The most recent innovations in cardiorenal medicine and the challenges this specialty faces in the near future were the focus of the 10th Annual Scientific Meeting of the Cardiorenal Forum. The meeting was held at The Royal College of Obstetricians and Gynaecologists, London, on October 1st 2015, and endorsed by the Renal Association and the British Society for Heart Failure. Drs Thomas Gilpin and Amanda Laird report on its highlights.
Acute heart failure
The first of the clinical heart failure sessions, delivered by Professor Theresa McDonagh (King’s College Hospital, London), considered the definition of acute heart failure (AHF) and how this has been simplified over recent years from a minefield of overlapping statements set out in 2008. Acute hypertensive heart failure, acutely decompensated chronic heart failure, acute coronary syndrome (ACS) and heart failure, right heart failure – amongst other terminology – have now been categorised into:
- ‘puffers’ – pulmonary oedema, fluid distribution error and
- ‘bloaters’ – peripheral oedema with genuine fluid overload.
Whilst this new terminology is broad and possibly ambiguous, it is anticipated that this basic categorisation will lead to a simplification of acute management and more streamlined care. There is a limited evidence base for the management of acute heart failure and the traditional management has altered very little. However, there is an emphasis on the detection and early management of hypoxia in patients presenting in pulmonary oedema.
The 2014 National Institute for Heath and Care Excellence (NICE) guidelines for acute heart failure (CG187) downgraded a number of treatments, which had previously been used without evidence base. These are now recommended only for certain situations:
- Opiates should only be considered if the patient has severe anxiety or distress.
- Continuous positive airways pressure (CPAP) and non-invasive ventilation (NIV) should not routinely be used but reserved for those in whom initial medical therapies have failed. NIV can be considered acutely in those with cardiogenic pulmonary oedema and acidaemia. In patients with respiratory failure, reduced conscious level and exhaustion intermittent positive pressure ventilation (IPPV) should be considered.
- Diuretics (for ‘bloaters’) were shown in a 2005 Cochrane Library review by Salvador et al. (doi: 10.1002/14651858.CD003178.pub3) to have superiority when a continuous loop diuretic was infused rather than intermittent intravenous boluses. Loop diuretics remain the mainstay of AHF management through initial vasodilator effect and subsequent diuresis in patients presenting with total body fluid excess (as opposed to redistribution).
- Dopamine use in AHF has limited evidence. The ROSE-HF (Renal Optimization Strategies Evaluation in Acute Heart Failure) study demonstrated that renal dose dopamine should not be used routinely in patients with AHF and an estimated glomerular filtration rate (eGFR) of 15-60 ml/kg/min. There was no reduction in 60- or 180-day mortality or heart failure (HF) hospitalisation. But the jury remains out as clinical practice often leans towards the use of dopamine in AHF in those who fail to respond to intravenous diuretics with marked fluid overload. This is an area in much need of a randomised controlled trial (RCT).
- Inotropes are no longer routinely recommended in AHF.
- Nitrates should not be used in the routine management of AHF. Uncontrolled drops in blood pressure are closely associated with an increase in mortality and therefore they should only be used in specific circumstances (myocardial ischaemia, severe hypertension) and in a level two high care area.
On the horizon, RELAX-AHF (Relaxin in Acute Heart Failure) is an ongoing RCT comparing serelaxin (recombinant human relaxin – a vasodilator with additional properties) to standard care and placebo. It has been powered to look at improving dyspnea, reduction of cardiovascular (CV) mortality and hospital admission for HF. This study will hopefully build on early promising data.
Chronic heart failure
Professor John McMurray (University of Glasgow) summarised the evidence on the latest advances and touched on projects for the future in this complex and ever evolving subspecialty. The link between chronic kidney disease (CKD) and CV disease is well established, and this is particularly apparent when considering heart failure.
What more can be done in terms of neurohormonal manipulation? Spironolactone and eplerenone are well established as successful adjuncts to angiotensin-converting enzyme (ACE) inhibitors and beta blockers in the management of heart failure with reduced ejection fraction, currently holding a firm 1A evidence base. Non-steroidal mineralocorticoid receptor antagonists are an exciting new area of research with stage III clinical trials ongoing. FINESSE-HF (Finerenone Trial to Investigate Efficacy and Safety to Eplerenone in Patients with Heart Failure) is assessing finerone versus eplerenone use following hospitalisation for heart failure, with CV death or heart failure hospitalisation as primary end points.
Even though well-established and effective treatment regimes are available, thinking ‘outside the box’ and considering novel therapies are vital for continuing dynamic change and improvements in mortality for complex disease processes. PARADIGM-HF prospectively compared the angiotensin receptor–neprilysin inhibitor, sacubitril-valsartan (LCZ696), to well-established enalapril. The primary end point was set as death from CV causes or hospitalisation secondary to heart failure. The trial was stopped early due to the significant superiority of LCZ696 over enalapril in respect to mortality and overall safety. This novel agent blocks the deleterious effects of the activated renin-angiotensin system but also augments the counter-regulatory vasodilator and natriuretic pathways. It is likely that this agent will transform the management of patients with heart failure with reduced ejection fraction and become first-line treatment instead of ACE inhibitor/angiotensin receptor blockers.
Diagnosis and monitoring of disease progression is key through both qualitative symptomatic assessment and quantifiable biochemical marker analysis. Professor Paul Collinson (St George’s University London) provided the latest update on biomarkers in both CV and renal disease. Both troponin I and troponin T are powerful predictors of CV mortality in patients with CKD but there is an ongoing debate as to the reasoning behind elevated levels of troponin being detected. Is it failure of troponin clearance or fragmentation of the molecule? The jury is still out on this issue.
Promising ideas for the future
Fibroblast growth factor 23 (FGF23) is a protein secreted by osteocytes in response to elevated calcitriol. Whilst work with this biomarker is in the early days, its use in identifying patients with CKD whom may benefit from aggressive management of phosphate metabolism is promising. Early results also suggest that significantly raised FGF23 levels in CKD could be a direct contributor to myocardial, vascular and renal tissue injury.
Iron deficiency in cardiorenal disease
Professor Iain Macdougall (King’s College Hospital, London) presented a thorough overview of the pathophysiology and treatment of anaemia in patients with CKD and those on renal replacement therapy. He firstly reminded us that iron deficiency is the leading cause of anaemia in renal patients; European studies (such as PRESAM and ESAM) show that 30–61% of CKD patients have iron deficiency anaemia (IDA). The investigations most helpful in establishing IDA are serum ferritin, transferrin saturations and percentage of hypochromic red blood cells. The 2015 NICE guideline ‘Chronic kidney disease: managing anaemia (NG8)’ has set treatment targets aiming for a serum ferritin >100 µg/ml, TSats >20% and <10% hypochromic red blood cell counts (RBCs).
The question remains, however, how can we best treat iron deficiency in CKD. Oral iron is cheap but is poorly tolerated and often poorly absorbed. FIND-CKD (a randomised trial of intravenous ferric carboxymaltose versus oral iron in patients with CKD and iron deficiency anaemia) demonstrated that high-dose intravenous iron resulted in a faster rise in haemoglobin (Hb) compared to oral or low-dose intravenous iron and patients overall achieved a higher Hb. PIVOTAL (Proactive Intravenous Iron Therapy in Haemodialysis Patients) is a UK prospective RCT in haemodialysis patients. This compares regular monthly intravenous iron infusion with treatment directed by a serum ferritin <200 µg/l. The primary end point is time to all-cause mortality and composite of non-fatal cardiovascular events. This trial will hopefully guide future management of iron deficiency in the dialysis population.
Anaemia is also prevalent in the heart failure population and is an independent risk factor for adverse outcomes in heart failure patients. Iron deficiency has also been shown to be an independent risk factor for all-cause mortality regardless of Hb level. The FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure) and CONFIRM-HF (Ferric Carboxymaltose Evaluation on Performance in Patients with Iron Deficiency in Combination with Chronic Heart Failure) trials demonstrate that correction of this iron deficiency (with intravenous iron) was associated with improvements in quality of life, heart failure symptoms and exercise tolerance.
These studies have led to the development of the IRONMAN (Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency) trial, led by Dr Paul Kalra (Queen Alexandra Hospital, Portsmouth), a prospective RCT recruiting patients with left ventricular systolic dysfunction and IDA. This will compare giving intravenous iron to keep ferritin levels above 100 µg/ml and Tsats >25% to normal standard care. The primary end points are CV mortality and hospitalisation due to heart failure. Patients (n=1,300) will be followed for two years and the trial started recruitment in early 2016. We look forward to exciting new developments in a modifiable risk factor where therapeutic intervention could provide improvement in patient mortality and morbidity.
Cardio-oncology – a novel problem!
Advancement in oncology treatment and improved life expectancy in many cancer patients has created a new challenge for cardiologists. Dr Alexander Lyon (Royal Brompton Hospital, London) introduced a new emerging subspecialty in cardiology and the service provided at the Royal Brompton Hospital.
Many chemotherapy agents are associated with cardio-toxic effects. A study by Bowles EJA et al. (J Natl Cancer Inst 2012;104:1293–305 doi: 10.1093/jnci/djs401) found that 12.5% of breast cancer patients treated with trastuzumab (Herceptin®) developed heart failure within five years. The new tyrosine kinase inhibitors in renal cell carcinoma are increasing survival but are all associated with an increased incidence of CV side effects including hypertension and reduced left ventricular ejection fraction. With this knowledge, is there any way of predicting which patients will be affected and therefore prevent potential long-term CV complications?
Early detection of abnormalities of myocardial function with speckle tracking echocardiography and elevated serum cardiac biomarkers during chemotherapy can predict which patients are vulnerable. Cardinale D et al. (Circulation 2004;109:2749–54 doi: 10.1161/CIRCULATIONAHA.106.635144) published data showing patients with a troponin rise during treatment with anthracyclines had an increased risk of cardiovascular events. It has been shown in small studies that initiation of an ACE inhibitor and beta blocker may reduce CV events. This warrants further evaluation to establish if this can be an effective preventative strategy.
A cardio-oncology service has been initiated at the Royal Brompton Hospital, which serves to pre-assess high-risk patients and optimise primary prevention. Follow up is provided to those patients who have developed CV complications as a result of their cancer treatment. This aims to reduce cardiac problems in survivors and support optimal cancer treatment.
Updates in nephrology
Professor Maarten Taal (Royal Derby Hospital, Derby) gave an update of recent trials involving CKD patients and CV risk. CKD is associated with increased CV and all-cause mortality. A meta-analysis of over 24 studies involving greater than 600,000 patients, found in the general population urinary albumin to creatinine ratio (ACR) and eGFR improve cardiac risk prediction, with the greatest effect seen in CV mortality and heart failure. In those with CKD, these measurements are in fact better risk predictors than any of the other traditional Framingham CV risk factors.
The significance of raised cardiac biomarkers in the CKD population remains uncertain. The CRIC (Chronic Renal Insufficiency Cohort) study, a prospective cohort study of >3,000 patients with CKD without HF at baseline, showed elevated high sensitivity troponin and NT-pro BNP levels were associated with increased incidence of HF. This may reflect subclinical cardiac injury that progresses to HF even in the early stages of CKD and therefore are independent predictors of HF in the CKD population.
SHARP (Study of Heart and Renal Protection) demonstrated improved CV outcomes in patients treated with simvastatin/ezetimibe compared to placebo in the CKD population. The effect in primary prevention, however, was unclear. A meta-analysis by Major RW et al. (Clin J Am Soc Nephrol 2015;10:732–9 doi: 10.2215/CJN.07460714) of six randomly controlled trials of primary prevention with lipid-lowering agents in patients with CKD stage 1−3, found statins are effective in reducing CV disease when used in primary prevention and therefore are now recommended in all patients with CKD stages 1−3.
A wealth of other data highlighting the recent advances in cardiorenal medicine were presented during the day, supported by several clinical cases. There was stimulating passionate debate between cardiologists and nephrologists and we look forward to next year’s conference.
Thomas R Gilpin
Queen Alexandra Hospital, Portsmouth
Queen Alexandra Hospital, Portsmouth