| Objective: Heart failure (HF) is a epidemic disease in 21 century. We have had many advances in the treatments of congestive heart failure (CHF), but the mortality of severe HF is very high. Therefore, to explore the new approach for improvement of prognosis is of an important value. Recently, it has been confirmed that routine treatments with angiotensin-converting enzyme inhibitor(ACEI), diuretics, cardiac glycoside, andβ-blocker combined with smaller dose of spironolactone (mean 26mg/d) could improve the prognosis of severe HF. Over the last decade, we had obtained a lot of clinical experience in using higher dosage of spironolactone in treatment of the severe HF patients. It showed larger dose of spironolactone was superior over smaller dose of spironolactone in clinical practice, yet, there was no significant increase of hyperkalemia occurance in our observational study, especially in combination with other diuretics. Thus we designed this study to observe the changes of the cardiac function, electrolytes and creatinine of serum and urine, after spironolactone intervention in larger or smaller dosage, and provided the safety evidence for higher dosage of spironolactone using. Methods: including criteria were: CHF patients with New York Heart Association(NYHA) III～IV class, left ventricular ejection fraction (LVEF)<35%, and left ventricular end-diastolic diameter (LVEDD)>55cm, serum potassium <5.0mmol/L, and serum creatinine <2.5mg/dL. We enrolled 59 patients with age range from 57 to 80 years old (male 29, female 20). The following patients were excluded: including acute coronary syndrome; severe malignant arrhythmia; primary hepatic failure ; cancer and other life-threatening diseases ; k+≥5.0mmol/L;Cr≥2.5mg/dl; Primary operable valvular heart disease; congenital heart disease; received a potassium-sparing diuretic within 30 days before the first dose of study medicine; hyperthyreosis; lung heart disease. All the patients routinly received therapy with angiotensin-converting enzyme inhibitor(ACEI), diuretics, cardiac glycoside, andβ-block combined. After the patients'conditions stabilized at least 2 weeks, they were randomized into smaller dosage spironolactone group (≤40mg/d ) and larger dosage spironolactone group(≥60mg ). There were 24 patients in the smaller dosage spironolactone group and 25 patients in the larger dosage spironolactone group. We increased frusemide dosage or supplemented potassium according to their levels of serum potassium and the degrees of fluid retention. Generally the dosage of diuretics in larger dosage spironolactone group was larger than those in smaller dosage spironolactone group. The spironolactone dosage, the type and dosage of other diuretics were determined by the experienced clinical physicians carefully.Cardiac function parameters were measured at baseline and 3 months after intervention. Urine electrolytes and creatinine were measured at baseline and day1, 2, 3 and week1, 3. Serum electrolytes and creatinine were measured at baseline and week1, 2, 3 and month 1, 3. During the monitoring, if serum potassium increased over 5.3mmol/L but below 6.0mmol/L, then firstly doubled hydrochlorothiazide or added frusemide, at the same time, spironolactone should be adjusted according to serum potassium status (spironolactone decreased to 60mg in larger dosage group, or spironolactone decreased to 20mg in smaller dosage group). Serum potassium was measured after 1 week, if serum potassium did not decrease(5.3mmol/L≤K+<6.0mmol/L, diuretics dosage was added continually , until serum potassium was lower to less than 5.0mmol/L. If serum potassium still did not decreased to the standard range, this patient stopped using sprinolactone. During the monitoring, there were serum creatinine increased over 2.5mg/dl, gynecomastia and breast pain occurred in male patients, breast pain and menstrual disorder occurred in female patients, then we decreased spironolactone to 60 mg/d in larger dosage group, or 20 mg/d in smaller dosage group. If serum creatinine did not decrease (Cr≥2.5mg/dl) or the above-mentioned symptoms was not released, then we stopped using sprinolactoneTo compare ACE inhibitor dosage, each patient's ACE inhibitor dose was converted to its equivalent in milligrams of captopril by assigning equality to the daily maximum recommended dose of each ACE inhibitor as established in national guidelines.We used SPSS13.0 software pack to performed all the data statistical-analysis. All the measurement data was denoted by mean±standard deviation (SD) , students t test was used. Chi-square test was used for analysis of categoricy data. We used compared two samples wilcoxon rank sun test to analysis the date of scale sore. Repeated-measurement-design-ANOVA was used to denote the difference among the different times and LSD-t was used when the difference was significant. We take p<0.05 as statistic significant level.Results: 1 The average dosage of spironolactone was 101.6±38.70mg/d in larger dosage group and 28.33±9.17mg/d in smaller dosage group respectively, which was similar to the dosage used in RALES , so it could be used as a standard contrast in the latter.2 One patient withdrew from study for deterioration of CHF in smaller dosage group. One patients had hyperkalemia (k+﹥5.5mmol/L ) and another had renal deterioration (Cr﹥2.5mg/dl) in larger dosage group. One patient in larger dosage group and one in smaller dosage group discontinued treatment for the other reasons. There was no patient died in both groups.3 The clinical charactertics wre well matched at baseline (Table 1) 4 Drug dosage in the study period: with respect of ACEI , there was not significant difference in two groups (p>0.05), as for hydrochlorothiazide, larger dosage group was higher than in smaller dosage group (p<0.05), there was more people need frusemide in larger dosage group (p<0.05) (Table 2)5 The urine potassium, creatinine were not markedly difference in two groups before and after treatment (Table 3). At the end of the first week, the serum sodium decreased markedly in both of the two groups, and decreased more seriously in the larger dosage group (P<0.05). The serum sodium of the two groups recovered after adjusting the diuretics dosage. After 3 months of therapy, serum potassium, magnesium and creatine increased compared with baseline in both groups (P<0.05), but it was not clinically important(Table 4). The serum magnesium increased more in larger dosage group than that in smaller dosage group(P<0.05) (Table 4). Two patients developed gynecomastia in larger dosage group whereas none in smaller dosage group, but there was not statistical difference in two groups.6 After 3 months of treatment, LVEF,LVMI,LVEDVI,LVESVI were all improved compared with baseline in both groups (p<0.01), however, therapentic effects was superior in the larger dosage group over the smaller group (p<0.05). (Table 5)Conclusion: Compared with the smaller dosage, spironolactone in larger dosage was better in reversing the ventricular remodeling and improving cardiac systolic function, and did not decrease urine potassium, creatinine excretion. All data showed, compared with the smaller dosage, serum potassium, magnesium, creatinine increased in larger dosage group. However we prevented the occurancce of severe renal function damage and hyperkalemia by adjusting spironolactone dosage, adding diuretica. Compared with the smaller dosage, the adverse events of gynecomastia did not increased markedly in larger dosage group. Inconclusion, our data showed it was safe to use spirolactone in larger dosage to moderate,severe heart failure patients if monitoring serum potassium level and renal function regularly, adding the dosage of duretics correctly,... |
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