Effects of canrenoate plus angiotensin-converting enzyme inhibitors versus angiotensin-converting enzyme inhibitors alone on systolic and diastolic function in patients with acute anterior myocardial infarction

Article Outline

• Abstract
• Materials and methods
  • Populations and eligibility criteria
  • Exclusion criteria
  • Anterior MI classification and treatment
  • Study protocol
  • Follow-up
  • Statistical analysis
• Results
  • Follow-up
• Discussion
  • Limitations of the study
• References
• Copyright

Background

Aldosterone (ALDO) exerts profibrotic effects, acting via the mineralocorticoid receptors in cardiovascular tissues. Aldosterone antagonism in combination with angiotensin-converting enzyme inhibition may better protect against the untoward effects of ALDO than angiotensin-converting enzyme inhibition alone.

Methods

In a double-blind randomized study, the tolerability and efficacy of canrenoate (25 mg/d) plus captopril versus captopril alone were evaluated in 510 patients with an acute anterior myocardial infarction (MI), a serum creatinine concentration <2.0 mg/dL, and a serum potassium level <5.0 mmol/L. Three hundred forty-one patients received captopril and 25-mg canrenoate (group A). Group B (346 patients) received captopril and placebo. At baseline and at 10, 90, and 180 days after admission, Doppler echocardiography was performed.

Results

Clinical and demographic aspects were similar in both groups. In addition, baseline cardiac enzyme levels, left ventricular function, and incidence of surgical interventions and angioplasty were comparable. Overall, creatinine, blood urea, and serum potassium levels did not show significant differences between groups. However, in 18 patients in group A, increases in serum potassium levels to >5.5 mEq/L and creatinine levels to >2.0 mg/L after 10 days of treatment were observed. At 180 days, the mitral E-wave–A-wave ratio was higher (P = .0001) and left ventricular end-systolic volume was smaller (P = .0001) in patients treated with canrenoate than in those receiving placebo. No further side effects were observed during the study period.

Conclusions

Our data suggest that the combination of captopril plus canrenoate is well tolerated after an acute MI and has beneficial effect on systolic and diastolic parameters and may decrease post-MI remodeling.

Activation of the renin-angiotensin-aldosterone (ALDO) system (RAAS) during the acute and subacute phases of myocardial infarction (MI) may have direct consequences for the heart, including an abnormal accumulation of collagen and fibrosis. Aldosterone plays a pivotal role in this part of cardiac remodeling, an effect that may be prevented by the ALDO receptor antagonist spironolactone, which inhibits fibroblast collagen turnover.¹, ², ³ In a rabbit model of balloon-induced vascular injury, ALDO administration enhances vascular wall thickening, whereas spironolactone inhibits the fibrointimal hyperplasia, which is responsible for this thickening.⁴ Local cardiac ALDO synthesis is likely to be involved in cardiac fibrosis in an autocrine and/or paracrine fashion. Angiotensin-converting enzyme (ACE) inhibition may not sufficiently prevent this effect of ALDO. Some reports have shown a partial escape of ALDO in patients treated with ACE inhibitors.⁵, ⁶ In another study, ramipril and spironolactone (25 mg, 3 times a day) beneficially affected ventricular remodeling after anterior MI (AMI).⁷ The recent RALES trial showed a significant reduction in mortality, nonfatal hospitalization, and sudden death in patients with heart failure (HF) who are receiving an ACE inhibitor plus spironolactone as compared with those receiving ACE inhibitor without spironolactone.⁸ Canrenoate, which is used in this study, is rapidly converted to canrenone, which represents the common active metabolite of spironolactone and canrenoate. Accordingly, canrenoate may have a pharmacologic profile that is comparable to that of spironolactone. In our previous pilot studies, we showed that ALDO receptor antagonism, in addition to ACE inhibition, beneficially affects systolic and diastolic left ventricular (LV) function during the first 3 months after an anterior infarction. We observed that the combination ACE inhibitor plus canrenoate showed an unexpected early significant improvement in the ratio of the E-wave to A-wave peak velocities (E/A ratio) compared with captopril alone. Because this parameter is unspecific and the changes are small and not reaching normal values, we planned to enroll a larger number of patients and to verify echocardiographic data in the long term.⁹, ¹⁰, ¹¹ The study investigates the effects of intravenous canrenoate, administered in addition to ACE inhibition, early after infarction, and the long-term effect of the combination on systolic and diastolic ventricular function.

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Materials and methods 

Populations and eligibility criteria 

From March 1999 to June 2003, 1125 patients were admitted consecutively to the hospital with suspected AMI. The criteria of eligibility included a first episode of AMI, Killip class I to II, an acceptable echocardiographic window, and admittance to the hospital within 4 hours of the onset of symptoms (pain). Patients were included when an ST elevation of >1 mm in the peripheral leads and/or 2 mm in precordial leads, involving >1 lead, was present, with concomitant alterations of the segmentary kinetics in the echocardiogram performed at entry. There was no age limit. Informed consent was obtained from all patients. The protocol of the study was approved by the ethics committee of our hospital.

Exclusion criteria 

Patients who had left bundle-branch block on the admission electrocardiogram (ECG), a history of cardiomyopathy, or HF were excluded, as were patients receiving ACE inhibitors, β-blockers, angiotensin II receptor antagonists, and mineralocorticoid receptor antagonists. Patients who showed no enzymatic alterations after thrombolysis were classified as having unstable angina and were excluded from the study, and those showing basal creatine kinase values higher than normal at entry were classified as having late AMI (>4 hours of onset of symptoms) and were also excluded from the study. In addition, patients with a serum creatinine concentration of >2.0 mg/dL and/or a serum potassium concentration of >5.0 mEq/L at entry were excluded.

Anterior MI classification and treatment 

Anterior MIs were classified as anterior according to the localization of the alterations in segmental contractility in the echocardiogram performed at entry and according to the localization of the alterations of the ST segment in the standard 12-lead ECG with V₃R through V₄R lead performed at entry, before starting the treatments. All patients received our standard treatment: nitrates, heparin, aspirin, ticlopidine or clopidogrel, statins, ACE inhibitors, and, when possible, intravenous and, subsequently, oral β-blockade. The thrombolytic drug used was the accelerated recombinant tissue plasminogen activator (100 mg) and, in the last 3 years, also the combination between 50 mg of rtPA and glycoprotein IIb/IIIa inhibitors.

Study protocol 

After the initial evaluation at entry, patients were randomly assigned in a double-blind fashion to receive either 25 mg/d of canrenoate intravenously (1 mg/h) or a matching placebo for the first 72 hours, followed by a once daily oral dose of 25-mg canrenoate or a matching placebo. In this way, all patients received canrenoate or placebo 4 to 6 hours after the onset of symptoms. Patients received 6.25-mg captopril orally as first dose between 2 to 4 hours after admission. Blood pressure (BP), heart rate (HR), and ECG were monitored continuously, were recorded on tape (first 6 hours), and then were analyzed to check any rhythm disturbance. Ventricular tachycardia and ventricular fibrillation were recorded. Blood creatine kinase (CK) concentrations were measured every 3 hours during the first 24 hours and then every 6 hours until they returned to normal values. Provided that BP was >100, captopril doses were subsequently increased up to the maximum dose tolerated. Laboratory measurements, including measurements of serum potassium and serum creatinine levels, were performed daily during the study period (8-12 days), on day 90, and after 180 days. Study medication could be withheld in the event of hyperkalemia of >5.5 mEq/L and a serum creatinine concentration of >2.5 mg/dL. Before discharge, patients underwent 24-hour Holter monitoring to evaluate late ventricular arrhythmias, taking into account only those in Lown class >2, as well as a symptom-limiting exercise test. All patients entered into the study underwent a hemodynamic investigation with coronary angiogram. Percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) were performed according to angiographic findings and LV function. Patients enrolled in the study continued treatment after discharge. They were regularly followed up as outpatients.

Follow-up 

Patients enrolled in the study were regularly followed up as outpatients, and they were also submitted to exercise testing after 1, 3, and 6 months, as well as laboratory measurements (urea, potassium, and creatinine values).

On admission (just after randomization) and on day 10, day 90, and day 180 after the admission, echocardiography was carried out according to a standard procedure. Patients lie in the left lateral position during the examination; echocardiographic recordings were obtained at the end of the expiratory phase during normal breathing, and apical 4- and 2-chamber views were used. The end-systolic volume (ESV) and end-diastolic volume (EDV) were measured. The modified Simpson rule, which uses 2 cross-section views (4- and 2-chamber apical views), was followed.¹² The transmitral flow velocity was measured using pulsed-wave Doppler, with the sample volume positioned between the mitral leaflet tips during diastole.¹³ The E/A ratio, E-wave deceleration time (dec. time), and the isovolumetric relaxation time (IVRT) were measured on 3 separate beats and then averaged. Two observers blinded to the clinical and ECG data evaluated the 2-dimensional echocardiographic images. In case of discrepancy, the 2-dimensional echocardiographic images were again reviewed, and a decision was made by consensus. The mean of 3 measurements was used. The interobserver and intraobserver coefficients of variation were 4% and 3%, respectively.

Statistical analysis 

Results are expressed as mean ± SD. Data were analyzed by the 2-tailed t test to identify differences between the groups and the analysis of variance for repeated measures with Bonferroni correction for intragroup data. Nominal data were analyzed by χ² test; P < .05 was considered to be significant. We performed a multiple regression sample size calculation based on a β value of .10 (90% power) and an α value of .05. The sample size calculated was related to echocardiographic variables (ESV, ejection fraction [EF], E/A ratio, IVRT, and dec. time). The maximum sample size obtained for these variables was 340 per group, and this number was assumed as the minimum one for this study.

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Results 

Only 687 patients met the entry criteria: 480 patients received thrombolytic treatment, and 98 of these did not show reperfusion (and they underwent rescue PTCA or CABG); and 207 patients were not suitable for thrombolysis (132 underwent primary PTCA). We obtained 2 groups: canrenoate group (341 patients) and placebo group (346 patients). The patients who underwent angiography had an IRA patency or no patency, corresponding to the classification of reperfusion based on noninvasive diagnosis. The groups were similar with regard to age, sex, diabetes, smoking habits, hypertension, CK enzymatic peak, adjuvant therapy, EF, ESV, and incidence of CABG or PTCA. Table I shows the clinical data of all enrolled patients. Table I, Table II, Table III show the results of both groups.

Table I. Clinical data and results of all patients enrolled

NS, Not significant; F, female; M, male; VT, ventricular tachycardia.

Table II. Changes in echocardiographic data at entry and at 10, 90, and 180 days after treatment

Analysis between groups was performed by 2-tailed t test, and intragroup by analysis of variance.

Table III. Laboratory measurements on admission and at 10, 90, and 180 days

Analysis between groups was performed by 2-tailed t test, and intragroup by analysis of variance.

Follow-up 

Of the 687 randomized patients, 63 were lost to follow-up during the study, 22 patients died in the canrenoate group because of re-AMI (10 patients) and HF (12 patients), and 32 patients died in the placebo group (14 re-AMI and 18 HF). Twelve patients had MI during surgery and were excluded. An additional 26 patients refused to continue the study, and 22 patients had an increase in serum potassium concentration of >5.5 mEq/L (mean 5.7 ± 0.2) and creatinine level of >2.0 mg/L (mean 2.5 ± 0.8) after 10 days of treatment (18 from the canrenoate group and 4 patients from the placebo group) and discontinued treatment with rapid (3 days) normalization of these values. Forty-eight nonfatal ischemic events were observed at follow-up: 16 episodes of angina and 6 episodes of nonfatal re-AMI in the canrenoate group, and 18 episodes of angina and 8 episodes of nonfatal re-AMI in the placebo group, which did not lead to exclusion from the study (Table IV). Five hundred ten patients completed the study period of 180 days (251 from the canrenoate group and 259 from the placebo group) and underwent echocardiographic examination (Table II, Figure 1). The mitral E/A ratio, IVRT, dec. time, and ESV at 180 days differed significantly from baseline values in both groups. When the E/A ratio, EDV, ESV, EF, IVRT, and dec. time for the groups at 180 days were compared, the values for the canrenoate group differed significantly from those of the placebo group. The ESV decreased more in the canrenoate group, whereas the E/A ratio improved more (P = .0001 and P = .0001, respectively, vs placebo) (Table II, Figure 1). The canrenoate group also showed a significant increase in EF, whereas, in the placebo group, the EF did not show any significant increase. Reperfused patients (from the canrenoate group) versus unreperfused patients (from the canrenoate group) showed a significant improvement in all the echocardiographic data (Table V). A further comparison between patients also treated with β-blockers versus those not receiving β-blockers (from the canrenoate group) showed that β-blocker treatment determined a better but not significant trend in echocardiographic data (Table VI). Electrolytes and serum creatinine and urea concentrations increased significantly from baseline in both groups (Table III). Although, at 180 days, serum creatinine tended to be higher than with placebo, this difference was not significant. Neither did SB-P nor HRs differ during the study (SB-P of 112 ± 14 mm Hg and HR of 74 ± 12 beat/min at entry and SB-P of 114 ± 8 mm Hg and HR of 66 ± 8 beat/min after 180 days in the canrenoate group vs SB-P of 114 ± 12 mm Hg and HR of 78 ± 11 beat/min at entry and SB-P of 117 ± 9 mm Hg and HR of 67 ± 13 beat/min after 180 days in the placebo group).

Table IV. Events during follow-up

	Canrenoate	Placebo
Dropouts	33	30
Mortality	22	32
Re-AMI	10	14
HF	12	18
Nonfatal AMI (during surgery)	7	5
Refused consent	15	12
Potassium >5.5 (mEq/L) (total)	18	4
Potassium >6.0 (mEq/L)	4	0
Ischemic events	22	26
Angina	16	18
Re-AMI	6	8

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• Figure 1. 

  Changes in systolic and diastolic echocardiographic parameters in the treatment group (▪) and in the placebo group (♦).

Table V. Echocardiographic data at entry and at 10, 90, and 180 days after treatment in canrenoate reperfused group versus canrenoate unreperfused group

Analysis between groups was performed by 2-tailed t test, and intragroup, by analysis of variance.

Table VI. Echocardiographic data at entry and at 10, 90, and 180 days after treatment in canrenoate, with β-blockers and ACE inhibitors group versus canrenoate plus ACE inhibitor group

Analysis between groups was performed by 2-tailed t test, and intragroup by analysis of variance. B-block, β-blockers; Canr, canrenoate; ACE-I, ACE inhibitors.

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Discussion 

This study indicates that ALDO receptor antagonism with canrenoate, in addition to ACE inhibition, improves cardiac relaxation and systolic performance during the first 6 months after an acute MI, as compared with the effect of an ACE inhibitor alone. This effect not necessarily relates to LV dysfunction, the average LV EF being only minimally decreased. In addition, patients with a history of HF or with HF at baseline were excluded. Thus, in this study, the effects of canrenoate on LV dilatation and on indices reflecting the diastolic properties of the heart were observed in what might be viewed as a moderate infarct without major cardiac dysfunction. The systolic function tended to improve in contrast to the effects of placebo, whereas ESV decreased; and the improved diastolic function indices suggest a direct effect of canrenoate on the remodeling process, already apparent 3 months after the index MI and more evident 6 months after AMI. In contrast, ACE inhibition alone did not result in a similar effect. These results support our previous pilot studies⁹, ¹⁰, ¹¹ and show that a larger sample was able to evidence significant improvements in some data regarding diastolic and systolic function that were not evidenced in the pilot studies. These findings support the concept that ALDO plays an important direct role in the remodeling process by mechanisms other than its well-known effects on circulating electrolytes. They also support the large controlled EPHESUS study, which showed that the addition of eplerenone in patients who had AMI with LV dysfunction (EF <40%) and who are receiving ACE inhibition treatment was able to reduce mortality and hospitalization.¹⁴ In addition, the study showed a reduction in the risk for sudden death from cardiac causes. Our study was different: the EPHESUS study enrolled patients with reduced EF (<40%), whereas we included patients with EF >40% at baseline; and our patients received canrenoate intravenously at entry and 72 hours after, orally, whereas EPHESUS patients received eplerenone 3 to 14 days after AMI.¹⁴ Our end points were only systolic and diastolic performances. A recent report confirmed the results of our pilot study,⁹ showing that the combination therapy of mineral receptor antagonist (MRA) and ACE inhibitor that is started at onset, immediately after revascularization, can prevent LV dilatation more effectively and improve the LV EF in patients with a first AMI better than ACE inhibitor alone. In addition, it was evidenced that MRA suppressed the transcardiac extraction of ALDO through the heart during the acute and subacute phases of AMI and that MRA suppressed cardiac collagen synthesis occurring during the acute to subacute phase of AMI.¹⁵ In this study, diastolic performance was not investigated, and the sample of patients was limited and selected. In addition, in our study, significant improvements in cardiac volumes and diastolic function were already observed after 3 months, whereas in the previously mentioned study these indices were evidenced only after a month. We are not able to explain this difference even if the 2 populations were similar.

For many years, it was believed that the inhibition of the RAAS with ACE inhibitor would significantly suppress the formation of ALDO. Conversely, the combination of an ALDO receptor blocker and an ACE inhibitor has been relatively considered as contraindicated because of the potential hyperkalemia. Several studies support that ACE inhibitor only transiently suppress the ALDO production.⁵, ⁶, ¹⁶, ¹⁷, ¹⁸

There are several explanations for this. First, many different stimuli contribute to ALDO secretion over and above angiotensin II, including plasma potassium levels, corticotropin, and nitric oxide. Secondly, ACE inhibitors are not able to suppress angiotensin II production over time; possible alternative pathways for its production, for example, chymases, are present in organs such as the heart. The RALES pilot study¹⁹ and the subsequent large RALES trial study⁸ have showed that, when initiated carefully, low doses of spironolactone (25 mg) in combination with an ACE inhibitor and a loop diuretic are effective in decreasing mortality and cardiovascular hospitalization in patients with advanced HF but are also safe, with no more patients acquiring severe hyperkalemia than placebo. Consequently, ALDO receptor antagonists are currently recommended in the treatment of advanced HF, on top of ACE inhibition and β-blockade. The classic view of the importance of ALDO in the pathophysiology of HF relates to its ability to increase serum sodium and potassium loss. However, it has now been shown that ALDO also causes myocardial and vascular fibrosis,¹, ²⁰ endothelial dysfunction and diminished vascular compliance,¹⁸, ²¹ baroreceptor dysfunction, and reduced norepinephrine uptake by the heart,²² in addition to circulating and cardiac electrolyte disturbances, including potassium loss. Together, these changes may lead to diastolic dysfunction and stiffening of the heart, arrhythmias, and ischemic events that are likely to lead to worsening cardiac dysfunction, HF, and death. In addition to the classic adrenal biosynthetic pathway, steroid hormone production occurs in various other organs, including the brain,²³ the vasculature, and the heart.²⁴, ²⁵ Angiotensin II is an important regulator of ALDO biosynthesis and secretion in the adrenal cortex, and probably, also in the heart.²⁶, ²⁷, ²⁸ In AMI, local tissue angiotensin II production is enhanced, and it is probable that this may be one of the factors leading to increased cardiac ALDO production in AMI. A recent study suggested that MI is associated with a 3.7-fold increase in myocardial ALDO levels,²⁹ which could be involved in subsequent cardiac fibrosis and inadequate norepinephrine handling by the heart. Aldosterone produced in the heart does not contribute to circulating ALDO concentrations. Its concentration within the heart, however, greatly exceeds circulating concentrations, suggesting that cardiac ALDO generation has autocrine or paracrine properties.³⁰ Therefore, it is conceivable that treatment strategies may involve a 2-pronged approach, using ALDO antagonist both to prevent myocardial fibrosis on vascular and myocardial tissues, and to strengthen the effects of ACE inhibitors. The importance of the RAAS in the cardiovascular system was also evidenced in our recent studies that showed, in the young healthy subjects with ACE-DD polymorphism, a higher incidence of hypertension.³¹ In addition, we observed also that, after a 6-year follow-up, the young healthy subjects with ACE-DD and without any risk factors, enclosed in family history, evidenced a significant alteration of diastolic performance.³² With this scenario in mind, we considered it would be of interest to test the association between captopril and canrenoate in the early phases of post-AMI. We selected patients with AMI because they are at a higher risk for cardiac dysfunction and possibly have a greater infarct extension, and are more likely to undergo significant myocardial reparation processes and more extensive collagen deposition. Hence, these patients were considered the most likely candidates to benefit from canrenoate. Patients receiving captopril plus canrenoate showed a significant improvement in E/A ratio and ESV after 180 days of treatment compared with those receiving captopril alone. No side effects were observed besides hyperkalemia in some patients. These data suggested that canrenoate in combination with ACE inhibitor leads to less diastolic dysfunction, possibly through reduced collagen production, than ACE inhibitor alone. Our data suggest a question: is it correct to wait for the symptomatic HF before giving the inhibitors of mineral receptors or to try to prevent the development of HF? Further investigations are required.

Limitations of the study 

Limitations of the study include the relative short term of observation and the relatively large percentage of dropouts. Because of the small number of patients, we cannot show possible beneficial effects on morbidity and mortality. It is of interest, therefore, that, in our study, significant improvements in cardiac volumes and diastolic function were already observed after 3 months. As regards dropouts, there was no difference between groups in the number of patients dropping out or, importantly, in the numbers of patients with serious adverse cardiac events, for example, infarction or death. More patients were excluded with hyperkalemia in the canrenoate group. This is not in accordance with the RALES and EPHESUS studies and may reflect that, in RALES and EPHESUS, potassium levels were checked more frequently and treatment with study medication adapted more than the current study.

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