Beta-Blockers to Prevent Gastroesophageal Varices in Patients with Cirrhosis
Schaumsklerosierung der Varikose | Springer for Research & Development
N Engl J Med ; Nonselective beta-adrenergic blockers decrease portal pressure and prevent variceal hemorrhage, was Terry Varizen. Was Terry Varizen 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 was Terry Varizen patientsor placebo patients.
The primary end point was the development was Terry Varizen gastroesophageal varices or variceal hemorrhage, was Terry Varizen. Endoscopy and HVPG measurements were repeated yearly. Full 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 was Terry Varizen frequently among patients with a baseline HVPG of less than 10 mm Hg and among those in whom the HVPG decreased by more than 10 percent at one was Terry Varizen and more frequently among those in whom the HVPG increased by was Terry Varizen than 10 percent at one year.
Full Text of Results Nonselective beta-blockers are ineffective in preventing varices in unselected patients with cirrhosis and portal hypertension and are associated with an increased number folterte Varizen adverse events.
Full Text of Discussion Randomized, was Terry Varizen, controlled trials have demonstrated that nonselective beta-blockers prevent variceal hemorrhage in patients with varices. In 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 was Terry Varizen at 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 manuscript preparation.
Patients were enrolled between August and March and followed until September Was Terry Varizen patients had cirrhosis and portal hypertension, as defined by an HVPG of at least 6 mm Hg; did not have gastroesophageal 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 absence of gastroesophageal varices was determined unanimously at endoscopy by two staff endoscopists who were present during the entire procedure and who evaluated the procedure independently.
Exclusion criteria included ascites requiring diuretics, hepatocellular carcinoma, splenic- or portal-vein thrombosis, concurrent illnesses expected to decrease life expectancy to less than one year, the use of any drug or procedure affecting splanchnic hemodynamics or portal pressure, was Terry Varizen, primary biliary cirrhosis or primary sclerosing cholangitis, was Terry Varizen, contraindications to beta-blocker therapy, pregnancy, was Terry Varizen, or alcohol intake during the dose-titration phase.
Of patients screened for varices, 63 percent had none. Of these patients, 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 open-label timolol was administered orally, was Terry Varizen. 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 cause was defined as a long-standing history of alcohol 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 was Terry Varizen. Patients were assessed clinically at baseline, one and three months after randomization, and every three months thereafter.
At each visit, the heart rate, pill count, was Terry Varizen, occurrence was Terry Varizen adverse events, and alcohol consumption were determined and blood was obtained for hematologic and biochemical measurements.
To maintain study blinding, the patient's heart rate was measured by the study nurse and not by the investigators, was Terry Varizen. 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 was Terry Varizen Behandlung von trophischen Geschwüren Fraktion 3 of one of the following: Variceal hemorrhage was defined as any hematemesis or melena in a patient in whom endoscopy showed active bleeding from an esophageal or gastric varix, an esophageal or gastric varix with an adherent clot, or varices but no other source of bleeding.
In addition, acute, clinically significant bleeding as a result of portal hypertensive gastropathy defined by the need for a 2-unit transfusion, a 6-point drop in the hematocrit, or a drop of more than 20 mm Hg in systolic blood pressure with a change in the patient's posture was considered a primary end point. Secondary end points was Terry Varizen the development of ascites or encephalopathy, liver 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 considered 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 trophischen Geschwüren Minsk was empowered to recommend termination of the study on the basis of concern about safety 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 percent the rate without treatment 6,7 to 30 percent, given a statistical power of 80 percent to detect an absolute difference of 20 percent between the was Terry Varizen 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. Qualitative variables were compared by means of Fisher's exact test.
Wilcoxon's rank-sum test was used to compare continuous variables or ordinal data. 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, was Terry Varizen, at the time of transplantation or death, or at the was Terry Varizen 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 was Terry Varizen of the SAS statistical software package.
A total of patients underwent randomization: Was Terry Varizen median time from screening endoscopy to randomization was 29 days range, 8 to There were no significant differences between groups 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 timolol was The dose had to be reduced in 29 patients 26 in the timolol group vs. Adherence to treatment was considered adequate if the pill count showed more than 70 percent adherence; this degree of adherence was achieved in 86 patients in the timolol group 80 percent and 88 patients in the placebo group 84 percent.
A total of 84 patients reached the primary end point of varices or 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, 78 percent, and 57 percent, was Terry Varizen, respectively, in the placebo group.
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 end point of the study, occurred in eight patients in the Varizen Magengefäße group and six patients in the placebo group. A comparison of the 84 patients who reached the primary end point with the patients who did not reach the primary end point revealed that the following baseline variables differed at a P value of less than 0.
The incidence of moderate or severe adverse events was higher in the timolol group than in the placebo group 48 percent [52 patients] vs, was Terry Varizen.
None of the complications were fatal. The average reduction in the heart rate from baseline was 17 percent in 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, was Terry Varizen, the HVPG decreased by a median of 1, was Terry Varizen. 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 Figure 3C.
However, there were no significant differences between groups in the increases in HVPG. In this placebo-controlled study, was Terry Varizen, treatment with a nonselective beta-blocker, timolol, did not prevent gastroesophageal varices in unselected patients with cirrhosis and portal hypertension and was associated with an increased number of was Terry Varizen 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 differences 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 was Terry Varizen hours.
The average decrease in heart rate in the timolol group was 17 percent. This reduction is smaller than the range of 20 to 26 percent median, 24 percent reported in studies of beta-blockers in the primary prophylaxis of variceal hemorrhage and is probably due to the lower baseline heart rate median, 73 beats per minute in our study than in primary-prophylaxis studies of patients with varices median, 80 beats per minute 9, or secondary-prophylaxis studies of patients with varices median, 84 beats per minute.
The lack of an overall significant change in the HVPG may was Terry Varizen explain our negative results. Although it is possible that positive results could have been obtained if the dose of timolol had been higher, drug intolerance limited our ability to increase the dose further in this group of patients with compensated cirrhosis, was Terry Varizen, most of whom were reluctant to tolerate even minimal side effects.
A major finding of our study was the effect of baseline HVPG on outcomes. This finding supports the definition of clinically significant portal hypertension 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 had these favorable HVPG responses, indicating that timolol had a beneficial effect, but one that was not sufficient to tip the balance in favor of beta-blockers. Conversely, we also found that increases in portal pressure were associated with the development of varices, although timolol apparently had no ability to prevent this increase in HVPG.
In conclusion, was Terry Varizen, even though the role of nonselective beta-blockers in preventing 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 the 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 prevention of gastroesophageal varices.
Supported by a grant RO1to Dr. We are indebted to was Terry Varizen endoscopists, interventional radiologists, pathologists, study coordinators, nurses, and fellows at each of the four participating centers who were part of the Portal Hypertensive Collaborative Group and who contributed to the performance and successful completion Kombucha für Krampfadern the study; and to Was Terry Varizen.
Die Sklerosierungstherapie hat ihren festen Stellenwert in der Behandlung von retikulären Varizen und Seitenästen. Reddy P, Wickers J, Terry T et al.
Sclerotherapy is a standardized method in the treatment of reticular veins and tributary varicose veins. The use of foamed sclerosing agents has improved the effectivity of the method also for large subcutaneous veins and saphenous veins. With a low profile of side effects and good cost effectiveness, was Terry Varizen, foam sclerotherapy is an alternative and additional method to operative was Terry Varizen endovenous treatment of varicose veins.
The position of this method in comparison with the other options has to be defined by randomized comparative studies in the future. Authors Authors and affiliations F. Pannier Email author E. Aktuelle Chirurgie der Varikosis. Foam sclerotherapy of varicose veins.
Cavezzi A, Frullini A Echosclerotherapy in the short saphenous vein insufficiency: Cavezzi A, Frullini A Il ruola della mousse sclerosante nella ecosclerosi safenica e delle varici recidive. Results at 2 years. J Am Acad Dermatol A prospective randomized study. Fegan WG Continous compression technique of infecting varicose veins.
Feied CF Deep vein thrombosis: J Dermatol Surg Oncol: Feuerstein W Schwere anaphylaktische Reaktion auf Hydroxypolyaethoxydodecan. Fisher DA Regarding extensive tissue necrosis following high concentration sclerotherapy for varicose veins. Flückiger P Nichtoperative retrograde Varizenverödung mit Varisylschaum. Schweiz Med Wochenschr Frullini A, Cavezzi A Ultrasound guided sclerotherapy in the treatment of long saphenaous vein insufficiency. Vasomed 11 [Suppl 1]: Henriet J P ed Foam sclerotherapy state of the art.
Frullini A, Cavezzi A Sclerosing foam in the treatment of varicose veins and teleangiectases: Frullini A New technique in producing sclerosing faom in a disposable syringe, was Terry Varizen. Georgiev M Postsclerotherapy hyperpigmentations, was Terry Varizen.
J Dermatol Surg Oncol Eur J Dermatol 9: Gobin JP The sclerotherapy position in recurrent varicose veins treatment, Goldman PM Polidocanol aethoxysklerol for sclerotherapy of superficial venules and telangiectasias. Goldmann PM Complications of sclerotherapy. Gloviczki, P, J Yao eds Handbook of venous disorders. Henriet JP One year experience with sclerotherapy of reticular veins and telangiectases using polidocanol foam in daily routine: Hohlbaum G Über iatrogene Schäden bei der Varizensklerosierung.
Malouf GM Ambulatory venous surgery versus sclerotherapy. Hawaii Med J Massay RA Regarding the use of compression stockings after sclerotherapy. McCoy S, Evans A, was Terry Varizen, Spurrier N Sclerotherapy for leg telangiectasia—a blinded comparative trial of polidocanol and hypertonic saline. Mc Donagh B Comments on the use of post-sclerotherapy compression. Effects of increasing concentrations of polidocanol. Rabe E Hrsg Grundlagen der Phlebologie, 3.
Viavital, Köln Google Scholar. Rabe E et was Terry Varizen. Viavital, Köln, S Google Scholar. Seydewitz V, was Terry Varizen, Staubesand J Das ultrastrukturelle Substrat der Wirkung paravasal und intraarteriell applizierter Sklerosierungsmittel: Acetylsalicylsäure Thrombophlebitis experimenteller Beitrag zum Problem iatrogener Schäden nach Sklerotherapie.
Schadeck Was Terry Varizen Duplex-kontrollierte Sklerosierungsbehandlung der Vena saphena magna. Schadeck Was Terry Varizen Echo-sclerotherapy. Tessari L, Cavezzi A, Frullini A Preliminary experience with a new sclerosing foam in the treatment of varicose veins. Practice guidelines and sclerotherapy procedures. Glovicki P, Yao J eds Handbook of venous disorders. Controlled comparative study of duration of compression and its effects on clinical outcome.
Wenner L Improvement of immediate and long-term results in sclerotherapy. Wollmann JC The history of sclerosing foams, was Terry Varizen. Yamaki T, Nozaki M, Iwasaka S Comparative study of duplex-guided foam sclerotherapy and duplex guided liquid sclerotherapy was Terry Varizen the treatment of superficial venous insufficiency. Pannier 1 2 Email author E, was Terry Varizen.
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