Anti-remodelling effect of canrenone in patients with mild chronic heart failure (AREA IN-CHF study): final results

AIMS: To test whether canrenone, an aldosterone receptor antagonist, improves left ventricular (LV) remodelling in NYHA class II heart failure (HF). Aldosterone receptor antagonists improve outcome in severe HF, but no information is available in NYHA class II. METHODS AND RESULTS: AREA IN-CHF is a randomized, double-blind, placebo-controlled study testing canrenone on top of optimal treatment in NYHA class II HF with low ejection fraction (EF) to assess 12-month changes in LV end-diastolic volume (LVEDV). Brain natriuretic peptide (BNP) was also measured. Information was available for 188 subjects on canrenone and 194 on placebo. Left ventricular end-diastolic volume was similarly reduced (-18%) in both arms, but EF increased more (P = 0.04) in the canrenone (from 40% to 45%) than in the placebo arm (from 40-43%). Brain natriuretic peptide (n = 331) decreased more in the canrenone (-37%) than in the placebo arm (-8%; P < 0.0001), paralleling a significant reduction in left atrial dimensions (-4% vs. 0.2%; P = 0.02). The composite endpoint of cardiac death and hospitalization was significantly lower in the canrenone arm (8% vs. 15%; P = 0.02). CONCLUSION: Canrenone on top of optimal treatment for HF did not have additional effects on LVEDV, but it increased EF, and reduced left atrial size and circulating BNP, with potential beneficial effects on outcome. A large-scale randomized study should be implemented to confirm benefits on cardiovascular outcomes in patients with HF in NYHA class I

Effect of canrenone on left ventricular mechanics in patients with mild systolic heart failure and metabolic syndrome: The AREA-in-CHF study.

Background and aim: We analyzed the effect of the mineralocorticoid receptor antagonist canrenone on LV mechanics in patients with or without metabolic syndrome (MetS) and compensated (Class II NYHA) heart failure (HF) with reduced ejection fraction (EF ≤ 45%) on optimal therapy (including ACE-i or ARB, and β-blockers). Methods and results: From a randomized, double-blind placebo-controlled trial (AREA-in-CHF), patients with (73 on canrenone [Can] and 77 on placebo [Pla]), based on modified ATPIII definition (BMI≥30kg/m2 instead of waist girth) or without MetS (146 by arm). In addition to traditional echocardiographic parameters, we also evaluated myocardial mechano-energetic efficiency (MME) based on a previously reported method. At baseline, Can and Pla did not differ in age, BMI, blood pressure (BP), metabolic profile, BNP, and PIIINP. Compared with MetS-Pla, and controlling for age, sex and diabetes, at the final control MetS-Can exhibited increased MME, preserved E/A ratio, and decreased atrial dimensions (0.04&lt;0.0001). At baseline, degree of diastolic dysfunction was similar in MetS-Can and MetS-Pla but after 12 months, diastolic function improved in MetS-Can, compared to MetS-Pla (p&lt;0.002): moderate-to-severe diastolic dysfunction decreased from 26% to 12% with canrenone whereas it was unchanged with placebo (both 26%). Can, but not Pla, reduced BNP in both patients with or without MetS (p&lt;0.0001). Conclusions: Treatment with canrenone given on the top of optimal therapy in patients with MetS and chronic, stabilized HF with reduced EF, protects deterioration of MME, improves diastolic dysfunction and maximizes the decrease in BNP. © 2010 Elsevier B.V

Effect of spironolactone and its metabolites on contractile property of isolated rat aorta rings.

EUR. J. MED. CHEM

Aldosterone receptor blockade improves left ventricular remodeling and increases ventricular fibrillation threshold in experimental heart failure

Objectives: To investigate the effects of aldosterone receptor blockade in postinfarction heart failure. Methods: Eighty-seven rats with moderate myocardial infarction were randomized to receive either no drug or canrenone, the active metabolite of spironolactone, 20 mg/kg/day, or ramipril, 1 mg/kg/day, or a combination of the two drugs. Treatment was initiated 1 month after coronary ligation and lasted 4 weeks. Echocardiography was performed at baseline and after 4 weeks. LV catheterization, isolated heart studies, morphometric histology, myocardial norepinephrine and SERCA-2 mRNA were assessed at the end of the treatment period. Results: Infarct sizes were 33±3, 32±3, 34±3, and 34±4% in the placebo, canrenone, ramipril, and combination groups, respectively. Canrenone attenuated LV remodeling, improved LV systolic and diastolic function, and markedly reduced interstitial and perivascular fibrosis. These effects were increased by concomitant ramipril therapy. Moreover, myocardial norepinephrine content was decreased while ventricular fibrillation threshold significantly augmented by canrenone. SERCA-2 levels remained unchanged. Conclusions: Canrenone attenuated LV dilation and interstitial remodeling, and improved LV filling dynamics and systolic function in the rat model of postinfarction heart failure. Addition of ramipril conferred further cardioprotection. Canrenone also reduced myocardial norepinephrine content and increased ventricular fibrillation threshold. The data provide a potential explanation for the decreased sudden death observed in the RALES study. The mechanisms of action of aldosterone inhibition are still poorly understood, despite its proven efficacy in heart failure. Rats with postinfarction heart failure were randomized to receive for 1 month either no drug or canrenone, or ramipril, or a combination of canrenone and ramipril. Canrenone treatment was associated with a significant attenuation of LV dilation, better LV diastolic and systolic dynamics, and a marked reduction of reactive fibrosis. These effects were enhanced by concomitant ramipril therapy. Moreover, canrenone increased ventricular fibrillation threshold and reduced myocardial norepinephrine content. The data may explain the reduced mortality demonstrated by the RALES

Ambulatory blood pressure parameters after canrenone addition to existing treatment regimens with maximum tolerated dose of angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor blockers plus hydrochlorothiazide in uncontrolled hypertensive patients

Luigina Guasti,1,* Giovanni Gaudio,2,* Alessandro Lupi,3 Marinella D&rsquo;Avino,4 Carla Sala,5,6 Amedeo Mugellini,7 Vito Vulpis,8 Salvatore Felis,9 Riccardo Sarzani,10,11 Massimo Vanasia,12 Pamela Maffioli,7 Giuseppe Derosa7 1Research Center on Dyslipidemia, Internal Medicine 1, University of Insubria, Varese, Italy; 2Internal Medicine Division, Ospedale Angelo Bellini, ASST Valle Olona Somma, Varese, Italy; 3Cardiology Unit, ASL VCO Verbania-Domodossola, Verbania, Italy; 4Unit for the Treatment of Arterial Hypertension, Ospedale Cardarelli, Napoli, Italy; 5Department of Clinical Sciences and Community Health, University of Milan, Milano, Italy; 6Cardiovascular Unit, Fondazione IRCCSS Policlinico, Milano, Italy; 7Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; 8Unit for the Diagnosis and Treatment of Arterial Hypertension, Department of Internal Medicine, Policlinico di Bari, Bari, Italy; 9Cardiology Unit, Ospedale Garibaldi, Catania, Italy; 10ESH Center of Hypertension, Internal Medicine and Geriatrics, University Politecnica delle Marche, Ancona, Italy; 11IRCCS-INRCA, Ancona, Italy; 12THERABEL GiEnne Pharma, Milano, Italy *These authors contributed equally to this work Background: Blockade of the renin&ndash;angiotensin&ndash;aldosterone system is a cornerstone in cardiovascular disease prevention and hypertension treatment. The relevance of ambulatory blood pressure monitoring (ABPM) has been widely confirmed for both increasing the accuracy of blood pressure (BP) measurements, particularly in pharmacological trials, and focusing on 24&nbsp;h BP prognostic parameters. The aim of this study was to assess the effects of canrenone addition on ambulatory BP in uncontrolled hypertensive patients already treated with the highest tolerated dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor (AT1R) antagonists plus hydrochlorothiazide (HCT). Methods: ABPM was performed at baseline and after 3&nbsp;months of combination therapy in 158 outpatients with stage 1 or 2 hypertension who were randomized to add canrenone (50&nbsp;or 100&nbsp;mg) to the pre-existing therapy with ACE inhibitors or AT1R antagonists plus HCT. Twenty-four-hour systolic and diastolic BPs were considered normalized when the values were&nbsp;&lt;130 and &lt;80&nbsp;mmHg, respectively. Results: The addition of canrenone was associated with a reduction in systolic and diastolic BPs (24&nbsp;h and daytime and nighttime; P&lt;0.001), mean arterial pressures (P&lt;0.001), and pulse pressures (P&lt;0.01). The &Delta; 24&nbsp;h systolic/diastolic BPs were -13.5&plusmn;11.2/-8&plusmn;8&nbsp;mmHg and -16.1&plusmn;13.5/-11.2&plusmn;8.3&nbsp;mmHg (50 and 100&nbsp;mg/day, respectively). In the 50&nbsp;mg arm, the 24&nbsp;h systolic and diastolic BPs were normalized in 67.5% and 74% of the patients, respectively, and in 61.6% and 68.5% of the patients in the 100&nbsp;mg arm, respectively (P&lt;0.05; P= not significant for 50 vs 100&nbsp;mg). The percentage of patients whose nocturnal decrease was &gt;10% with respect to diurnal values did not change during combination therapy. Conclusion: Canrenone addition to ACE inhibitors or AT1R antagonists plus HCT was associated with a significant reduction of 24&nbsp;h BP and to an increased number of patients meeting 24&nbsp;h ABPM targets in a clinical setting of uncontrolled stage 1 or 2 hypertension. Keywords: ambulatory blood pressure, canrenone, RAAS, ACE inhibitors, AT1R antagonis