大剂量螺内酯对充血性心力衰竭患者电解质、肌酐及心功能影响的研究
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摘要
目的:心力衰竭是21世纪的流行病,尽管心力衰竭治疗有了很大进展,但是严重心力衰竭死亡率仍居高不下,年死亡率高达50%左右,探讨新的改善预后的措施具有重要价值。RALES试验已经证实,在常规应用血管紧张素转换酶抑制剂(ACEI)、利尿剂、强心剂和β-肾上腺素能受体阻滞剂基础上,联合应用小剂量螺内酯(平均26mg/d)能够有效降低病死率,并改善严重慢性心力衰竭的心功能。大剂量螺内酯(≥60mg/d)抢救严重心力衰竭,我们已取得了初步成功的经验,而同时螺内酯的副作用却没有显著的增多。本研究拟通过大、小剂量螺内酯分别干预,观察用药前后各项心功能指标改变,并测定血、尿电解质、肾功能指标变化,以期观察大剂量螺内酯对左心室重构和心功能的影响,并为应用大剂量螺内酯的安全性提供依据。
方法:选择我院2005-2～2006-9心内科住院治疗收缩性心力衰竭患者(NYHAⅢ～Ⅳ级LVEF<35%)49例,且左室舒张末期内径( LVEDD ) >55mm、血清钾<5.0mmol/L、血肌酐<2.5mg/dl。其中,男性29例,女性20例,年龄57-80岁,平均69.5±7.6岁。除外急性冠脉综合征(急性心肌梗死、不稳定性心绞痛),严重恶性室性心律失常、原发性肝衰竭、恶性肿瘤及其它威胁生命的疾病、先天性心脏病、原发性瓣膜性心脏病、在第一剂研究药物开始应用前30天应用过其它保钾利尿剂、甲状腺功能亢进症和肺心病。所有患者入选前均接受强心剂、利尿剂、ACEI、和β-受体阻滞剂等常规治疗,病情稳定2周以上,采用随机数字表将受试者随机分为小剂量螺内酯组(24名),大剂量螺内酯组(25名)。所有病人入选前均未曾使用任何醛固酮拮抗剂,小剂量组在常规治疗基础上加用螺内酯(≤40mg/d),大剂量组在常规治疗基础上加用螺内酯(≥60mg/d)。两组均可视液体潴留及血钾浓度情况加用呋噻米或补钾治疗,大剂量组适当加大利尿剂的剂量。
入选患者于治疗前及治疗3个月时检测各项心功能指标。治疗前及治疗后第1、2、3天、1、3周检测尿电解质、肌酐,治疗前及治疗后第1、2、3周、第1、3个月均监测血电解质、肾功能一次。检测中如血钾升高5.3mmol/L≤K+<6.0mmol/L ,首先加大排钾利尿剂剂量(例如:氢氯噻嗪用量加倍或加用20mg呋噻米等),并根据情况调整螺内酯剂量(大剂量组螺内酯最低可调至60mg/d,小剂量组最低可调至20mg/d);一周后复查血钾,如血钾依然升高5.3mmol/L≤K+<6.0mmol/L,则根据病人情况继续加大排钾利尿剂剂用量,直至血钾降至<5.0mmol/L,若依然未降至此标准则停用螺内酯。检测中如发现血肌酐≥2.5mg/dl,男性患者如出现不能耐受的乳房发育、乳房疼痛,女性患者如出现乳房疼痛、月经失调等症状,则把大剂量组螺内酯减至60mg/d,小剂量组减至20mg/d,如血肌酐仍≥2.5mg/dl或上述症状无缓解则停用螺内酯。
最终对用药情况进行统计时为了容易评估ACEI的剂量,每个病人的ACEI剂量通过ACC/AHA心衰指南中建立的指定相等的每种ACEI推荐的每天最大剂量转换成与它相等的卡托普利的毫克数,即150mg卡托普利与40mg衣那普利、40mg福辛普利、40mg赖诺普利、40mg喹那普利、10mg雷米普利相等。
所用数据输入SPSS13.0统计软件包进行统计,计量资料用均数±标准差表示,组间比较采用t检验,组内治疗前后比较用配对t检验,计数数据采用X2检验,其他两样本比较用wilcoxon秩和检验。电解质数据应用重复测量方差分析,各组间多重比较采用LSD-t检验P<0.05为统计学有显著性差异。
结果: 1大剂量组螺内酯平均用量101.60±38.70mg/d;小剂量组螺内酯平均用量28.33±9.17mg/d,与RALES试验中螺内酯目标用量(平均26mg/d)相近,故可视为标准对照。
2试验过程中,小剂量组患者1例因心衰恶化退出试验;大剂量组高血钾(>5.5mmol/L)1例,血肌酐>2.5mg/dl 1例;因其他原因两组各有1例失访;两组均无死亡病例。
3两组间治疗前基线年龄、性别、血压、心功能分级、LVEF、LVMI、LVEDVI、LVESVI、血钾、血镁、血肌酐、尿钾、尿镁、尿肌酐等无统计学差异(P值>0.05),两组数据均衡,具有可比性(见附表1)。
4两组的基线用药情况:大、小剂量组平均ACEI用量无差别;大剂量组氢氯噻嗪、呋塞米平均用量或应用百分比高于小剂量组,两组间差异有统计学意义(P<0.05)。(见附表2)
5与治疗前相比治疗第3周时,尿钾、尿镁、尿肌酐等指标均无明显改变,两组间比较无明显差异(P>0.05)(见附表3)。用药1周后,大、小剂量组血钠指标均有所下降,两组与治疗前相比均有显著性差异(P<0.05),两组间比较大剂量组血钠下降更为显著(P<0.05),但3个月后均基本返回到治疗前水平(见附表4)。与治疗前相比治疗第3个月时,血钾、血镁、血肌酐等指标,两组均有所升高,两组与治疗前相比均有显著性差异(P值均<0.05 ) ,两组间比较大剂量组血镁升高更为显著(P<0.05)(见附表4)。大剂量螺内酯组有2名男性患者发生乳房发育,但均可耐受,小剂量组未观察到此现象,两组比较无差异(P>0.05)。
6治疗3个月时,两组LVEF、LVMI、LVEDVI、LVESVI均较治疗前有明显改善,且有统计学差异(P值均<0.01);但治疗3个月时,上述指标组间同期比较,大剂量组改善更为显著(P值均<0.05)(见附表5)。
结论:大剂量螺内酯能够有效改善慢性心衰患者的左室功能,且与小剂量螺内酯相比,其逆转心室重构及提高心肌收缩功能作用尤为明显。与小剂量螺内酯组相比较,大剂量螺内酯并未明显减少尿肌酐、尿钾、尿镁排泄,其虽可使血肌酐、血钾、血镁浓度轻度升高,但在调整剂量及加用利尿剂后并不会引起肾功能损害和高钾血症。与小剂量组相比,乳房发育的副作用无显著增加。因此,只要注意监测血钾浓度及肾功能,适当增加排钾利尿剂的剂量,应用大剂量螺内酯治疗CHF还是安全的。
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 sprinolactone
To 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,
方法:选择我院2005-2～2006-9心内科住院治疗收缩性心力衰竭患者(NYHAⅢ～Ⅳ级LVEF<35%)49例,且左室舒张末期内径( LVEDD ) >55mm、血清钾<5.0mmol/L、血肌酐<2.5mg/dl。其中,男性29例,女性20例,年龄57-80岁,平均69.5±7.6岁。除外急性冠脉综合征(急性心肌梗死、不稳定性心绞痛),严重恶性室性心律失常、原发性肝衰竭、恶性肿瘤及其它威胁生命的疾病、先天性心脏病、原发性瓣膜性心脏病、在第一剂研究药物开始应用前30天应用过其它保钾利尿剂、甲状腺功能亢进症和肺心病。所有患者入选前均接受强心剂、利尿剂、ACEI、和β-受体阻滞剂等常规治疗,病情稳定2周以上,采用随机数字表将受试者随机分为小剂量螺内酯组(24名),大剂量螺内酯组(25名)。所有病人入选前均未曾使用任何醛固酮拮抗剂,小剂量组在常规治疗基础上加用螺内酯(≤40mg/d),大剂量组在常规治疗基础上加用螺内酯(≥60mg/d)。两组均可视液体潴留及血钾浓度情况加用呋噻米或补钾治疗,大剂量组适当加大利尿剂的剂量。
入选患者于治疗前及治疗3个月时检测各项心功能指标。治疗前及治疗后第1、2、3天、1、3周检测尿电解质、肌酐,治疗前及治疗后第1、2、3周、第1、3个月均监测血电解质、肾功能一次。检测中如血钾升高5.3mmol/L≤K+<6.0mmol/L ,首先加大排钾利尿剂剂量(例如:氢氯噻嗪用量加倍或加用20mg呋噻米等),并根据情况调整螺内酯剂量(大剂量组螺内酯最低可调至60mg/d,小剂量组最低可调至20mg/d);一周后复查血钾,如血钾依然升高5.3mmol/L≤K+<6.0mmol/L,则根据病人情况继续加大排钾利尿剂剂用量,直至血钾降至<5.0mmol/L,若依然未降至此标准则停用螺内酯。检测中如发现血肌酐≥2.5mg/dl,男性患者如出现不能耐受的乳房发育、乳房疼痛,女性患者如出现乳房疼痛、月经失调等症状,则把大剂量组螺内酯减至60mg/d,小剂量组减至20mg/d,如血肌酐仍≥2.5mg/dl或上述症状无缓解则停用螺内酯。
最终对用药情况进行统计时为了容易评估ACEI的剂量,每个病人的ACEI剂量通过ACC/AHA心衰指南中建立的指定相等的每种ACEI推荐的每天最大剂量转换成与它相等的卡托普利的毫克数,即150mg卡托普利与40mg衣那普利、40mg福辛普利、40mg赖诺普利、40mg喹那普利、10mg雷米普利相等。
所用数据输入SPSS13.0统计软件包进行统计,计量资料用均数±标准差表示,组间比较采用t检验,组内治疗前后比较用配对t检验,计数数据采用X2检验,其他两样本比较用wilcoxon秩和检验。电解质数据应用重复测量方差分析,各组间多重比较采用LSD-t检验P<0.05为统计学有显著性差异。
结果: 1大剂量组螺内酯平均用量101.60±38.70mg/d;小剂量组螺内酯平均用量28.33±9.17mg/d,与RALES试验中螺内酯目标用量(平均26mg/d)相近,故可视为标准对照。
2试验过程中,小剂量组患者1例因心衰恶化退出试验;大剂量组高血钾(>5.5mmol/L)1例,血肌酐>2.5mg/dl 1例;因其他原因两组各有1例失访;两组均无死亡病例。
3两组间治疗前基线年龄、性别、血压、心功能分级、LVEF、LVMI、LVEDVI、LVESVI、血钾、血镁、血肌酐、尿钾、尿镁、尿肌酐等无统计学差异(P值>0.05),两组数据均衡,具有可比性(见附表1)。
4两组的基线用药情况:大、小剂量组平均ACEI用量无差别;大剂量组氢氯噻嗪、呋塞米平均用量或应用百分比高于小剂量组,两组间差异有统计学意义(P<0.05)。(见附表2)
5与治疗前相比治疗第3周时,尿钾、尿镁、尿肌酐等指标均无明显改变,两组间比较无明显差异(P>0.05)(见附表3)。用药1周后,大、小剂量组血钠指标均有所下降,两组与治疗前相比均有显著性差异(P<0.05),两组间比较大剂量组血钠下降更为显著(P<0.05),但3个月后均基本返回到治疗前水平(见附表4)。与治疗前相比治疗第3个月时,血钾、血镁、血肌酐等指标,两组均有所升高,两组与治疗前相比均有显著性差异(P值均<0.05 ) ,两组间比较大剂量组血镁升高更为显著(P<0.05)(见附表4)。大剂量螺内酯组有2名男性患者发生乳房发育,但均可耐受,小剂量组未观察到此现象,两组比较无差异(P>0.05)。
6治疗3个月时,两组LVEF、LVMI、LVEDVI、LVESVI均较治疗前有明显改善,且有统计学差异(P值均<0.01);但治疗3个月时,上述指标组间同期比较,大剂量组改善更为显著(P值均<0.05)(见附表5)。
结论:大剂量螺内酯能够有效改善慢性心衰患者的左室功能,且与小剂量螺内酯相比,其逆转心室重构及提高心肌收缩功能作用尤为明显。与小剂量螺内酯组相比较,大剂量螺内酯并未明显减少尿肌酐、尿钾、尿镁排泄,其虽可使血肌酐、血钾、血镁浓度轻度升高,但在调整剂量及加用利尿剂后并不会引起肾功能损害和高钾血症。与小剂量组相比,乳房发育的副作用无显著增加。因此,只要注意监测血钾浓度及肾功能,适当增加排钾利尿剂的剂量,应用大剂量螺内酯治疗CHF还是安全的。
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 sprinolactone
To 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,
引文
1 Rochar, williamsGH. Rationale for the use of Aldosterone antagonists in congestive heart failure. Drugs, 2002,62:723～731
2 Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med, 1999, 341:709～17
3 The RALES Investigation. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol 1996;78:902～907
4 Sharon A,Heart,Md,FACC.ACC/AHA guidelines for the evalution and management of Chronic Heart failure in the Aldult.J Am Coll Cardiol,2001,44:2101～2113
5 Struthers AD. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure. J Card Fail,1996,2:47～54
6 McMahon EG.Recent studies with eplerenone,a novel selective Aldosterone receptor antagonist. Curr OpinPharmacol,2001,1:190～196
7 Pitt B, Remme W, Zannad F, et al. Eplerenone,a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med ,2003,348:1309～1321
8 Sharon A, Heart, Md, FACC. 2005 ACC/AHA guidelines for the evalution and management of Chronic Heart failure in the Aldult
9 Tsatsui H, Spinale FG, Nagatsu M, et al. Effects of chronic beta-adrenergic blockade on the left ventricular ang cardiocyte abnormalities of chronic canine mitral regurgitation. J Clin Invest, 1994,93:2639～2648
10 Hayashi M, Tsutamoto T, Wada A, et al. Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterioracute myocardial infarction. Circulation, 2003, 27: 2559～2565
11 Sigel AV, Centrella M, Eghbali-Webb M. Regulation of proliferative response of cardiac fibroblasts by transforming growth factor-beta1. J Mol Cell Cardiol, 1996, 28:1921～1929
12 Petrov VV, Fagard RH, Lijnen PJ. Transforming growth factor-beta induces angiotensin-converting enzyme synthesis in ratcardiac fibroblasts during their differentiation to myofibroblasts. J Renin Angiotensin Aldosterone Syst, 2000, 1: 342～352
13 Brown NJ, Kim KS, Chen YQ, et al. Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. J Clin Endocrinol Metab,2000, 85: 336～344
14 Odawara M, Asano M, Yamashita K. Life-threatening hyperkalaemia caused by angiotensin-converting enzyme-inhibitor and diuretics. Diab Med, 1997,14: 169～170
15 Eric J, Eichorn MD, Michael R, et al. Medical therapy can improve the biological properties of the chronically failying heart.Circulation,1996,194:2285～2296
16 Reardon LC, Macpherson DS. Hyperkalemiain outpatients using angiotensin – converting enzyme inhibitors. Arch Intern Med, 1998,158:26～32
17 Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin-II receptor blocker and angiotensin- converting- enzyme inhibitor in non-diabetic renal disease(COOPERATE): a randomised controlled trial. Lancet ,2003,361:117～24.
18 Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med, 2001,345:1667～1675
19 McMurray J, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet,2003;362:767～771
20 Pfeffer M, McMurray J, Velazquez E, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure,left ventricular dysfunction, or both. N EnglJMed, 2003,349:1893～1906.
21 ZannadF, AllaF, DoussetB, et al. Limitation of excessive extra cellular matrix turn over may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure. Circulation, 2000,102:2700～2701
22 Tang WHW, Vagelos RH, Yee YG, et al. Neurohormonal and clinical responses to high-versus low-dose enalap ril therapy in chronic heart failure1. J Am Coll Cardiol, 2002, 39: 70～78
23 Tamirisa KP, Aaronson KD, Koelling TM. Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure. American Heart Journal, 2004,148: 971～978
24 Diercks GF, Overdiek JW, van Veldhuisen DJ. Effect of aldosterone antagonism in heart failure:pharmacotherapeutic options. Ned Tijdschr Geneeskd, 2001,145:204～208
25 Braunstein GD. Gynecomastia. N Engl J Med 1993,328:490～495
26 Neuman JF. Evaluation and treatment of gynecomastia. Am Fam Physician. 1997,55:1835–1844
27 Raunstein GD. Aromatase and gynecomastia. Endocr Relat. Cancer. 1999,6:315～324
1 Zannad F.Angiotensin-converting enzyme inhibitor and spironolactone combination therapy.New objectives in congestive heart failure treatment. Am J Cardiol,1993, 71:34～39
2 Van Vliet AA, Donker AJ, Nauta JJ,et al. Spironolactone in congestive heart failure refractory to high-dose loop diureti. Am J Cardiol, 1993,71:21～28
3 Barr CS, Lang CC, Hanson J, et al Effect of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. AM J Cardiol, 1995,76:1259～1265
4 itt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Endl J Med 1999 sep 2;341(10):709～717
5 Tsutamoto T, Wada A, Maeda K,et al. Spironolactone inhibits the transcardiac extraction of aldosterone in patients with congestive heart failure. J AM Coll Cardiol, 2000 ,36:838～844
6 Tsutamoto T, Wada A, Maeda K, et al. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Colol Cardiol ,2001, 37:1228～1233
7 Zannad F, Alla F, Dousset B, et al. Limitataion of excessiveextracellular matrix turnover may contribute to surviva benefit of spironolactone therapy in patients with congestive heart failure:insights from the randomized aldactone evaluation study (RALES). Circulation, 2000,102:2700～2706
8 Cserhalmi L. Effect of combined captopril-spironolactone therapy of cardiac insufficiency o kidney function and serum electrolyte values. Orv Hetil, 1998,139:63～66
9 Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized aldactone Evaluation Study[RALES].Am J Cardiol, 1996,78:902～907
10 Vanpee D, Swine CH. Elderly heart failure patients with drug-induced serious hyperkalemia. Aging (Milano), 2000 ,12:315～319
11 Francis J, Weiss RM, Wei SG, Central mineralocorticoid teceptor blockade improves volume regulation and reduces sympathetic drive in heart failure. Am J physiol Heart Cire physiol , 2001,281:2241～2251
12 Kasama S, Toyama T, Kumakura H, et al. Effects ofspironolactone on cardiac sympathetic nerve activity andleft ventricular remodeling in patients with dilatedcardiomyopathy. J Am Coll Cardiol, 2003, 41:574～581
13 Kasama S, Toyama T, Kumakura H, et al. Spironolactoneimproves cardiac sympathetic nerve activityand symptomsin patients with congestive heart failure. J Nucl Med, 2002, 43: 1279～1285
14 Yee KM, Pringle SD, Struthers AD, et al. Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure. J Am Coll Cardiol ,2001, 37:1800～1807
15 MacFadyen RJ, Barr CS, Struthers AD, et al. Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res, 1997,35:30～34
16 Moser DK, Stevenson WG, Woo MA, et al. Timing ofsudden death in patients with heart failure. J Am CollCardial, 1994, 24: 963～967
17 Amires FJ, Mansur A, Coelho O, et al. Effect of spironolactone on ventricular arrhythmias in congestive heart failure , secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol, 2000,85:1207～1211
18 Khan NU, Movahed A. The rale of aldosterone andaldosterone-receptor antagonists in heart failure. RevCardiovasc Med, 2004, 5: 71～81
19 Han YL,Tong M,Jing QM, et al. Combined therapy of captopril and spironolactone for refractory congestive heart failure. Chin Med J,1994,107:688～692
20 Cserhalmi L Effect of combined captopril-spironolactone therapy of cardiac insufficiency o kidney function and serum electrolyte values. Orv Hetil, 1998 ,139:63～66
21 Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized aldactone Evaluation Study[RALES]. Am J Cardiol, 1996,78:902～907
22 Tamirisa KP, Aaronson KD, Koelling TM. Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure. American Heart Journal,2004, 148: 971～978
23 Diercks GF, Overdiek JW, van Veldhuisen DJ. Effect of aldosterone antagonism in heart failure:pharmacotherapeutic options. Ned Tijdschr Geneeskd ,2001,145:204～208
24 Jeunemaitre X. Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol ,1987, 60:820～825
25 Oats AJ. Exciting new drugs on the horizon-eplerenone, a selective receoto antagenis (SARA). Int J Cardiol 2001 ,80:1～4
26 John J.V. McMurray. Treatment of Heart Failure with Spironolactone Trial and Tribulations. N Engl J Med, 2004 351:526～528
2 Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med, 1999, 341:709～17
3 The RALES Investigation. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol 1996;78:902～907
4 Sharon A,Heart,Md,FACC.ACC/AHA guidelines for the evalution and management of Chronic Heart failure in the Aldult.J Am Coll Cardiol,2001,44:2101～2113
5 Struthers AD. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure. J Card Fail,1996,2:47～54
6 McMahon EG.Recent studies with eplerenone,a novel selective Aldosterone receptor antagonist. Curr OpinPharmacol,2001,1:190～196
7 Pitt B, Remme W, Zannad F, et al. Eplerenone,a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med ,2003,348:1309～1321
8 Sharon A, Heart, Md, FACC. 2005 ACC/AHA guidelines for the evalution and management of Chronic Heart failure in the Aldult
9 Tsatsui H, Spinale FG, Nagatsu M, et al. Effects of chronic beta-adrenergic blockade on the left ventricular ang cardiocyte abnormalities of chronic canine mitral regurgitation. J Clin Invest, 1994,93:2639～2648
10 Hayashi M, Tsutamoto T, Wada A, et al. Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterioracute myocardial infarction. Circulation, 2003, 27: 2559～2565
11 Sigel AV, Centrella M, Eghbali-Webb M. Regulation of proliferative response of cardiac fibroblasts by transforming growth factor-beta1. J Mol Cell Cardiol, 1996, 28:1921～1929
12 Petrov VV, Fagard RH, Lijnen PJ. Transforming growth factor-beta induces angiotensin-converting enzyme synthesis in ratcardiac fibroblasts during their differentiation to myofibroblasts. J Renin Angiotensin Aldosterone Syst, 2000, 1: 342～352
13 Brown NJ, Kim KS, Chen YQ, et al. Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. J Clin Endocrinol Metab,2000, 85: 336～344
14 Odawara M, Asano M, Yamashita K. Life-threatening hyperkalaemia caused by angiotensin-converting enzyme-inhibitor and diuretics. Diab Med, 1997,14: 169～170
15 Eric J, Eichorn MD, Michael R, et al. Medical therapy can improve the biological properties of the chronically failying heart.Circulation,1996,194:2285～2296
16 Reardon LC, Macpherson DS. Hyperkalemiain outpatients using angiotensin – converting enzyme inhibitors. Arch Intern Med, 1998,158:26～32
17 Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin-II receptor blocker and angiotensin- converting- enzyme inhibitor in non-diabetic renal disease(COOPERATE): a randomised controlled trial. Lancet ,2003,361:117～24.
18 Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med, 2001,345:1667～1675
19 McMurray J, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet,2003;362:767～771
20 Pfeffer M, McMurray J, Velazquez E, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure,left ventricular dysfunction, or both. N EnglJMed, 2003,349:1893～1906.
21 ZannadF, AllaF, DoussetB, et al. Limitation of excessive extra cellular matrix turn over may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure. Circulation, 2000,102:2700～2701
22 Tang WHW, Vagelos RH, Yee YG, et al. Neurohormonal and clinical responses to high-versus low-dose enalap ril therapy in chronic heart failure1. J Am Coll Cardiol, 2002, 39: 70～78
23 Tamirisa KP, Aaronson KD, Koelling TM. Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure. American Heart Journal, 2004,148: 971～978
24 Diercks GF, Overdiek JW, van Veldhuisen DJ. Effect of aldosterone antagonism in heart failure:pharmacotherapeutic options. Ned Tijdschr Geneeskd, 2001,145:204～208
25 Braunstein GD. Gynecomastia. N Engl J Med 1993,328:490～495
26 Neuman JF. Evaluation and treatment of gynecomastia. Am Fam Physician. 1997,55:1835–1844
27 Raunstein GD. Aromatase and gynecomastia. Endocr Relat. Cancer. 1999,6:315～324
1 Zannad F.Angiotensin-converting enzyme inhibitor and spironolactone combination therapy.New objectives in congestive heart failure treatment. Am J Cardiol,1993, 71:34～39
2 Van Vliet AA, Donker AJ, Nauta JJ,et al. Spironolactone in congestive heart failure refractory to high-dose loop diureti. Am J Cardiol, 1993,71:21～28
3 Barr CS, Lang CC, Hanson J, et al Effect of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. AM J Cardiol, 1995,76:1259～1265
4 itt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Endl J Med 1999 sep 2;341(10):709～717
5 Tsutamoto T, Wada A, Maeda K,et al. Spironolactone inhibits the transcardiac extraction of aldosterone in patients with congestive heart failure. J AM Coll Cardiol, 2000 ,36:838～844
6 Tsutamoto T, Wada A, Maeda K, et al. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Colol Cardiol ,2001, 37:1228～1233
7 Zannad F, Alla F, Dousset B, et al. Limitataion of excessiveextracellular matrix turnover may contribute to surviva benefit of spironolactone therapy in patients with congestive heart failure:insights from the randomized aldactone evaluation study (RALES). Circulation, 2000,102:2700～2706
8 Cserhalmi L. Effect of combined captopril-spironolactone therapy of cardiac insufficiency o kidney function and serum electrolyte values. Orv Hetil, 1998,139:63～66
9 Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized aldactone Evaluation Study[RALES].Am J Cardiol, 1996,78:902～907
10 Vanpee D, Swine CH. Elderly heart failure patients with drug-induced serious hyperkalemia. Aging (Milano), 2000 ,12:315～319
11 Francis J, Weiss RM, Wei SG, Central mineralocorticoid teceptor blockade improves volume regulation and reduces sympathetic drive in heart failure. Am J physiol Heart Cire physiol , 2001,281:2241～2251
12 Kasama S, Toyama T, Kumakura H, et al. Effects ofspironolactone on cardiac sympathetic nerve activity andleft ventricular remodeling in patients with dilatedcardiomyopathy. J Am Coll Cardiol, 2003, 41:574～581
13 Kasama S, Toyama T, Kumakura H, et al. Spironolactoneimproves cardiac sympathetic nerve activityand symptomsin patients with congestive heart failure. J Nucl Med, 2002, 43: 1279～1285
14 Yee KM, Pringle SD, Struthers AD, et al. Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure. J Am Coll Cardiol ,2001, 37:1800～1807
15 MacFadyen RJ, Barr CS, Struthers AD, et al. Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res, 1997,35:30～34
16 Moser DK, Stevenson WG, Woo MA, et al. Timing ofsudden death in patients with heart failure. J Am CollCardial, 1994, 24: 963～967
17 Amires FJ, Mansur A, Coelho O, et al. Effect of spironolactone on ventricular arrhythmias in congestive heart failure , secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol, 2000,85:1207～1211
18 Khan NU, Movahed A. The rale of aldosterone andaldosterone-receptor antagonists in heart failure. RevCardiovasc Med, 2004, 5: 71～81
19 Han YL,Tong M,Jing QM, et al. Combined therapy of captopril and spironolactone for refractory congestive heart failure. Chin Med J,1994,107:688～692
20 Cserhalmi L Effect of combined captopril-spironolactone therapy of cardiac insufficiency o kidney function and serum electrolyte values. Orv Hetil, 1998 ,139:63～66
21 Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized aldactone Evaluation Study[RALES]. Am J Cardiol, 1996,78:902～907
22 Tamirisa KP, Aaronson KD, Koelling TM. Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure. American Heart Journal,2004, 148: 971～978
23 Diercks GF, Overdiek JW, van Veldhuisen DJ. Effect of aldosterone antagonism in heart failure:pharmacotherapeutic options. Ned Tijdschr Geneeskd ,2001,145:204～208
24 Jeunemaitre X. Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol ,1987, 60:820～825
25 Oats AJ. Exciting new drugs on the horizon-eplerenone, a selective receoto antagenis (SARA). Int J Cardiol 2001 ,80:1～4
26 John J.V. McMurray. Treatment of Heart Failure with Spironolactone Trial and Tribulations. N Engl J Med, 2004 351:526～528