Fabrizio Morandi

The patient perspective : Quality of life in advanced heart failure with frequent hospitalisations

End of life is an unfortunate but inevitable phase of the heart failure patients journey. It is often preceded by a stage in the progression of heart failure defined as advanced heart failure, and characterised by poor quality of life and frequent hospitalisations. In clinical practice, the efficacy of treatments for advanced heart failure is often assessed by parameters such as clinical status, haemodynamics, neurohormonal status, and echo/MRI indices. From the patients perspective, however, quality-of-life-related parameters, such as functional capacity, exercise performance, psychological status, and frequency of re-hospitalisations, are more significant. The effects of therapies and interventions on these parameters are, however, underrepresented in clinical trials targeted to assess advanced heart failure treatment efficacy, and data are overall scarce. This is possibly due to a non-universal definition of the quality-of-life-related endpoints, and to the difficult standardisation of the data collection. These uncertainties also lead to difficulties in handling trade-off decisions between quality of life and survival by patients, families and healthcare providers. A panel of 34 experts in the field of cardiology and intensive cardiac care from 21 countries around the world convened for reviewing the existing data on quality-of-life in patients with advanced heart failure, discussing and reaching a consensus on the validity and significance of quality-of-life assessment methods. Gaps in routine care and research, which should be addressed, were identified. Finally, published data on the effects of current i.v. vasoactive therapies such as inotropes, inodilators, and vasodilators on quality-of-life in advanced heart failure patients were analysed.

Repetitive use of levosimendan for treatment of chronic advanced heart failure: Clinical evidence, practical considerations, and perspectives: An expert panel consensus

BACKGROUNDnThe intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan.nnnMETHODS AND RESULTSnA panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience.nnnCONCLUSIONSnThe current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.

Proportion of patients needing an implantable cardioverter defibrillator on the basis of current guidelines: impact on healthcare resources in Italy and the USA. Data from the ALPHA study registry

AIMSnImplantable cardioverter defibrillators (ICD) improve survival in selected patients with left ventricular dysfunction or heart failure (HF). The objective is to estimate the number of ICD candidates and to assess the potential impact on public health expenditure in Italy and the USA.nnnMETHODS AND RESULTSnData from 3513 consecutive patients (ALPHA study registry) were screened. A model based on international guidelines inclusion criteria and epidemiological data was used to estimate the number of eligible patients. A comparison with current ICD implant rate was done to estimate the necessary incremental rate to treat eligible patients within 5 years. Up to 54% of HF patients are estimated to be eligible for ICD implantation. An implantation policy based on guidelines would significantly increase the ICD number to 2671 implants per million inhabitants in Italy and to 4261 in the USA. An annual increment of prophylactic ICD implants of 20% in the USA and 68% in Italy would be necessary to treat all indicated patients in a 5-year timeframe.nnnCONCLUSIONnImplantable cardioverter defibrillator implantation policy based on current evidence may have significant impact on public health expenditure. Effective risk stratification may be useful in order to maximize benefit of ICD therapy and its cost-effectiveness in primary prevention.

Heart rate as a prognostic marker and therapeutic target in acute and chronic heart failure

Since increased heart rate (HR) is associated with higher mortality in several cardiac disorders, HR is considered not only a physiological indicator but also a prognostic and biological marker. In heart failure (HF), it represents a therapeutic target in chronic phase. The use or up-titration of beta-blockers, a milestone in HF with reduced left ventricular ejection fraction (LVEF) treatment, is at times limited by patients hemodynamic profile or intolerance. Ivabradine, a HR-lowering drug inhibiting the f-current in pacemaker cells, has been shown to improve outcome in patients with chronic HF, in sinus rhythm with increased HR beyond beta-blocker therapy. The rationale for this review is to update the role of HR as a prognostic biomarker and a potential therapeutic target in other scenarios than chronic HF; namely, in patients with coexisting atrial fibrillation (AF), in HF with preserved LVEF (HFpEF), in acute HF, and in patients discharged after an episode of acute HF. Preliminary studies and case reports that evaluated the use of ivabradine in the setting of acute HF will be summarized. Recent results of HR reduction in the setting of HFpEF with ivabradine will be presented. Finally, data from large registries and trials that evaluated the prognostic impact of HR in patients with acute HF and sinus rhythm or AF will be reviewed, showing that only patients in sinus rhythm may benefit from HR reduction.

Clinical Presentation and Outcome in a Contemporary Cohort of Patients with Acute Myocarditis: The Multicenter Lombardy Registry

Background: There is controversy about the outcome of patients with acute myocarditis (AM), and data are lacking on how patients admitted with suspected AM are managed. We report characteristics, in-hospital management, and long-term outcome of patients with AM based on a retrospective multicenter registry from 19 Italian hospitals. Methods: A total of 684 patients with suspected AM and recent onset of symptoms (<30 days) were screened between May 2001 and February 2017. Patients >70 years of age and those >50 years of age without coronary angiography were excluded. The final study population comprised 443 patients (median age, 34 years; 19.4% female) with AM diagnosed by either endomyocardial biopsy or increased troponin plus edema and late gadolinium enhancement at cardiac magnetic resonance. Results: At presentation, 118 patients (26.6%) had left ventricular ejection fraction <50%, sustained ventricular arrhythmias, or a low cardiac output syndrome, whereas 325 (73.4%) had no such complications. Endomyocardial biopsy was performed in 56 of 443 (12.6%), and a baseline cardiac magnetic resonance was performed in 415 of 443 (93.7%). Cardiac mortality plus heart transplantation rates at 1 and 5 years were 3.0% and 4.1%. Cardiac mortality plus heart transplantation rates were 11.3% and 14.7% in patients with complicated presentation and 0% in uncomplicated cases (log-rank P<0.0001). Major AM-related cardiac events after the acute phase (postdischarge death and heart transplantation, sustained ventricular arrhythmias treated with electric shock or ablation, symptomatic heart failure needing device implantation) occurred in 2.8% at the 5-year follow-up, with a higher incidence in patients with complicated forms (10.8% versus 0% in uncomplicated AM; log-rank P<0.0001). &bgr;-Adrenoceptor blockers were the most frequently used medications both in complicated (61.9%) and in uncomplicated forms (53.8%; P=0.18). After a median time of 196 days, 200 patients had follow-up cardiac magnetic resonance, and 8 of 55 (14.5%) with complications at presentation had left ventricular ejection fraction <50% compared with 1 of 145 (0.7%) of those with uncomplicated presentation. Conclusions: In this contemporary study, overall serious adverse events after AM were lower than previously reported. However, patients with left ventricular ejection fraction <50%, ventricular arrhythmias, or low cardiac output syndrome at presentation were at higher risk compared with uncomplicated cases that had a benign prognosis and low risk of subsequent left ventricular systolic dysfunction.

Repetitive use of levosimendan in advanced heart failure: need for stronger evidence in a field in dire need of a useful therapy

Patients in the latest stages of heart failure are severely compromised, with poor quality of life and frequent hospitalizations. Heart transplantation and left ventricular assist device implantation are viable options only for a minority, and intermittent or continuous infusions of positive inotropes may be needed as a bridge therapy or as a symptomatic approach. In these settings, levosimendan has potential advantages over conventional inotropes (catecholamines and phosphodiesterase inhibitors), such as sustained effects after initial infusion, synergy with beta-blockers, and no increase in oxygen consumption. Levosimendan has been suggested as a treatment that reduces re-hospitalization and improves quality of life. However, previous clinical studies of intermittent infusions of levosimendan were not powered to show statistical significance on key outcome parameters. A panel of 45 expert clinicians from 12 European countries met in Rome on November 24-25, 2016 to review the literature and envision an appropriately designed clinical trial addressing these needs. In the earlier FIGHT trial (daily subcutaneous injection of liraglutide in heart failure patients with reduced ejection fraction) a composite Global Rank Score was used as primary end-point where death, re-hospitalization, and change in N-terminal-prohormone-brain natriuretic peptide level were considered in a hierarchical order. In the present study, we tested the same end-point post hoc in the PERSIST and LEVOREP trials on oral and repeated i.v. levosimendan, respectively, and demonstrated superiority of levosimendan treatment vs placebo. The use of the same composite end-point in a properly powered study on repetitive levosimendan in advanced heart failure is strongly advocated.

Abnormal coronary vasoreactivity in transient left ventricular apical ballooning (tako-tsubo) syndrome

BACKGROUNDnThe exact etiology and pathophysiologic mechanisms of tako-tsubo syndrome (TTS) remain controversial.nnnOBJECTIVEnTo further evaluate the abnormal coronary vasoreactivity and its possible anatomical substrate in TTS.nnnMETHODSnWe studied 47 patients (46 women; age 67±12years) who underwent diagnostic cardiac catheterization and evaluation of coronary vasoreactivity by sequential acetylcholine (Ach), nitroglycerine and adenosine testing with angiographic and intracoronary pressure-Doppler flow monitoring. Coronary artery wall morphology was also evaluated by intravascular ultrasound (IVUS) imaging in 45 vessels of 43 patients.nnnRESULTSnAbnormal coronary vasoconstriction to Ach stimulation was elicited in 40 patients (85%) involving the LAD artery and its branches in 39 (83%). Abnormal microvascular function was seen in 39 (83%) patients. Overall, hyperemic microvascular resistance index (HMR) was higher and Doppler coronary flow velocity reserve (CFVR) was lower in the LAD artery territory as compared to the reference territories (2.64±1.23 vs 2.05±0.56; p=0.008 and 1.95±0.7 vs 2.3±0.6; p=0.018, respectively). IVUS revealed no plaque rupture, dissection or thrombosis but occult plaque formation and myocardial bridging were found as a possible anatomical substrate of endothelial dysfunction in 67% and 48.8% patients respectively.nnnCONCLUSIONSnA global failure of coronary vasomotor function was demonstrated in most TTS patients. These findings implicate abnormal vasoconstrictive response to the activation of the sympathetic system as a potential mechanism involved in the pathogenesis of myocardial stunning in TTS.nnnPERSPECTIVESnCompetency in medical knowledge: Abnormal coronary vasoconstriction secondary to endothelial dysfunction may actively contribute to the clinical manifestation of acute coronary syndromes in patients with non-obstructive coronary disease. Translational outlook 1: TTS patients reveal a global failure of vasomotor function with both vasoconstrictive response to acetylcholine and increased hyperemic microvascular resistances in the territory of myocardial stunning. They may also show occult coronary atherosclerosis and myocardial bridging as the anatomic substrates of endothelial dysfunction. Translational outlook 2: The cardiac phenotype of TTS includes a high prevalence of coronary vasomotor disturbances. These findings implicate abnormal vasoconstrictive response to the activation of the sympathetic system as a potential mechanism involved in the pathogenesis of TTS in post-menopausal women. Thus, a systematic evaluation of coronary vasoreactivity could better characterize the syndrome.

La frequenza cardiaca e la prognosi nello scompenso cardiaco acuto e cronico

Heart rate (HR) is not only a physical sign but also a biomarker. High HR in several cardiac disorders is associated with increased mortality. In heart failure (HF), HR represents an important therapeutic target, both in the acute and chronic phase. Beta-blockers are a milestone of recommended treatments in HF patients with reduced ejection fraction. However, hemodynamic profile or intolerance may limit the use or the optimization of beta-blocker treatment, both during hospitalization and outpatient follow-up. More recently, ivabradine has become available, a drug that lowers HR by blocking the I(f) current in the pacemaker cells at the sinoatrial node level. In the SHIFT trial, ivabradine was shown to improve the outcome of patients with chronic HF, in sinus rhythm, with HR >70 b/min while on beta-blockers. Preliminary data have shown that this drug has a good safety profile and lowers effectively HR even during hospitalization due to worsening HF. However, further studies are warranted to understand if an earlier administration of ivabradine can lead to a better prognosis beyond symptom control and improved hemodynamics. In patients with atrial fibrillation and HF, the target is the restoration of sinus rhythm, alternatively rate control should be pursued with beta-blockers, amiodarone or digitalis, even if there is no clear evidence of an association between ventricular rate response in patients with atrial fibrillation at discharge after an HF hospitalization and major cardiovascular events. In this review, the studies that point to a role of HR both as a biomarker and a therapeutic target in patients with acute and chronic HF are described. In addition, the proportions of patients who do not reach target HR values at discharge after an acute decompensated HF episode or in the chronic phase are evaluated based on the Italian registries.

Scheduled intermittent inotropes for Ambulatory Advanced Heart Failure. The RELEVANT-HF multicentre collaboration

BACKGROUNDnAmbulatory Advanced Heart Failure (AAHF) is characterized by recurrent HF hospitalizations, escalating diuretic requirements, intolerance to neurohormonal antagonists, end-organ dysfunction, short-term reduced life expectancy despite optimal medical management (OMM). The role of intermittent inotropes in AAHF is unclear. The RELEVANT-HF registry was designed to obtain insight on the effectiveness and safety of compassionate scheduled repetitive 24-hour levosimendan infusions (LEVO) in AAHF patients.nnnMETHODSn185 AAHF NYHA class III-IV patients, with ≥2 HF hospitalizations/emergency visits in the previous 6u202fmonths and systolic dysfunction, were treated with LEVO at tailored doses (0.05-0.2u202fμg/kg/min) without prior bolus every 3-4u202fweeks. We compared data on HF hospitalizations (percent days spent in hospital, DIH) in the 6u202fmonths before and after treatment start.nnnRESULTSnInfusion-related adverse events occurred in 23 (12.4%) patients the commonest being ventricular arrhythmias (16, 8.6%). During follow-up, 37 patients (20%) required for clinical instability treatment adjustments (decreases in infusion dose, rate of infusion or interval). From the 6u202fmonths before to the 6u202fmonths after treatment start we found lower DIH (9.4 (8.2) % vs 2.8 (6.6) %, pu202f<u202f0.0001), cumulative number (1.3 (0.6) vs 1.8 (0.8), pu202f=u202f0.0001) and length of HF admissions (17.4 (15.6) vs 21.6 (13.4) days, pu202f=u202f0.0001). One-year survival was 86% overall and 78% free from death/LVAD/urgent transplant.nnnCONCLUSIONSnIn AAHF patients, who remain symptomatic despite OMM, LEVO is well tolerated and associated with lower overall length of hospital stay during six months. This multicentre clinical experience underscores the need for a randomized controlled trial of LEVO impact on outcomes in AAHF patients.