SATEWITE SESSION
Ageing and heart failure:
what's new?
Stockholm, 5 September 2005
In this satellite symposium, organised and sponsored by Menarini International, the main issues of the management of elderly patients with chronic heart failure (HF) were discussed, as well as the specific role of the novel, third-generation 5-blocking agent, nebivolol. The session was chaired by G. Noll (Zurich, Switzerland) and J. Soler-Soler (Barcelona, Spain). According to the most recent European guidelines for diagnosis and treatment of chronic HF (ESC update 2005), nebivolol is added to the 5-blocking agents for this indication, based on the recent, randomised SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure) trial, which is the only trial to investigate the efficacy of -blockade in the elderly, thus in a more real-world scenario. T F. Luscher(Zurich, Switzerland) addressed the causes and consequences ofHF and the risk of HF, especially for the high-age group. HF is shifting to the higher age groups because it is a final common pathway of most cardiac diseases, especially survivors of an acute myocardial infarction. Moreover, HF is prominent in patients with hypertension, diabetes mellitus and the metabolic syndrome. Ageing itself, or in combination with any ofthese risk factors, will increase the incidence of HF dramatically in the next decades, especially in patients over the age of65 years. It has been estimated that the five-year risk ofdeveloping HF is approximately 0.2% in men of4O years and 8.3% in men of 80 years, both with a lifetime risk of about 20%. Thus, HF can be considered an important epidemic of this century. Besides systolic HF, the clinical syndrome of HF may also occur in the presence of preserved systolic left ventricular (LV) fimction. Symptoms and signs ofHF, such as dyspnoea, exercise intolerance and elevated levels of BNP, are all observed in diastolic HF, as a result of impaired filling pressures and stiffening of the cavity with reduced compliance due to structural changes in the LV wall mainly caused by an increase in fibrosis 0. Kamp VU University Medical Centre, Amsterdam E-mail: [email protected]
28
and nonmuscular cells. Appropriate therapy for patients with diastolic HF has only demonstrated marginal effects in a few trials, for example the CHARMpreserved (Effects of Candesartan in Patients with Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction) trial. In the SENIORS trial nebivolol, which not only inhibits the sympathetic nervous system but also stimulates nitric oxide in endothelial cells, has confirmed a beneficial effect, also in patients with preserved systolic LV function. The second presentation was by U. Landmesser (Hanover, Germany), who discussed the relation between endothelial dysfunction and chronic HF. Impaired endothelium-dependent relaxation of the conduit and resistance arteries in patients with HF is at least in part due a reduced availability of the endogenous vasodilator nitric oxide (NO). Ageing is associated with a marked impairment in endotheliumdependent vasodilation. In severe HF, the endothelial production ofvasoconstricting factors such as angiotensin II or endothelin is increased. It was recently shown in a clinical study that endothelial dysfunction, examined by flow-dependent vasodilation ofthe radial artery, represented an independent predictor of cardiac mortality and hospitalisation over a median follow-up period of four years. These findings have been confirmed by others and also in a cohort of HF patients with mild systolic LV dysfunction (NYHA I to II). Endothelium produces numerous vasoactive substances; however, NO derived from nitric oxide synthase has received major attention and plays an important role. The impaired NO synthase derived NO availability may have other pathophysiological implications for the heart as well, such as increased LV remodelling, and impaired mobilisation of endothelial progenitor cells. Overexpression of the eNOS gene in mice within the endothelium attenuated HF and improved survival. The reverse was also true in mice with eNOS deficiency, and mortality was increased. Nebivolol increases endothelial NO release, probably via interaction with the recently discovered P, receptor and the oestrogen receptor. In comparison with carvedilol, nebivolol has a more potent antioxidant effect. It is currently not known whether this will bring Netherlands Heart Joumal, Volume 13, Supplement 2, November 2005
C
27th Congress of the European Society of Cardiology
about a more favourable clinical outcome and improve patient tolerance, but the favourable results of the SENIORS trial are supportive. Next, M. Metra (Brescia, Italy) discussed the systolic and diastolic LV function in HF in more detail. Systolic HF is characterised by objective evidence of LV dysfunction, usually by echocardiography. Diastolic HF is mainly characterised by diastolic dysfunction. This is not always easy to ascertain, and thus in clinical practice it is often a diagnosis of exclusion: HF with preserved systolic LV function or probable diastolic HF. A definitive diagnosis of diastolic HF can only be made by demonstrating evidence of diastolic dysfunction, e.g. upwards shift and to the left of the pressure-volume loop and/or by strict echo-Doppler criteria, including tissue Doppler. The new guidelines for the diagnosis and treatment of acute HF of the ESC (2005) have defined these entities, also including the definition ofpossible diastolic HF. These forms of HF are more common in the elderly and in women. The prevalence of HF with preserved systolic LV function is estimated between 13 to 74%, due to a lack of consensus in diagnosing. In patients with HF and preserved systolic LV function, a reduction in LV filling pressures was observed with nebivolol both at rest and during exercise with an improvement in exercise tolerance compared with atenolol. One-third of the patients in the SENIORS trial had HF and preserved systolic LV function, and this trial can thus be placed with the few randomised controlled trials examining this condition, namely the CHARM-preserved and the older DIG (Digitalis Investigators Group) trial. The last speaker was A. Coats (Sydney, Australia), who explained modem tailored management of chronic HF from old and new insights from the SENIORS trial. Previous HF trials have recruited primarily middleaged (mean: 62 years) male patients with low ejection fraction (75 years), a higher proportion offemales and a higher number ofpatients with HF and preserved systolic LV function. Furthermore, there is an underutilisation of 5-blocker therapy in chronic HF patients, especially >75 years. In an Italian registry, older age was the main reason not to prescribe a 1-blocker. The SENIORS trial evaluated the effects of nebivolol in elderly patients with HF with or without systolic LV dysfunction in 2128 patients aged .70 years with a history of HF with hospital admission within the previous year or an
#c
Nethcriands Heart Journal, Volume 13, Supplemant 2, November 2005
ejection fraction 35%). The combined outcome (all-cause death or cardiovascular hospitalisation) occurred in 332 (31.1%) patients on nebivolol compared with 375 (35.3%) on placebo, a relative risk reduction of 14%. When comparing the effects ofthe 1-blocking agents used in COPERNICUS (The Carvedilol Prospective Randomised Survival) trial, CIBIS II (Cardiac Insufficiency Bisoprolol Study) and MERIT-HF (Metopropol CR/XL Randomised Intervention Trial on Congestive Heart Failure) in the elderly subgroups (age >65 years) with a subgroup of SENIORS (70 to 75 years and EF
Ageing and heart failure:
what's new?
Stockholm, 5 September 2005
In this satellite symposium, organised and sponsored by Menarini International, the main issues of the management of elderly patients with chronic heart failure (HF) were discussed, as well as the specific role of the novel, third-generation 5-blocking agent, nebivolol. The session was chaired by G. Noll (Zurich, Switzerland) and J. Soler-Soler (Barcelona, Spain). According to the most recent European guidelines for diagnosis and treatment of chronic HF (ESC update 2005), nebivolol is added to the 5-blocking agents for this indication, based on the recent, randomised SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure) trial, which is the only trial to investigate the efficacy of -blockade in the elderly, thus in a more real-world scenario. T F. Luscher(Zurich, Switzerland) addressed the causes and consequences ofHF and the risk of HF, especially for the high-age group. HF is shifting to the higher age groups because it is a final common pathway of most cardiac diseases, especially survivors of an acute myocardial infarction. Moreover, HF is prominent in patients with hypertension, diabetes mellitus and the metabolic syndrome. Ageing itself, or in combination with any ofthese risk factors, will increase the incidence of HF dramatically in the next decades, especially in patients over the age of65 years. It has been estimated that the five-year risk ofdeveloping HF is approximately 0.2% in men of4O years and 8.3% in men of 80 years, both with a lifetime risk of about 20%. Thus, HF can be considered an important epidemic of this century. Besides systolic HF, the clinical syndrome of HF may also occur in the presence of preserved systolic left ventricular (LV) fimction. Symptoms and signs ofHF, such as dyspnoea, exercise intolerance and elevated levels of BNP, are all observed in diastolic HF, as a result of impaired filling pressures and stiffening of the cavity with reduced compliance due to structural changes in the LV wall mainly caused by an increase in fibrosis 0. Kamp VU University Medical Centre, Amsterdam E-mail: [email protected]
28
and nonmuscular cells. Appropriate therapy for patients with diastolic HF has only demonstrated marginal effects in a few trials, for example the CHARMpreserved (Effects of Candesartan in Patients with Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction) trial. In the SENIORS trial nebivolol, which not only inhibits the sympathetic nervous system but also stimulates nitric oxide in endothelial cells, has confirmed a beneficial effect, also in patients with preserved systolic LV function. The second presentation was by U. Landmesser (Hanover, Germany), who discussed the relation between endothelial dysfunction and chronic HF. Impaired endothelium-dependent relaxation of the conduit and resistance arteries in patients with HF is at least in part due a reduced availability of the endogenous vasodilator nitric oxide (NO). Ageing is associated with a marked impairment in endotheliumdependent vasodilation. In severe HF, the endothelial production ofvasoconstricting factors such as angiotensin II or endothelin is increased. It was recently shown in a clinical study that endothelial dysfunction, examined by flow-dependent vasodilation ofthe radial artery, represented an independent predictor of cardiac mortality and hospitalisation over a median follow-up period of four years. These findings have been confirmed by others and also in a cohort of HF patients with mild systolic LV dysfunction (NYHA I to II). Endothelium produces numerous vasoactive substances; however, NO derived from nitric oxide synthase has received major attention and plays an important role. The impaired NO synthase derived NO availability may have other pathophysiological implications for the heart as well, such as increased LV remodelling, and impaired mobilisation of endothelial progenitor cells. Overexpression of the eNOS gene in mice within the endothelium attenuated HF and improved survival. The reverse was also true in mice with eNOS deficiency, and mortality was increased. Nebivolol increases endothelial NO release, probably via interaction with the recently discovered P, receptor and the oestrogen receptor. In comparison with carvedilol, nebivolol has a more potent antioxidant effect. It is currently not known whether this will bring Netherlands Heart Joumal, Volume 13, Supplement 2, November 2005
C
27th Congress of the European Society of Cardiology
about a more favourable clinical outcome and improve patient tolerance, but the favourable results of the SENIORS trial are supportive. Next, M. Metra (Brescia, Italy) discussed the systolic and diastolic LV function in HF in more detail. Systolic HF is characterised by objective evidence of LV dysfunction, usually by echocardiography. Diastolic HF is mainly characterised by diastolic dysfunction. This is not always easy to ascertain, and thus in clinical practice it is often a diagnosis of exclusion: HF with preserved systolic LV function or probable diastolic HF. A definitive diagnosis of diastolic HF can only be made by demonstrating evidence of diastolic dysfunction, e.g. upwards shift and to the left of the pressure-volume loop and/or by strict echo-Doppler criteria, including tissue Doppler. The new guidelines for the diagnosis and treatment of acute HF of the ESC (2005) have defined these entities, also including the definition ofpossible diastolic HF. These forms of HF are more common in the elderly and in women. The prevalence of HF with preserved systolic LV function is estimated between 13 to 74%, due to a lack of consensus in diagnosing. In patients with HF and preserved systolic LV function, a reduction in LV filling pressures was observed with nebivolol both at rest and during exercise with an improvement in exercise tolerance compared with atenolol. One-third of the patients in the SENIORS trial had HF and preserved systolic LV function, and this trial can thus be placed with the few randomised controlled trials examining this condition, namely the CHARM-preserved and the older DIG (Digitalis Investigators Group) trial. The last speaker was A. Coats (Sydney, Australia), who explained modem tailored management of chronic HF from old and new insights from the SENIORS trial. Previous HF trials have recruited primarily middleaged (mean: 62 years) male patients with low ejection fraction (75 years), a higher proportion offemales and a higher number ofpatients with HF and preserved systolic LV function. Furthermore, there is an underutilisation of 5-blocker therapy in chronic HF patients, especially >75 years. In an Italian registry, older age was the main reason not to prescribe a 1-blocker. The SENIORS trial evaluated the effects of nebivolol in elderly patients with HF with or without systolic LV dysfunction in 2128 patients aged .70 years with a history of HF with hospital admission within the previous year or an
#c
Nethcriands Heart Journal, Volume 13, Supplemant 2, November 2005
ejection fraction 35%). The combined outcome (all-cause death or cardiovascular hospitalisation) occurred in 332 (31.1%) patients on nebivolol compared with 375 (35.3%) on placebo, a relative risk reduction of 14%. When comparing the effects ofthe 1-blocking agents used in COPERNICUS (The Carvedilol Prospective Randomised Survival) trial, CIBIS II (Cardiac Insufficiency Bisoprolol Study) and MERIT-HF (Metopropol CR/XL Randomised Intervention Trial on Congestive Heart Failure) in the elderly subgroups (age >65 years) with a subgroup of SENIORS (70 to 75 years and EF
