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Cardiovascular Drugs and Therapy

, Volume 26, Issue 2, pp 131–143 | Cite as

Effects of Candesartan on Left Ventricular Function, Aldosterone and BNP in Chronic Heart Failure

  • Aneta Aleksova
  • Serge Masson
  • Aldo P. Maggioni
  • Donata Lucci
  • Renato Urso
  • Lidia Staszewsky
  • Stefano Ciaffoni
  • Giuseppe Cacciatore
  • Gianfranco Misuraca
  • Michele Gulizia
  • Lucio Mos
  • Gianni Proietti
  • Calogero Minneci
  • Roberto Latini
  • Gianfranco Sinagra
  • on the behalf of the CandHeart Investigators
Article

Abstract

Purpose

Heart failure (HF) is characterized by activation of neurohormonal systems such as aldosterone and natriuretic peptides. In the absence of published data, CandHeart trial was designed to assess the effects on left ventricular (LV) function, aldosterone and brain natriuretic peptide (BNP) of candesartan in patients with HF and preserved (LVEF ≥ 40%) or depressed (LVEF <40%) LV systolic function.

Methods

A total of 514 patients with stable symptomatic NYHA II-IV HF and any left ventricular ejection fraction (LVEF)were randomized to candesartan (target dose 32 mg once daily) as add-on therapy or standard medical therapy alone. Standardized echocardiographic exams were performed locally under central quality control, whereas biomarkers were assayed in a core laboratory.

Results

The majority of patients (73.3%) were NYHA II and on ACE inhibitors (91.8%) and beta-blockers (85.4%). Mean age was 66 ± 11 years. Mean LVEF was 36.2 ± 9.7% and 24.9% of patients had LVEF ≥ 40%. LVEF increased significantly more in the candesartan group (p = 0.09 at 12 weeks and p = 0.01 at 48 weeks) and left ventricular end-diastolic diameter decreased in candesartan group (p = 0.05 at 12 weeks). Candesartan significantly reduced aldosterone at 48 weeks (p = 0.009). BNP was reduced similarly over time in both study groups (p = 0.35 and p = 0.98 at 12 and 48 weeks, respectively). There were 6.6% of discontinuations of candesartan for adverse events.

Conclusions

In CandHeart, the addition of candesartan to standard medical treatment did not reduce circulating BNP more than standard therapy (primary endpoint), but it significantly improved LV function and produced a marked decrease in aldosterone levels at study end.

Key words

Heart failure Aldosterone Natriuretic peptide Left ventricular ejection fraction Candesartan 

Introduction

Regardless of the recent advances in medical treatment, left ventricular (LV) dysfunction associated with signs of heart failure (HF) is associated to a significant morbidity and mortality [1]. This syndrome is characterized by activation of different neurohormonal systems and with consequent elevation of circulating levels of various hormones including aldosterone and natriuretic peptides [2].

Aldosterone has been implicated as a contributor to structural remodeling of the heart [3, 4], and its plasma concentrations have been independently associated with all-cause and cardiovascular mortality not only in patients with chronic HF [5, 6].The B-type natriuretic peptide (BNP) is a cardiac hormone synthesized in the atrial and ventricular myocardium and released in response to ventricular wall stress due to volume expansion and pressure overload [7]. BNP has been found to be a highly sensitive and specific marker for LV dysfunction [8, 9, 10], and a powerful predictor of outcomes, so that it is being tested as guidance to therapy of HF [11].

The standard recommended treatment for HF with ACE inhibitors and beta-blockers improves LV remodeling and outcomes by decreasing neurohormonal activation [12]. Less marked are the benefits obtainable with the addition of an angiotensin II receptor antagonist (ARB) to an ACE inhibitor. In the Val-HeFT trial, the addition of the ARB, valsartan, in patients already receiving optimal therapy for HF was associated with further decrease in mortality/morbidity, but not of mortality alone [13]. Consistent with the clinical benefits, the addition of valsartan caused sustained reduction in BNP [14] and aldosterone plasma concentrations [6]. In CHARM overall, candesartan decreased mortality and morbidity [15], specifically in patients with reduced LV function [16], but no data were published on its effects either on circulating BNP or on aldosterone since those of RESOLVD Pilot trial [17].

Based (a) on the evidences on the relation between neurohormone levels and cardiovascular events in patients with HF, (b) on the fact that the effects observed in RESOLVD Pilot and Val-HeFT studies[13] refer to patients with impaired LV systolic function, the present study was designed to investigate the effects of a 3-month treatment with high-dose candesartan as add-on therapy in patients with HF and preserved (LVEF ≥ 40%) or depressed (LVEF <40%) LV systolic function, versus standard therapy.

Patients and methods

Study design

The CandHeart trial (Effects of Candesartan Cilexetil vs. Standard Therapy on Serum Levels of Brain Natriuretic Peptide in Patients Suffering from Chronic Heart Failure with Depressed and Preserved Systolic Function) was a 48-week, add-on, multicentre, open-label, randomized, parallel groups study in patients suffering from congestive HF. Patients aged ≥18 years, of both genders, with stable symptomatic NYHA II-IV HF and any LVEF measured at screening visit, and who provided a written informed consent were eligible. Patients with LVEF >40% had to be hospitalized for cardiovascular events during the past 12 months before randomization. Exclusion criteria were history of prior treatment with ARBs within 2 weeks from screening; severe or malignant hypertension (SBP/DBP > 180/110 mmHg); symptomatic hypotension; prior acute myocardial infarction, stroke or transient ischemic attack (TIA), percutaneous transluminal coronary angioplasty (PTCA) or coronary artery by-pass graft (CABG) within 1 month from screening; hemodynamically relevant arrhythmias or cardiac valvular defect; prior implant of pacemakers, cardiac resynchronization therapy or cardioverters within 6 months from randomization; constrictive pericarditis or active myocarditis; likelihood of cardiac surgical intervention during the overall treatment period; evidence of angina pectoris in the previous month; poorly controlled diabetes mellitus (blood glucose > 140 mg/mL or HbA1c > 8%); untreated thyroid dysfunction; renal artery stenosis; angio-edema of any etiology; significant liver (AST, ALT, total bilirubin or alkaline phosphatase > 2x the upper limit of normal range) or renal impairment (serum creatinine > 2.0 mg/dL or serum potassium > 5.0 mmol/L); anemia of any etiology (Hb <10.5 g/dL) or any other clinically relevant hematological disease; pregnant or lactating females or females at risk of pregnancy; any disease with malabsorption; presence of any non-cardiac disease that is likely to significantly shorten life expectancy; history of chronic alcohol or drug/substance abuse, or presence of other conditions potentially able to affect study subjects’ compliance; known allergy, sensitivity or intolerance to study drugs and/or study drugs’ formulation ingredients; patients unlikely to comply with the protocol or unable to understand the nature, scope and possible consequences of the study; participation in another trial in the month preceding study entry.

At baseline visit, eligible patients satisfying all the inclusion criteria and none of the exclusion criteria were centrally randomized either to candesartan cilexetil added to their ongoing standard therapy (group 1) or to the continuation of their ongoing standard therapy for HF (group 2). In group 1 candesartan cilexetil was administered at an initial dose of 4 mg o.d. (one tablet) and, if tolerated, it was up titrated to 8 mg (one tablet o.d.) after 2 weeks of treatment, to 16 mg (one tablet o.d.) after 4 weeks of treatment, and to 32 mg (two tablets of 16 mg o.d.) after 6 weeks of treatment.

Eight clinical visits were performed at screening, randomization, and 2, 4, 6, 12, 24 and 48 weeks after randomization.

The study was funded by Takeda Italia Farmaceutici and endorsed by the Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO). The ANMCO Research Center independently performed data analyses. The study was approved by all appropriate National Regulatory Authorities and Ethics Committees of the participating centers. The study was registered at Clinical Trials.gov number, NCT00843154.

Blood and urine collection and analysis

A venous blood sample of 18 mL was drawn from patients resting for at least 15 min, centrifuged at 4°C within 10 min, and plasma was divided into aliquots and stored at −70°C for centralized assays of BNP (automated immunoassay, Beckman Coulter DxL800) and aldosterone (radioimmunoassay, DiaSorin). A fresh morning urine sample was collected and stored at −70°C until analyzed centrally for urinary albumin-to-creatinine ratio (UACR), as previously described [18]. BNP was measured at baseline, and week 12 and 48. Aldosterone and UACR were measured at baseline and week 48. All the assays were done in a blind fashion.

Echocardiography

Sites were qualified by a central core echocardiographic laboratory after sending duplicate recordings and readings of all views and measurements required by the protocol. Echocardiographic exams were performed at the beginning of the study, at week 12 and at week 48 of follow-up. LVEF and LV internal diameter in diastole (LVIDD) were measured using standard echocardiography. Patients with LVEF ≥ 40% were assigned to the preserved LV systolic function subgroup and patients with LVEF <40% were assigned to the depressed LV systolic function subgroup. Left (LAA) and right (RAA) atrial dimensions were assessed as area and diameters. E and A wave peak velocity at pulsed Doppler of transmitralic flow were measured together with deceleration time of E wave (E-DT). Just for sites having appropriate facilities, the following additional measurements were made: peak systolic velocity (Sa), early (Ea) and late (Aa) diastolic velocities, acceleration time of Ea (measured from onset to peak Ea) and deceleration time derived by linear extrapolation of Ea to baseline.

Thirty percent of all echocardiographic exams performed during the study were randomly selected and read at the core laboratory by an experienced cardiologist unaware of study group and visit. The quality of recordings was defined by a scoring system with a scale from 0 to 32 points, 32 being the best quality. For accuracy the reproducibility of LVIDD, LVEF and LAA measurements between sites and core lab was analyzed. Average quality score from 142 echocardiograms was 20 ± 5 (SD), and 78% of them presented good or optimal quality. The mean difference [19] between sites and core lab in LVIDD measurements was −0.34 ± 2.10 mm and the coefficient of variability was 3.5%; corresponding values for LAA were −0.02 ± 2.20 cm2 and 9.6%, respectively. The comparison of site’s and core lab LVEF <40% vs. ≥ 40% revealed a 5.1% disagreement (Cohen’s Kappa = 0.78).

Outcomes

The primary objective of the study was to evaluate the effects of the maximum tolerated dose of candesartan cilexetil up to 32 mg o.d., added to ongoing standard therapy, versus ongoing standard therapy, on 3-month (12-week) changes of BNP from baseline, in patients affected by HF with depressed or preserved LV systolic function. The secondary objectives of the study after a 48-week treatment period were to assess:1) change of BNP at 48 weeks from baseline values; 2) changes from baseline of aldosterone. Other exploratory analyses included(1) changes from baseline of LVEF, LVIDD, E wave peak velocity/A wave peak velocity (E/A), deceleration time of E wave (E-DT), atrial dimensions; (2) changes from baseline of BP and heart rate (HR); (3) persistence of active treatment and discontinuation rate; (4) quality of life by Kansas City Cardiomyopathy Questionnaire (KCCQ).

Tolerability

Adverse events were recorded at each study visit. Laboratory safety parameters were assessed at study enrollment, and 4, 12, 24 and 48 weeks thereafter.

Statistical analysis

A sample size of 1,300 patients (650/group) was calculated according to an expected 20% BNP reduction in candesartan vs. control group assuming a power of 80%, with a 2-tail alpha of 0.05 and 15% of drop-out. For each patient the differences between randomization and follow-up (i.e. 12 and 48 weeks, when applicable) measurements were computed. and candesartan effect was tested by comparing these differences between study groups using a non parametric test (Mann–Whitney or Wilcoxon rank sum test), since the data transformations used did not normalize the data distribution.

The relationship between BNP concentrations at baseline (randomization) and echocardiographic variables was investigated dividing the patients into 3 groups according to tertiles of BNP and providing the by-group descriptive statistics of the values. Kruskall-Wallis test was used to test the differences between more than 2 groups.

Changes between 12 and 48 weeks and basal values of echocardiographic variables were compared between study groups (candesartan vs. standard therapy) by Kruskall-Wallis test.

All statistical analyses were performed using the program R [20] and the packages Design [21], Hmisc [22], RODBC [23] and Rcmdr [24].

Results

In CandHeart trial, 514 patients were enrolled from December 13, 2005 to May 27, 2008 at 70 clinical centers in Italy. The study was stopped before reaching the target number of patients since an interim analysis by the DSMB showed that an unacceptable number of patients (n = 1500 per group) would have been needed to show the observed difference in 3-month change of BNP with the predefined power of 0.80, when data on 371 patients were available. In addition, the unexplained decrease in BNP over time in the control group supported the perception of futility in the continuation of the study. The characteristics of patients overall and according to the treatment are shown in Table 1. Baseline and follow up BNP concentrations were available for 498 patients since in 5 patients BNP concentrations were undetectable and in 11 patients at least one sample was missing.
Table 1

Baseline characteristics of all patients according to study group and to LV ejection fraction at randomization

 

All patients

Candesartan

Standard therapy

p value

LVEF < 40%

LVEF ≥ 40%

p value

N (%)

514 (100)

256 (49.8)

258 (50.2)

 

386 (75.1)

128 (24.9)

 

Age (years)

66 (11)

66 (11)

66 (11)

0.67

66 (11)

66 (12)

0.89

Age > 70 years (%)

39.5

39.5

39.5

0.94

38.3

43.0

0.41

Males (%)

76.1

76.2

76

0.96

79.0

67.2

0.009

BMI (kg/m2)

27.5(4.3)

27.6(4.5)

27.4(4.2)

0.62

27.3 (4.3)

28.2 (4.5)

0.06

SBP/DBP (mmHg)

129(17)/77 (9)

129.4(18)/78(9)

128.7(17)/77(9)

0.76/0.28

127 (16)/77 (4)

134 (19)/78 (5)

0.0002/0.09

HR (bpm)

68.9 (13)

69 (13)

68.7 (14)

0.59

68 (13)

67 (14)

0.17

NYHA II class (%)

73.3

72.3

74.4

0.65

73.8

71.9

0.75

History of hypertension (%)

50.9

53.3

48.5

0.31

47.9

59.8

0.03

Diabetes mellitus (%)

25.9

26.6

25.2

0.80

25.1

28.1

0.58

Current smokers (%)

15.2

19.5

10.8

0.009

15.8

13.8

0.58

COPD (%)

19.1

19.5

18.6

0.88

17.6

23.4

0.19

Previous MI (%)

39.0

35.3

42.6

0.11

41.7

30.7

0.04

Previous PCI (%)

22.6

22.3

22.9

0.95

23.3

20.3

0.56

Previous CABG (%)

14.8

14.4

15.1

0.93

16.8

8.6

0.03

CV hospitalizations in the previous year (%)

58.0

58.6

57.4

0.85

47.4

89.8

<0.0001

Etiology of HF (%)

 Ischemic

49.8

48.8

50.8

0.72

52.3

42.2

0.06

 Hypertensive

18.9

19.5

18.2

0.79

14.2

32.8

<0.0001

 Dilatative

22.4

21.5

23.3

0.71

25.4

13.3

0.006

 Others

8.9

10.2

7.8

0.42

8.0

11.7

0.28

History of AF (%)

9.3

11.7

7.0

0.09

7.1

14.1

0.007

AF (%)

15.3

15.5

15.1

1.00

13.6

21.1

0.07

Laboratory parameters

 Hemoglobin (g/dl)

13.9(1.4)

13.9(1.5)

13.9(1.4)

0.45

14.0 (1.4)

13.7 (1.5)

0.05

 Glucose (mg/dl)

111(33)

110(33)

111 (33)

0.34

110 (33)

112 (33)

0.39

 Total cholesterol (mg/dl)

184(44)

184 (49)

183(40)

0.63

186 (45)

178 (43)

0.07

 Creatinine (mg/dl)

1.1(0.3)

1.1(0.3)

1.1(0.3)

0.22

1.1 (0.3)

1.0 (0.3)

0.03

 eGFR (ml/min/1.73 m2)

72.5(19.8)

73.6(19.8)

71.5(19.9)

0.29

72.2 (19.7)

73.4 (20.3)

0.56

 BNP (pg/mL)

252(336)

240(322)

263.6(349)

0.49

282 (365)

163 (202)

<0.0001

 Aldosterone (pg/mL)

168.9(120.9)

166.7(110.9)

171(130.2)

0.68

168 (118)

172 (130)

0.75

 UACR (mg/g)

73.6(370.9)

68.3(229.2)

78.8(470.9)

0.61

75 (398)

69 (271)

0.86

QRS duration (ms)

116.6(36.6)

117.4(40.2)

115.8(32.7)

0.96

120.9 (38.2)

103.1 (27.0)

<0.0001

Echocardiography

 LVEF (%)

36.2 (9.7)

36.6 (10.2)

35.7 (9.2)

0.26

32.0 (5.7)

48.7 (8.2)

NA

 LVEF <0.40 (%)

75.1

73.0

77.1

0.33

NA

NA

NA

 LVIDD/BSA (mm/cm2)

33.4 (5.4)

33.1 (5.3)

33.8 (5.8)

0.10

34.6 (5.3)

30.1 (4.3)

<0.0001

 DT (ms)

206.8 (78.7)

207 (79.3)

206.6 (78.4)

0.94

199 (76)

231 (82)

0.0002

 E/A

1.3 (3.5)

1.4 (4.9)

1.3 (1.2)

0.14

1.4 (1.7)

1.3 (1.4)

0.77

 TAPSE (mm)

21.8 (15.5)

22.4 (15.3)

21.1 (15.7)

0.14

21.3 (14.2)

23.3 (18.9)

0.30

 LAA (mm2)

24.2 (8.6)

24.4 (8.9)

24 (8.4)

0.67

24.3 (8.4)

24.1 (9.2)

0.82

 RAA (mm2)

17.8 (6.3)

17.7 (5.7)

17.9 (6.8)

0.98

17.9 (6.4)

17.5 (6.0)

0.45

Background therapy (%)

 ACE inhibitors

91.8

91.4

92.2

0.85

93.0

88.3

0.13

 Beta blockers

85.4

85.2

85.7

0.97

88.3

76.6

0.002

 Calcium channel blockers

12.6

13.7

11.6

0.57

9.8

21.1

0.002

 Digitalis

21.4

19.9

22.9

0.48

19.7

26.6

0.13

 Amiodarone

11.5

11.3

11.6

0.97

11.1

12.5

0.80

 Diuretics

86.6

88.3

84.9

0.32

86.5

86.7

0.92

 Aldosterone receptor antagonists

35.2

34.0

36.4

0.62

36.0

32.8

0.58

 Statins

48.6

45.3

51.9

0.16

51.3

40.6

0.05

Data shown as mean (SD) for continuous variables and frequency (%) for categorical variables. Abbreviations: ACE angiotensin converting enzyme; AF atrial fibrillation; BMI body mass index; BNP B-type natriuretic peptide; BSA body surface area; CABG coronary artery bypass graft; COPD chronic obstructive pulmonary disease; eGFR estimated glomerular filtration rate; LAA left atrial area; LVEF left ventricular ejection fraction; LVIDD LV internal diameter in diastole; MI myocardial infarction; NA not applicable; PCI percutaneous intervention; RAA right atrial area; TAPSE tricuspid annular plane systolic excursion; UACR urine albumin/creatinine ratio

The patients were more likely to be males (76.1%), with mean age of 66 ± 11 years, and 39.5% of them were older than 70 years. The mean LVEF was 36.2 ± 9.7% and 24.9% of patients had LVEF ≥ 40%. The majority of patients had mild symptoms of HF (NYHA II 73.3%). The most common etiology of HF was ischemic heart disease, independently of the presence of depressed or preserved LVEF. Fifty eight percent of patients were hospitalized for cardiovascular events during the past 12 months before randomization. A history of hypertension was present in 50.9% of the patients and 25.9% had a diabetes mellitus. Most patients were treated with ACE inhibitors (91.8%) and beta-blockers (85.4%). Mean daily doses of the 3 most prescribed ACE inhibitors were: 16 mg enalapril, 14 mg lisinopril, 6.3 mg ramipril, with about half of the patients on recommended daily doses. There were 35.2% of all patients taking aldosterone antagonists. Baseline characteristics of patients randomized to candesartan were similar to those of patients randomized to standard treatment except for higher prevalence of smokers in the candesartan group (Table 1). The same characteristics are shown by LVEF < or ≥40% at randomization: the 2 groups significantly differ by sex, hypertensive etiology, BNP, QRS duration and LVIDD.

Most patients (62%) reached the target dose of 32 mg/day of candesartan during the first 3 months of follow up (average 25 mg/day, SD 10 mg, range [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32]). On average, the exposure to candesartan per patient was 262 ± 126 days (median 336; IQR 172–346) over 48 weeks of follow up. On average, the compliance to candesartan (i.e. extent of exposure to study treatment/time of observation) was 93.7 ± 19.1% (median 100%; IQR 99.7–100).

At 12 weeks there was no significant difference in the changes of systolic blood pressure (SBP) (p = 0.39) in the candesartan and standard therapy arm. Between baseline and 48 weeks, SBP declined by a mean of −1.5 ± 16.7 mmHg in the candesartan group and increased by a mean of 2.0 ±16.4 mmHg in the standard therapy group, p = 0.02. Over time differences in diastolic blood pressure between the study groups were observed (p = 0.12 at 12 weeks; p = 0.6 at 48 weeks) though not statistically significant.

B-type natriuretic peptide

Median plasma BNP concentration at baseline was 147 [63–304] pg/mL (n = 498), not different between the candesartan arm (141 [62–295] pg/mL, n = 247) and standard therapy arm (157 [65–320] pg/mL, n = 251, p = 0.49). As expected, BNP was significantly higher at baseline in patients with LVEF < 40% than in patients with LVEF ≥ 40% (168 [66–361] pg/mL vs. 99 [38–199] pg/mL respectively; p = 0.033).

BNP was reduced over time (12 and 48 weeks) in both study groups, but no significant difference between the treatment groups was observed (Fig. 1). Absolute reduction (median) over 12 weeks (primary endpoint of the study) was −18 pg/mL in the candesartan arm (n = 194) compared to −11 pg/mL in the standard therapy (n = 210; p = 0.35). Corresponding values at 48 weeks were −17 and −24 pg/mL (p = 0.98). The observed reduction might suggest the presence of a small effect of the candesartan treatment vs. the standard therapy which was not statistically significant due to the very high between and within subject variability.
Fig. 1

Effects of candesartan on the change from randomization in brain natriuretic peptide (BNP) and aldosterone. Effects of candesartan (filled bars) and standard therapy (empty bars) on the change from randomization to week 12 or 48 in the plasma concentrations of brain natriuretic peptide (BNP) and aldosterone. Data are presented as median values with p-values for between-treatment comparisons (Wilcoxon rank sum test). The number of patients in each group is shown with the bar

These results were confirmed in the per-protocol analysis performed in 361 out of 404 patients (89%) available for analysis of the primary endpoint (i.e. selecting patients taking study medication for at least 80% of the first 3 months of observation, who did not use ARBs during the study period, who did not have cardiovascular events within 1 month prior to the screening visit and without laboratory value abnormalities). Absolute reduction (median) over 12 weeks was −18 pg/mL in the candesartan arm (n = 170) compared to −8 pg/mL in the standard therapy (n = 191; p = 0.58). No significant difference was found in 12-week BNP changes (pg/mL) between treatment groups even after stratification according to baseline LVEF (292 pts < 40% vs. 112 pts ≥ 40%): −15 candesartan vs. −2 control in LVEF ≥ 40%; −21 candesartan vs. −21 control in LVEF < 40% group.

Aldosterone

Median baseline aldosterone plasma concentration was 143 [90–212] pg/mL (n = 501), similar in the candesartan (143 [88–216] pg/mL, n = 248) and standard therapy arm (141 [90–201] pg/mL, n = 253, p = 0.68). Baseline aldosterone concentration was similar in patients with depressed and preserved LVEF (145 [90–210] pg/mL and 139 [86–214] pg/mL, respectively; p = 0.57). The treatment with candesartan was associated with statistically significant reduction of aldosterone at 48 weeks (−13 [−64 to −29] pg/mL in candesartan vs. +4 [−42 to +58] pg/mL in controls, p = 0.009, Fig. 1).

Urinary albumin-to-creatinine ratio

Median UACR at baseline was 10.2 [4.0–29.9] mg/g (n = 486), similar in the candesartan (9.6 [4.0–29.5] mg/g, n = 241) and standard therapy arms (11.1 [4.0–30.0] mg/g, n = 245, p = 0.61). Also the baseline UACR was not different in patients with LVEF higher and lower than 40% (11.1 [4.1–31.6] mg/g and 10.1 [4.0–29.5] mg/g respectively). There were no differences in the 48-week changes in UACR in the candesartan group (0.1 [−5.4 to 10.7] mg/g, n = 194) and in the standard therapy group (0.0 [−5.8 to 8.3] mg/g, n = 194, p = 0.58, Wilcoxon rank sum test).

Echocardiography

Echocardiographic variables at baseline were not different between study groups (Table 1). A strong correlation was observed between baseline BNP (by tertiles) and baseline LVEF (Fig. 2a), indexed LVIDD (2b), left atrial area (2c), tricuspid annular plane systolic excursion (TAPSE) (2d), but not with basal parameters of LV diastolic function (i.e. E/A, E/e’). At variance with BNP, aldosterone levels were found to be unrelated to any of the echo variables at baseline.
Fig. 2

Baseline echocardiographic parameters according to baseline BNP concentration. Box plots showing the relation between tertiles of baseline BNP concentration and baseline median levels and interquartile range of the echocardiographic parameters: a left ventricular ejection fraction (LVEF), b indexed left ventricular diameter in diastole (LVIDd/BSA), c left atrial area and d tricuspid annular plane systolic excursion (TAPSE). Groups were compared with the Kruskall-Wallis test. The number of patients in each category varies from 149 to 169. Tertiles of BNP: T1 < 81, T2 81-221, T3 ≥ 222 pg/mL

LVEF increased in the candesartan group more than in the standard therapy group, at 12 weeks (p = 0.09 Wilcoxon test, Fig. 3), and at 48 weeks (p = 0.01 Wilcoxon test, Fig. 3). The increase in LVEF observed with candesartan was mostly limited to the patients with LVEF < 40% (p < 0.01).Left ventricular end-diastolic diameter decreased at 12 weeks by 16% in candesartan and 0.0% in standard therapy (p = 0.05, Fig. 3).Left atrial area decreased at 12 weeks in candesartan by 2.1% and by 3.3% at 48 weeks (p = 0.11 and p = 0.04 vs. standard therapy) (Fig. 3). No other echocardiographic variables showed statistically significant differences by study group in their changes over time.
Fig. 3

Effects of candesartan on the change from randomization in echocardiographic parameters. Effects of candesartan (filled bars) and standard therapy (empty bars) on the change from randomization to week 12 or 48 in the left ventricular ejection fraction (LVEF), indexed left ventricular internal diameter in diastole (LVIDd/BSA) and left atrial area. Data are presented as median values with p-values for between-treatment comparisons. Groups were compared with the Kruskall-Wallis test. The number of patients in each group is shown with the bar

NYHA class

The number and proportion of patients into each NYHA class at baseline, week 12 and week 48, by study treatment were calculated and the number of patients improving in NYHA class in each arm were compared. All patients were in NYHA class II to IV at the time of randomization. After 12 weeks of treatment more patients in the candesartan arm improved, but the difference with standard therapy was not statistically significant (p = 0.27). At week 48 of follow-up, 105 patients (20.4%) improved their NYHA functional class (60 pts in candesartan vs. 45 pts in standard therapy, p = 0.09).

Quality of life outcomes

Baseline overall summary score of KCCQ was 69.8 (Q1-Q3 50.9-82.8) in candesartan and 71.1 (Q1-Q3 53.6-84.7) in standard therapy (p = 0.49). Both treatment groups significantly improved their KCCQ scores at the end of the follow-up compared with the baseline assessment, but the improvement was more prominent in candesartan than in standard therapy group (median KCCQ overall summary score improvement +8.2 vs. + 4.9, p = 0.055). Patients with >5 points increase in overall KCCQ summary score (clinically meaningful) were 57% in candesartan and 49% in standard therapy group (p = 0.17).

Safety and tolerability

Few patients in the candesartan group permanently discontinued the therapy before the end of the study (27 subjects; 10.5%). The discontinuation was due mainly to adverse events (i.e. hypotension, hyperkalemia, asthenia, allergic reaction, pulmonary edema, acute renal failure with hyperkalemia, anemia together with increase in AST) (17 patients) and patient’s decision (5 patients). Protocol deviation, consent withdrawal and investigator decision accounted for only 5 cases.

Safety assessment was based on adjudicated clinical events and on abnormal laboratory values; over 1-year follow up 14 deaths and 102 hospitalizations for any cause were recorded. Data by study group are reported in Table 2: no statistically significant differences were found.
Table 2

Clinical and laboratory events over 1-year follow up by study group

Event

Candesartan (256 pts)

Standard therapy (258 pts)

All-cause death

6

8

Death for CV causes

4

5

All-cause hospitalizations

41

33

Hospitalizations for CV reasons

29

25

Hospitalizations for worsening HF

10

13

Serum creatinine > 2.5 mg/dL

1

2

Serum potassium > 5.5 mEq/L

15

17

Serum potassium > 6.0 mEq/L

4

2

All events were adjudicated by an independent Event Committee. Differences between study groups were never statistically significant. Number of patients pts with ≥1 non-fatal event are reported in the table. CV cardiovascular

Discussion

The primary endpoint of CandHeart, the change in BNP over 3 months, was not significantly affected by candesartan when compared to control. However, the combination of candesartan and standard medical therapy was associated with significantly more important decline in aldosterone levels. This data together with the observed slight rise of aldosterone in standard medical treatment arm indicates more complete blockade of RAAS with dual RAAS inhibition. Accordingly, a small but statistically significant decrease in SBP in the candesartan but not in the control group was observed at study end.

CandHeart trial demonstrates that addition of candesartan to standard medical treatment, in patients with symptomatic HF with either preserved or depressed LV systolic function, is associated with a significant increase of the LVEF over time. Reverse atrial remodeling was observed in terms of LAA decrease over time. The beneficial effect of the combination therapy on LVEF persisted and was even more conspicuous after 48 weeks of treatment, consistent with the slow onset of action of ARBs on cardiac remodeling. A trend towards symptomatic benefit of candesartan was also apparent from the improvement in NYHA class and in quality of life, although not statistically significant. In congestive HF, the overactivation of the RAAS system causes elevation of aldosterone levels, associated with worsening of hemodynamic responsiveness through excessive sodium retention with expansion of the extracellular volume. Further, aldosterone contributes to the progression of HF by promoting perivascular and interstitial myocardial fibrosis, acting via mineralocorticoid receptors in the heart [3, 4]. The treatment with the aldosterone receptor antagonist spironolactone could improve left ventricular volume and mass index [25]. In Val-HeFT an ARB valsartan added to background therapy for heart failure produced sustained reduction in plasma aldosterone, sustained regression of left ventricular remodeling and significant reduction in the mortality and morbidity combined endpoint [6]. A favorable effect of the addition of candesartan on LV remodeling similar to that found in CandHeart was reported in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot trial [26]. Further, in the CHARM trial the treatment with candesartan significantly reduced cardiovascular deaths and admissions for heart failure [15]. In CandHeart, the observed effect of candesartan on RAAS blockade and the consequent favorable effect on LV remodeling is consistent with an overall trend towards better functional class and quality of life though not statistically significant. At variance with previous evidences [17], the reduction in aldosterone plasma concentrations in candesartan group was still evident after 48 weeks. This sustained effect may be at least in part ascribed to the higher daily dose of candesartan in CandHeart (25 mg) when compared to RESOLVD Pilot (target daily dose 16 mg) [17].

CandHeart trial further demonstrated the favorable safety profile of candesartan in patients with symptomatic HF irrespective of LV function and age, thus confirming the results of RESOLVD Pilot trial [17]. However, there was no significant difference between the groups in the change in the level of BNP during the follow-up.

BNP, mainly but not exclusively originating from the ventricles, is increased with the severity of HF due to LV dysfunction, and this raise is correlated to the hemodynamic parameters such as pulmonary capillary wedge pressure and LVEF [10]. Also in CandHeart strong correlation between BNP and LVEF was found. Moreover, baseline concentrations of BNP were comparable to those reported for other large scale multicenter trials such as GISSI-HF [27] and Val-HeFT [14]. Though, the significant improvement of LVEF by candesartan was not associated with a decrease of BNP when compared to controls. This finding is in contrast with the previous published evidence [17] on biohumoral effects of ARBs in chronic HF. In RESOLVD Pilot, candesartan + enalapril induced a significant decrease in BNP over 43 weeks, while the decrease in aldosterone observed at 17 weeks was no longer present after 43 weeks. In addition, the combination therapy improved LVEF and LV volumes measured by radionuclide angiography, similar to results obtained by echocardiography in CandHeart. While in RESOLVD Pilot the decrease in BNP was associated to an improvement in LV volumes and function in patients not on betablockers, this was not the case in CandHeart [28]. Val-HeFT findings on 4,284 patients showed that the addition of valsartan to standard medical treatment was associated with significantly more important decrease in BNP, associated to a reduction in LVIDD and an increase in LVEF[14]. This discrepancy may be related to differences between patient population in severity of the LV dysfunction and concomitant treatment medication. Patients enrolled in Val-HeFT were more frequently in more advanced NYHA class, had lower LVEF and were less frequently treated with beta blockers, and aldosterone receptor antagonists compared to CandHeart [13], even if more than half of the patients were on lower-than-recommended dosages. Thus, in this contemporary population more intensively treated with neurohormonal blockers, even if underdosed, little room is left for further benefit from the addition of candesartan. In fact, in Val-HeFT[13], the decrease in BNP by valsartan was attenuated in patients with background therapy with both ACE inhibitors and β-blockers. Furthermore, in CandHeart one fourth of patients had HF with preserved LVEF. In the I-PRESERVE trial [29] that randomized 4,128 patients with LVEF ≥ 45% and followed them for a mean of about 4 years, the ARB irbesartan did not reduce NT-proBNP levels compared to placebo.

In order to put the biohumoral data of CandHeart in context, baseline levels of BNP, aldosterone and UACR from previous relevant studies in chronic HF are reported in Table 3. Notwithstanding differences in the analytical methods (the molecular forms and types of assays are poorly standardized, especially for natriuretic peptides) and statistics used, baseline concentrations of BNP and aldosterone in the CandHeart trial compared fairly well with the levels reported in other clinical trials that enrolled patients with chronic HF of different severity, etiology and phenotypic characteristics.
Table 3

Circulating biomarker levels in some clinical trials that enrolled patients with chronic HF

Clinical study

No. patients with biomarkers

BNP (pg/mL)

Aldosterone (pg/mL)

UACR (mg/g)

Reference

CandHeart

498

147 [63–304]

143 [90–212]

10.2 [4.0–29.9]

Present study

RESOLVD Pilot

769

≈184 (mean)

≈125 (mean)

NA

[17]

RALES

107

≈71 (geometric mean)

≈124 (geometric mean)

NA

[31]

Val-HeFT

4300

97 [41–238]

101 [60–170]

NA

[32]

AREA IN-CHF

467

88 [35–185]

118 [75–177]

NA

[33]

A-HeFT

683

≈184 (mean)

NA

NA

[34]

ALOFT

302/190

210 (median)

80 (median)

56% patients with normal albuminuria, 33% with micro-, 11% with macroalbuminuria

[35, 36]

CHARM

2310

NA

NA

58% patients with normal albuminuria, 30% with micro-, 11% with macroalbuminuria

[37]

GISSI-HF

1233/2131

141 [61–291]

NA

8.7 [1.5–30.9]; 75% patients with normal albuminuria, 20% with micro-, 5% with macroalbuminuria

[18, 27]

Data are presented as median concentration [Q1-Q3] unless otherwise specified. NA not available

Another possible explanation may be the fact that once a patient is enrolled in a trial, her/his management improves, as well as surrogate endpoints, such as blood pressure, irrespective of the study treatments [30]. The significant decrease in BNP in both study groups found in CandHeart may therefore reflect optimization of therapy of HF, which can be envisaged considering that most of ACEi and betablockers were underdosed. The lack of blinding of the investigator may have led to uncontrolled biases in prescription and dose regimens of recommended drugs. Indeed, in the candesartan arm a statistically significant reduction of the use of ACE inhibitors (from 91.4% at randomization to 80.9% at the end of study, p < 0.05) and aldosterone receptor antagonists (from 34% to 18.6%, p < 0.05) was observed, while background therapy in the control arm did not undergo statistically significant changes during the study course.

The relatively small sample size, may have also influenced the results due to insufficient statistical power to show a difference in the primary endpoint.

In conclusion, in CandHeart, the addition of candesartan to standard medical treatment appeared to be well tolerated and significantly attenuated RAAS activation in HF, as suggested by a marked decrease in aldosterone levels at study end together with a blood pressure reduction. Moreover, candesartan significantly improved LV function, but it did not reduce circulating BNP more than standard therapy.

Participating centers and investigators

Switzerland Lugano (T Moccetti, M Bondio, E Pasotti). Italy Orbassano (P Greco Lucchina, L Montagna), Savigliano (B Doronzo, D Pancaldo), Codogno (T Resasco), Monza (A Mortara, M Bonadies), Bergamo (A Gavazzi, M Senni), Brescia (C Alicandri1, E Radaelli1), Manerbio (E Renaldini, A Alasa), Cremona (S Pirelli, S Verde, R Procopio), Pieve di Corriano (MC Brunazzi, M Negretti), Pavia (F Cobelli), Trento (G Cioffi, A Serafini) Conegliano (P Bocca), Mirano (P Sarto), Camposampiero (P Piovesana), Udine (D Miani, MC Albanese, V Biundo), Palmanova (MG Baldin, R Cesanelli, R Gortan), San Daniele del Friuli (L Mos, S Martina, O Vriz),Tolmezzo (M Bonin, A. Di Chiara), Trieste (G Sinagra, A Aleksova, L Massa), Pietra Ligure (F Chiarella), Modena (L Brugioni), Bologna (S Urbinati, G Labanti), Ferrara (R Ferrari, A Fucile), Faenza (R Casanova, A Patroncini), Cesena (F Tartagni, A Tisselli), Firenze (C Minneci, GM Santoro, A Sarti), Bagno a Ripoli (A Zuppiroli), Perugia (G Ambrosio, G Alunni), Terni (Gianni Proietti, Giorgio Proietti, M Bernardinangeli), Senigallia (N Ciampani, E Falchetti), Ancona (GP Perna, D Gabrielli, M Manfrin), Ascoli Piceno (L Moretti, G Gregori, L Partemi), Roma, San Camillo (P Tanzi), Roma, San Giovanni Addolorata (A Boccanelli, N Pagnoni), Roma, San Filippo Neri (M Santini), Colleferro (M Mennuni), Formia (F Carta), Campobasso (G Fiore, C De Vincenzo, P Quaranta), Caserta, San Sebastiano, UO Cardiologia UTIC (F Mascia, A Vetrano, A Izzo), Caserta, San Sebastiano, Cardiologia Riabilitativa e Preventiva (A Palermo, L Forte), Napoli, Policlinico Univ. Federico II (M Chiariello, P Perrone Filardi), Salerno (F Silvestri), Oliveto Citra (M De Cristofaro), Sarno (V Messina, F Olivieri), Scafati (C Nave), Battipaglia (T Di Napoli, S Romanzi, M Punzi), Mercato San Severino (V Capuano, F Franculli), Terlizzi (P Caldarola, A Tota), Foggia (M Di Biase), San Giovanni Rotondo (A Facciorusso, G Di Stolfo), Cosenza (R Caporale, G Misuraca), Catanzaro (V Ciconte, U Talarico), Soriano Calabro (L Anastasio, T Vetró), Scilla (M Musolino), San Marco Argentano (G Musca, O Cuccurullo), Siracusa (E Mossuti, G Romano), Augusta (L La Marca), Catania, Osp. Vittorio Emanuele II (A La Rosa), Catania, Ferrarotto, Div. Clinicizzata di Cardiologia (C Tamburino, G Cantarella, M Catalano), Catania, Ferrarotto (G Leonardi, V Randazzo), Catania, Garibaldi Nesima (M Gulizia, GM Francese, A Portale), Milazzo (F Badessa), Barcellona Pozzo di Gotto (V Ventura), Cefalù (T Cipolla, D Armata), Palermo, Civico e Benfratelli (D Albanese), Palermo, Villa Sofia, Cardiologia I e UTIC (V Cirrincione, F Ingrillì), Palermo, Cervello, Cardiologia I (A Ledda, G Geraci).

Footnotes

  1. 1.

    deceased.

Notes

Acknowledgments

The authors are grateful to Alessandra Fionda and Daniela Angeletti, Takeda Italia Farmaceutici, for their continuous and enthusiastic support to the trial. We thank Giancarlo Giudici and Massimo Grigolon from Biosite Italy for analytical support.

Funding sources and disclosures

The CandHeart trial was supported by a grant from Takeda Italia Farmaceutici, Italy. Drs. Maggioni and Latini have received institutional research support

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Aneta Aleksova
    • 1
  • Serge Masson
    • 2
  • Aldo P. Maggioni
    • 3
  • Donata Lucci
    • 3
  • Renato Urso
    • 3
    • 4
  • Lidia Staszewsky
    • 2
  • Stefano Ciaffoni
    • 5
  • Giuseppe Cacciatore
    • 6
  • Gianfranco Misuraca
    • 7
  • Michele Gulizia
    • 8
  • Lucio Mos
    • 9
  • Gianni Proietti
    • 10
  • Calogero Minneci
    • 11
  • Roberto Latini
    • 2
  • Gianfranco Sinagra
    • 1
  • on the behalf of the CandHeart Investigators
  1. 1.Cardiovascular Department“Ospedali Riuniti” and University of TriesteTriesteItaly
  2. 2.Department of Cardiovascular ResearchIstituto di Ricerche Farmacologiche “Mario Negri”MilanItaly
  3. 3.ANMCO Research CenterFlorenceItaly
  4. 4.Department of Neurological and Behavioral ScienceUniversity of Siena, Pharmacology SectionSienaItaly
  5. 5.Laboratory of Clinical Chemistry, Ospedale Sacro Cuore Don CalabriaNegrarItaly
  6. 6.Department of Cardiovascular Diseases, San Giovanni-Addolorata HospitalRomeItaly
  7. 7.Division of Cardiology, Ospedale Santissima AnnunziataCosenzaItaly
  8. 8.Cardiology Unit, Ospedale Garibaldi-NesimaCataniaItaly
  9. 9.Cardiology Unit, Ospedale Sant’AntonioSan Daniele del FriuliItaly
  10. 10.Cardiology Unit, Azienda ASL 4TerniItaly
  11. 11.Cardiology Unit, Ospedale San Giovanni di DioFlorenceItaly

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