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Comparison of angiotensin-converting enzyme inhibitor alone and in combination with irbesartan for the treatment of heart failure
International Journal of Cardiology 125 (2008) 16 – 21 www.elsevier.com/locate/ijcard
Comparison of angiotensin-converting enzyme inhibitor alone and in combination with irbesartan for the treatment of heart failure Leo Chi-Chiu Kum, Gabriel Wai-Kwok Yip, Pui-Wai Lee, Yat-Yin Lam, Eugene B. Wu, Anna Kin-Yin Chan, Jeffrey Wing-Hong Fung, Joseph Yat-Sun Chan, Qing Zhang, Shun-Ling Kong, Cheuk-Man Yu ⁎ Division of Cardiology, SH Ho Cardiovascular and Stroke Centre, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Received 20 July 2006; received in revised form 12 January 2007; accepted 17 February 2007 Available online 16 April 2007
Abstract Objective: Angiotensin-converting enzyme inhibitor (ACEI) is beneficial in patients with congestive heart failure (CHF). Some, but not all, angiotensin receptor blocker (ARB) was demonstrated to be effective as “add-on” therapy. We investigated whether irbesartan is useful as an add-on therapy in CHF. Design: Randomized control trial. Setting: Single center. Patients: 50 CHF patients on stable doses of ACEI. Interventions: Add-on therapy with irbesartan (300 mg/day) or continuation of conventional therapy (control group) for 1 year. Main outcome measures: Serial clinical and echocardiographic assessment were performed as baseline, 3 months and 1 year after therapy. Results: There was no difference in clinical characteristics between 2 groups. Patients in the add-on therapy group had significant increase in 6-Minute Hall-Walk distance (351 ± 89 to 392 ± 84 m, P b 0.01), achieved higher METs exercise time on treadmill test (3.9 ± 1.1 to 4.6 ± 1.3 METs, P = 0.01), reduction of NYHA Class (2.4 ± 0.5 to 2.0 ± 0.8, P b 0.005) and improvement of QOL score (28 ± 19 to 17 ± 18, P b 0.05). These parameters were not improved in the control group and a worsening of exercise capacity was observed (P b 0.05). A reduction of left ventricular end-systolic diameter (4.94 ± 0.85 vs 4.30 ± 1.17 cm, P b 0.05) was observed in the add-on group. At the end of 1 year, more patients have normal or abnormal relaxation pattern in the add-on group than the control group (82% vs 53% χ2 = 7.1, P = 0.02). Blood pressure and renal function were unchanged in both groups. Conclusion: The addition of irbesartan to conventional ACEI therapy in CHF further improves symptoms, exercise capacity and quality of life without adverse effects on hemodynamics and renal function. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Heart failure; Angiotensin-converting enzyme inhibitor; Angiotensin receptor blocker; Echocardiography
1. Introduction Angiotensin II plays an important role in the pathogenesis of chronic heart failure. Many clinical trials have demonstrated benefits of angiotensin-converting enzyme inhibitors (ACEI) on morbidity and mortality of chronic heart failure ⁎ Corresponding author. Tel.: +852 2632 3594; fax: +852 2637 5643. E-mail address: [email protected] (C.-M. Yu). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.02.016
[1–3]. However, despite the use of ACEI, β-blockers and spironolactone, hospitalization related to heart failure is still common and the mortality is still high [4]. Given the fact that ACEI cannot achieve complete blockade of the effect of Angiotensin II in the heart and blood vessels [5,6], addition of angiotensin receptor blockers (ARB) may supplement the inhibition of Angiotensin II and hence provides further clinical benefits. Several trials had been conducted to test this hypothesis utilizing different ARB. In the Valsartan Heart
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Failure Trial (VAL-HeFT), valsartan was shown to reduce the combined end-point of mortality and morbidity and improved clinical signs and symptoms in patients with heart failure [7]. However, the post hoc observation of an adverse effect on mortality and morbidity in the subgroup receiving valsartan, ACEI and β-blocker raises concern about the potential safety of this specific combination. In the CHARMAdded trial [8], the addition of candesartan to ACEI and other standard treatment leads to further clinically important reduction in relevant cardiovascular events in patients with chronic heart failure and reduced left-ventricular ejection fraction. Our study aimed to determine whether the addition of irbesartan, another ARB, to conventional treatment for chronic heart failure with reduced left ventricular ejection fraction can provide extra benefits in terms of clinical outcome and echocardiographic parameters. 2. Methods 2.1. Patients Fifty consecutive patients with chronic stable heart failure being followed up in the heart failure clinic of a university teaching hospital were recruited. They were suffering from left ventricular systolic dysfunction with an ejection fraction b 50% and already put on regular ACEI therapy for at least 3 months. These patients had moderate heart failure with New York Heart Association class II or III. Previous heart failure symptoms were adjudicated by typical signs and symptoms, and radiological appearance of pulmonary congestion. The etiology was ischemic in 33 (66%) patients and non-ischemic in 17 (34%) patients. These patients had been put on stable anti-heart failure medication for at least 3 months. The use of medications was compatible with current practice (Table 1). Change of medications was discouraged during the study period. Exclusion criteria including patients with recent acute coronary syndrome, recent percutaneous coronary intervention or recent heart failure decompensation within 3 months of study enrolment; patients with major systemic illness; and patients with malignancy or disease with survival likely to be less than 1 year. The Ethics Committee of the institution approved the study protocol, and all patients gave written informed consent. 2.2. Protocol Patients were randomly assigned to add-on therapy with irbesartan (300 mg daily) or continuation of conventional therapy (control group) for a period of 1 year. Randomization was carried out with a computer-generated list of random numbers. The patients were aware of the treatment assignment since we did not use placebo tablets for those assigned to conventional therapy. Baseline assessment including NYHA class, 6-Minute Hall-Walk test (6MHW) and Minnesota Living with Heart Failure Questionnaire for
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quality of life assessment and peak exercise capacity (metabolic equivalents achieved, or METs) on the treadmill test according to Chronotropic Assessment Exercise Protocol. These assessments of functional exercise capacities did not take into account of body weight and composition because the comparison was made for the same patient at 3 months and 1 year and we did not expect any significant change in these parameters during the follow-up period. During every visit at baseline, 3 months and 1 year, sitting blood pressure was measured after at least 5 minute rest using an validated electronic blood pressure device (Omron Corp. Model HEM-757). All the measurements were made in the same designated room for research clinic patients. In addition, 24-hour ECG monitoring and echocardiography were performed. Standard echocardiography with Doppler studies was performed (Vivid 5, Vingmed-General Electric, Horten, Norway). The LV dimension and ejection fraction were measured by 2-dimension-guided M-mode method according to the guidelines of American Society of Echocardiography [9]. LV diastolic function was performed by Doppler echocardiographic to interrogate the transmitral inflow pattern and standard diastolic parameters [10,11]. All these assessment were performed at 3-month and 1-year follow-up. Staffs involved in the assessment of these clinical and echocardiographic parameters were blinded of the treatment assignment. Table 1 Clinical characteristics of heart failure patients in the add-on and control groups Add-on group Age, years Gender, male: female Etiology of heart failure, ischemic: non-ischemic NYHA class, II:III Hypertension Diabetes mellitus Previous myocardial infarction SBP, mm Hg DBP, mm Hg Left ventricular ejection fraction, % Aspirin Diuretics β-Blocker Nitrate Statin Digoxin ACEI: Perindopril Enalapril Fosinopril Lisinopril Captopril
Control group
P value
66.0 ± 11.3 68.9 ± 9.5 19:6 17:8 17:8 16:9
NS χ2 = 0.40, P = NS χ2 = 0.09, P = NS
14:11 5 (20%) 8 (32%) 9 (36%) 123 ± 21 70 ± 11 35.0 ± 11.8
9:16 4 (16%) 10 (40%) 11 (44%) 123 ± 22 67 ± 14 33.8 ± 12.9
χ2 = 2.01, P = NS χ2 = 0.14, P = NS χ2 = 1.79, P = NS χ2 = 0.33, P = NS NS NS NS
17 (68%) 22 (88%) 16 (64%) 15 (60%) 15 (60%) 3 (12%) 25 (100%) 10 (40%) 4 (16%) 7 (28%) 3 (12%) 1 (4%)
16 (64%) 21 (84%) 16 (64%) 17 (68%) 12 (48%) 2 (8%) 25 (100%) 10 (40%) 4 (16%) 8 (32%) 2 (8%) 1 (4%)
χ2 = 0.09, P = NS χ2 = 0.17, P = NS χ2 = 0.00, P = NS χ2 = 1.48, P = NS χ2 = 1.28, P = NS χ2 = 0.22, P = NS χ2 = 0.00, P = NS χ2 = 1.39, P = NS χ2 = 1.39, P = NS χ2 = 1.39, P = NS χ2 = 1.39, P = NS χ2 = 1.39, P = NS
NYHA, New York Heart Association; MI, myocardial infarction; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; ACEI, angiotensin converting enzyme inhibitor. NS, Not statistically significant.
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2.3. Statistics Data were analyzed using a statistical software program (SPSS for Windows, version 10.0.7, SPSS Inc., Chicago, Illinois, USA). For the comparison of parametric variables at different time-points of assessment, paired sample t-test with Bonferroni correction was used. The comparison of parametric variables between the two treatment groups was performed by unpaired sample t-test. The comparison of categorical data between the two treatment groups was performed by Pearson χ2 test. Life table estimated actuarial survival was calculated by Kaplan–Meier curves where the Log-rank χ2 was estimated. The results were expressed as mean ± standard deviation. A P value b 0.05 was considered as statistically significant. 3. Results There was no difference in age, gender, clinical characteristics as well as baseline clinical and echocardiographic parameters between the add-on and control groups (Table 1). The medications were similar in the two groups, including the prescription pattern of ACEI. Systolic and diastolic blood pressures were similar in both groups at baseline (Table 1). All the patients tolerated the drug without any withdrawal due to major side effect and there was no attrition. 3.1. Clinical assessment In the add-on group, there was significant improvement in NYHA class at 3-month (P b 0.01) and 1-year follow-up (P b 0.005). There was also improvement of 6MHW distance (P b 0.01), maximal METs achieved (P b 0.01) and quality of life score (P b 0.05) at 1-year assessment (Table 2). In the control group, none of the clinical parameters showed the improvement during follow-up. Rather, reduction of maxiTable 2 Changes in clinical parameters at baseline, 3 months and 1 year in the group of add-on therapy with irbesartan
6MHW, m NYHA class METS QOL score Holter: SVE, % VE, % SBP, mm Hg DBP, mm Hg Creatinine, μmol/L
Baseline
3 months
1 year
351 ± 89 2.4 ± 0.5 3.9 ± 1.1 28 ± 19
376 ± 92 2.2 ± 0.4⁎ 4.3 ± 1.2 19 ± 16
392 ± 84⁎ 2.0 ± 0.8† 4.6 ± 1.3⁎ 17 ± 18‡
0.58 ± 1.83 2.86 ± 6.97 123 ± 21 70 ± 11 107 ± 16
0.56 ± 1.27 3.20 ± 6.88 118 ± 20 64 ± 10⁎ 106 ± 19
0.60 ± 1.52 1.31 ± 2.75§ 125 ± 17 67 ± 8 108 ± 15
NYHA, New York Heart Association; METS, Metabolic Equivalent (3.5 mL O2/kg per min), QOL, Quality of Life; SVE, supraventricular ectopics; VE, ventricular ectopics, SBP, systolic blood pressure; DBP, diastolic blood pressure. ⁎P ≤ 0.01 vs baseline, †P ≤ 0.005 vs baseline, ‡P b 0.05 vs baseline, §P = 0.05 vs 3 months.
Table 3 Changes in clinical parameters at baseline, 3 months and 1 year in the control group
6MHW, m NYHA class METS QOL Score Holter SVE, % VE, % SBP DBP Creatinine, μmol/L
Baseline
3 months
1 year
348 ± 73 2.7 ± 0.5 3.9 ± 1.3 26 ± 18
341 ± 69 2.4 ± 0.5 3.6 ± 1.1 22 ± 17
319 ± 106 2.6 ± 0.5 3.1 ± 0.7‡ 20 ± 15
0.69 ± 1.74 1.86 ± 3.26 123 ± 22 67 ± 14 122 ± 30
0.94 ± 1.81 2.05 ± 4.72 127 ± 25 68 ± 15 120 ± 45
1.82 ± 3.29 1.25 ± 1.91 133 ± 27 65 ± 12 124 ± 24
‡
P ≤ 0.005 vs baseline. See Table 2 for abbreviations.
mal exercise capacity was observed at 1-year follow-up (P b 0.005) (Table 3). 24-Hour ECG monitoring revealed a trend of improvement of the percentage of ventricular premature beats in the add-on group between 3-month and 1year follow-up (P = 0.05) (Table 2), without change in the incidence of supraventricular premature beats. There was no change in the incidence of supraventricular or ventricular premature beats in the control group (Table 3). 3.2. Systolic and diastolic functions In the add-on group, an increase in ejection fraction was observed in both time-points and it reached statistical significance at 3 months. For left ventricular (LV) dimensions, a significant decrease in LV end-systolic diameter was observed at 1 year, while a borderline decrease in LV enddiastolic diameter was also observed (Table 4). By contrast, no improvement was observed in the control group, rather, an increase in left atrial diameter was observed at 1 year (P = 0.02 vs baseline) (Table 5). Table 4 Changes in echocardiographic parameters at baseline, 3 months and 1 year in the group of add-on therapy with irbesartan
FS, % EF, % LVDs, cm LVDd, cm LAD, cm MV-E, cm/s MV-A, cm/s E/A DT, ms IVRT, ms
Baseline
3 months
1 year
18.1 ± 7.4 35.0 ± 11.8 4.94 ± 0.85 5.96 ± 0.83 4.02 ± 0.69 60.4 ± 15.7 72.7 ± 18.9 0.94 ± 0.45 235 ± 88 119 ± 30
21.3 ± 7.1 42.1 ± 11.7⁎ 4.61 ± 1.08 5.81 ± 1.06 3.95 ± 0.96 61.3 ± 11.8 80.2 ± 21.3§ 0.77 ± 0.21 241 ± 61 115 ± 32
21.4 ± 6.4 39.9 ± 17.5 4.30 ± 1.17† 5.57 ± 0.91‡ 3.87 ± 0.60 54.2 ± 19.9 76.1 ± 20.8 0.80 ± 0.24 238 ± 67 122 ± 34
FS, Fractional shortening; EF, ejection fraction; LVDs, left ventricular endsystolic diameter; LVDd, left ventricular end-diastolic diameter; LAD, left atrial diameter; MV-E, peak transmitral early diastolic filling velocity; MVA, peak transmitral atrial filling velocity; E/A, ratio of MV-E to MV-A; DT, deceleration time; IVRT, isovolumic relaxation time. ⁎P = 0.02 vs baseline, †P = 0.02 vs baseline, ‡P = 0.06 vs baseline, §P = 0.01 vs baseline.
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With respect to diastolic function, it was present in all the heart failure patients, with abnormal relaxation pattern in 84%, pseudonormal in 5% and restrictive filling pattern in 11% in the add-on group, and was 63%, 16% and 21% respectively in the control group, without inter-group difference in prevalence (χ2 = 1.9, P = NS). At the end of 1 year, the prevalence was changed with a normal pattern in 9%, ARP in 73%, pseudonormal in 9% and RFP in 9% in the add-on group, and was 0%, 53%, 5% and 42% respectively in the control group, which was significant between the two groups (χ2 = 7.1, P = 0.02). For individual diastolic parameters, there was a significant increase in peak transmitral atrial filling velocity after 3 months (P = 0.01) in the add-on group, though it was not significant at 12 months (Table 4). Other parameters of LV diastolic function remain unchanged. In the control group, there was no change in LV diastolic parameters throughout the study period (Table 5). 3.3. Clinical outcome In the add-on group, 2 patients died, 1 due to sudden cardiac death and the other due to septicemia. In the control group, 1 patient died of sudden cardiac death. There were 12 patients who had hospitalization due to cardiovascular causes, with 10 due to decompensated heart failure, 1 with acute myocardial infarction and 1 with unstable angina pectoris. When the composite endpoint of mortality and/or cardiovascular hospitalization was compared, there was a trend towards a lower event rate in the add-on group (20% vs 40%, Log-rank χ2 = 2.71, P = 0.099) (Fig. 1). 3.4. Effect on blood pressure and renal function In both the add-on and the control groups, blood pressure did not change significantly during 1-year follow-up. However, in the add-on group, the diastolic blood pressure was slightly but significantly lower at 3 months but not 1 year. (64 ± 10 mm Hg at 3 months vs 70 ± 11 mm Hg at baseline, P b 0.01 by paired sample t-test with Bonferroni
Table 5 Changes in echocardiographic parameters at baseline, 3 months and 1 year in the control group
FS, % EF, % LVDs, cm LVDd, cm LAD, cm MV-E, cm/s MV-A, cm/s E/A DT, ms IVRT, ms
Baseline
3 months
1 year
16.3 ± 8.3 33.8 ± 12.9 4.99 ± 1.04 6.08 ± 0.86 4.16 ± 0.72 70.4 ± 33.5 72.2 ± 27.4 1.18 ± 0.85 218 ± 75 108 ± 56
18.1 ± 8.3 36.4 ± 14.4 4.94 ± 1.05 5.97 ± 0.91 4.07 ± 0.61 73.7 ± 26.5 73.2 ± 28.5 1.24 ± 1.03 185 ± 92 132 ± 73
18.7 ± 6.5 38.1 ± 10.3 4.74 ± 1.23 6.12 ± 1.03 4.41 ± 0.56⁎† 74.9 ± 24.0 78.4 ± 21.7 1.08 ± 0.75 220 ± 79 127 ± 44
⁎P = 0.02 vs baseline, †P = 0.004 vs 3 months. See Table 4 for abbreviations.
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Fig. 1. Actuarial cardiovascular event-free survival curve for add-on therapy and control groups.
correction Table 2.) Renal function in terms of serum creatinine was not affected during the follow-up period in both groups. Significant hyperkalaemia needing treatment was not found in both groups. 4. Discussion This study investigated the effect of the addition of irbesartan to conventional therapy in terms of symptomatic improvement, change of echocardiographic parameters and cardiovascular morbidity and mortality in patients with moderate heart failure. All of the patients recruited into this study had been adequately treated with ACEI for at least 3 months while 64% of our patients had been treated with beta-blockers. No patients were taking spironolactone during the study period because spironolactone therapy for heart failure was not commonly practiced in the study center at that time. This study showed that add-on therapy of irbesartan could improve heart failure symptoms on top of conventional treatment by ACEI and beta-blocker, without any apparent adverse effects on blood pressure and renal function. The NYHA class of patients treated with add-on therapy improved from the mean of 2.4 to the mean of 2.0 over the 1-year study period (P b 0.005), whereas there is no significant improvement of NYHA class of patients treated with conventional therapy over the 1-year study period (2.7 at baseline vs 2.6 at 1 year, P = NS). Add-on therapy could also significantly improve exercise tolerance assessed by 6Minute Hall-Walk distance and treadmill exercise test as shown in Table 2. These changes could have a positive impact on patients' activity of daily living and quality of life and this was reflected by the significant improvement of QOL score at 1 year (Table 2). Apart from symptomatic improvement, irbesartan add-on therapy might retard the progression of left ventricular remodeling in chronic heart failure patients. A significant reduction in left ventricular end-systolic diameter at 12 months was observed in the irbesartan add-on group
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and there was a borderline reduction in left ventricular enddiastolic diameter. Improvement of ejection fraction was also observed at 3-month follow-up. Although this study was conducted with a relatively small patient number for a modest period of follow-up, such benefit on left ventricular function is already evident. For diastolic assessment, marked increase in the proportion of patient having a restrictive filling pattern over the study period was observed in the control group (21% at baseline raised to 42% at 12 months) whereas proportion of patients having a restrictive filling pattern in diastole was similar in the add-on group at both baseline and at 12 months. This finding suggests that irbesartan add-on therapy might be able to retard the progression of diastolic dysfunction in chronic moderate heart failure patients. The increase in left atrial size in 12-month follow-up in the control group indicates an increased atrial filling pressure, which is commonly observed in restrictive filling pattern of diastolic dysfunction [10]. As diastolic dysfunction is another determinant of prognosis in patients with systolic heart failure [12], this may implicate on a more favorable prognosis which need to be substantiated by further studies. This study is not powered to compare the difference in outcome in the 2 treatment groups. However, a trend of improved clinical outcome was also observed in the add-on group, with a 50% lower in the relative risk for combined end-point of mortality and cardiovascular events. The difference is mainly due to a lower cardiovascular hospitalizations but not mortality. Our findings have suggested that addition of irbesartan might confer additional benefits to conventional therapy for chronic heart failure without any apparent adverse effects on renal function and blood pressure. Although it may not be a class effect, the beneficial role of valsartan and candesartan to improve heart failure hospitalization have been reported in large, multicenter, controlled trials [7,8]. In the VAL-HeFT trial which evaluated the add-on effect of valsartan to class II and III heart failure treatments, there was reduction in hospitalizations and improvement of NYHA class, quality of life, as well as symptoms and signs of heart failure [7]. However, the study failed to demonstrate an improvement in mortality and the post-hoc observation of an adverse effect on morbidity and mortality was observed in the subgroup receiving valsartan, ACEI and beta-blocker raises concern about the potential safety of this specific combination. In VAL-HeFT trial, usage of ACEI was 93% but was only 35% for beta-blocker. In contrast, in the current study 64% of patients received beta-blockers and all of the patients received ACEI for at least 3 months before recruitment. Even in the setting of such high rate of beta-blockade and ACE inhibition, add-on treatment with irbesartan has beneficial effect on soft clinical end-points similar to that of VAL-HeFT. In fact, VAL-HeFT study also demonstrated a reduction of LV diameter and gain in ejection fraction starting from 3 months to 24 months which were similar to our observations [13]. However, in VAL-HeFT study only
the subgroup that had been put on ACEI and beta-blocker did not show left ventricular reverse remodelling. Therefore, the definite benefits of add-on irbesartan therapy need to be confirmed by large, randomized, controlled study. In the CHARM-Added trial, nearly 100% of the study subjects were taking ACEI, 56% were taking beta-blockers and 17% of patients were taking spironolactone [8]. In addition to the beneficial effects shown by our study and ValHeFT, this trial also demonstrated significant reduction in cardiovascular death over 3.5 years. This result, as different from those observed in other multicenter trials of heart failure with ARB therapy, illustrates the potential difference in therapeutic efficacy of different ARBs which is more than a “class effect” [7,14]. 4.1. Limitation of the study Our study has several limitations. First of all, the small sample size was not intended to demonstrate significant difference of cardiovascular outcome between the add-on and the control groups. Therefore, the study rather focused primarily on soft clinical end-points and echocardiographic assessment. Secondly, the relatively short follow-up period did not provide data on the sustained benefits of add-on irbesartan therapy beyond one year. Thirdly, our patients were not blinded of treatment assignments. This may create bias due to placebo effect in the functional assessment. Fourthly, none of the patients was taking spironolactone during the study period; therefore, this study could not evaluate the effect of combination of irbesartan and spironolactone. 5. Conclusion In conclusion, irbesartan add-on therapy on top of ACEI and beta-blockers in the treatment of systolic heart failure could further improve symptoms, exercise capacity and quality of life. It may have extra benefits in the regression of left ventricular remodeling and deterioration of cardiac systolic and diastolic function. Addition of irbesartan 300 mg daily also appears to have no significant adverse effects on blood pressure and renal function. References [1] The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302. [2] The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429–35. [3] Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303–10. [4] Popovic JR, Kozak LJ. National Hospital Discharge Survey: annual summary, 1998. Vital and health statistics. Series 13, vol. 148. Washington, D.C.: Government Printing Office; September 2000. DHHS publication no. (PHS) 2000-1719.
L.C.-C. Kum et al. / International Journal of Cardiology 125 (2008) 16–21 [5] Kawamura M, Imanashi M, Matsushima Y, et al. Circulating angiotensin II levels under repeated administration of lisinopril in normal subjects. Clin Exp Pharmacol Physiol 1992;19:547–53. [6] Jorde UP, Ennezat PV, Lisker J, et al. Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation 2000;101:844–6. [7] Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–75. [8] McMurray JJ, 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 CHARMAdded trial. Lancet 2003;362:767–71. [9] Sahn DJ, DeMaria A, Kisslo J, et al. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072–83. [10] Yu CM, Sanderson JE, Shum IO, et al. Diastolic dysfunction and natriuretic peptides in systolic heart failure. Higher ANP and BNP
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levels are associated with the restrictive filling pattern. Eur Heart J 1996;17:1694–702. Yu CM, Lin H, Yang H, et al. Progression of systolic abnormalities in patients with “isolated” diastolic heart failure and diastolic dysfunction. Circulation 2002;105:1195–201. Yu CM, Sanderson JE. Different prognostic significance of right and left ventricular diastolic dysfunction in heart failure. Clin Cardiol 1999;22:504–12. Wong M, Staszewsky L, Latini R, et al. Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol 2002;40:970–5. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial — the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582–7.
Comparison of angiotensin-converting enzyme inhibitor alone and in combination with irbesartan for the treatment of heart failure Leo Chi-Chiu Kum, Gabriel Wai-Kwok Yip, Pui-Wai Lee, Yat-Yin Lam, Eugene B. Wu, Anna Kin-Yin Chan, Jeffrey Wing-Hong Fung, Joseph Yat-Sun Chan, Qing Zhang, Shun-Ling Kong, Cheuk-Man Yu ⁎ Division of Cardiology, SH Ho Cardiovascular and Stroke Centre, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Received 20 July 2006; received in revised form 12 January 2007; accepted 17 February 2007 Available online 16 April 2007
Abstract Objective: Angiotensin-converting enzyme inhibitor (ACEI) is beneficial in patients with congestive heart failure (CHF). Some, but not all, angiotensin receptor blocker (ARB) was demonstrated to be effective as “add-on” therapy. We investigated whether irbesartan is useful as an add-on therapy in CHF. Design: Randomized control trial. Setting: Single center. Patients: 50 CHF patients on stable doses of ACEI. Interventions: Add-on therapy with irbesartan (300 mg/day) or continuation of conventional therapy (control group) for 1 year. Main outcome measures: Serial clinical and echocardiographic assessment were performed as baseline, 3 months and 1 year after therapy. Results: There was no difference in clinical characteristics between 2 groups. Patients in the add-on therapy group had significant increase in 6-Minute Hall-Walk distance (351 ± 89 to 392 ± 84 m, P b 0.01), achieved higher METs exercise time on treadmill test (3.9 ± 1.1 to 4.6 ± 1.3 METs, P = 0.01), reduction of NYHA Class (2.4 ± 0.5 to 2.0 ± 0.8, P b 0.005) and improvement of QOL score (28 ± 19 to 17 ± 18, P b 0.05). These parameters were not improved in the control group and a worsening of exercise capacity was observed (P b 0.05). A reduction of left ventricular end-systolic diameter (4.94 ± 0.85 vs 4.30 ± 1.17 cm, P b 0.05) was observed in the add-on group. At the end of 1 year, more patients have normal or abnormal relaxation pattern in the add-on group than the control group (82% vs 53% χ2 = 7.1, P = 0.02). Blood pressure and renal function were unchanged in both groups. Conclusion: The addition of irbesartan to conventional ACEI therapy in CHF further improves symptoms, exercise capacity and quality of life without adverse effects on hemodynamics and renal function. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Heart failure; Angiotensin-converting enzyme inhibitor; Angiotensin receptor blocker; Echocardiography
1. Introduction Angiotensin II plays an important role in the pathogenesis of chronic heart failure. Many clinical trials have demonstrated benefits of angiotensin-converting enzyme inhibitors (ACEI) on morbidity and mortality of chronic heart failure ⁎ Corresponding author. Tel.: +852 2632 3594; fax: +852 2637 5643. E-mail address: [email protected] (C.-M. Yu). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.02.016
[1–3]. However, despite the use of ACEI, β-blockers and spironolactone, hospitalization related to heart failure is still common and the mortality is still high [4]. Given the fact that ACEI cannot achieve complete blockade of the effect of Angiotensin II in the heart and blood vessels [5,6], addition of angiotensin receptor blockers (ARB) may supplement the inhibition of Angiotensin II and hence provides further clinical benefits. Several trials had been conducted to test this hypothesis utilizing different ARB. In the Valsartan Heart
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Failure Trial (VAL-HeFT), valsartan was shown to reduce the combined end-point of mortality and morbidity and improved clinical signs and symptoms in patients with heart failure [7]. However, the post hoc observation of an adverse effect on mortality and morbidity in the subgroup receiving valsartan, ACEI and β-blocker raises concern about the potential safety of this specific combination. In the CHARMAdded trial [8], the addition of candesartan to ACEI and other standard treatment leads to further clinically important reduction in relevant cardiovascular events in patients with chronic heart failure and reduced left-ventricular ejection fraction. Our study aimed to determine whether the addition of irbesartan, another ARB, to conventional treatment for chronic heart failure with reduced left ventricular ejection fraction can provide extra benefits in terms of clinical outcome and echocardiographic parameters. 2. Methods 2.1. Patients Fifty consecutive patients with chronic stable heart failure being followed up in the heart failure clinic of a university teaching hospital were recruited. They were suffering from left ventricular systolic dysfunction with an ejection fraction b 50% and already put on regular ACEI therapy for at least 3 months. These patients had moderate heart failure with New York Heart Association class II or III. Previous heart failure symptoms were adjudicated by typical signs and symptoms, and radiological appearance of pulmonary congestion. The etiology was ischemic in 33 (66%) patients and non-ischemic in 17 (34%) patients. These patients had been put on stable anti-heart failure medication for at least 3 months. The use of medications was compatible with current practice (Table 1). Change of medications was discouraged during the study period. Exclusion criteria including patients with recent acute coronary syndrome, recent percutaneous coronary intervention or recent heart failure decompensation within 3 months of study enrolment; patients with major systemic illness; and patients with malignancy or disease with survival likely to be less than 1 year. The Ethics Committee of the institution approved the study protocol, and all patients gave written informed consent. 2.2. Protocol Patients were randomly assigned to add-on therapy with irbesartan (300 mg daily) or continuation of conventional therapy (control group) for a period of 1 year. Randomization was carried out with a computer-generated list of random numbers. The patients were aware of the treatment assignment since we did not use placebo tablets for those assigned to conventional therapy. Baseline assessment including NYHA class, 6-Minute Hall-Walk test (6MHW) and Minnesota Living with Heart Failure Questionnaire for
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quality of life assessment and peak exercise capacity (metabolic equivalents achieved, or METs) on the treadmill test according to Chronotropic Assessment Exercise Protocol. These assessments of functional exercise capacities did not take into account of body weight and composition because the comparison was made for the same patient at 3 months and 1 year and we did not expect any significant change in these parameters during the follow-up period. During every visit at baseline, 3 months and 1 year, sitting blood pressure was measured after at least 5 minute rest using an validated electronic blood pressure device (Omron Corp. Model HEM-757). All the measurements were made in the same designated room for research clinic patients. In addition, 24-hour ECG monitoring and echocardiography were performed. Standard echocardiography with Doppler studies was performed (Vivid 5, Vingmed-General Electric, Horten, Norway). The LV dimension and ejection fraction were measured by 2-dimension-guided M-mode method according to the guidelines of American Society of Echocardiography [9]. LV diastolic function was performed by Doppler echocardiographic to interrogate the transmitral inflow pattern and standard diastolic parameters [10,11]. All these assessment were performed at 3-month and 1-year follow-up. Staffs involved in the assessment of these clinical and echocardiographic parameters were blinded of the treatment assignment. Table 1 Clinical characteristics of heart failure patients in the add-on and control groups Add-on group Age, years Gender, male: female Etiology of heart failure, ischemic: non-ischemic NYHA class, II:III Hypertension Diabetes mellitus Previous myocardial infarction SBP, mm Hg DBP, mm Hg Left ventricular ejection fraction, % Aspirin Diuretics β-Blocker Nitrate Statin Digoxin ACEI: Perindopril Enalapril Fosinopril Lisinopril Captopril
Control group
P value
66.0 ± 11.3 68.9 ± 9.5 19:6 17:8 17:8 16:9
NS χ2 = 0.40, P = NS χ2 = 0.09, P = NS
14:11 5 (20%) 8 (32%) 9 (36%) 123 ± 21 70 ± 11 35.0 ± 11.8
9:16 4 (16%) 10 (40%) 11 (44%) 123 ± 22 67 ± 14 33.8 ± 12.9
χ2 = 2.01, P = NS χ2 = 0.14, P = NS χ2 = 1.79, P = NS χ2 = 0.33, P = NS NS NS NS
17 (68%) 22 (88%) 16 (64%) 15 (60%) 15 (60%) 3 (12%) 25 (100%) 10 (40%) 4 (16%) 7 (28%) 3 (12%) 1 (4%)
16 (64%) 21 (84%) 16 (64%) 17 (68%) 12 (48%) 2 (8%) 25 (100%) 10 (40%) 4 (16%) 8 (32%) 2 (8%) 1 (4%)
χ2 = 0.09, P = NS χ2 = 0.17, P = NS χ2 = 0.00, P = NS χ2 = 1.48, P = NS χ2 = 1.28, P = NS χ2 = 0.22, P = NS χ2 = 0.00, P = NS χ2 = 1.39, P = NS χ2 = 1.39, P = NS χ2 = 1.39, P = NS χ2 = 1.39, P = NS χ2 = 1.39, P = NS
NYHA, New York Heart Association; MI, myocardial infarction; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; ACEI, angiotensin converting enzyme inhibitor. NS, Not statistically significant.
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2.3. Statistics Data were analyzed using a statistical software program (SPSS for Windows, version 10.0.7, SPSS Inc., Chicago, Illinois, USA). For the comparison of parametric variables at different time-points of assessment, paired sample t-test with Bonferroni correction was used. The comparison of parametric variables between the two treatment groups was performed by unpaired sample t-test. The comparison of categorical data between the two treatment groups was performed by Pearson χ2 test. Life table estimated actuarial survival was calculated by Kaplan–Meier curves where the Log-rank χ2 was estimated. The results were expressed as mean ± standard deviation. A P value b 0.05 was considered as statistically significant. 3. Results There was no difference in age, gender, clinical characteristics as well as baseline clinical and echocardiographic parameters between the add-on and control groups (Table 1). The medications were similar in the two groups, including the prescription pattern of ACEI. Systolic and diastolic blood pressures were similar in both groups at baseline (Table 1). All the patients tolerated the drug without any withdrawal due to major side effect and there was no attrition. 3.1. Clinical assessment In the add-on group, there was significant improvement in NYHA class at 3-month (P b 0.01) and 1-year follow-up (P b 0.005). There was also improvement of 6MHW distance (P b 0.01), maximal METs achieved (P b 0.01) and quality of life score (P b 0.05) at 1-year assessment (Table 2). In the control group, none of the clinical parameters showed the improvement during follow-up. Rather, reduction of maxiTable 2 Changes in clinical parameters at baseline, 3 months and 1 year in the group of add-on therapy with irbesartan
6MHW, m NYHA class METS QOL score Holter: SVE, % VE, % SBP, mm Hg DBP, mm Hg Creatinine, μmol/L
Baseline
3 months
1 year
351 ± 89 2.4 ± 0.5 3.9 ± 1.1 28 ± 19
376 ± 92 2.2 ± 0.4⁎ 4.3 ± 1.2 19 ± 16
392 ± 84⁎ 2.0 ± 0.8† 4.6 ± 1.3⁎ 17 ± 18‡
0.58 ± 1.83 2.86 ± 6.97 123 ± 21 70 ± 11 107 ± 16
0.56 ± 1.27 3.20 ± 6.88 118 ± 20 64 ± 10⁎ 106 ± 19
0.60 ± 1.52 1.31 ± 2.75§ 125 ± 17 67 ± 8 108 ± 15
NYHA, New York Heart Association; METS, Metabolic Equivalent (3.5 mL O2/kg per min), QOL, Quality of Life; SVE, supraventricular ectopics; VE, ventricular ectopics, SBP, systolic blood pressure; DBP, diastolic blood pressure. ⁎P ≤ 0.01 vs baseline, †P ≤ 0.005 vs baseline, ‡P b 0.05 vs baseline, §P = 0.05 vs 3 months.
Table 3 Changes in clinical parameters at baseline, 3 months and 1 year in the control group
6MHW, m NYHA class METS QOL Score Holter SVE, % VE, % SBP DBP Creatinine, μmol/L
Baseline
3 months
1 year
348 ± 73 2.7 ± 0.5 3.9 ± 1.3 26 ± 18
341 ± 69 2.4 ± 0.5 3.6 ± 1.1 22 ± 17
319 ± 106 2.6 ± 0.5 3.1 ± 0.7‡ 20 ± 15
0.69 ± 1.74 1.86 ± 3.26 123 ± 22 67 ± 14 122 ± 30
0.94 ± 1.81 2.05 ± 4.72 127 ± 25 68 ± 15 120 ± 45
1.82 ± 3.29 1.25 ± 1.91 133 ± 27 65 ± 12 124 ± 24
‡
P ≤ 0.005 vs baseline. See Table 2 for abbreviations.
mal exercise capacity was observed at 1-year follow-up (P b 0.005) (Table 3). 24-Hour ECG monitoring revealed a trend of improvement of the percentage of ventricular premature beats in the add-on group between 3-month and 1year follow-up (P = 0.05) (Table 2), without change in the incidence of supraventricular premature beats. There was no change in the incidence of supraventricular or ventricular premature beats in the control group (Table 3). 3.2. Systolic and diastolic functions In the add-on group, an increase in ejection fraction was observed in both time-points and it reached statistical significance at 3 months. For left ventricular (LV) dimensions, a significant decrease in LV end-systolic diameter was observed at 1 year, while a borderline decrease in LV enddiastolic diameter was also observed (Table 4). By contrast, no improvement was observed in the control group, rather, an increase in left atrial diameter was observed at 1 year (P = 0.02 vs baseline) (Table 5). Table 4 Changes in echocardiographic parameters at baseline, 3 months and 1 year in the group of add-on therapy with irbesartan
FS, % EF, % LVDs, cm LVDd, cm LAD, cm MV-E, cm/s MV-A, cm/s E/A DT, ms IVRT, ms
Baseline
3 months
1 year
18.1 ± 7.4 35.0 ± 11.8 4.94 ± 0.85 5.96 ± 0.83 4.02 ± 0.69 60.4 ± 15.7 72.7 ± 18.9 0.94 ± 0.45 235 ± 88 119 ± 30
21.3 ± 7.1 42.1 ± 11.7⁎ 4.61 ± 1.08 5.81 ± 1.06 3.95 ± 0.96 61.3 ± 11.8 80.2 ± 21.3§ 0.77 ± 0.21 241 ± 61 115 ± 32
21.4 ± 6.4 39.9 ± 17.5 4.30 ± 1.17† 5.57 ± 0.91‡ 3.87 ± 0.60 54.2 ± 19.9 76.1 ± 20.8 0.80 ± 0.24 238 ± 67 122 ± 34
FS, Fractional shortening; EF, ejection fraction; LVDs, left ventricular endsystolic diameter; LVDd, left ventricular end-diastolic diameter; LAD, left atrial diameter; MV-E, peak transmitral early diastolic filling velocity; MVA, peak transmitral atrial filling velocity; E/A, ratio of MV-E to MV-A; DT, deceleration time; IVRT, isovolumic relaxation time. ⁎P = 0.02 vs baseline, †P = 0.02 vs baseline, ‡P = 0.06 vs baseline, §P = 0.01 vs baseline.
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With respect to diastolic function, it was present in all the heart failure patients, with abnormal relaxation pattern in 84%, pseudonormal in 5% and restrictive filling pattern in 11% in the add-on group, and was 63%, 16% and 21% respectively in the control group, without inter-group difference in prevalence (χ2 = 1.9, P = NS). At the end of 1 year, the prevalence was changed with a normal pattern in 9%, ARP in 73%, pseudonormal in 9% and RFP in 9% in the add-on group, and was 0%, 53%, 5% and 42% respectively in the control group, which was significant between the two groups (χ2 = 7.1, P = 0.02). For individual diastolic parameters, there was a significant increase in peak transmitral atrial filling velocity after 3 months (P = 0.01) in the add-on group, though it was not significant at 12 months (Table 4). Other parameters of LV diastolic function remain unchanged. In the control group, there was no change in LV diastolic parameters throughout the study period (Table 5). 3.3. Clinical outcome In the add-on group, 2 patients died, 1 due to sudden cardiac death and the other due to septicemia. In the control group, 1 patient died of sudden cardiac death. There were 12 patients who had hospitalization due to cardiovascular causes, with 10 due to decompensated heart failure, 1 with acute myocardial infarction and 1 with unstable angina pectoris. When the composite endpoint of mortality and/or cardiovascular hospitalization was compared, there was a trend towards a lower event rate in the add-on group (20% vs 40%, Log-rank χ2 = 2.71, P = 0.099) (Fig. 1). 3.4. Effect on blood pressure and renal function In both the add-on and the control groups, blood pressure did not change significantly during 1-year follow-up. However, in the add-on group, the diastolic blood pressure was slightly but significantly lower at 3 months but not 1 year. (64 ± 10 mm Hg at 3 months vs 70 ± 11 mm Hg at baseline, P b 0.01 by paired sample t-test with Bonferroni
Table 5 Changes in echocardiographic parameters at baseline, 3 months and 1 year in the control group
FS, % EF, % LVDs, cm LVDd, cm LAD, cm MV-E, cm/s MV-A, cm/s E/A DT, ms IVRT, ms
Baseline
3 months
1 year
16.3 ± 8.3 33.8 ± 12.9 4.99 ± 1.04 6.08 ± 0.86 4.16 ± 0.72 70.4 ± 33.5 72.2 ± 27.4 1.18 ± 0.85 218 ± 75 108 ± 56
18.1 ± 8.3 36.4 ± 14.4 4.94 ± 1.05 5.97 ± 0.91 4.07 ± 0.61 73.7 ± 26.5 73.2 ± 28.5 1.24 ± 1.03 185 ± 92 132 ± 73
18.7 ± 6.5 38.1 ± 10.3 4.74 ± 1.23 6.12 ± 1.03 4.41 ± 0.56⁎† 74.9 ± 24.0 78.4 ± 21.7 1.08 ± 0.75 220 ± 79 127 ± 44
⁎P = 0.02 vs baseline, †P = 0.004 vs 3 months. See Table 4 for abbreviations.
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Fig. 1. Actuarial cardiovascular event-free survival curve for add-on therapy and control groups.
correction Table 2.) Renal function in terms of serum creatinine was not affected during the follow-up period in both groups. Significant hyperkalaemia needing treatment was not found in both groups. 4. Discussion This study investigated the effect of the addition of irbesartan to conventional therapy in terms of symptomatic improvement, change of echocardiographic parameters and cardiovascular morbidity and mortality in patients with moderate heart failure. All of the patients recruited into this study had been adequately treated with ACEI for at least 3 months while 64% of our patients had been treated with beta-blockers. No patients were taking spironolactone during the study period because spironolactone therapy for heart failure was not commonly practiced in the study center at that time. This study showed that add-on therapy of irbesartan could improve heart failure symptoms on top of conventional treatment by ACEI and beta-blocker, without any apparent adverse effects on blood pressure and renal function. The NYHA class of patients treated with add-on therapy improved from the mean of 2.4 to the mean of 2.0 over the 1-year study period (P b 0.005), whereas there is no significant improvement of NYHA class of patients treated with conventional therapy over the 1-year study period (2.7 at baseline vs 2.6 at 1 year, P = NS). Add-on therapy could also significantly improve exercise tolerance assessed by 6Minute Hall-Walk distance and treadmill exercise test as shown in Table 2. These changes could have a positive impact on patients' activity of daily living and quality of life and this was reflected by the significant improvement of QOL score at 1 year (Table 2). Apart from symptomatic improvement, irbesartan add-on therapy might retard the progression of left ventricular remodeling in chronic heart failure patients. A significant reduction in left ventricular end-systolic diameter at 12 months was observed in the irbesartan add-on group
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and there was a borderline reduction in left ventricular enddiastolic diameter. Improvement of ejection fraction was also observed at 3-month follow-up. Although this study was conducted with a relatively small patient number for a modest period of follow-up, such benefit on left ventricular function is already evident. For diastolic assessment, marked increase in the proportion of patient having a restrictive filling pattern over the study period was observed in the control group (21% at baseline raised to 42% at 12 months) whereas proportion of patients having a restrictive filling pattern in diastole was similar in the add-on group at both baseline and at 12 months. This finding suggests that irbesartan add-on therapy might be able to retard the progression of diastolic dysfunction in chronic moderate heart failure patients. The increase in left atrial size in 12-month follow-up in the control group indicates an increased atrial filling pressure, which is commonly observed in restrictive filling pattern of diastolic dysfunction [10]. As diastolic dysfunction is another determinant of prognosis in patients with systolic heart failure [12], this may implicate on a more favorable prognosis which need to be substantiated by further studies. This study is not powered to compare the difference in outcome in the 2 treatment groups. However, a trend of improved clinical outcome was also observed in the add-on group, with a 50% lower in the relative risk for combined end-point of mortality and cardiovascular events. The difference is mainly due to a lower cardiovascular hospitalizations but not mortality. Our findings have suggested that addition of irbesartan might confer additional benefits to conventional therapy for chronic heart failure without any apparent adverse effects on renal function and blood pressure. Although it may not be a class effect, the beneficial role of valsartan and candesartan to improve heart failure hospitalization have been reported in large, multicenter, controlled trials [7,8]. In the VAL-HeFT trial which evaluated the add-on effect of valsartan to class II and III heart failure treatments, there was reduction in hospitalizations and improvement of NYHA class, quality of life, as well as symptoms and signs of heart failure [7]. However, the study failed to demonstrate an improvement in mortality and the post-hoc observation of an adverse effect on morbidity and mortality was observed in the subgroup receiving valsartan, ACEI and beta-blocker raises concern about the potential safety of this specific combination. In VAL-HeFT trial, usage of ACEI was 93% but was only 35% for beta-blocker. In contrast, in the current study 64% of patients received beta-blockers and all of the patients received ACEI for at least 3 months before recruitment. Even in the setting of such high rate of beta-blockade and ACE inhibition, add-on treatment with irbesartan has beneficial effect on soft clinical end-points similar to that of VAL-HeFT. In fact, VAL-HeFT study also demonstrated a reduction of LV diameter and gain in ejection fraction starting from 3 months to 24 months which were similar to our observations [13]. However, in VAL-HeFT study only
the subgroup that had been put on ACEI and beta-blocker did not show left ventricular reverse remodelling. Therefore, the definite benefits of add-on irbesartan therapy need to be confirmed by large, randomized, controlled study. In the CHARM-Added trial, nearly 100% of the study subjects were taking ACEI, 56% were taking beta-blockers and 17% of patients were taking spironolactone [8]. In addition to the beneficial effects shown by our study and ValHeFT, this trial also demonstrated significant reduction in cardiovascular death over 3.5 years. This result, as different from those observed in other multicenter trials of heart failure with ARB therapy, illustrates the potential difference in therapeutic efficacy of different ARBs which is more than a “class effect” [7,14]. 4.1. Limitation of the study Our study has several limitations. First of all, the small sample size was not intended to demonstrate significant difference of cardiovascular outcome between the add-on and the control groups. Therefore, the study rather focused primarily on soft clinical end-points and echocardiographic assessment. Secondly, the relatively short follow-up period did not provide data on the sustained benefits of add-on irbesartan therapy beyond one year. Thirdly, our patients were not blinded of treatment assignments. This may create bias due to placebo effect in the functional assessment. Fourthly, none of the patients was taking spironolactone during the study period; therefore, this study could not evaluate the effect of combination of irbesartan and spironolactone. 5. Conclusion In conclusion, irbesartan add-on therapy on top of ACEI and beta-blockers in the treatment of systolic heart failure could further improve symptoms, exercise capacity and quality of life. It may have extra benefits in the regression of left ventricular remodeling and deterioration of cardiac systolic and diastolic function. Addition of irbesartan 300 mg daily also appears to have no significant adverse effects on blood pressure and renal function. References [1] The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302. [2] The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429–35. [3] Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303–10. [4] Popovic JR, Kozak LJ. National Hospital Discharge Survey: annual summary, 1998. Vital and health statistics. Series 13, vol. 148. Washington, D.C.: Government Printing Office; September 2000. DHHS publication no. (PHS) 2000-1719.
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