Efficacy and safety of two dosages of canrenone as add‐on therapy in hypertensive patients taking ace‐inhibitors or angiotensin II receptor blockers and hydrochlorothiazide at maximum dosage in a randomized clinical trial: The ESCAPE‐IT trial

Abstract

Summary Aim To evaluate the effects of canrenone as add‐on therapy in patients already treated with angiotensin‐converting enzyme inhibitors ( ACE ‐I) or angiotensin II receptor blockers ( ARB s) and hydrochlorothiazide at the maximum dosage (25 mg/d). Method In this randomized, open‐label, controlled trial, we enrolled 175 Caucasian patients with essential hypertension not well controlled by concomitant ACE ‐I or ARB s and hydrochlorothiazide. At baseline, 87 patients (57 males and 30 females) were randomized to add canrenone 50 mg, and 88 (56 males and 32 females) patients to canrenone 100 mg, once a day, for 3 months. At baseline and after 3 months, we evaluated blood pressure ( BP ), pulse pressure ( PP ), heart rate ( HR ), fasting plasma glucose ( FPG ), homeostasis model assessment insulin ( HOMA Index), lipid profile, electrolytes, uric acid, estimated glomerular filtration rate ( eGFR ), plasma urea, aldosterone, B‐type natriuretic peptide ( BNP ), and galectin‐3. Results Blood pressure decreased with both dosages of canrenone, with a better effect with canrenone 100 mg (−20.26 vs −23.68 mm Hg for SBP , and −10.58 vs −12.38 mm Hg for DBP ), without a clinically relevant increase in potassium levels. We did not observe any differences regarding FPG or HOMA Index, nor of lipid profile, with the exception of triglycerides, which increased compared to baseline with canrenone 50 mg (+0.25 vs +0.34 mE q/L). Creatinine slightly increased with canrenone 100 mg (+0.02 vs +0.05 mg/dL), although no variations of eGFR were observed in neither groups. There was an increase in aldosterone levels with canrenone 50 mg. No changes in BNP or galectin‐3 were recorded. Conclusion Both canrenone dosages gave a decrease in blood pressure, with a better effect with the higher dose, with only a slight increase in potassium and creatinine levels, which were not clinically relevant. Clinical Trials Registration Eudract number: 2010‐023606‐13; ClinicalTrials.gov NCT 02687178.

A randomized, double-blind clinical trial of canrenone vs hydrochlorothiazide in addition to angiotensin II receptor blockers in hypertensive type 2 diabetic patients

“… 6 The effects of canrenone on BP were already previously reported in two previous papers where the authors reported that the systolic and diastolic BP (24 h, daytime and nighttime) and mean arterial and pulse pressures were significantly reduced when canrenone was added to the preexisting therapy. 10 , 11 Moreover, the authors did not observe any significant differences between canrenone 50 and 100 mg: among patients treated with canrenone 50 mg, 67.5% and 74% normalized the 24 h systolic and diastolic BP, respectively, and among patients treated with 100 mg, 61.6% and 68.5% ( p not significant for 50 vs 100 mg). 10 …”

“… 10 , 11 Moreover, the authors did not observe any significant differences between canrenone 50 and 100 mg: among patients treated with canrenone 50 mg, 67.5% and 74% normalized the 24 h systolic and diastolic BP, respectively, and among patients treated with 100 mg, 61.6% and 68.5% ( p not significant for 50 vs 100 mg). 10 …”

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

“…As already reported for the whole population, we did not observe clinically relevant side effects in the group of patients undergoing ABPM, and in particular, no threatening hypotension episodes were seen during the 24 h BP monitoring. 24 This may be due in part to patient selection, including those patients who were already tolerant of ACE or AT1R blockade in terms of renal perfusion. As expected based on previously published literature, an increase in serum K was observed in conjunction with a non-clinically relevant increase in serum creatinine at the higher doses.…”

“…The detailed study design has been described previously. 24 This study presents a secondary analysis focused on ABPM. Besides ABPM, all patients had a complete clinical evaluation, office visit BP measurements, and routine laboratory examinations at baseline (pre-study canrenone addition) and 3 months after canrenone addition.…”

“…The study inclusion and exclusion criteria have been already described. 24 Briefly, inclusion criteria included several parameters: 1) office BP values ≥140/90 mmHg; 2) undergoing ongoing therapy with maximal tolerated dose for at least 2 months of ACE inhibitors or AT1R antagonists plus HCT 25 mg/day; 3) both sexes; 4) age >45 and <75 years; 5) grade 1 or 2 hypertension; 6) body mass index (BMI) ≤35 kg/m 2 ; and 7) giving informed consent to the study.…”