Donah Zachariah

Drug therapy for heart failure in older patients—what do they want?

Chronic heart failure (CHF) is predominantly seen in older patients, and therefore real life medicine often requires the extrapolation of findings from trials conducted in much younger populations. Prescribing patterns and potential benefits in the elderly are heavily influenced by polypharmacy and co-morbid pathologies. Increasing longevity may become less relevant in the frail elderly, whereas improving quality of life (QoL) often becomes priority; the onus being on improving wellbeing, maintaining independence for longer, and delaying institutionalisation. Specific studies evaluating elderly patients with CHF are lacking and little is known regarding the tolerability and side-effect profile of evidence based drug therapies in this population. There has been recent interest on the impact of heart rate in patients with symptomatic CHF. Ivabradine, with selective heart rate lowering capabilities, is of benefit in patients with CHF and left ventricular systolic dysfunction in sinus rhythm, resulting in reduction of heart failure hospitalisation and cardiovascular death. This manuscript will focus on CHF and the older patient and will discuss the impact of heart rate, drug therapies and tolerability. It will also highlight the unmet need for specific studies that focus on patient-centred study end points rather than mortality targets that characterise most therapeutic trials. An on-going study evaluating the impact of ivabradine on QoL that presents a unique opportunity to evaluate the tolerability and impact of an established therapy on a wide range of real life, older patients with CHF will be discussed.

Is cardiac resynchronisation therapy feasible, safe and beneficial in the very elderly?

Objective To evaluate whether cardiac resynchronisation therapy (CRT) implantation was feasible and safe in octogenarians and the association with symptoms. Methods Consecutive patients undergoing CRT implantation were recruited from two UK centers. Patients grouped according to age: < 80 & ≥ 80 years. Baseline demographics, complications and outcomes were compared between those groups. Results A total of 439 patients were included in this study, of whom 26% were aged ≥ 80 years. Octogenarians more often received cardiac resynchronization therapy pacemaker in comparison to cardiac resynchronisation therapy-defibrillator. Upgrade from pacemaker was common in both groups (16% < 80 years vs. 22% ≥ 80 years, P = NS). Co-morbidities were similarly common in both groups (overall diabetes: 25%, atrial fibrillation: 23%, hypertension: 45%). More patient age ≥ 80 years had significant chronic kidney disease (CKD, estimated glomerular filtration rate < 45 mL/min per 1.73 m2, 44% vs. 22%, P < 0.01). Overall complication rates (any) were similar in both groups (16% vs. 17%, P = NS). Both groups demonstrated symptomatic benefit. One-year mortality rates were almost four fold greater in octogenarians as compared with the younger cohort (13.9% vs. 3.7%, P < 0.01). Conclusions CRT appears to be safe in the very elderly despite extensive co-morbidity, and in particular frequent severe CKD. Symptomatic improvement appears to be meaningful. Strategies to increase the appropriate identification of elderly patients with CHF who are potential candidates for CRT are required.

CLINICAL UTILITY OF BIOMARKERS IN CHRONIC KIDNEY DISEASE AND CHRONIC HEART FAILURE

Biomarkers have an increasingly important clinical role in managing patients with heart failure as well as those with kidney disease, both common conditions with generally poor prognostic outcomes and huge impacts on healthcare economics. For patients with chronic heart failure, biomarkers have become centre place in streamlining diagnostic pathways as well as identifying those with worse prognosis. There is much interest in the role for biomarkers in identifying patients at risk of acute kidney injury, although a number of these currently remain as research tools or are in the early stages of evaluation in clinical practice. Patients with cardiorenal syndrome represent a particular challenge to the clinician, and recent studies have suggested a valuable clinical role for certain biomarkers in this setting, either on their own or in combination. This paper will focus on biomarkers with a current clinical role in patients with cardiorenal disease (natriuretic peptides and neutrophil gelatinase-associated lipocalin), although brief reference will be made to other biomarkers with potential future application.

OPTIMAL MANAGEMENT OF CHRONIC HEART FAILURE IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Chronic kidney disease and chronic heart failure are closely interlinked; an abnormality in one system adversely impacts upon the function of the other. Despite the wealth of evidence available for beneficial treatment strategies in chronic heart failure, the prognosis remains poor and optimum therapy under-utilised. The applicability of proven therapies to patients with co-morbidity remains a particular challenge, especially since marked renal impairment has often been an exclusion criteria in major studies. In this article we discuss the epidemiology and pathophysiology of the two conditions and then focus on the aspects of treatment most pertinent to those patients with heart failure patients and concomitant chronic kidney disease.

Monitoring of arrhythmia and sudden death in a hemodialysis population: The CRASH-ILR Study

Introduction It has been suggested that sudden cardiac death (SCD) contributes around 50% of cardiovascular and 27% of all-cause mortality in hemodialysis patients. The true burden of arrhythmias and arrhythmic deaths in this population, however, remains poorly characterised. Cardio Renal Arrhythmia Study in Hemodialysis (CRASH-ILR) is a prospective, implantable loop recorder single centre study of 30 established hemodialysis patients and one of the first to provide long-term ambulatory ECG monitoring. Methods 30 patients (60% male) aged 68±12 years receiving hemodialysis for 45±40 months with varied etiology (diabetes 37%, hypertension 23%) and left ventricular ejection fraction (LVEF) 55±8% received a Reveal XT implantable loop recorder (Medtronic, USA) between August 2011 and October 2014. ECG data from loop recorders were transmitted at each hemodialysis session using a remote monitoring system. Primary outcome was SCD or implantation of a (tachy or bradyarrhythmia controlling) device and secondary outcome, the development of arrhythmia necessitating medical intervention. Results During 379,512 hours of continuous ECG monitoring (mean 12,648±9,024 hours/patient), there were 8 deaths—2 SCD and 6 due to generalised deterioration/sepsis. 5 (20%) patients had a primary outcome event (2 SCD, 3 pacemaker implantations for bradyarrhythmia). 10 (33%) patients reached an arrhythmic primary or secondary end point. Median event free survival for any arrhythmia was 2.6 years (95% confidence intervals 1.6–3.6 years). Conclusions The findings confirm the high mortality rate seen in hemodialysis populations and contrary to initial expectations, bradyarrhythmias emerged as a common and potentially significant arrhythmic event.

Managing patients with cardiorenal syndrome: time to look to the gut?

Chronic kidney disease (CKD) is an extremely common comorbidity in patients with chronic heart failure (CHF). Studies have consistently shown that it is an independent predictor of mortality and adverse cardiovascular events. Treating patients with CHF and advanced CKD presents a particular challenge. While the evidence base for treating patients with CHF is among the strongest for any disease, patients with severe renal impairment have generally been excluded from major studies. Fear that antagonists of the renin–angiotensin–aldosterone system will precipitate end-stage renal disease in such patients often leads to inappropriate underutilization. The potential adverse impact on each other’s function from an abnormality in either of these organ systems led to Ronco and colleagues proposing a classification for cardiorenal syndrome which included five subtypes. It is a logical classification for differentiating between acute and chronic interactions and identifying the responsible organ system driving pathophysiological abnormalities in each clinical scenario. It also highlights the associated risk. There are, however, major limitations of this classification; each subtype may co-exist with another and clinical presentations are commonly not so clearly delineated. For example, a patient with decompensated heart failure is more likely to develop acute kidney injury if they have underlying CKD and/or systemic illness such as diabetes or vascular disease. In many respects this classification highlights our limited understanding of the pathophysiological abnormalities that drive these interactions and therefore adds little, if any, value to defining the management of the patient sitting in front of you. Cardiologists and nephrologists must work together to coordinate quality research into this area and evaluate novel treatment strategies. Optimization of fluid balance for patients with CHF is crucial to relieve symptoms. Recent data suggest that congestion per se may also impact on disease progression. The presence of venous congestion, be it elevated jugular venous pressure, orthopnoea, oedema, or ascites, predicts worse outcome and is independently related to lower estimated glomerular filtration rate (eGFR). The detrimental effects of venous congestion on renal function are predominantly seen in the presence of pre-existing renal hypoperfusion, which in turn is driven by reduced cardiac output. Invariably optimization of fluid balance necessitates the use of diuretics. This itself may incur some cost, and for patients with advanced CHF and/or CKD is hugely challenging. Kidney function may deteriorate further (acute kidney injury, associated with adverse outcomes) and resistance to loop diuretics may supervene. There are a number of ways to counteract this. For example, the addition of mineralocorticoid receptor antagonists (MRAs, aldosterone blockers) and thiazide diuretics enhances renal sodium excretion by ‘progressive nephron blockade’. Recent data from the EMPHASIS-HF study have shown that MRAs (in this case eplerenone) have a major impact on prognosis even in patients with mildly symptomatic CHF. Prognostic benefit is likely to relate to beneficial antagonism of aldosterone-mediated cardiac and renal fibrosis. Current guidelines recognize an expanded indication for MRA use. Initiation and up-titration of MRAs may be limited by the development of severe hyperkalaemia. In ‘real life’ this may be more apparent than that seen in carefully monitored clinical trials. Juurlink et al. showed that following publication of the RALES study, the spironolactone prescription rate went up from 34 per 1000 patients (in 1994 pre-RALES) to 149 per 1000 patients by late 2001 (P , 0.001). The rate of hospitalization for hyperkalaemia also rose from 2.4 per 1000 patients in 1994 to 11.0 per 1000 patients in 2001 (P , 0.001), and the associated mortality rose from 0.3 per 1000 to 2.0 per 1000 patients (P , 0.001). In the EMPHASIS-HF study, potassium levels exceeding 5.5 mmol/L were seen in 11.8% of patients receiving eplerenone vs 7.2% of those in the placebo group (P , 0.001). In the subgroup of patients with eGFR ,60 mL/min/1.73 m, figures of

CHALLENGES TO ADVANCING THE EVIDENCE BASE FOR NEPHROLOGY: THE TIME IS RIGHT FOR COLLABORATION

INTRODUCTION Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD) (Foley 2010). These patients have a greater incidence of myocardial infarction (MI), chronic heart failure (CHF) and stroke, with a greater morbidity and mortality following one of these events (Go et al. 2004). Patients who develop acute kidney injury (AKI) in the context of cardio-vascular events, for example MI, have poor outcome (De Leeuw et al. 2002). The robust evidence base behind most cardiological interventions becomes less applicable in the presence of CKD; significant CKD is a common exclusion criterion in most landmark trials. Clinical trials in the dialysis population are scarce, often with limited numbers of participants and correspondingly low statistical power.

7TH ANNUAL SCIENTIFIC MEETING OF THE UK CARDIORENAL FORUM

BACKGROUND The Cardiorenal Forum (UK) was formed in 2006 to highlight the important clinical overlap, which exists when patients present with a primary cardiovascular (CV) or renal condition. The annual meeting, now in its seventh year, is always well attended and continues toprovide a platform for discussion and educationwith a key aim of leading to improved care for this group of patients. This year’s meeting on 5 October 2012, focussed on many of the clinical complexities that arise in managing patients with cardiorenal disease, including diabetes and other co-morbidities, as well as discussing ongoing studies. The full programme can be seen at www.cardiorenalforum.com and a summary of the papers presented on the day is discussed here.