Clinical research European Heart Journal (2006) 27, 562–568 doi:10.1093/eurheartj/ehi735 Heart failure Effects of nebivolol in elderly heart failure patients with or without systolic left ventricular dysfunction: results of the SENIORS echocardiographic substudy Stefano Ghio1*, Giulia Magrini1, Alessandra Serio1, Catherine Klersy2, Alessandro Fucilli3, `ki4, Pal Karpati5, Giacomo Mordenti6, Angela Capriati6, Aleksandr Ronasze Philip A. Poole-Wilson7, and Luigi Tavazzi1 on behalf of the SENIORS investigators 1 Division of Cardiology, IRCCS Policlinico San Matteo, Pavia, Italy; 2 Biometry and Clinical Epidemiology Unit, IRCCS ´terfy Hospital, Policlinico San Matteo, Pavia, Italy; 3 Cardiology Department, Arcispedale S. Anna, Ferrara, Italy; 4 Pe Budapest, Hungary; 5 St Stepan Hospital I, Budapest, Hungary; 6 Menarini Ricerche SpA, Florence, Italy; and 7 National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK Received 22 July 2005; revised 20 December 2005; accepted 22 December 2005; online publish-ahead-of-print 27 January 2006 See page 506 for the editorial comment on this article (doi:10.1093/eurheartj/ehi693) KEYWORDS Aims The SENIORS trial recently demonstrated that nebivolol reduces the composite risk of all-cause mortality and cardiovascular hospital admission in elderly patients with chronic heart failure and, importantly, that ejection fraction does not influence the clinical effects of nebivolol. An echocardiographic substudy was designed to evaluate the effects of nebivolol on systolic and diastolic left ventricular (LV) function in patients stratified according to the presence or absence of systolic LV dysfunction. Methods and results The substudy randomized 112 patients in 29 European centres, of whom 104 were evaluable for the study; 43 had an ejection fraction (EF) 35% and 61 had an EF . 35%. LV end-systolic volume (ESV), EF, mitral valve E/A ratio, and E-wave deceleration time were assessed at baseline and after 12 months. Echocardiograms were submitted to a core laboratory to perform quantitative analysis in blinded condition. In the group with EF 35%, nebivolol reduced ESV (adjusted difference between treatments 25.8 mL, 95%CI: 246.6; 25.0, P ¼ 0.016) and improved EF (adjusted difference between treatments 4.6%, 95%CI: 1.3;7.9, P ¼ 0.008); no changes were observed in the E/A ratio or E-wave deceleration time. In EF . 35% group, no significant changes in either systolic or diastolic parameters were observed. Conclusion In patients with heart failure and advanced systolic LV dysfunction, nebivolol reduces ventricular size and improves EF. The absence of detectable changes with standard echocardiography in patients with predominant diastolic heart failure questions the mechanism of benefit on morbidity/mortality in such patients. Introduction A better understanding of the complex pathogenesis and of the natural history of the heart failure (HF) process has led to substantial changes in the therapeutic approach over the last decades. Beta-blockers, once contraindicated drugs, are now considered a cornerstone in the treatment of patients with HF.1–3 However, patients in the general population differ from those enrolled in HF trials by usually being older and more frequently having a preserved left ventricular (LV) function.4–6 The SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Hospitalisation in Seniors with Heart Failure) study was undertaken to evaluate the effects of nebivolol, a selective beta1-blocker with vasodilator properties, in elderly HF patients, regardless of *Corresponding author. Tel: þ39 0382 503718; fax: þ39 0382 501884. E-mail address: [email protected] the presence of an impairment of systolic LV function.7 This trial was successful in demonstrating that nebivolol reduces the composite risk of all-cause mortality and cardiovascular hospital admission, regardless of the baseline ejection fraction (EF).8 This information is of the utmost importance because over the recent years, HF with preserved systolic function has emerged as a clinical entity, representing a sizeable proportion of all patients with HF.9–12 Its treatment has remained empirical, not only because we lack evidence-based management strategies but also because of many uncertainties concerning its definition and its pathophysiology.13–17 In particular, the role of beta-blockers in patients with diastolic dysfunction has been addressed in only few previously published studies.18,19 Although the SENIORS trial has now provided evidence that beta-blockade with nebivolol is clinically effective in HF patients with normal or mildly reduced LVEF, the mechanisms underlying the efficacy of nebivolol & The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: [email protected] Downloaded from by guest on October 21, 2014 Heart failure; Diastole; Echocardiography Effects of nebivolol in elderly HF patients with or without systolic LV dysfunction in these patients are still unknown. Therefore, it is important to clarify whether nebivolol can improve systolic and/or diastolic LV function in HF patients in whom the predominant cardiac dysfunction does not lead to an impairment of LV contractility at rest. An echocardiographic substudy was set in the SENIORS study to provide a mechanistic explanation for the main clinical outcome of the trial. The specific objectives of the substudy were to evaluate the reverse remodelling effects of nebivolol in patients with chronic HF and advanced systolic LV dysfunction and to assess the effects of nebivolol on both systolic and diastolic LV function in patients presenting with either normal or mildly impaired systolic function, classified on the basis of EF (35 or .35%). Methodology Design Echocardiographic qualification In order to join the SENIORS echocardiographic substudy, each centre had to go through a qualification procedure. The approval of a site for inclusion in SENIORS was based on the assessment of videotapes submitted to the Echocardiographic Core Laboratory of a single echo in one patient and of duplicate echos (recorded within 24 h) in a second patient. In the event of an initial disqualification, the centre was given one or more opportunities to submit further recordings until approval; 95% of the centres were qualified at the first attempt. Recording and analysis of echocardiographic examinations Two-dimensional echos were recorded by the investigator by commercially available instruments and recorded on Super VHS videotapes. The echos were submitted to the Core Laboratory at the Cardiology Division of Policlinico San Matteo, Pavia, Italy, to centralize quantitative analysis in blinded conditions. At the Core Laboratory, a specialized software for image processing enabled the capture of images on videotapes, the analysis and the storage of the images together with the numerical data. Each parameter was measured three times, and the average value of the three measurements was taken as a data point. All readings were made by qualified technicians and subsequently reviewed by a senior echocardiographer. Reproducibility at the Core Laboratory has been previously reported.20 The diastolic and systolic diameters of the left ventricle (LV) were measured in M-mode recordings obtained in the parasternal long-axis view. The end-diastolic volume (EDV) and end-systolic volume (ESV) of the LV were obtained in apical four-chamber view, using the single-plane area– length method, and EF was calculated as (EDV 2 ESV)/ EDV 100%. The degree of mitral regurgitation (MR) was assessed as the area of the colour flow Doppler regurgitant jet divided by the area of the left atrium in systole in apical four-chamber view. On the pulsed Doppler transmitral flow velocity curve, the peak velocities of rapid LV filling (E-wave) and atrial contraction (A-wave) and the deceleration time (DT) of the E-wave were measured and the velocity ratio (E/A) was calculated; DT , 115 ms was used to identify a restrictive filling pattern. The tricuspid annular plane systolic excursion (TAPSE) was used as an indicator of right ventricular function. The areas of both left and right atria were measured in diastole and systole and a fractional area change was accordingly calculated. Statistical analysis Owing to the exploratory nature of the study, no formal sample size calculation was performed; a total number of 100 patients were considered sufficient to investigate trial objectives. Descriptive statistics were computed as mean and SD for continuous variables and number of non-missing observations and percentages for categorical variables. The change in LVEF between baseline and 12 months or last observation available (primary efficacy variable) was analysed by means of a general linear model having treatment as major covariate and adjusted by baseline LVEF. The same model was applied for the secondary efficacy variables. The analysis was performed separately in patients with advanced systolic LV dysfunction (EF 35%), whereas those with normal function (EF . 50%) and those with mildly impaired systolic function (EF between 36 and 50%) were pooled together. We acknowledge the fact that the discussion on how to define preserved LV function in HF is still ongoing.13,14,21 We repeated all analysis using different EF thresholds; however, as the results were highly consistent, we report only on the original cut-off of EF% which reflects the stratification of patients used in the SENIORS trial. Stata 8 (Stata Corp., College Station, TX, USA) was used for computations. A two-sided P-value ,0.05 was considered statistically significant. The assumptions of normal distribution and of constant variance underneath the applied statistical models were assessed by means of the plots of standardized residuals against fitted values and standardized residuals against normal probability plot (qqplot). Results Study patients Out of the 112 patients enrolled, 6 patients had to be excluded from further analysis because of poor quality of Downloaded from by guest on October 21, 2014 The SENIORS study is an international, double-blind, placebo-controlled, parallel-group trial, which randomly allocated 2128 patients with chronic HF to nebivolol or placebo.8 The major inclusion criteria were age 70 years and a clinical history of chronic HF on top of standard background cardiovascular therapy for HF with one of the following: either documented LVEF 35% or documented hospital admission within the previous 12 months with the discharge diagnosis of congestive HF. Nebivolol or placebo tablets were identical in appearance and were provided in identical packaging. The initial dose of nebivolol or placebo was 1.25 mg once daily; uptitration was performed in a stepwise manner every 1–2 weeks, using incremental doses of 2.5 and 5 mg up to the target dose of 10 mg or the maximum tolerated dose over a maximum of 16 weeks. The echocardiographic substudy was run in 29 centres (participants are listed in the table in the appendix) and enrolled 112 patients. The study plan included two-dimensional and Doppler echocardiographic examinations (echo) before randomization and after 12 months or the last available echo for patients who prematurely terminated the study. 563 564 S. Ghio et al. Figure 1 Effects of nebivolol in patients with LVEF 35% Nebivolol and placebo patients of this subgroup population were well comparable with regard to all echocardiographic variables at baseline. After 12 months of therapy, enddiastolic and end-systolic volumes (ESV) increased in the placebo group and decreased in the nebivolol group. Mean LV ESV decreased from 160 to 141 mL in the nebivolol group and increased from 159 to 166 mL under placebo, the adjusted difference between treatments being 25.8 mL (95%CI: 246.6; 25.0), reaching statistical significance (P ¼ 0.016). Mean LVEF remained substantially unchanged in the placebo group (28.1% at baseline vs. 28.0% at 12 months) and improved in the nebivolol group (from 27.0 to 31.6% at 12 months), with an adjusted difference between treatments of 4.6% (95%CI: 1.3;7.9), P ¼ 0.008. Mean LV EDV decreased in the nebivolol group (from 219 mL at baseline to 202 mL at 12 months), whereas it increased under placebo (from 219 mL at baseline to 227 mL at 12 months) with an adjusted difference between treatments of 23.3 mL, (95%CI: 248.7;2.1), P ¼ 0.071. In both treatment groups, MR was of mild degree at baseline and remained substantially unchanged after 12 months of treatment. Only two patients had a restrictive filling pattern at baseline; no significant change was observed in the E/A ratio or DT after 12 months. The TAPSE was normal at baseline and did not change during follow-up (Table 2). Effects of nebivolol in patients with LVEF > 35% This subgroup includes 25 patients with an LVEF between 36 and 50% and 36 patients with LVEF . 50%. Only one patient had a restrictive filling pattern at baseline. At baseline, patients allocated to placebo showed a somewhat lower mean LVEF and higher mean LV ESV and EDV compared with nebivolol patients. After 12 months of treatment, changes in all echocardiographic parameters related to the systolic or the diastolic function of the left ventricle did not differ significantly between nebivolol- and placebotreated patients (Table 3). Discussion The two main findings of the echocardiographic substudy of the SENIORS trial are (i) in elderly HF patients with advanced systolic LV dysfunction, nebivolol exerted a significant Downloaded from by guest on October 21, 2014 the echocardiographic images at baseline and another two patients were excluded because of no post-baseline assessment (Figure 1). Therefore, the analysis population of the present study encompasses 104 patients; their clinical characteristics are shown in Table 1. Forty-three patients turned out to have advanced systolic LV dysfunction (EF 35%) and 61 had either normal systolic function or mildly impaired systolic function. No relevant differences were found between the two treatment groups (placebo and nebivolol) at baseline. There were no major differences between the treatment groups with regard to pre-treatment of CHF. Merely antiarrhythmic treatment was more common among placebo patients and treatment with Caþþ antagonists more common among nebivolol patients. Overall, no major difference was found in clinical characteristics between patients enrolled in the substudy and patients enrolled in the SENIORS main study, with the possible exception of a higher percentage of patients with EF . 35% enrolled in the substudy (58% in the substudy vs. 35% in the main study). Mean values of LVEF could not be directly compared between the substudy and the main study, because in the main study, LVEF was assessed by local investigators, using different imaging techniques as an entry criterion, whereas in the substudy, it was centrally evaluated in the echocardiographic core laboratory. Similar to the main study, 67% of the nebivolol patients and 72% of the placebo patients participating in the substudy reached the target dose of nebivolol 10 mg once daily, the mean maintenance dose achieved at the end of the titration phase being 7.4 + 3.7 mg in the nebivolol group and 8.1 + 3.3 mg in the placebo group. Patient flow. Effects of nebivolol in elderly HF patients with or without systolic LV dysfunction 565 Table 1 Clinical characteristics of patients enrolled in the echocardiographic substudy and in the main study SENIORS studya ECHO substudy Placebo (n ¼ 50) Nebivolol (n ¼ 1067) Placebo (n ¼ 1061) 75.0 + 4.4 20 (37.0) 3 (5.5) 36 (66.7) 15 (27.8) 0 (0) 27 (50.0%) 138.2 + 16.0 81.8 + 8.6 77.5 + 12 7.4 + 3.7 75.5 + 3.9 15 (30.0) 3 (6.0) 31 (62.0) 15 (30.0) 1 (2) 34 (68%) 141.0 + 19.0 83.1 + 11.2 78.7 + 11.8 8.1 + 3.3 76.1 + 4.8 410 (38.4) 32 (3) 603 (56.5) 413 (38.7) 19 (1.8) 380 (35.7%)2 138.6 + 20.1 80.5 + 10.8 79.2 + 13.6 7.7 + 3.6 76.1 + 4.6 375 (35.3) 29 (2.7) 597 (56.3) 411 (38.7) 24 (2.3) 372 (35.2%)b 139.5 + 21.1 80.6 + 11.3 78.9 + 13.7 8.5 + 3.1 43 (79.6) 34 (67.0) 42 (84.0) 36 (72.0) 815 (80.4) 688 (67.9) 881 (87.1) 805 (79.6) 41 (82.0) 43 (86.0) 1 (2.0) 11 (22.0) 17 (34.0) 5 (10.0) 13 (26.0) 6 (12.0) 24 (48.0) 12 (24.0) 42 (77.8) 48 (88.9) 2 (3.7) 17 (31.5) 17 (31.5) 17 (31.5) 15 (27.8) 4 (7.4) 27 (50.0) 6 (11.1) 915 (85.8) 872 (81.7) 66 (6.2) 307 (28.8) 415 (38.9) 122 (11.4) 217 (20.3) 149 (14.0) 456 (42.7) 114 (10.7) 907 (85.5) 876 (82.6) 75 (7.1) 280 (26.4) 422 (39.8) 145 (13.7) 238 (22.4) 164 (15.5) 441 (41.6) 122 (11.5) Data are number of patients (%) or mean (+SD). a The SENIORS study (n ¼ 2128) includes the population of the ECHO substudy (n ¼ 104). b Echo measurements in the main SENIORS study were not centralized. reverse remodelling effect, the extent of which is comparable with that previously documented with other betablockers in younger populations, and (ii) in patients with either normal systolic function or mild systolic dysfunction, no difference was observed in echocardiographic indices of systolic or diastolic LV function compared with placebo. Beneficial effects of nebivolol in HF patients with LV systolic dysfunction Several studies have shown that beta-blockers improve LV function in HF patients with systolic LV dysfunction.22–25 The echocardiographic substudy of the SENIORS trial extends the evidence of the benefits with beta-blockade to nebivolol, a third generation highly selective beta1-blocker with associated vasodilator activity mediated through increased nitric oxide release.26,27 The changes in LV diameters and volumes and EF lead to the conclusion that the effects of nebivolol are substantially similar to those of previously tested beta-blockers. The model-adjusted reduction in ESV by 25.8 mL and the model-adjusted increase in EF by 4.6% obtained by nebivolol when compared with placebo are in line with the 15.3 mL/m2 decrease in ESV index and the 5.8% increase in EF observed after 12 months of carvedilol treatment compared with placebo reported in the echocardiographic substudy of the Australia–New Zealand trial.23 Directionally similar changes of LV geometry and function have been obtained with bisoprolol.24 In fact, the M-mode data from the CIBIS echocardiographic substudy demonstrate that 5-month therapy with this beta-blocker did not change end-diastolic dimensions but improved LV fractional shortening. LVEF has been reported to improve by 8% and ESV index to decrease by 26 mL/m2 after 6 months of metoprolol treatment in the MERIT-HF substudy. These data are not directly comparable because the authors used magnetic resonance imaging to assess the reverse remodelling effects of therapy.25 In the SENIORS substudy, the echocardiographic examination also included the recording of Doppler variables related to the LV filling and of the TAPSE as an index of right ventricular function. None of those parameters was significantly improved by nebivolol. However, the reduction in the E/A ratio, the prolongation in E-wave DT, and the increase in left atrial fractional change point towards a reduction in end-diastolic pressure, and the slight improvement in TAPSE points towards a reduction in pulmonary artery pressure, given that the systolic function of the right ventricle is highly dependent on afterload.28 Overall, the reverse remodelling effect of nebivolol in chronic HF patients with systolic LV dysfunction could be the key explanation for the improvement in the composite end-point of all-cause death or cardiovascular hospital admission found in the SENIORS trial.8 Nebivolol in patients with normal or mildly impaired LV systolic function Although the importance of HF with normal or mildly impaired systolic LV function has been increasingly recognized over the last years, there were no large, randomized, controlled clinical outcome trials in patients having this condition until recently. The CHARM-Preserved study showed a Downloaded from by guest on October 21, 2014 Age (years) Women (%) NYHA class I (%) II (%) III (%) IV (%) EF .35% Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (b.p.m) Maintenance dose (mg) Maintenance dose level reached 5 mg(%) 10 mg(%) CHF pre-treatment Diuretic ACE-inhibitor (%) Angiotensin II antagonist (%) Aldosterone antagonist (%) Cardiac glycoside (%) Antiarrhythmic (%) Lipid-lowering drug (%) Vitamin K antagonist (%) Aspirin (%) Calcium antagonist (%) Nebivolol (n ¼ 54) 566 S. Ghio et al. Table 2 Effects of nebivolol in patients with LVEF 35% .Nebivolol (n ¼ 27) LVEF (%) MR E/A EDT (ms) TAPSE (mm) LVEDV (mL) LVESV (mL) LAESA (cm2) LAFAC (%) Placebo (n ¼ 16) Baseline 12 months Baseline 12 months 27.0 + 4.9 5.3 + 3.4 1.7 + 1.1 172 + 50 1.7 + 0.4 219 + 63 160 + 50 24.8 + 6.6 24.0 + 13.3 31.6 + 7.3 5.2 + 4.2 1.1 + 0.7 207 + 46 1.9 + 0.4 202 + 63 141 + 50 25.9 + 6.0 29.1 + 9.9 28.1 + 4.6 5.0 + 3.9 0.9 + 0.7 183 + 54 1.8 + 0.3 219 + 41 159 + 35 24.1 + 10.4 28.6 + 11.0 28.0 + 6.9 5.2 + 4.1 0.9 + 0.8 185 + 72 1.7 + 0.4 227 + 54 166 + 48 26.5 + 9.5 26.2 + 9.8 Estimated treatment difference (95%CI) P-value 4.58 21.10 20.30 10.70 0.21 223.30 225.80 21.39 3.52 0.008 0.345 0.350 0.691 0.067 0.071 0.016 0.608 0.363 (1.27; 7.89) (23.45; 1.24) (20.95; 0.36) (245.61; 67.02) (20.02; 0.44) (248.67; 2.07) (246.60; 25.00) (26.99; 4.20) (24.39; 11.44) A general linear regression model having treatments as major covariate and adjusted by baseline value is adopted. Data are presented as mean + SD. The P-value refers to the estimated treatment difference in echo parameters of the placebo vs. the nebivolol group. The comparison is adjusted for the baseline value of the relevant echo parameter. LVEDD, LV end-diastolic diameter; E/A, ratio of early to late peak mitral velocity; EDT, E-wave deceleration time; LVEDV, LV end-diastolic volume; LVESV, LV end-systolic volume; LAESA, left atrial end-systolic area; LAFAC, left atrial fractional area change. Table 3 Effects of nebivolol in patients with LVEF .35% Nebivolol (n ¼ 27) Baseline 12 months Baseline 12 months 54.5 + 8.9 2.8 + 1.7 0.9 + 0.6 200 + 39 2.2 + 0.3 118 + 42 56 + 30 21.5 + 5.6 29.15 + 11.1 55.5 + 8.2 2.7 + 2.5 0.9 + 0.7 207 + 37 2.3 + 0.3 112 + 39 54 + 29 19.3 + 5.3 36.7 + 13.5 49.0 + 8.1 4.2 + 3.4 0.9 + 0.5 192 + 37 2.0 + 0.3 145 + 48 77 + 35 25.5 + 6.8 27.2 + 11.4 50.2 + 8.6 4.5 + 4.0 1.0 + 0.5 202 + 50 2.1 + 0.3 137 + 46 71 + 35 26.0 + 7.3 28.4 + 9.7 Estimated treatment difference (95%CI) P-value 0.02 (23.05; 3.10) 20.50 (23.25; 2.25) 20.01 (20.34; 0.32) 10.04 (219.97; 40.06) 0.20 (20.04; 0.44) 21.92 (213.92; 10.08) 21.49 (211.55; 8.57) 20.66 (23.29; 1.97) 5.63 (21.84; 13.09) 0.988 0.711 0.956 0.500 0.098 0.750 0.768 0.614 0.135 A general linear regression model having treatments as major covariate and adjusted by relevant baseline echo parameter is adopted. non-significant reduction in the composite end-point of cardiovascular death or HF hospitalization with candesartan.29 The SENIORS trial showed both a significant overall treatment effect and a virtually identical estimate of risk reduction for patients with low or preserved EF. The echocardiographic substudy of the SENIORS trial gives us the possibility to verify whether the clinical benefit of nebivolol treatment in patients with mildly impaired or preserved LV systolic function can be explained by an improvement in LV function. Not unexpectedly, given that LV volumes and EF were not markedly impaired at baseline in these patients, nebivolol had no effect on parameters of LV systolic function. The absence of detectable changes in diastolic parameters is a finding that needs to be explained. Theoretically, there are several reasons why nebivolol might improve diastolic function. Beta-blockade may improve diastolic function by prolonging the diastolic filling time more than the ejection time, thus improving myocardial perfusion and metabolism.30 The increased nitric oxide release caused by nebivolol might also improve early relaxation.31 Although the SENIORS echocardiographic substudy showed no difference in Doppler parameters, it would be simplistic to conclude that nebivolol had no effect on diastolic LV function. Rather, the possibility should be considered that standard Doppler echocardiography is not sensitive enough to detect the changes in diastolic function caused by this drug. Doppler filling parameters must be interpreted cautiously when used as indices of diastolic function. Filling velocities reflect the pressure gradients between the left atrium and the left ventricle, which depend not only on the diastolic LV properties but also on loading conditions and atrial compliance; heart rate may also play an important role.32,33 Cardiac catheterization using high-fidelity micromanometer-tipped catheters is necessary to identify abnormalities in active relaxation or in diastolic stiffness of the left ventricle.17 Future studies using more specific echocardiographic approaches to the evaluation of diastolic function34–36 are planned to determine how beta-blockade affects diastolic function. Further studies should also differentiate patients with normal EF from patient with mildly impaired EF; pooling these patients is, in fact, another limitation of the present study. Whether or not nebivolol can improve LV diastolic function leaves another question unanswered, namely whether a change in cardiac function is the explanation for the improvement in the composite end-point of all-cause mortality or cardiovascular hospital admission observed in patients with slightly impaired LV systolic function in the SENIORS trial. The efficacy of beta-blockade in patients with systolic HF is strongly associated with an improvement in systolic function, but this should not lead to the conclusion that beta-blockade Downloaded from by guest on October 21, 2014 LVEF (%) MR E/A EDT (ms) TAPSE (mm) LVEDV (mL) LVESV (mL) LAESA (cm2) LAFAC (%) Placebo (n ¼ 34) Effects of nebivolol in elderly HF patients with or without systolic LV dysfunction has to be effective in patients with preserved systolic function because of the direct effect of beta-blockers on diastolic function. There are many differences between systolic HF and diastolic HF. Diastolic HF may be more fluctuating both symptomatically and pathophysiologically than systolic HF. The destabilization which dominates the clinical picture of diastolic HF is often precipitated by the onset of tachyarrhythmias or by a sudden severe blood pressure increase that most probably exacerbates a condition of latent asymptomatic diastolic dysfunction.37 Diastolic HF is common in elderly and hypertensive patients, and ageing and hypertension are characterized by increased deposition of interstitial collagen, perivascular fibrosis in the myocardium, and stiffening of the vascular wall.38 The efficacy of nebivolol in the syndrome of diastolic HF might, therefore, be related not only or not predominantly to an improvement in baseline diastolic function. Possibly, the prevention of episodes of excessive tachycardia and of severe blood pressure rise, as well as a modulation of the vascular tone and of the elasticity of the vascular system exerted by nebivolol, may also play a significant role in improving the outcome in such patients. In the light of this hypothesis, the peculiar pharmacological properties of nebivolol, which is not only 567 an highly selective beta1-blocker but is also able to induce nitric oxide endothelial release, might underlie a specific beneficial action of this beta-blocker in predominantly diastolic HF, similar to that observed in patients with arterial hypertension.19 Conclusions Nebivolol showed a beneficial reverse remodelling effect in HF patients with systolic LV dysfunction. This effect is comparable with those previously documented with other beta-blockers. In patients with preserved systolic function or mild systolic dysfunction, the absence of detectable changes in Doppler echocardiographic indices raises the issue of how nebivolol improves the morbidity–mortality outcome in these patients. Several hypotheses need to be investigated in future studies. Conflict of interest: S.G. receives honoraria for consultancy to an electro-medical company. L.T and P.A.P.-W. have received honoraria for speaking on aspects of heart failure at meetings funded by companies in the pharmaceutical industry. G.M. and A.C. are employees of Menarini Ricerche S.p.A. All have participated in or are involved in other studies or research projects funded by industry. Appendix Hospital City Country Main investigator Sonographer I. Interni Klinika FN U SVATe ´ Anny Brno Czech Republic Lenka Spinarova Kardiologicka’ Ambulance INT. ODD. Nemocnice Milosrdnych Bratri Statni Slezka Nemocnice I INT. ODD. Nemocnice TGM INT. ODD. Nemocnice S. Poliklinikon V Teplice Kardiologicke Oddeleni, FN Bohunice Hospital Jablonec NAD Nisou NSP Ivancice INT. ODD. Nemocnice Hungarian Institute of Cardiology Uzsoki Hospital I, Medical Department Karolyi Hospital Cardiology Elisabeth Hospital I, Medical Department Jahn F. DEL_PESTI Hospital Gottsegen Gyo ¨rgu Hungarian Institute of Cardiology St Ference Hospital State Hospital of Cardiology St Stephan Hospital Policlinico S. Matteo Arcispedale S. Anna Ospedale S. Vit O E S. Spirito OSP. S. Luca CNR Institute of Cardiolgy of Academy of Medical Science of Ukraine Lugansk Clinical Multiprophil City Hospital No. 1 Kyiv Medical Academy of Post-graduate Education Crimea State Medical University Institute of Urgent and Recovery Surgery Zaporizzhia State Medical University Northwick Park Hospital Trebic Brno Opava Hodonin Teplice Brno Bohunice Jablonec NAD Nisou Ivancice Budapest Budapest Budapest Budapest Budapest Budapest Czech Republic Czech Republic Czech Republic Czech Republic Czech Republic Czech Republic Czech Republic Czech Republic Hungary Hungary Hungary Hungary Hungary Hungary Jiri Toman Lenka Spinarova Jiri Carda Bohumil Filipensky Pollak Pospisil Reichert Borivoj Semrad Dag Tichy Vales Josef Borbola Bela Palossy Laszlo Regos Aladar Ronaszeki Karoly Toth Josef Vanyi Miskolc Balatonfu ¨rED Budapest Pavia Ferrara Alcamo (TP) Milano Pisa Kiev Hungary Hungary Hungary Italy Italy Italy Italy Italy Ukraine Lugansk Mudr Jiri Carda Bohumil Filipensky Pollak P. Obrtlik J. Vana J. Ziembova Dag Tichy Vales Gizella Vigh Peter Fu ¨p ¨lo Laszlo Csuro ¨s Erzsebet Sperr Janos Fiok De Gizella Vigh Istvan Varga Jozsef Masszi Imre Lukacs Alessandra Serio Fucilli Figlia Sa Branzi A. Morales Lutay Ukraine Istvan Varga Gabor Veress Pal Karpati L. Uigi Tavazzi Roberto Ferrari Francesco Ippolito Gianfranco Parati Danilo Neglia Aleksandr Parkhomenko Yuriy Koltchin Kiev Ukraine Volodymyr Kovalenko E. Rey Simferopol Donetsk Zaporizhzhia Harrow Ukraine Ukraine Ukraine UK Volodymir Kubyshkin Nikolaj Vatunin Vadimi Vizir Roxy Senior A.V. Legkonogov Stolika A. Berezin R. Janarhandran, L. Burden Potapenko Downloaded from by guest on October 21, 2014 Table A1 Participating sites 568 References 20. Ghio S, Freemantle N, Serio A, Magrini G, Scelsi L, Pasotti M, Tavazzi L. Baseline echocardiographic characteristics of heart failure patients enrolled in a large European multicenter trial (CArdiac REsynchronization Heart Failure study). Eur J Echo 2005, Epub ahead of print. 21. Lenzen MJ, Scholte OP, Reimer WJM, Boersma E, Vantrimpont PJMJ, Follath F, Swedberg K, Cleland J, Komajda M. Differences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey. Eur Heart J 2004;25: 1214–1220. 22. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, Kubo SH, Narahara KA, Ingersholl H, Krueger S, Young S, Shusterman N for the MOCHA investigators. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996;94:2807–2816. 23. Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N. Left ventricular remodelling with carvedilol in patients with congestive heart failure due to ischemic heart disease. J Am Coll Cardiol 1997;29: 1060–1066. 24. Lechat P, Escolano S, Golmard JL, Lardoux H, Witchitz S, Henneman JA, Maisch B, Hetzel M, Jaillon P, Boissel JP, Mallet A on behalf of the CIBIS investigators. Prognostic value of bisoprolol-induced hemodynamic effects in heart failure during the cardiac insufficiency bisoprolol study. Circulation 1997;96:2197–2205. 25. Groenning BA, Nilson JC, Sondengaard L, Fritz-Hansen T, Larsson HBW, Hildebrandt PR. Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol 2000;36:2072–2080. 26. Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomised, double blind, cross-over study. Circulation 2001;104:511–514. 27. Ignarro LJ. Experimental evidences of nitric oxide-dependent vasodilatory activity of nebivolol, a third-generation b-Blocker. Blood Press 2004;13:3–17. 28. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, Arbustini E, Recusani F, Tavazzi L. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001;37:183–188. 29. Yusuf S, Pfeffer M, Sweberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J. Effects of candesartan in patients with chronic heart failure and preserved left ventricular ejection fraction: the CHARM-preserved trial. Lancet 2003;362:777–781. 30. Wallhaus TR, Taylor M, De Grado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 2001;103:2441–2446. 31. Paulus WJ, Shah AM. NO and cardiac diastolic function. Cardiovasc Res 1999;43:595–606. 32. Appleton C, Hatle LK, Popp RL. Relation of transmitral flow velocity patterns to left ventricular diastolic function: new insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12:426–440. 33. Choong CY, Abascal VM, Thomas JD, Guerrero JL, McGlew S, Weyman AE. Combined influence of ventricular loading and relaxation on the transmitral flow velocity profile in dogs measured by Doppler echocardiography. Circulation 1988;78:672–683. 34. Garcia MJ, Smedira NG, Greenberg NL, Main M, Firstenberg MS, Odabashian J, Thomas JD. Color M-mode Doppler flow propagation velocity is a preload insensitive index of left ventricular relaxation: animal and human validation. J Am Coll Cardiol 2000;35:201–208. 35. Garcia MJ, Ares MA, Asher C, Rodriguez L, Vandervoort P, Thomas JD. An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454. 36. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quinones MA. Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1533. 37. Gandhi SK, Powers JC, Nomeir A, Fowle K, Kitzman DW, Rankin KM, Little WC. The pathogenesis of acute pulmonary oedema associated with hypertension. N Engl J Med 2001;344:17–22. 38. Wei JY. Age and the cardiovascular system. N Engl J Med 1992; 327:1735–1739. Downloaded from by guest on October 21, 2014 1. The CIBIS-II investigators and committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trail. Lancet 1999;353:9–13. 2. The MERIT-HF study group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trail in congestive heart failure (MERIT-HF). Lancet 1999;353:9–13. 3. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A; Roecker Eb, Schultz MK, deMets DL. Carvedilol prospective randomised cumulative survival study group. Effects of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–1658. 4. Di Lenarda A, Scherillo M, Maggioni AP, Acquarone N, Ambrosio GB, Annicchiarico M, Bellis P, Bellotti P, De Maria R, Lavecchia R, Lucci D, Mathieu G, Opasich C, Porcu M, Tavazzi L, Cafiero M. Current presentation and management of heart failure in cardiology and internal medicine hospital units: a tale of two worlds—The TEMISTOCLE study. Am Heart J 2003;146:e12. 5. Cowie MR, Fox KF, Wood DA, Metcalfe C, Thompson SG, Coats AJ, PooleWilson PA, Sutton GC. Hospitalization of patients with heart failure. A population-based study. Eur Heart J 2002;23:877–885. 6. Avezum A, Tsuyuki RT, Pogue J, Yusuf S. Beta-blocker therapy for congestive heart failure: a systematic overview and critical appraisal of the published trials. Can J Cardiol 1998;8:1045–1053. 7. Shibata MC, Flather MD, Bohm M, Borbola J, Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, Parkhomenko A, Soler-Soler J, Tavazzi L, Toman J, Van Veldhuisen DJ, Coats AJS, Poole-Wilson P. Study of the effect of nebivolol intervention on outcomes and rehospitalisation in seniors with heart failure (SENIORS). Rationale and design. Inter J Cardiol 2002;86:77–85. 8. Flather MD, Shibata MC, Coats AJS, Van Veldhuisen DJ, Parkomenko A, Borbola J, Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, Soler-Soler J, Tavazzi L, Spinarova L, Toman J, Bo ¨hm M, Anker SD, Thompson SG, Poole-Wilson PA on behalf of the SENIORS investigators. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215–225. 9. Vasan RS, Benjmin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart-failure: an epidemiologic perspective. J Am Coll Cardiol 1995;26:1565–1574. 10. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics and prognosis. J Am Coll Cardiol 2004;43:317–327. 11. Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left-ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999;33:1948–1955. 12. Senni M, Redfield MM. Heart failure with preserved systolic function. J Am Coll Cardiol 2001;38:1277–1282. 13. European Study Group on Heart Failure. How to diagnose diastolic heart failure. Eur Heart J 1998;19:990–1003. 14. Zile MR, Gaasch WH, Carroll JD, Feldman MD, Aurigemma GP, Schaer GL, Ghali JK, Liebson PR. Heart failure with a normal ejection fraction. Is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation 2001;104:779–782. 15. Burkhoff D, Maurer MS, Packer M. Heart failure with a normal ejection fraction: is it really a disorder of diastolic function? Circulation 2003;107:656–658. 16. Banerjee P, Clark AL, Nikitin N, Cleland JGF. Diastolic heart failure. Paroxysmal or chronic? Eur J Heart Fail 2004;6:427–431. 17. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure. Abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 2004;350:1953–1959. 18. Bergstro ¨m A, Andersson B, Edner M, Nylander E, Persson H, Dahlstro ¨m U. Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart Fail 2004; 6:453–461. 19. Nodari S, Metra M, Dei Cas L. b-Blocker treatment of patients with diastolic heart failure and arterial hypertension. A prospective randomised, comparison of the long-term effects of atenolol vs nebivolol. Eur J Heart Fail 2003;5:621–627. S. Ghio et al.
© Copyright 2024