceal bleeding. THE ROLE OF HEMODYNAMIC MEASUREMENTS AND VARICEAL BLEEDING An HVPG of 12 mmHg or more is necessary for the formation and subsequent bleeding of esophageal varices. Over the last few years there has been increasing evidence that HVPG is one of the most important tests predicting the risk of recurrent variceal bleeding and survival in patients with portal hypertension. Analyzing the hemodynamic events in a prospective randomized trial of propranolol versus placebo in prevention of first variceal hemorrhage, Groszmann et alZ7found that none of the 21 patients in whom the initially elevated HVPG had decreased to 12 mmHg or less bled from the varices. They concluded that reduction of HVPG to less than 12 mmHg protects patients from
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variceal bleeding and prolongs survival. In assessing the relation between portal pressure response to pharmacotherapy and risk of recurrent variceal hemorrhage in patients with cirrhosis, Feu et all6 found that patients in whom the HPVG fell to 12 mmHg or less were completely protected from the risk of rebleeding. They also found that a reduction in HVPG of more than 20% of baseline was associated with significant reduction of recurrent variceal hemorrhage. In an RCT comparing the combination of nadolol and isosorbide-5-mononitrate to sclerotherapy for prevention of variceal rebleeding, Villanueva et a153also found that bleeding was significantly reduced when the HVPG decreased by 20% or more and did not recur in any patient in whom a follow-up HVPG was below 12 mmHg. Merkel et a134found that HVPG was significantly higher in patients with cirrhosis and esophageal varices who bled during follow-up than in those who did not. They concluded that HVPG measurements were as important as Child-Pugh score in prognosticating variceal bleeding. Studies by Merkel et al?* Gluud et a1,2l and Barrett et aP also found the HVPG to have prognostic significance for survival in patients with cirrhosis and esophageal varices. Hemodynamic measurements have become more than a research tool and can be very useful for monitoring effectiveness of therapy. SUMMARY AND CONCLUSION
Patients with large esophageal varices who are deemed compliant and have no contraindications to P-blocker therapy should be started on nonselective P-adrenergic blockers (Fig. 5). The dose should be titrated to a 25% decrease in resting heart rate, a resting heart rate of 55 to 60 beats per minute, or development of symptoms, in which case the dose should be decreased until the patient's symptoms abate. If available, measurements of the HVPG at baseline and 3 months can be very helpful in ascertaining the response to treatment and in making the appropriate adjustments (e.g., adding a second drug). Sclerotherapy or endoscopic variceal ligation are the preferred therapies for treatment of acute esophageal variceal bleeding. Concomitant use of vasoactive drugs can supplement endoscopic treatment. They offer the advantage of early administration as soon as the diagnosis is suspected while awaiting endoscopy. Unlike endoscopic treatment, they decrease portal pressure and are the only established treatment for nonvariceal sources of bleeding related to portal hypertension. Once the index bleed is controlled, the patient should be started on treatment to reduce the high risk of recurrent variceal hemorrhage (Fig. 6). For patients with well-compensated cirrhosis, pharmacologic therapy may be desirable. For less compliant patients or patients with decompensated cirrhosis, an endoscopic technique, such as variceal ligation, may be preferable. Combinations of pharmacologic agents or pharmacologic agents and endoscopic procedures may offer hope for better control, but their efficacy needs to be demonstrated in RCTs. For patients who
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Cirrhosis (Small Esophageal Esophageal
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Figure 5. Algorithm for prevention of initial variceal hemorrhage for patients with cirrhosis and esophageal varices.
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Figure 6. Algorithm for prevention of recurrent variceal hemorrhage in patients with cirrhosis and prior variceal bleeding episode.
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rebleed despite maximal pharmacologic or endoscopic therapy, a TIPS procedure, surgically created shunt, or liver transplantation should be considered, with the decision based on the patient's condition and the local availability of these options.
References 1. Andreani T, Poupon RE, Balkau B, et al: Preventive therapy of first gastrointestinal bleeding in patients with cirrhosis: Results of a controlled trial comparing proprano101, endoscopic sclerotherapy and placebo. Hepatology 12:1413-1419, 1990 2. Angelic0 M, Carli R, l'iat C, et al: Isosorbide-5-mononitrateversus propranolol in the prevention of first bleeding in cirrhosis. Gastroenterology 104:1460-1465, 1993 3. Barret G, Bosch J, Garcia-Tsao G, et al: Hepatic venous pressure gradient as a predictor of survival in patients with cirrhosis. Hepatology 122350, 1990 4. Beppu K, Inokuchi K, Koyanagi N, et al: Prediction of variceal hemorrhage by esophageal endoscopy. Gastrointest Endosc 27213-218, 1981 5. Bernard B, Lebrec D, Mathurin P, et al: Beta-adrenergic antagonists in the prevention of gastrointestinal rebleeding in patients with cirrhosis: A meta-analysis. Hepatology 25~63-70,1997 6. Besson I, Ingrand P, Person B, et al: Sclerotherapy with or without octreotide for acute variceal bleeding. N Engl J Med 333:555-560, 1995 7. Burroughs AK, Hamilton G, Phillips A, et al: A comparison of sclerotherapy with staple transection of the esophagus for the emergency control of bleeding from esophageal varices. N Engl J Med 32L857-862, 1989 8. Cales P, Desmorat H, Vine1 Jl',et a1 Incidence of large oesophageal varices in patients with cirrhosis: Application to prophylaxis of first bleeding. Gut 31:1298-1302, 1990 9. Colman J, Jones P, Finch C, et al: Propranolol in the prevention of variceal hemorrhage in alcoholic cirrhotic patients. Hepatology 12:851, 1990 10. Conn H O The rational evaluation and management of portal hypertension. In Schaffner F, Sherlock S, Leevy CM (eds): The Liver and Its Diseases. New York, Intercontinental, 1974, pp 289-306 11. Conn HO, Grace ND, Bosch J, et al: Propranolol in the prevention of the first hemorrhage from esophageal varices: Results of a randomized double blind cooperative clinical trial. Hepatology 13:902-912, 1991 12. DAmico G, Pagliaro L, Bosch J: The treatment of portal hypertension: A metaanalytic review. Hepatology 22332-354, 1995 13. Dagradi AE: The natural history of esophageal varices in patients with alcoholic liver cirrhosis: An endoscopic and clinical study. Am J Med 5752&540,1972 14. Escorsell A, Bandi JC, Francois E, et al: Desensitation of the effects of intravenous octreotide in cirrhotic patients with portal hypertension. Hepatology 24207A, 1996 15. Feu F, DAmico G, Bosch J: The acute bleeding episode: Advances in drug therapy. In Arroyo V, Bosch J, Rodes J (eds): Treatments in Hepatology. Barcelona, Masson SA, 1995, p 9 16. Feu F, Garcia-Pagan JC, Bosch J, et al: Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet 346:105&1059, 1995 17. Garceau AJ, Chalmers TC, The Boston Inter-Hospital Liver Group: The natural history of cirrhosis: I. Survival with esophageal varices. N Engl J Med 268:469-473, 1963 18. Garcia-Pagan JC, Feu F, Navasa M, et al: Long-term haemodynamic effects of isosorbide 5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol 11~189-195,1990 19. Garcia-Pagan JC, Navasa M, Bosch J, et al: Enhancement of portal pressure reduction by the association of isosorbide-5-mononitrate to propranolol administration in patients with cirrhosis. Hepatology 11:230-238, 1990
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20. Garcia-Tsao G, Groszmann RJ, Fisher RL, et a1 Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 5:419424, 1985 21. Gluud C, Henriksen JH, Nielsen G: Prognostic indicators in alcoholic cirrhotic men. Hepatology 8222-227, 1988 22. Grace ND: Variceal hemorrhage: Pharmacologic approach. In McDermott WV, Bothe A (eds): Surgery of the Liver. Boston, Blackwell Scientific Publications, 1988, pp 303'314
I _ -
23. Grace ND: Management of portal hypertension. The Gastroenterologist 1:39-58, 1993 24. Grace N D Pharmacological prevention of variceal hemorrhage. In Arroyo V, Bosch J, Rodes J (eds): Treatment in Hepatology. Barcelona, Masson SA, 1995, p 23 25. Grace ND, Muench H, Chalmers TC: The present status of shunts for portal hypertension in cirrhosis. Gastroenterology 50:684-691, 1966 26. Graham D, Smith JL: The course of patients after variceal hemorrhage. Gastroenterology 80:800-809, 1981 27. Groszmann RJ, Bosch J, Grace ND, et a1 Hernodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 99:1401-1407, 1990 27a. Hosking SW, Doss W, El-Zeiny H, et al: Pharmacologic constriction of the lower esophageal sphincter: A simple method of arresting variceal hemorrhage. Gut 29:1098-1102, 1988 28. Ideo G, Bellati G, Fesce E, et al: Nadolol can prevent the first gastrointestinal bleeding in cirrhosis: A prospective, randomized study. Hepatology 8:6-9, 1988 29. Ink 0, Martin T, Poynard T, et a1 Does elective sclerotherapy improve the efficacy of long-term propranolol for prevention of recurrent bleeding in patients with severe cirrhosis: A prospective multicenter, randomized trial. Hepatology 16:912-919, 1992 30. International Octreotide Varices Study Group: Double blind RCT of 5 day octreotide versus placebo, associated with sclerotherapy for trial/failures. Hepatology 24:352A, 1996 31. Lebrec D, Poynard T, Capron JP, et al: Nadolol for prophylaxis of gastrointestinal bleeding in patients with cirrhosis: A randomized trial. J Hepatology 7118-125, 1988 32. Levacher S, Letoumelin P, Pateron D, et a1 Early administration of terlipressin plus glyceryl trinitrate to control active upper gastrointestinal bleeding in cirrhotic patients. Lancet 346:865-868, 1995 33. Lopes GM, Grace N D Gastroesophageal varices: Prevention of bleeding and rebleeding. Gastroenterol Clin North Am 22:801-820, 1993 34. Merkel C, Bolognesi M, Bellon S, et al: Prognostic usefulness of hepatic vein catheterization in patients with cirrhosis and esophageal varices. Gastroenterology 102973979, 1992 35. Merkel C , Gatta A, Amodio P, et a1 Nadolol or nadolol plus isosorbide-5-mononitrate in the prophylaxis of first variceal bleeding in patients with cirrhosis: Interim analysis of a multicenter study. J Hepatol 8:S147-S148, 1993 36. O'Connor KW, Lehman G, Yune H, et a1 Comparison of three nonsurgical treatments for bleeding esophageal varices. Gastroenterology 96:899-906, 1989 37. Pagliaro L, DAmico G, Pasta L, et a1 Portal hypertension in cirrhosis: Natural history. In Bosch J, Groszmann RJ (eds): Portal Hypertension: Pathophysiology and Treatment. Oxford, Blackwell Scientific Publications, 1994, p 72 38. Pagliaro L, DAmico G, Sorensen TIA, et a1 Prevention of first bleeding in cirrhosis: A meta-analysis of randomized trials of nonsurgical treatment. Ann Intern Med 11759-70, 1992 39. Pascale JP, Cales P, A Multicenter Study Group: Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 317856-861, 1987 40. Perez-Ayuso R, Pique JP, Bosch J, et al: Propranolol in prevention of recurrent bleeding from severe portal hypertensive gastropathy in cirrhosis. Lancet 33714311434, 1991 41. Polio J, Groszmann RJ: Hernodynamic factors in the development and rupture of esophageal varices: A pathophysiologic approach to treaGent. Semin Liver Dis 6:318, 1986
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42. Poynard T, Cales P, Pasta L, et al: Beta-adrenergic-antagonistdrugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices: An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. N Engl J Med 324:1532-1538, 1991 43. Primignani M, Andreoni B, Carpinelli L, et al: Sclerotherapy plus octreotide versus sclerotherapy alone in the prevention of early rebleeding from esophageal varices: A randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 21:13221327, 1995 44. Rigau J, Bosch J, Bordas JM, et al: Endoscopic measurement of variceal pressure in cirrhosis: Correlation with portal pressure and variceal hemorrhage. Gastroenterology 96:873-880, 1989 45. Rig0 GP, Merighi A, Chalen NJ, et al: A prospective study of the ability of three endoscopic classifications to predict hemorrhage from esophageal varices. Gastrointest Endosc 38425429, 1992 46. Rodriguez-Perez F, Groszmann RJ: Pharmacologic treatment of portal hypertension. Gastroenterol Clin North Am 21:15-40, 1993 47. Soderlund C, Magnusson I, Torngren S, et a1 Terlipressin (triglycyl-lysine vasopressin) controls acute bleeding oesophageal varices. A double-blind randomized, placebo-controlled trial. Scand J Gastroenterol 25:622430, 1990 48. Sung JJY, Chung SCS, Yung MY, et al: Prospective randomized study of effect of octreotide on rebleeding from oesophageal varices after endoscopic ligation. Lancet 346:1666-1669, 1995 49. Teres J, Planas R, Panes J, et al: Vasopressin/nitroglycerin infusion vs. esophageal tamponade in the treatment of acute variceal bleeding: A randomized controlled trial. Hepatology 11:964-968, 1990 50. The Italian Multicenter Project for Propranolol in Prevention of Bleeding: Propranolol prevents first gastrointestinal bleeding in nonascitic cirrhotic patients: Final report of a multicenter randomized trial. J Hepatology 9:75-83, 1989 51. The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices: Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices: A prospective multicenter study. N Engl J Med 319:983-989, 1988 52. The PROVA Study group: Prophylaxis of first hemorrhage from esophageal varices by sclerotherapy, propranolol or both in cirrhotic patients: A randomized multicenter trial. Hepatology 14:1016-1024, 1991 53. Villanueva C, Balanzo J, Novella MT, et a1 Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding. N Engl J Med 334:1624-1629, 1996 54. Vorobioff J, Picabea E, Gamen M, et a1 Propranolol compared with propranolol plus isosorbide dinitrate in portal-hypertensive patients: Long-term hemodynamics and renal effects. Hepatology 18:477-484, 1993 Address reprint requests to Norman D. Grace, MD Division of Gastroenterology Faulkner Hospital 1153 Centre Street Boston, MA 02130-3446
PORTAL HYPERTENSION
+ .20
PHARMACOLOGIC THERAPY OF PORTAL HYPERTENSION AND VARICEAL HEMORRHAGE Norman D. Grace, MD, FACP, FACG, and Kanishka Bhattacharya, MD
NATURAL HISTORY
Development of esophageal varices is a common and potentially life-threatening complication of portal hypertension. In a prospective study of patients with compensated cirrhosis, primarily of alcoholic origin, and no esophageal varices on initial endoscopic examination, 23% of patients developed esophageal varices at 1 year and 50% at 2 years.* Forty-two percent of patients with small varices at the onset of the study progressed to large varices during a mean follow-up of 16 months. In a similar study dealing primarily with patients who had hepatitis C as the cause of cirrhosis, 16% developed varices at 2 years and 30% at 6 years.37Once patients have developed varices, between 25% to 35% will experience an episode of variceal hemorrhage, with the highest risk occurring during the initial year after the diagnosis of v a r i c e ~In . ~patients ~ who survive the initial episode of variceal bleeding, the risk of recurrent bleeding is 30% at 6 weeks and nearly 70% at 1 year.26The mortality for each individual episode of variceal bleeding is between 30% and 50%, depending on the clinical status of the patient. Garceau et all7 reported that 34% of deaths in patients with cirrhosis and esophageal varices were attributable to upper gastrointestinal hemorrhage, with an additional 32% dying from liver failure. Between 10%
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and 15% of patients succumb to variceal bleeding within 1 year of diagnosis of esophageal varices. These grim statistics have stimulated considerable interest in the development of therapies for the treatment and prevention of variceal hemorrhage. PHYSIOLOGIC BASIS FOR PHARMACOTHERAPY
Portal pressure is a product of portal venous blood flow and intrahepatic and portocollateral resistance. In patients with cirrhosis, portal hypertension is initiated by an increase in intrahepatic and portocollatera1 resistance, followed by an increase in portal venous blood flow. This increase in flow is initiated by a decrease in systemic vascular resistance as a result of vasodilatation. The increase in hepatic resistance is due to a combination of fixed architectural defects, dynamic effects of humoral factors on perivenular and perisinusoidal stellate cell-derived myofibroblasts, and changes in the smooth muscle component of the portocollateral vessels. Nitric oxide is the humoral agent primarily responsible for the development of this systemic vasodilatation, with glucagon, prostaglandins, tumor necrosis factor (TNF)-a, other cytokenes, and autonomic nervous system dysfunction also playing significant roles. The dynamic component of intrahepatic resistance seems to be modulated by elevated levels of endothelin, a decreased production of nitric oxide, and alterations in circulating levels of angiotensin 11, norepinephrine, and serotonin. The vasodilatation leads to an increase in plasma volume, cardiac output and portal venous blood flow. Pharmacologic therapy is based on the ability to alter the hemodynamics of portal hypertension, either by decreasing portal venous blood flow or decreasing intrahepatic and portocollateral resistance. Two classes of drugs, vasoconstrictors and vasodilators, have been evaluated in animal models and cirrhotic patients. Vasoconstricting agents include vasopressin, somatostatin, somatostatin analogs (octreotide), and nonselective P-adrenergic blockers that act by decreasing splanchnic blood flow. The vasodilating agents include nitroglycerin, long-acting nitrates, prazosin, and serotonin antagonists, ketanserin and ritanserin, which act primarily by altering hepatic and portocollateral resistance. A secondary and less significant mechanism of vasodilators is a reflex splanchnic vasoconstriction secondary to production of peripheral vasodilatation. WHY DO VARICES BLEED?
In patients with alcoholic cirrhosis, a hepatic venous pressure gradient (HVPG) of 12 mmHg or more is necessary for the development of variceal bleeding, although the absolute level of HVPG does not seem to be a significant factor.20Risk factors for initiation of variceal bleeding include the size of varices, the presence of endoscopic red color signs,
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Child's classification, and active alcohol consumption in patients with 13, 51 Prognostic indices using these criteria have alcoholic liver di~ease.~, been able to identify patients at higher risk for variceal hemorrhage, but still miss a significant number of patients who have a lower score but nevertheless experience variceal bleeding.45Estimating variceal wall tension has been evaluated in an attempt to better assess the relationship between variceal size and pressure.41,44, 46 A modification of Laplace's law states that: Variceal wall tension (T)
=
TP(TPl - TP,) X r X w-'
where, TP is the transmural pressure, TP, is the intraluminal pressure in the vessel, TP, is the esophageal intraluminal pressure, r is the radius of the vessel, and w is the wall thickness of the vessel. In portal hypertension, increasing portocollateral flow leads to an increase in TP,, resulting in progressive variceal dilatation with thinning of the variceal wall. When the maximal expanding capacity of the variceal wall is attained, further increases in the radius of the varix precipitate vessel rupture. PREVENTION OF FIRST VARICEAL HEMORRHAGE
Due to the high morbidity and mortality associated with variceal bleeding, therapy that would prevent the initial variceal hemorrhage might be expected to influence survival favorably. This concept prompted surgeons in the 1950s to perform portasystemic shunts to reduce portal pressure in patients with cirrhosis and esophageal varices. Although portacaval shunts were very effective in preventing variceal bleeding, randomized controlled trials (RCTs) demonstrated that they were associated with a high mortality due to an increase in hepatic failure and hepatic encephalopathy, and were therefore unsuitable for prophylactic therapy.'O, 25 In a meta-analysis of 19 RCTs evaluating prophylactic sclerotherapy to obliterate esophageal varices, Pagliaro et a13*used a scoring system to evaluate quality of the design and execution of the RCTs. There was an inverse correlation between the quality of design of the sclerotherapy trials and the reporting of favorable results. Although the meta-analysis showed sclerotherapy to be effective in preventing first variceal hemorrhage and in improving survival, the heterogeneity of the studies and issues of quality of design, especially in some of the more positive studies, have prompted investigators to abandon this technique for prevention of first variceal hemorrhage. PHARMACOLOGIC THERAPY
Although various agents have been shown to reduce portal pressure in animal models, only the effects of nonselective P-adrenergic blockers
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(propranolol, nadolol) and long-acting nitrates (isosorbide-5-mononitrate) have been evaluated in prospective RCTs. There are nine RCTs (seven published articles and two abstracts) comparing propranolol or nadolol to placebo for prevention of first variceal bleeding. A meta-analysis of the seven published studies shows a significant benefit of P-adrenergic blockers in the prevention of initial variceal bleeding ( P < 0.01) (Fig. 1) and a trend toward reduction of mortality ( P = 0.11) (Fig. 2).,, In the analysis of Pagliaro et a1,38all the RCTs received excellent scores for quality of design, and the results are homogeneous. Pooling data from the seven published trials, 16.3% of patients randomized to receive P-blockers developed upper gastrointestinal hemorrhage compared to 27.2% of control patients, a reduction of 40% in the risk of bleeding. Although five of the studies using P-blockers achieved a significant reduction in the incidence of initial variceal bleeding, only the trial by Pascal et a139reported a survival benefit. In a threeway randomization between propranolol, sclerotherapy, or placebo, propranolol was significantly better than either sclerotherapy or placebo in prevention of first variceal bleed, with no differences reported between the latter two groups'; there was a trend toward improved survival in the propranolol group. A four-way randomization between propranolol, sclerotherapy, the combination of propranolol and sclerotherapy, and a control group revealed a similar incidence of variceal bleeding in each
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Figure 1. Randomized, controlled trials of (A) nonselective beta-adrenergic blockers (propranolol and nadolol) versus (5)placebo for the prevention of first variceal hemorrhage. These results are for bleeding from all sites. Results for bleeding from esophageal varices alone are similar. The odds ratio for the group is 0.52; 95% confidence interval, 0.38-0.71 (p
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Pascal Italian
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Figure 2. Randomized, controlled trials of (A) nonselective beta-adrenergic blockers (propranolol and nadolol) versus (6)placebo for the prevention of first variceal hemorrhage. For prevention of mortality, odds ratio for the group is 0.75; 95% confidence interval, 0.57-1.03 (p = 0.1 12). (From Grace ND:Management of portal hypertension. Gastroenterologist 1:39,1993; with permission.)
of the four groups; however, survival was slightly better in the propran0101 and control groups when compared to patients treated with sclerotherapy.52Only one of the studies, which was published as an abstract, showed a higher incidence of bleeding in patients treated with propranolo1 when compared to placebo9; however, inclusion of these data in a meta-analysis does not alter the favorable outcome for patients on pblockers. Four of the trials found that patients classified as Child’s B benefited most from beta blocker therapy.l, 11, 28, 39 The study by the Italian Multicenter Project showed a significant benefit only in patients classified as Child’s A.50Lebrec et a131found no difference in the incidence of bleeding events in patients classified as Child’s A or B when compared to their control groups. The trial by the PROVA group did not present data correlating bleeding events with Child’s cla~sification.~~ Only 61 patients classified as Child’s C were included in these trials, a sample size too small to draw conclusions about the usefulness of @-blockersin patients with decompensated ~ i r r h o s i s . ~ ~ The presence of ascites is a well-established risk factor for variceal bleeding. Two of the trials showed @-blockersto be effective in patients with ascites at time of randomization,’l, 28 whereas another found propranolol to be more effective in patients without as cite^.^^ Poynard et a142analyzed four of the European studies and found that @-blockers were effective in preventing first variceal bleeding in patients with a~cites.~~
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Eighty-two percent of patients in these RCTs had large varices at time of entry to the trials. Only three of the trials included patients with small varices, a sample size inadequate to assess the effect of P-blocker therapy in this group of patients.24 Side effects of propranolol were severe enough to warrant discontinuation of therapy in 7%, 119'0, 14%, 17%, and 27% of patients respectively. In those treated with nadolol these figures were 3% and 4%, respectively. Unlike propranolol, nadolol is less lipophilic, is not metabolized by the liver, and does not cross the blood brain barrier. These differences may contribute to nadolol being better tolerated. In patients in whom P-blockers are contraindicated or patients who are unable to take @blockers because of significant side effects, longacting nitrates may be a reasonable alternative. Garcia-Pagan et all8 demonstrated that isosorbide-5-mononitrate given over a 3-month period produced a sustained reduction in HVPG. Angelic0 et a12compared isosorbide-5-mononitrate and propranolol in a controlled trial for prevention of first variceal bleeding and found that both drugs were equally efficacious in the prevention of first gastrointestinal hemorrhage; however, patients with isosorbide-5-mononitrate had less asthenia as a side effect. Another study comparing nadolol plus isosorbide-5-mononitrate with nadolol alone for the prevention of first variceal bleeding reported very few bleeding events in either group of ~atients.3~ There is emerging evidence that the risk of variceal bleeding is strongly related to HPVG. A reduction of HPVG by 20% and especially below 12 mmHg, is important in preventing bleedingz7Garcia-Pagan et all9 showed that the combination of propranolol and isosorbide-5mononitrate resulted in a greater reduction of HVPG than with propran0101 alone. Isosorbide-5-mononitrate achieved a reduction in HVPG in several patients who initially had not responded to propranolol. Vorobioff et a1- similarly demonstrated a greater reduction of HVPG in patients on propranolol and isosorbide dinitrate when compared to patients on propranolol alone. Combination therapy with a P-blocker and a longacting nitrate may benefit patients on P-blocker therapy who do not respond sufficiently to P-blockade, as evidenced by a significant lowering of HVPG. CONTROL OF ACUTE VARICEAL BLEEDING Initial management of acute variceal bleeding includes establishment of adequate venous access, replenishment of blood volume with packed red blood cells and fresh frozen plasma, and intubation to protect the airway in actively bleeding unstable patients. For actively bleeding patients, prophylactic antibiotic therapy may be of value. Pharmacologic treatment with vasoactive drugs may be started in the emergency room while the patient is awaiting endoscopy to determine the source of bleeding. RCTs have shown sclerotherapy to be superior to balloon tampon-
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ade or pharmacologic agents for the initial control of acute esophageal variceal bleeding, with a success rate of 75% to 90?0.~’In an RCT by Burroughs et a1,7 a single session of sclerotherapy controlled variceal bleeding in 62% of patients; two sessions successfully controlled bleeding in 78% of patients, but additional sessions of sclerotherapy were of minimal benefit. Because of the significant local and systemic complications associated with the use of sclerotherapy, pharmacologic treatment may be a reasonable alternative for stable patients with a relatively minor bleeding episode. Although the data are somewhat limited, endoscopic variceal ligation has a success rate similar to sclerotherapy, with far fewer complications. PHARMACOLOGICAGENTS Vasopressin Vasopressin has been used extensively for treatment of acute variceal bleeding. It acts by causing sphlanchnic vasoconstriction, a decrease in portal venous blood flow, and subsequently, a fall in portal venous pressure. RCTs have shown that vasopressin successfully controls acute variceal bleeding in 52% of patients compared to 18% for placebozz; however, its usage is associated with a high rate of recurrent bleeding and with significant complications, including myocardial and peripheral ischemia, bradycardia, hypertension, hyponatremia, and fluid retention. Moreover, the RCTs evaluating vasopressin did not demonstrate improvement in survival. Vasopressin Plus Nitroglycerin The addition of nitroglycerin to vasopressin has ameliorated many of the vasoconstrictive side effects of vasopressin. A meta-analysis of three controlled trials showed that vasopressin plus nitroglycerin was superior to vasopressin alone for the control of acute variceal bleeding12; however, Teres et a149reported better control of variceal bleeding with balloon tamponade compared to vasopressin and nitroglycerin. Nitroglycerin can be given sublingually, transdermally, or intravenously. Of these, the intravenous route is preferable as the dose can be titrated more easily. Somatostatin/Octreotide RCTs have demonstrated somatostatin to be superior to a placebo in one of two trials, superior to vasopressin, and comparable to glypressin, balloon tamponade, and sclerotherapy for control of acute variceal hemorrhage.” Although somatostatin was well tolerated with very few side
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effects, its use was not associated with any significant improvement in survival. Octreotide, a synthetic analogue of somatostatin, has a longer halflife (1.5 hours), but its effectiveness in reducing portal pressure remains in question. A recent study reported rapid tachyphylaxis developing after an initial bolus dose followed by intravenous infusion of octreotide, with failure to maintain an initial reduction in the HVPG."' Octreotide for the control of acute variceal bleeding has been found comparable to vasopressin, glypressin (triglycyl-lysine vasopressin) plus nitroglycerin, balloon tamponade, and sclerotherapy, but the sample size in most of these studies was ~ma11.l~ A recent six-center trial failed to find octreotide more effective than a placebo for the control of acute variceal bleeding and the prevention of rebleeding with or without the concomitant use of sclerotherapy?O Octreotide may have some benefit when used in combination with sclerotherapy for the control of acute variceal bleeding, although the results from RCTs are mixed.6,43 One trial found comparable control of acute variceal bleeding, but less rebleeding when octreotide was combined with endoscopic variceal ligation compared to variceal ligation alone>*Despite the equivocal data for the efficacy of octreotide, it has become the most widely used pharmacologic agent in the United States for the control of acute variceal bleeding. Glypressin (Terlipressin)
Glypressin is a long-acting, relatively inert analogue of vasopressin that can be given as a bolus. In vivo it is gradually activated with cleavage of its N-terminal glycyl residue. This slow release of the active component has been associated with lower blood levels and fewer side effects when compared to a continuous infusion of vasopressin. RCTs have shown glypressin to be superior to a placebo or vasopressin and comparable to somatostatin or balloon tamponade for the control of acute variceal hemorrhage.12In one use of glypressin was associated with a significant survival benefit. In a double-blind study that evaluated the prehospital use of glypressin combined with glyceral trinitrate initiated at the patient's home or during transfer to the emergency room, pharmacologic therapy showed a reduction in mortality.32 These promising results, coupled with the lower incidence of side effects, makes glypressin an attractive substitute for vasopressin. In Europe, it has become a widely used pharmacologic agent for control of acute variceal hemorrhage; however, its use in the United States has not yet been approved by the Food and Drug Administration. Miscellaneous Drugs
Metoclopramide, domperidone, and pentagastrin have been reported to decrease azygos blood flow and also reduce blood flow in the
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distal esophagus submucosal venous plexus. Hoskins et a1 demonstrated metoclopramide to be superior to placebo in a small controlled study;27a however, this beneficial effect is yet to be corroborated by large trials. Pharmacologic or endoscopic therapy is successful in controlling bleeding in 75% to 90% of patients; however, for patients who do not respond to either form of therapy, alternative treatment should be sought. The most commonly used rescue procedure is the transjugular intrahepatic portosystemic shunt (TIPS). Alternative therapies include esophageal staple transection, surgical shunts, and liver transplantation for appropriate candidates. PREVENTION OF RECURRENT VARICEAL BLEEDING The risk of recurrent variceal hemorrhage in patients successfully treated for acute variceal hemorrhage approaches 70%, making it essential that all patients receive therapy to prevent rebleeding. Nonselective P-adrenergic blockers, sclerotherapy and endoscopic variceal ligation have all been shown to be effective in reducing the risk of recurrent variceal hemorrhage. PHARMACOLOGIC THERAPY Eleven RCTs have compared propranolol or nadolol to a placebo or no treatment for prevention of variceal rebleeding. Meta-analyses of the trials have demonstrated that p-adrenergic blockers are highly effective in reducing the risk of recurrent variceal hemorrhage (Fig. 3).5Pooling the data from these trials reveals that the risk of recurrent variceal bleeding was reduced from 65.9% in controls to 44.7% in patients on padrenergic blocker therapy, a 32% reduction in the risk of bleeding. Although (3-adrenergic blockers significantly reduced the risk of rebleeding, their effect on mortality is more controversial. Using the Mantel-Haentzel-Pet0 method, D'Amico et all2 report an odds ratio of 0.70 (0.48-1.02 95% CI) in favor of nonselective p-blockers for mortality rate, which is not quite statistically significant. The odds ratio does not change when the two papers published in abstract only are excluded (Fig. 4); however, using different statistical methodology (Der Simonian stratified meta-analysis), Bernard et a15 found a significant survival advantage for patients treated with (3-blockers. They report a relative risk of death of 1.27 for patients not receiving (3-blocker therapy, and they estimate that 14 patients need to be treated to prevent one death. The meta-analysis by D'Amico et a1 included only the 11 RCTs whereas Bernard et a15 included a 12th studyI4 that was not clearly randomized. Regardless of the statistical methodology used, it is clear that P-blocker therapy decreases the risk of recurrent variceal bleeding and probably offers a modest survival benefit. As relatively few patients with decompensated (Child's C ) cirrhosis
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Figure 3. Randomized, controlled trials of patients treated with (A) nonselective betaadrenergic blockers (propranolol, nadolol) compared with a (6)placebo for the prevention of recurrent gastrointestinal bleeding related to portal hypertension (all sites). Odds ratio for the group is 0.40; 95% confidence interval, 0.29-to 0.57 (P
were included in these trials, p-blocker therapy should be reserved for patients classified as Child’s A or a stable Child’s B. The time interval between the index bleed and initiation of therapy in these trials ranged from 12 hours to 21 days. As shown by Graham et a1,2‘jthe highest risk for rebleeding occurs within the first 2 weeks after the index bleed. Therefore, a delay in initiation of therapy could miss the group of patients with the highest risk. Although p-blocker therapy has been associated with side effects, including dyspnea, asthma, depression, bradycardia, headaches, and impotence, use of p-blockers in these trials was reasonably well tolerated. Initial concerns about development of hepatic encephalopathy and renal failure did not materialize. For patients who cannot tolerate or have contraindications to p-blocker therapy, long-acting nitrates might be a reasonable alternative, although more studies are needed to verify their efficacy. SCLEROTHERAPY VERSUS @-ADRENERGIC BLOCKERS ALONE OR IN COMBINATION WITH NITRATES
Eight published RCTs have compared the efficacy of sclerotherapy and propranolol in preventing variceal rebleeding; six of the trials
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Villeneuve Queniet Gaits Colombo
1
Sheen
Rossi
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1 -
Typical Odds Ratio - A 0.01
0.10
1.oo
10.00
100.00
Odds Ratio Figure 4. Randomized, controlled trials of patients treated with (A) nonselective betaadrenergic blockers (propranolol, nadolol) compared with a (6)placebo for the prevention of mortality. The odds ratio is 0.74; 95% confidence interval, 0.50-1.09 (P=O.124). (From Grace ND: Nonsurgical therapy of hemorrhage from esophageal varices. In Conn HO, Palmaz JC, Rosch J, Rossle M (eds): TIPS: Transjugular lntrahepatic Portasystemic Shunts. New York, Igaku-Shoin 1996, p 28; with permission.)
showed comparable efficacy in the prevention of recurrent variceal bleeding, whereas two favored sclerotherapy. None of the trials demonstrates a significant survival advantage for either therapy. Although a meta-analysis of the RCTs favors sclerotherapy for the prevention of recurrent variceal bleeding,12the marked heterogeneity among the studies, the differences in patient population, severity of disease, and technical aspects make it difficult to recommend one therapy over the other. In general, P-blocker therapy may be preferable for patients with compensated cirrhosis whereas endoscopic therapy might be used in less compliant patients or patients with decompensated cirrhosis. As discussed in the article by Slosberg and Keefe, endoscopic variceal ligation has been shown to be superior to sclerotherapy for prevention of recurrent variceal bleeding. Villanueva et a153compared a combination of nadolol and isosorbide mononitrate to sclerotherapy for prevention of variceal rebleeding. Nadolol and isosorbide mononitrate significantly decreased the risk of rebleeding from esophageal varices when compared to sclerotherapy, and was associated with a survival benefit just short of statistical significance ( P = 0.07).
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COMBINED SCLEROTHERAPY AND P-ADRENERGIC BLOCKERS
In seven published RCTs a combination of propranolol (often given only until varices have been obliterated by sclerotherapy) and sclerotherapy was compared with sclerotherapy alone for the prevention of recurrent variceal bleeding.12 In three of these studies the combination was found to be more effective, whereas in the remaining four the results were similar. In none of these trials was an improvement in survival reported. In two RCTs the combination of propranolol and sclerotherapy was compared to propranolol given alone. One of the studies demonstrated a significant benefit for the combination of propranolol and sclerotherapy in reducing variceal rebleeding,36whereas the other study showed a favorable trend for combined therapy.29Although further trials, especially with longer follow-up periods, are necessary to properly assess the benefits of combination therapy, the data available so far seem to support the use of combination endoscopic and pharmacologic therapy. PORTAL GASTROPATHY AND GASTRIC VARICES Portal gastropathy and gastric varices remain less common but important causes of bleeding in patients with portal hypertension. There are very few RCTs evaluating treatment, and most of the current regimens used are derived from anecdotal evidence or are extrapolated from trials on the management of esophageal varices; however, as portal gastropathy and gastric varices are consequences of portal hypertension, drugs that reduce HVPG should have a beneficial effect. In a singleblind randomized trial propranolol has been shown to reduce bleeding in both acute and chronic portal g a ~ t r o p a t h yVasoactive .~~ drugs like somatostatin and glypressin have been found to be effective in acute gastric variceal bleeding. THE ROLE OF HEMODYNAMIC MEASUREMENTS AND VARICEAL BLEEDING An HVPG of 12 mmHg or more is necessary for the formation and subsequent bleeding of esophageal varices. Over the last few years there has been increasing evidence that HVPG is one of the most important tests predicting the risk of recurrent variceal bleeding and survival in patients with portal hypertension. Analyzing the hemodynamic events in a prospective randomized trial of propranolol versus placebo in prevention of first variceal hemorrhage, Groszmann et alZ7found that none of the 21 patients in whom the initially elevated HVPG had decreased to 12 mmHg or less bled from the varices. They concluded that reduction of HVPG to less than 12 mmHg protects patients from
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variceal bleeding and prolongs survival. In assessing the relation between portal pressure response to pharmacotherapy and risk of recurrent variceal hemorrhage in patients with cirrhosis, Feu et all6 found that patients in whom the HPVG fell to 12 mmHg or less were completely protected from the risk of rebleeding. They also found that a reduction in HVPG of more than 20% of baseline was associated with significant reduction of recurrent variceal hemorrhage. In an RCT comparing the combination of nadolol and isosorbide-5-mononitrate to sclerotherapy for prevention of variceal rebleeding, Villanueva et a153also found that bleeding was significantly reduced when the HVPG decreased by 20% or more and did not recur in any patient in whom a follow-up HVPG was below 12 mmHg. Merkel et a134found that HVPG was significantly higher in patients with cirrhosis and esophageal varices who bled during follow-up than in those who did not. They concluded that HVPG measurements were as important as Child-Pugh score in prognosticating variceal bleeding. Studies by Merkel et al?* Gluud et a1,2l and Barrett et aP also found the HVPG to have prognostic significance for survival in patients with cirrhosis and esophageal varices. Hemodynamic measurements have become more than a research tool and can be very useful for monitoring effectiveness of therapy. SUMMARY AND CONCLUSION
Patients with large esophageal varices who are deemed compliant and have no contraindications to P-blocker therapy should be started on nonselective P-adrenergic blockers (Fig. 5). The dose should be titrated to a 25% decrease in resting heart rate, a resting heart rate of 55 to 60 beats per minute, or development of symptoms, in which case the dose should be decreased until the patient's symptoms abate. If available, measurements of the HVPG at baseline and 3 months can be very helpful in ascertaining the response to treatment and in making the appropriate adjustments (e.g., adding a second drug). Sclerotherapy or endoscopic variceal ligation are the preferred therapies for treatment of acute esophageal variceal bleeding. Concomitant use of vasoactive drugs can supplement endoscopic treatment. They offer the advantage of early administration as soon as the diagnosis is suspected while awaiting endoscopy. Unlike endoscopic treatment, they decrease portal pressure and are the only established treatment for nonvariceal sources of bleeding related to portal hypertension. Once the index bleed is controlled, the patient should be started on treatment to reduce the high risk of recurrent variceal hemorrhage (Fig. 6). For patients with well-compensated cirrhosis, pharmacologic therapy may be desirable. For less compliant patients or patients with decompensated cirrhosis, an endoscopic technique, such as variceal ligation, may be preferable. Combinations of pharmacologic agents or pharmacologic agents and endoscopic procedures may offer hope for better control, but their efficacy needs to be demonstrated in RCTs. For patients who
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Cirrhosis (Small Esophageal Esophageal
1 Observe 7-
p -Blockers
Baseline HVPG
Repeat Endoscopy 2 Years
Treatment for Acute Bleed
3 month HVPG
Continue Therapy
Add Long Acting
L
Figure 5. Algorithm for prevention of initial variceal hemorrhage for patients with cirrhosis and esophageal varices.
Child’s A,B Baseline HVPG
p Blockers
Variceal Ligation WL)
(EW Rebleed 3 month HVPG
No Bleed
Surveillance
Surgical Shunt
EVL for Recurrent Varices
HVPG -1to 4 2 mmHg
Continue Treatment
Child’s B,C
Long Acting
Figure 6. Algorithm for prevention of recurrent variceal hemorrhage in patients with cirrhosis and prior variceal bleeding episode.
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rebleed despite maximal pharmacologic or endoscopic therapy, a TIPS procedure, surgically created shunt, or liver transplantation should be considered, with the decision based on the patient's condition and the local availability of these options.
References 1. Andreani T, Poupon RE, Balkau B, et al: Preventive therapy of first gastrointestinal bleeding in patients with cirrhosis: Results of a controlled trial comparing proprano101, endoscopic sclerotherapy and placebo. Hepatology 12:1413-1419, 1990 2. Angelic0 M, Carli R, l'iat C, et al: Isosorbide-5-mononitrateversus propranolol in the prevention of first bleeding in cirrhosis. Gastroenterology 104:1460-1465, 1993 3. Barret G, Bosch J, Garcia-Tsao G, et al: Hepatic venous pressure gradient as a predictor of survival in patients with cirrhosis. Hepatology 122350, 1990 4. Beppu K, Inokuchi K, Koyanagi N, et al: Prediction of variceal hemorrhage by esophageal endoscopy. Gastrointest Endosc 27213-218, 1981 5. Bernard B, Lebrec D, Mathurin P, et al: Beta-adrenergic antagonists in the prevention of gastrointestinal rebleeding in patients with cirrhosis: A meta-analysis. Hepatology 25~63-70,1997 6. Besson I, Ingrand P, Person B, et al: Sclerotherapy with or without octreotide for acute variceal bleeding. N Engl J Med 333:555-560, 1995 7. Burroughs AK, Hamilton G, Phillips A, et al: A comparison of sclerotherapy with staple transection of the esophagus for the emergency control of bleeding from esophageal varices. N Engl J Med 32L857-862, 1989 8. Cales P, Desmorat H, Vine1 Jl',et a1 Incidence of large oesophageal varices in patients with cirrhosis: Application to prophylaxis of first bleeding. Gut 31:1298-1302, 1990 9. Colman J, Jones P, Finch C, et al: Propranolol in the prevention of variceal hemorrhage in alcoholic cirrhotic patients. Hepatology 12:851, 1990 10. Conn H O The rational evaluation and management of portal hypertension. In Schaffner F, Sherlock S, Leevy CM (eds): The Liver and Its Diseases. New York, Intercontinental, 1974, pp 289-306 11. Conn HO, Grace ND, Bosch J, et al: Propranolol in the prevention of the first hemorrhage from esophageal varices: Results of a randomized double blind cooperative clinical trial. Hepatology 13:902-912, 1991 12. DAmico G, Pagliaro L, Bosch J: The treatment of portal hypertension: A metaanalytic review. Hepatology 22332-354, 1995 13. Dagradi AE: The natural history of esophageal varices in patients with alcoholic liver cirrhosis: An endoscopic and clinical study. Am J Med 5752&540,1972 14. Escorsell A, Bandi JC, Francois E, et al: Desensitation of the effects of intravenous octreotide in cirrhotic patients with portal hypertension. Hepatology 24207A, 1996 15. Feu F, DAmico G, Bosch J: The acute bleeding episode: Advances in drug therapy. In Arroyo V, Bosch J, Rodes J (eds): Treatments in Hepatology. Barcelona, Masson SA, 1995, p 9 16. Feu F, Garcia-Pagan JC, Bosch J, et al: Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet 346:105&1059, 1995 17. Garceau AJ, Chalmers TC, The Boston Inter-Hospital Liver Group: The natural history of cirrhosis: I. Survival with esophageal varices. N Engl J Med 268:469-473, 1963 18. Garcia-Pagan JC, Feu F, Navasa M, et al: Long-term haemodynamic effects of isosorbide 5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol 11~189-195,1990 19. Garcia-Pagan JC, Navasa M, Bosch J, et al: Enhancement of portal pressure reduction by the association of isosorbide-5-mononitrate to propranolol administration in patients with cirrhosis. Hepatology 11:230-238, 1990
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20. Garcia-Tsao G, Groszmann RJ, Fisher RL, et a1 Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 5:419424, 1985 21. Gluud C, Henriksen JH, Nielsen G: Prognostic indicators in alcoholic cirrhotic men. Hepatology 8222-227, 1988 22. Grace ND: Variceal hemorrhage: Pharmacologic approach. In McDermott WV, Bothe A (eds): Surgery of the Liver. Boston, Blackwell Scientific Publications, 1988, pp 303'314
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23. Grace ND: Management of portal hypertension. The Gastroenterologist 1:39-58, 1993 24. Grace N D Pharmacological prevention of variceal hemorrhage. In Arroyo V, Bosch J, Rodes J (eds): Treatment in Hepatology. Barcelona, Masson SA, 1995, p 23 25. Grace ND, Muench H, Chalmers TC: The present status of shunts for portal hypertension in cirrhosis. Gastroenterology 50:684-691, 1966 26. Graham D, Smith JL: The course of patients after variceal hemorrhage. Gastroenterology 80:800-809, 1981 27. Groszmann RJ, Bosch J, Grace ND, et a1 Hernodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 99:1401-1407, 1990 27a. Hosking SW, Doss W, El-Zeiny H, et al: Pharmacologic constriction of the lower esophageal sphincter: A simple method of arresting variceal hemorrhage. Gut 29:1098-1102, 1988 28. Ideo G, Bellati G, Fesce E, et al: Nadolol can prevent the first gastrointestinal bleeding in cirrhosis: A prospective, randomized study. Hepatology 8:6-9, 1988 29. Ink 0, Martin T, Poynard T, et a1 Does elective sclerotherapy improve the efficacy of long-term propranolol for prevention of recurrent bleeding in patients with severe cirrhosis: A prospective multicenter, randomized trial. Hepatology 16:912-919, 1992 30. International Octreotide Varices Study Group: Double blind RCT of 5 day octreotide versus placebo, associated with sclerotherapy for trial/failures. Hepatology 24:352A, 1996 31. Lebrec D, Poynard T, Capron JP, et al: Nadolol for prophylaxis of gastrointestinal bleeding in patients with cirrhosis: A randomized trial. J Hepatology 7118-125, 1988 32. Levacher S, Letoumelin P, Pateron D, et a1 Early administration of terlipressin plus glyceryl trinitrate to control active upper gastrointestinal bleeding in cirrhotic patients. Lancet 346:865-868, 1995 33. Lopes GM, Grace N D Gastroesophageal varices: Prevention of bleeding and rebleeding. Gastroenterol Clin North Am 22:801-820, 1993 34. Merkel C, Bolognesi M, Bellon S, et al: Prognostic usefulness of hepatic vein catheterization in patients with cirrhosis and esophageal varices. Gastroenterology 102973979, 1992 35. Merkel C , Gatta A, Amodio P, et a1 Nadolol or nadolol plus isosorbide-5-mononitrate in the prophylaxis of first variceal bleeding in patients with cirrhosis: Interim analysis of a multicenter study. J Hepatol 8:S147-S148, 1993 36. O'Connor KW, Lehman G, Yune H, et a1 Comparison of three nonsurgical treatments for bleeding esophageal varices. Gastroenterology 96:899-906, 1989 37. Pagliaro L, DAmico G, Pasta L, et a1 Portal hypertension in cirrhosis: Natural history. In Bosch J, Groszmann RJ (eds): Portal Hypertension: Pathophysiology and Treatment. Oxford, Blackwell Scientific Publications, 1994, p 72 38. Pagliaro L, DAmico G, Sorensen TIA, et a1 Prevention of first bleeding in cirrhosis: A meta-analysis of randomized trials of nonsurgical treatment. Ann Intern Med 11759-70, 1992 39. Pascale JP, Cales P, A Multicenter Study Group: Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 317856-861, 1987 40. Perez-Ayuso R, Pique JP, Bosch J, et al: Propranolol in prevention of recurrent bleeding from severe portal hypertensive gastropathy in cirrhosis. Lancet 33714311434, 1991 41. Polio J, Groszmann RJ: Hernodynamic factors in the development and rupture of esophageal varices: A pathophysiologic approach to treaGent. Semin Liver Dis 6:318, 1986
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42. Poynard T, Cales P, Pasta L, et al: Beta-adrenergic-antagonistdrugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices: An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. N Engl J Med 324:1532-1538, 1991 43. Primignani M, Andreoni B, Carpinelli L, et al: Sclerotherapy plus octreotide versus sclerotherapy alone in the prevention of early rebleeding from esophageal varices: A randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 21:13221327, 1995 44. Rigau J, Bosch J, Bordas JM, et al: Endoscopic measurement of variceal pressure in cirrhosis: Correlation with portal pressure and variceal hemorrhage. Gastroenterology 96:873-880, 1989 45. Rig0 GP, Merighi A, Chalen NJ, et al: A prospective study of the ability of three endoscopic classifications to predict hemorrhage from esophageal varices. Gastrointest Endosc 38425429, 1992 46. Rodriguez-Perez F, Groszmann RJ: Pharmacologic treatment of portal hypertension. Gastroenterol Clin North Am 21:15-40, 1993 47. Soderlund C, Magnusson I, Torngren S, et a1 Terlipressin (triglycyl-lysine vasopressin) controls acute bleeding oesophageal varices. A double-blind randomized, placebo-controlled trial. Scand J Gastroenterol 25:622430, 1990 48. Sung JJY, Chung SCS, Yung MY, et al: Prospective randomized study of effect of octreotide on rebleeding from oesophageal varices after endoscopic ligation. Lancet 346:1666-1669, 1995 49. Teres J, Planas R, Panes J, et al: Vasopressin/nitroglycerin infusion vs. esophageal tamponade in the treatment of acute variceal bleeding: A randomized controlled trial. Hepatology 11:964-968, 1990 50. The Italian Multicenter Project for Propranolol in Prevention of Bleeding: Propranolol prevents first gastrointestinal bleeding in nonascitic cirrhotic patients: Final report of a multicenter randomized trial. J Hepatology 9:75-83, 1989 51. The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices: Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices: A prospective multicenter study. N Engl J Med 319:983-989, 1988 52. The PROVA Study group: Prophylaxis of first hemorrhage from esophageal varices by sclerotherapy, propranolol or both in cirrhotic patients: A randomized multicenter trial. Hepatology 14:1016-1024, 1991 53. Villanueva C, Balanzo J, Novella MT, et a1 Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding. N Engl J Med 334:1624-1629, 1996 54. Vorobioff J, Picabea E, Gamen M, et a1 Propranolol compared with propranolol plus isosorbide dinitrate in portal-hypertensive patients: Long-term hemodynamics and renal effects. Hepatology 18:477-484, 1993 Address reprint requests to Norman D. Grace, MD Division of Gastroenterology Faulkner Hospital 1153 Centre Street Boston, MA 02130-3446