Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis.

It is clearly established that beta-blockers decrease the risk of a first variceal bleeding in cirrhosis. We have recently shown that the addition of isosorbide mononitrate to nadolol decreases the rate of variceal bleeding in patients with cirrhosis and varices, compared with nadolol alone, after a median follow-up of 30 months. It is not established if the long-term treatment with the combination continues to be beneficial. Therefore, we assessed the long-term effect of this combination on first variceal bleeding, complications, and death. One hundred forty-six cirrhotic patients with esophageal varices included in a previously published multicenter, randomized study comparing nadolol (40-160 mg/d) with the combination nadolol plus isosorbide mononitrate (10-20 mg 3 times per day) were followed up for up to 7 years (median follow-up, 55 months). The primary end-point was variceal bleeding of any severity. Twenty-four patients (16 in the nadolol group, and 8 in the combination group) experienced variceal bleeding (log rank test, P =.02). Cumulative risk of bleeding was 29% and 12%, respectively (95% CI for the difference, 1%-23%). Two and 4 patients, respectively, had bleeding from portal hypertensive gastropathy (log rank test, P =.20). Thirty and 25 patients, respectively, died during follow-up (log rank test, P =.13). Twelve and 10 patients, respectively, had de novo occurrence of ascites during follow-up (log rank test, P =.29). In conclusion, nadolol plus isosorbide mononitrate is significantly more effective than nadolol alone in the long-term use. Side effects are few, and no deleterious effects on ascites occurrence or on survival occur after long-term use of this combination.

Randomised trial of nadolol alone or with isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Gruppo-Triveneto per L'ipertensione portale (GTIP)

BACKGROUND: The risk of having a first cirrhosis-associated variceal bleed is lowered by about 50% by beta-blockers. Use of beta-blockers is currently recommended for patients with cirrhosis and oesophageal varices that are at risk of bleeding. We aimed to test the effectiveness of isosorbide mononitrate as an adjunct to the beta-blocker nadolol in the prophylaxis of first variceal bleeding in these patients. METHODS: We did a randomised multicentre study to compare the non-selective beta-blocker, nadolol, with nadolol plus isosorbide mononitrate in 146 relatively well (Child-Pugh score < or = 11) patients who had oesophageal varices at risk of bleeding. Patients on nadolol alone received a single oral 40 mg daily dose. Every second day the dose was titrated to achieve 20-25% decrease in resting heart rate (maximum dose 160 mg daily). Patients receiving both drugs received nadolol as above then isosorbide mononitrate was added starting with 10 mg orally twice daily, which was increased to 20 mg unless hypotension or severe headache occurred. The main endpoint was the occurrence of variceal bleeding of any severity. Patients were followed up for up to 40 months. FINDINGS: During the study period 11 of 74 patients from the nadolol alone group and four of 72 from the nadolol plus isosorbide mononitrate group had variceal bleeding (log-rank test p = 0.03). Cumulative risk of variceal bleeding was 18% in the nadolol group and 7.5% in the combined treatment group (95% CI for difference 1-25%). Two patients in each group had a non-variceal bleed related to portal hypertension. 14 patients from the nadolol only group and eight from the combined treatment group died during the study period (log-rank test p = 0.09). Four and eight patients, respectively, had to discontinue one of the drugs because of side-effects. INTERPRETATION: Nadolol plus isosorbide mononitrate is significantly more effective than nadolol alone in the primary prophylaxis of variceal bleeding in relatively well patients with cirrhosis, and has few side-effects.

[Long term treatment of moderate to severe hypercholesterolemia with low dose statin. Comparison of simvastatin and pravastatin]. / Trattamento a lungo termine dell'ipercolesterolemia di grado moderato-severo con statine a picole dosi. Comparazione tra simvastatina e pravastatina.

Sixty-seven subjects with primary hypercholesterolemia were enrolled in an open study with "low dosages" of inhibitors of 3-hydroxy-3methylglutaril coenzyme A reductase. Patients were randomized in comparative and parallel study with simvastatin 10 mg (30 subjects) and pravastatin 20 mg (27 subjects) once in the evening for a treatment period of 12 months. At the end of the treatment the plasma concentrations of total and LDL cholesterol were reduced respectively by 21% (p < 0.001) and 29% (p < 0.001), plasma triglyceride concentration was reduced by 16%, high density lipoprotein (HDL) was increased by 2.9%. The efficacy of drugs was increasing during the study: at the third month 63% of subjects and at the twelfth month 89% of subjects showed a LDL < 160 mg/dL. In this study the drugs were well-tolerated, but 11 subjects showed a slight and transitory increase of CK. A treated group with simvastatin showed a similar decrease of the total cholesterol and LDL as that one treated with pravastatin. Pravastatin in comparison with simvastatin reduced significantly plasma triglycerides. There was no significant difference between the groups in the frequency of drug-related adverse effects. In conclusion "low dosages" of simvastatin and pravastatin in long term treatment were very efficacious in the reduction of total and LDL cholesterol. In our study, the decrease of total and LDL cholesterol was time-dependent, with the greatest reduction after sixth months. There were no significant differences between 10 mg of simvastatin and 20 mg of pravastatin on reduction of total and LDL cholesterol levels. Triglycerides decreased significantly only with pravastatin.

Optimizing the time-frame for the definition of bleeding-related death after acute variceal bleeding in cirrhosis.

OBJECTIVE: To identify the best time-frame for defining bleeding-related death after variceal bleeding in patients with cirrhosis. DESIGN: Prospective long-term evaluation of a cohort of 155 patients admitted with variceal bleeding. SETTING: Eight medical departments in seven hospitals in north-eastern Italy. METHODS: Non-linear regression analysis of a hazard curve for death, and Cox's multiple regression analyses using different zero-time points. RESULTS: Cumulative hazard plots gave two slopes, the first corresponding to the risk of death from acute bleeding, the second a baseline risk of death. The first 30 days were outside the confidence limits of the regression curve for the baseline risk of death. Using Cox's regression analysis, the significant predictors of overall mortality risk were balanced between factors related to severity of bleeding and those related to severity of liver disease. If only deaths occurring after 30 days were considered, only predictors related to the severity of liver disease were found to be of importance. CONCLUSION: Thirty days after bleeding is considered to be a reasonable time-frame for the definition of bleeding-related death in patients with cirrhosis and variceal bleeding.

Long-term effect of nadolol or nadolol plus isosorbide-5-mononitrate on renal function and ascites formation in patients with cirrhosis. GTIP Gruppo Triveneto per l'Ipertensione Portale.

The association beta-blockers plus nitrates has been reported to impair renal function and renal sodium handling, leading to increased risk of development of ascites, or worsening of a preexisting ascites, or increase in the requirements of diuretic agents. In 81 patients with cirrhosis and esophageal varices, participating in a multicenter controlled clinical trial of prophylaxis of variceal bleeding comparing nadolol (NAD) plus isosorbide-5-mononitrate (I5M) with NAD alone, renal function, presence of ascites, and diuretic requirements were assessed at inclusion and after 6 months of follow-up. No significant variation in s-urea or s-creatinine was observed in either group, Three patients in the nadolol group and two in the NAD plus I5M developed ascites at 6 months (P = .70), and a need to increase diuretic regimen was observed in four and three patients, respectively (P = .76). Decrease in heart rate and in mean arterial pressure was similar in the two groups. There was a significant correlation between increases in s-creatinine and decrease in mean arterial pressure in the whole series (P = .015). Only in patients treated with the association was there a significant larger proportion of patients ascitic who became anascitic, than of patients anascitic who became ascitic (P = .03). In patients treated with the association, there was a significantly larger decrease in hepatic venous pressure gradient (P = .05). It is concluded that patients treated with the association NAD plus I5M are not at increased risk of developing renal dysfunction or worsening of ascites compared with patients treated with NAD alone.(ABSTRACT TRUNCATED AT 250 WORDS)

[Arterial hypertension and hyporeninemic hypoaldosteronism. Description of a clinical case]. / Ipertensione arteriosa ed ipoaldosteronismo iporeninemico. Descrizione di un caso clinico.

In a clinical case of arterial hypertension with hypopotassiaemia and hyporeninaemic hypoaldosteronism due to the use of a dermatological cream containing 9-alpha-fluoroprednisolone, late identification of the iatrogenic cause forced attention on the differential diagnosis of the less frequent hyporeninaemic hypoaldosteronism.

Calcitonin and prolactin serum levels in heroin addicts: study on a methadone treated group.

Serum calcitonin (CT) and prolactin (PRL) levels were determined in 21 heroin addicts in hospital treatment with methadone. After withdrawal of heroin the values of CT 112.4 +/- 62.9 pg/ml, and PRL 19.1 +/- 10.1 ng/ml were both significantly higher (P less than 0.001) than in normal controls (62.2 +/- 43.8 pg/ml and 9.1 +/- 3.5 ng/ml, respectively). After withdrawal of methadone, i.e. 12 +/- 3.7 days after heroin withdrawal, CT values were 76.6 +/- 32.7 ng/ml (a significant level of P less than 0.02 towards initial values). No correlation was noted between CT and PRL values.

[Arterial hypertension induced by an excess of mineralocorticoids caused by abuse of nasal spray. Report of a case]. / Ipertensione arteriosa da eccesso di mineralcorticoidi dovuta ad abuso di spray nasale. Descrizione di un caso.

Among the various syndromes caused by excess mineralocorticoids, the factitious syndrome produced by excessive 9-alpha-fluorprednisolone inhalations is more common than might be expected, especially in places where the drug is easily obtained without a doctor's prescription. A fairly typical case of addiction to a nasal spray containing ephedrine hydrochloride and an imidazoline compound as well as the steroid is described. The diagnosis of the case is analysed with details of certain differences from similar cases reported in the literature and the modifications to clinical and instrumental parameters achieved after over two months' treatment with spironolactone are described.