Randomized study of effect of combining candesartan with fosinopril in patients with heart failure
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《中华医药杂志》英文版
Randomized study of effect of combining candesartan with fosinopril in patients with heart failure(pdf)
The First Hospital Affiliated to Chinese Medical University, Shenyang, Liaoning Province 110002,China
Correspondence to CHEN Yu-fei, Department of Cardiology,The First Hospital Affiliated to Chinese Medical University, Shenyang, Liaoning Province 110002,China
Tel:+86-24-81630251, E-mail:afei04@eyou.com
[Abstract] Objective To compare the efficacy of fosinopril alone and that of fosinopril combined with candesartan in patients with chronic heart failure.Methods A randomized controlled trial was conducted in this study. Sixty subjects were randomized into two groups, fosinopril alone and fosinopril combined with candesartan were administered. The course of treatment was 8 weeks.Results Compared with fosinopril only and fosinopril plus candesartan, fosinopril plus candesartan has better effects on the following indices : reduction of systolic and diastolic blood pressure(P>0.05), improvement of LVEF and LVDd(P<0.05). The two groups have similar influence on serum levels of potassium and creatinine (P>0.05).Conclusions The efficacy of fosinopril plus candesartan is superior to fosinopril alone on the CHF patients.
[Key words] candesartan; fosinopril; heart failure
INTRODUCTION
Multiple randomized, placebo controlled trials have demonstrated that angiotensin-converting-enzyme(ACE) inhibitors reduce the risk of death as well as the risk of major nonfatal cardiovascular events. Angiotensin-receptor blockers(ARB) offer an alternative approach to the inhibition of the renin-angiotensin system. The identification of a functioning chymase in human that is capable of generating angiotensin Ⅱ (AⅡ) independently of ACE provide a rationale for inhibiting the deleterious actions of angiotensin Ⅱ at rhe AT1receptor more completely with an ARB[3]. The discoveries of other angiotensin receptors with putatively favorable effects on cardiovascular function and structure support the hypothesis that angiotensin-receptor blockers may offer clinical benefits beyond those achieved with ACEI. Alternatively, since the augmentation of bradykinin levels may also contribute to the net therapeutic benefits of ACEI,concurrent treatment with an ACEI and an ARB might be the most effective strategy. Candesartan is a new kind of ARBs, we hope the efficacy of candesartan plus fosinopril is superior to fosinopril alone to the CHF patients.
MATERIALS AND METHODS
Materials
Sixty men and women, 18 years old or older, with a history and clinical finding of heart failure were eligible to participate in this study. Patients had heart failure of NYHA class Ⅱ～Ⅳ and were clinically stable. They had to have documented left ventricular dysfunction with an ejection fraction of less than 50 percent. The exclusion criteria included pregnancy, acute myocardial infarction, unstable angina, cardiac surgery or percutaneous transluminal angioplasty in the past 3 months,myocarditis bradycardia (heart rate (HR)<50 beats/min ) or hypotension (systolic blood pressure <90 mm Hg ),cerebral vascular accidents within 3 months,clinical important renal, hepatitis or hematological disorder (some study has proved that impaired renal function is independently associated with heightened risk for death,cardiovascular death, and hospitalized for heart failure in patients with CHF both preserved as well as reduced LVEF [5]), any terminal disease with a life expectancy of less than 1 year.
Methods
This is a randomized and controlled study. Eligible patients were randomly assigned in a 1∶1 ratio. The two group have similar distribution of age,sex,primary diseases and other background medications(beta-blockers, Digoxin, diuretics,etc.)(P>0.05). The patients who have used the ACEIs or ARBs must stop to use them for at least 2 weeks. They were assigned candesartan(8 mg/day) plus fosinopril(10 mg/day) and fosinopril(10 mg/day) alone and followed up for 8 weeks. Study visits took place at four-week intervals and the doses were not changed. Baseline evaluations included recording case history, signs,NYHA classes, blood chemistry (potassium, creatinine), indexes of echocardiography (LVEF, LVDd).
Statistical Analysis
Values are present as ±s. The data of our study were analyzed by SPSS 11.5 software. Sex, age, primary diseases and other background medications were analyzed by χ2 test. Changes in LVEF, LVDd, potassium and creatinine following the therapy were tested by t-test.
RESULTS
Three patients, 2 from the mono-therapy group and 1 from the combination therapy group, dropped out leaving 57 patients who could be followed for 8 weeks.
Base-line characteristics of the patients are similar(P>0.05).
Table 1 Baseline Patients Characteristics
Note:SBP systolic blood pressure; HF heart failure;IHD ischemic heart disease;DCM dilated cardiomyopathy
Comparing with the baseline, the SBP and DBP decreased but did not decreased significantly to the same degree in both groups.
Table 2 Blood Pressure(0 week, 4 weeks, 8 weeks)
LVEF increased at 4 weeks and 8 weeks but the two groups are similar comparing with 0 week at 4 weeks.LVEF of the combination therapy group did not decrease significantly at 8 weeks. LVDd of the mono-therapy group did not decrease significantly at 8 weeks. LVDd of the two groups are similar at 4 weeks but the combination therapy group decreased significantly at 8 weeks.
Table 3 LVEF, LVDd(0 week, 4 weeks, 8 weeks)
P1 4 weeks between the two groups, P2 8 weeks between the two groups, P3 compared 0 week with 4 weeks, P4 compared 0 week with 4 weeks
Figure 1 Changes of LVEF Figure 2 Changes of LVDd
Tolerability and Safety
The influence to potassium and creatinine of the two groups are similar (P>0.05). Cough leads 2 patients in the mono-therapy change their treatment.Each group had a patient hospitalization for heart failure.
DISCUSSION
We found that the combination of candesartan[1，2] and fosinopril therapy for 8 weeks at doses which are standard in China improved the LVEF, LVDd. Adding candesartan to standard heart failure treatment, often including an ACEI inhibitor, a β-blocker, or an aldosterone antagonist (or all 3) in CHF patients with LVEF≤40% can still obtain benefits. The trend in the changes in the LVEF, LVDd 8 weeks after therapy is consistent with the results of the multi-center double-blind randomized, paralleled, placebo-controlled trial of the CHARM study [4].CHARM has proved that candesartan significantly reduced all-cause mortality,cardiovascular death,and heart failure hospitalizations in patients with CHF and LVEF ≤40% when added to standard therapies[6].Cardiac function accessed by LVEF, so we can conclude that combination therapy in this study can significantly improve the cardiac function for at least 8 weeks. The superior benefit of LV reverse remodeling was noted with the combination therapy of candesartan and fosinopril through the decrease of LVDd.
In conclusion,this approach offers us an opportunity to make additional improvements in the poor prognosis of CHF patients when left ventricular systolic dysfunction is present by adding this ARB to other treatments that are proven to be efficacious in similar settings.Tolerability and safety are good.
REFERENCES
1. Sever PS. Key features of candesartan cilexetil and a comparison with other angiotensin Ⅱ receptor antagonists. J Hum Hypertens, 1999,12(Suppl 1):S3-S10.
2. Olihara T, Arakawa K. Clinical efficacy and tolerability of candesartan cilexetil. Candesartan Study Groups in Japan. J Hum Hypertens, 1999,12 (Suppl 1):S27-S31.
3. Petrie MC, Padmanabhan N, McDonald JE, Hillier C, Connell JM, McMurray JJ. Aangiotensin converting enzyme(ACE) and nonACE dependent angiotensin Ⅱ generation in resistance arteies from patients with heart failure and coronary heart disease. J Am Coll Cardiol, 2001, 37 : 613-21.
4. Pfeffer MA, Swedberg K, et al. CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure : the CHARM-Overall programme. Lancet, 2003,362(9386):759-66.
5. Hans L. Hillege,MD,et al.Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure.Circulation,2006,113:671-678.
6. James B. Young, MD;Mark E.Dunlap,MD,et al.Mortality and Morbidity Reduction With Candesartan in Patients With Chronic Heart Failure and Left Ventricular Systolic Dysfunction.Circulation,2004,110:2618-2626.
(Editor Emilian)(CHEN Yu-fei, LIANG Xiao-g)
The First Hospital Affiliated to Chinese Medical University, Shenyang, Liaoning Province 110002,China
Correspondence to CHEN Yu-fei, Department of Cardiology,The First Hospital Affiliated to Chinese Medical University, Shenyang, Liaoning Province 110002,China
Tel:+86-24-81630251, E-mail:afei04@eyou.com
[Abstract] Objective To compare the efficacy of fosinopril alone and that of fosinopril combined with candesartan in patients with chronic heart failure.Methods A randomized controlled trial was conducted in this study. Sixty subjects were randomized into two groups, fosinopril alone and fosinopril combined with candesartan were administered. The course of treatment was 8 weeks.Results Compared with fosinopril only and fosinopril plus candesartan, fosinopril plus candesartan has better effects on the following indices : reduction of systolic and diastolic blood pressure(P>0.05), improvement of LVEF and LVDd(P<0.05). The two groups have similar influence on serum levels of potassium and creatinine (P>0.05).Conclusions The efficacy of fosinopril plus candesartan is superior to fosinopril alone on the CHF patients.
[Key words] candesartan; fosinopril; heart failure
INTRODUCTION
Multiple randomized, placebo controlled trials have demonstrated that angiotensin-converting-enzyme(ACE) inhibitors reduce the risk of death as well as the risk of major nonfatal cardiovascular events. Angiotensin-receptor blockers(ARB) offer an alternative approach to the inhibition of the renin-angiotensin system. The identification of a functioning chymase in human that is capable of generating angiotensin Ⅱ (AⅡ) independently of ACE provide a rationale for inhibiting the deleterious actions of angiotensin Ⅱ at rhe AT1receptor more completely with an ARB[3]. The discoveries of other angiotensin receptors with putatively favorable effects on cardiovascular function and structure support the hypothesis that angiotensin-receptor blockers may offer clinical benefits beyond those achieved with ACEI. Alternatively, since the augmentation of bradykinin levels may also contribute to the net therapeutic benefits of ACEI,concurrent treatment with an ACEI and an ARB might be the most effective strategy. Candesartan is a new kind of ARBs, we hope the efficacy of candesartan plus fosinopril is superior to fosinopril alone to the CHF patients.
MATERIALS AND METHODS
Materials
Sixty men and women, 18 years old or older, with a history and clinical finding of heart failure were eligible to participate in this study. Patients had heart failure of NYHA class Ⅱ～Ⅳ and were clinically stable. They had to have documented left ventricular dysfunction with an ejection fraction of less than 50 percent. The exclusion criteria included pregnancy, acute myocardial infarction, unstable angina, cardiac surgery or percutaneous transluminal angioplasty in the past 3 months,myocarditis bradycardia (heart rate (HR)<50 beats/min ) or hypotension (systolic blood pressure <90 mm Hg ),cerebral vascular accidents within 3 months,clinical important renal, hepatitis or hematological disorder (some study has proved that impaired renal function is independently associated with heightened risk for death,cardiovascular death, and hospitalized for heart failure in patients with CHF both preserved as well as reduced LVEF [5]), any terminal disease with a life expectancy of less than 1 year.
Methods
This is a randomized and controlled study. Eligible patients were randomly assigned in a 1∶1 ratio. The two group have similar distribution of age,sex,primary diseases and other background medications(beta-blockers, Digoxin, diuretics,etc.)(P>0.05). The patients who have used the ACEIs or ARBs must stop to use them for at least 2 weeks. They were assigned candesartan(8 mg/day) plus fosinopril(10 mg/day) and fosinopril(10 mg/day) alone and followed up for 8 weeks. Study visits took place at four-week intervals and the doses were not changed. Baseline evaluations included recording case history, signs,NYHA classes, blood chemistry (potassium, creatinine), indexes of echocardiography (LVEF, LVDd).
Statistical Analysis
Values are present as ±s. The data of our study were analyzed by SPSS 11.5 software. Sex, age, primary diseases and other background medications were analyzed by χ2 test. Changes in LVEF, LVDd, potassium and creatinine following the therapy were tested by t-test.
RESULTS
Three patients, 2 from the mono-therapy group and 1 from the combination therapy group, dropped out leaving 57 patients who could be followed for 8 weeks.
Base-line characteristics of the patients are similar(P>0.05).
Table 1 Baseline Patients Characteristics
Note:SBP systolic blood pressure; HF heart failure;IHD ischemic heart disease;DCM dilated cardiomyopathy
Comparing with the baseline, the SBP and DBP decreased but did not decreased significantly to the same degree in both groups.
Table 2 Blood Pressure(0 week, 4 weeks, 8 weeks)
LVEF increased at 4 weeks and 8 weeks but the two groups are similar comparing with 0 week at 4 weeks.LVEF of the combination therapy group did not decrease significantly at 8 weeks. LVDd of the mono-therapy group did not decrease significantly at 8 weeks. LVDd of the two groups are similar at 4 weeks but the combination therapy group decreased significantly at 8 weeks.
Table 3 LVEF, LVDd(0 week, 4 weeks, 8 weeks)
P1 4 weeks between the two groups, P2 8 weeks between the two groups, P3 compared 0 week with 4 weeks, P4 compared 0 week with 4 weeks
Figure 1 Changes of LVEF Figure 2 Changes of LVDd
Tolerability and Safety
The influence to potassium and creatinine of the two groups are similar (P>0.05). Cough leads 2 patients in the mono-therapy change their treatment.Each group had a patient hospitalization for heart failure.
DISCUSSION
We found that the combination of candesartan[1，2] and fosinopril therapy for 8 weeks at doses which are standard in China improved the LVEF, LVDd. Adding candesartan to standard heart failure treatment, often including an ACEI inhibitor, a β-blocker, or an aldosterone antagonist (or all 3) in CHF patients with LVEF≤40% can still obtain benefits. The trend in the changes in the LVEF, LVDd 8 weeks after therapy is consistent with the results of the multi-center double-blind randomized, paralleled, placebo-controlled trial of the CHARM study [4].CHARM has proved that candesartan significantly reduced all-cause mortality,cardiovascular death,and heart failure hospitalizations in patients with CHF and LVEF ≤40% when added to standard therapies[6].Cardiac function accessed by LVEF, so we can conclude that combination therapy in this study can significantly improve the cardiac function for at least 8 weeks. The superior benefit of LV reverse remodeling was noted with the combination therapy of candesartan and fosinopril through the decrease of LVDd.
In conclusion,this approach offers us an opportunity to make additional improvements in the poor prognosis of CHF patients when left ventricular systolic dysfunction is present by adding this ARB to other treatments that are proven to be efficacious in similar settings.Tolerability and safety are good.
REFERENCES
1. Sever PS. Key features of candesartan cilexetil and a comparison with other angiotensin Ⅱ receptor antagonists. J Hum Hypertens, 1999,12(Suppl 1):S3-S10.
2. Olihara T, Arakawa K. Clinical efficacy and tolerability of candesartan cilexetil. Candesartan Study Groups in Japan. J Hum Hypertens, 1999,12 (Suppl 1):S27-S31.
3. Petrie MC, Padmanabhan N, McDonald JE, Hillier C, Connell JM, McMurray JJ. Aangiotensin converting enzyme(ACE) and nonACE dependent angiotensin Ⅱ generation in resistance arteies from patients with heart failure and coronary heart disease. J Am Coll Cardiol, 2001, 37 : 613-21.
4. Pfeffer MA, Swedberg K, et al. CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure : the CHARM-Overall programme. Lancet, 2003,362(9386):759-66.
5. Hans L. Hillege,MD,et al.Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure.Circulation,2006,113:671-678.
6. James B. Young, MD;Mark E.Dunlap,MD,et al.Mortality and Morbidity Reduction With Candesartan in Patients With Chronic Heart Failure and Left Ventricular Systolic Dysfunction.Circulation,2004,110:2618-2626.
(Editor Emilian)(CHEN Yu-fei, LIANG Xiao-g)