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N Engl J Med ; Nonselective beta-adrenergic blockers decrease portal pressure and prevent variceal hemorrhage. Their effectiveness in preventing varices is unknown. Full Text of Background We randomly assigned patients with cirrhosis and portal hypertension minimal hepatic venous pressure gradient [HVPG] of 6 mm Hg to receive timolol, a nonselective beta-blocker patientsor placebo patients.
The primary end point was the development of gastroesophageal varices or variceal hemorrhage. Endoscopy Anna Varizen HVPG measurements were repeated yearly. Anna Varizen Text of Methods During a median follow-up of Serious adverse events were more common among patients in the timolol group than among those in the placebo group 18 percent vs. Varices developed less frequently among patients with a baseline HVPG of less than 10 mm Hg and among those in whom the HVPG decreased Anna Varizen more than 10 percent at one year and more frequently among those in whom the HVPG increased by more than 10 percent at one year.
Full Text of Results Nonselective beta-blockers are ineffective in click to see more Anna Varizen in unselected patients with cirrhosis and portal hypertension and are associated with an increased Anna Varizen of adverse events. Full Text of Discussion Randomized, controlled trials have demonstrated that nonselective beta-blockers prevent variceal hemorrhage in patients with varices.
Anna Varizen fact, an experimental study demonstrated that beta-blockers prevent the development of portosystemic collateral vessels. The study was an investigator-initiated, randomized, double-blind, placebo-controlled, clinical trial conducted go here four sites. The protocol was approved by the institutional review board at each site, and all patients gave written informed consent.
Timolol maleate Blocadren and placebo were provided by Merck; Merck did not participate in any other aspect of the study, including study design, data analysis, and Anna Varizen preparation. Patients were enrolled between August and March and followed until September Eligible patients had cirrhosis and portal hypertension, as defined by an HVPG of at least 6 mm Hg; did not have Anna Varizen varices; and were older than 18 years and younger than 75 years of age.
The diagnosis of cirrhosis was either biopsy-proven or clinically suspected and confirmed by the finding of an HVPG of 10 mm Hg or greater. The Anna Varizen of gastroesophageal varices was determined unanimously at endoscopy by two staff endoscopists Anna Varizen were present during Anna Varizen entire procedure and who evaluated the procedure independently.
Exclusion criteria included ascites requiring diuretics, hepatocellular carcinoma, splenic- or portal-vein thrombosis, concurrent illnesses Anna Varizen to decrease life expectancy to less than one year, the use of any drug or procedure affecting splanchnic hemodynamics or portal pressure, primary biliary cirrhosis or primary sclerosing cholangitis, contraindications to beta-blocker therapy, pregnancy, or alcohol intake during the dose-titration phase.
Of patients screened for varices, 63 percent had none. Of these Anna Varizen, 43 percent were included in the study. The remaining were excluded for the following reasons: The dose of timolol or placebo to be used during the study was determined for each patient before randomization during a titration period in which Anna Varizen timolol was administered orally.
The starting dose of timolol was 5 mg per day and was increased by 5 mg every three days until one of the following occurred: After the titration period, patients were randomly assigned to receive timolol or an identical-appearing placebo tablet. The randomization code was generated by computer for each participating center. Patients were stratified according to the cause of cirrhosis alcoholic vs.
An alcoholic Anna Varizen was defined as a long-standing history of Anna Varizen ingestion exceeding 60 g per day. In patients with a dual alcoholic and viral cause, the classification of cirrhosis was based on the clinical and histologic findings. Patients were assessed clinically at Anna Varizen, one and three months after randomization, and every three months thereafter.
At each visit, the heart rate, pill count, occurrence of adverse events, and alcohol consumption were determined and blood was obtained for hematologic and biochemical measurements. At baseline and every year thereafter, upper endoscopy was performed and HVPG was measured as described elsewhere. The primary end points were the development of varices or variceal hemorrhage as identified unanimously at endoscopy by two staff endoscopists who were present during the entire procedure and who evaluated the procedure independently.
Varices were defined by the presence of one of the following: Variceal hemorrhage was defined as any hematemesis or melena in a patient in whom endoscopy showed active bleeding from Anna Varizen esophageal or gastric varix, an esophageal or gastric varix with an adherent clot, or varices but no other source of bleeding.
Secondary end points were the development of ascites or encephalopathy, Anna Varizen transplantation, or death. Data collection was terminated and treatment was considered to have failed when a patient reached the primary end point, underwent liver transplantation, or died. An adverse event was any event that required a diagnostic or therapeutic intervention.
All adverse events, regardless of their possible association with the disease or study treatment, were recorded. An adverse event was judged severe if it was Anna Varizen to endanger the health or safety of the patient. Members of a data and safety monitoring board were appointed by the National Institute of Diabetes and Digestive and Kidney Diseases and met every six months to review the progress of the study and accumulated data.
According to the protocol, one interim analysis was performed on October 26,after all patients had been enrolled. At that time, the data and safety monitoring board was empowered to recommend termination of the study Anna Varizen the basis of concern about Anna Varizen or in the presence of sufficient evidence to indicate that timolol was statistically superior to placebo.
The board voted unanimously to recommend continuation of the trial. We estimated that treatment with timolol would reduce the four-year cumulative probability of varices from 50 Anna Varizen the rate without treatment 6,7 to 30 percent, given a statistical power of 80 percent to detect visit web page absolute difference of 20 percent between the placebo and timolol groups at a two-sided alpha level of 0.
We estimated that the study would require patients, and we then increased this amount by 10 percent to account for the loss of patients to follow-up, yielding a total of patients. All analyses were conducted according to the intention-to-treat principle. Actuarial probabilities were calculated according to the Kaplan—Meier method and compared with use of the log-rank test.
Data were censored when the primary end point was reached, at the time of transplantation or death, or at the time of the last visit, whichever occurred first. A Cox proportional-hazards model was used to identify the variables that best explained the variability in the rates of primary end points, treatment failure, and survival. Calculations were performed with the use of the SAS Anna Varizen software package.
A total of patients underwent randomization: The median time from screening endoscopy to randomization was 29 days range, 8 to There were Yevpatoriya Behandlung von Krampfadern significant differences between Anna Varizen in the proportion of patients with alcohol-induced cirrhosis or in the HVPG. The median Child—Pugh score was 5 range, 5 to 9; scores can range from 5 to 15, with higher scores indicating more severe liver disease.
The median duration of follow-up was The median daily dose of Varizen und Zucker was The dose had to be reduced in Anna Varizen patients 26 in the timolol group vs.
Adherence to treatment was considered adequate if the pill count showed more than Anna Varizen percent adherence; this degree of adherence was achieved in 86 patients in the timolol group 80 percent and 88 Anna Varizen in the Anna Varizen group 84 percent.
A total of 84 patients reached the primary end point of varices Anna Varizen variceal bleeding: Cumulative percentages of patients who did not reach the primary end point at 12, 24, 36, and 60 months were 91 percent, 86 percent, 79 percent, and 60 percent, respectively, in the timolol group and 97 percent, 82 percent, Anna Varizen percent, and 57 percent, respectively, in the placebo Anna Varizen. The rates of the primary end point both overall and for the timolol group did not differ significantly when patients who had a reduction in the dose or stopped treatment were compared with those who did not have a reduction in the dose or discontinue treatment data not shown.
Hepatocellular carcinoma, which was not considered an Anna Varizen point of the study, occurred in eight patients in the timolol group and six see more in the placebo group. A comparison of the 84 patients who reached the primary end point with the Anna Varizen who did not reach the primary end point revealed that the following baseline variables differed at a Anna Varizen value of less than 0.
The incidence of Anna Varizen or severe adverse events was higher in the timolol group than in the placebo group 48 percent [52 patients] vs. None of the complications were fatal. The average reduction in the heart rate from baseline was 17 percent Anna Varizen the timolol group.
HVPG measurements were repeated at one year in patients 72 in the timolol group and 82 in the placebo group. As compared with baseline values, the HVPG decreased by a median of 1. Reductions in the HVPG of more than 10 percent Figure 3Bmore than 15 percent, and more than 20 percent were all associated with a significantly lower incidence of the primary end point. Conversely, an increase in the HVPG by more than 10 percent also correlated with an increased likelihood of reaching the end point Нашем Krampfadern an den Händen sein kann Этого 3C.
However, there were no significant differences between groups in the increases in HVPG. In this placebo-controlled study, Anna Varizen with a nonselective beta-blocker, timolol, did not prevent gastroesophageal varices in unselected Anna Varizen with cirrhosis and portal hypertension and was associated with an increased number of adverse effects.
A previous French study of the prevention of varices showed that, in patients without varices or with small varices, the development of large varices was more frequent among propranolol-treated patients than among patients who received placebo. Most of the patients had small varices, and significant Anna Varizen were confined to this subgroup of patients.
We used timolol, a potent nonselective beta-blocker, 10 and as shown in patients with essential hypertension, 11 once-daily dosing was sufficient to maintain the reduction in heart rate for at least 24 hours.
Anna Varizen average decrease in heart rate in Anna Varizen timolol group was 17 percent. This reduction is smaller than the range of 20 Anna Varizen 26 percent median, 24 percent Anna Varizen in studies of beta-blockers in the primary prophylaxis of variceal hemorrhage and is probably due to the lower baseline Anna Varizen rate median, 73 beats per minute in our study than in primary-prophylaxis studies of patients Anna Varizen varices median, 80 beats per minute 9, or secondary-prophylaxis studies of patients with varices Anna Varizen, 84 beats per minute.
The lack of an Anna Varizen significant change in the HVPG may partly explain our negative results. Although it is possible that positive results could have been obtained if the dose of timolol had Anna Varizen higher, drug intolerance limited our ability to increase the dose further in this group of patients with compensated Anna Varizen, most of whom were reluctant to tolerate even minimal side effects.
A major finding of our study was the effect of baseline Anna Varizen on outcomes. This finding supports the definition of clinically significant portal Anna Varizen as an HVPG of at least 10 mm Hg.
We confirmed the importance of lowering portal pressure shown in previous studies of patients with more advanced cirrhosis. An important finding was that more patients in the timolol group than in the placebo group Anna Varizen these favorable HVPG responses, indicating that timolol had a beneficial effect, but one that was not sufficient Anna Varizen tip the balance in favor of beta-blockers.
Conversely, we also found that increases in portal pressure were associated with the Anna Varizen of varices, although timolol apparently click Anna Varizen ability to prevent this increase in HVPG.
In conclusion, even though the role of nonselective beta-blockers in Anna Varizen variceal hemorrhage in patients who already have varices is well established, we found that nonselective beta-adrenergic blockers did not prevent varices in patients with cirrhosis and portal hypertension.
The use of beta-blockers cannot be widely recommended in this population because of its association with an increased incidence of serious side effects.
However, even in this population of patients with compensated cirrhosis, we have confirmed Anna Varizen predictive value of baseline HVPG levels and of a subsequent reduction in the HVPG by more than 10 percent, the latter of which should be the goal in the pharmacologic während der Schwangerschaft wie selbst geben, of gastroesophageal varices.
Supported by a grant Read moreto Dr.
We are indebted to the endoscopists, interventional radiologists, pathologists, study coordinators, nurses, and fellows Anna Varizen each of the four participating centers who were part of the Portal Hypertensive Collaborative Group and who contributed to the performance and successful completion of the study; and to A. Rand of the external advisory data and safety monitoring board.
Address reprint requests to Dr. Increased portal venous resistance hinders portal pressure reduction during the administration of beta-adrenergic blocking agents in Anna Varizen portal hypertensive model.
Effect of selective blockade of beta-2 adrenergic receptors on portal and systemic hemodynamics in a portal hypertensive rat model.