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Clinical Articles, Featured

Innovations in cardiorenal medicine

Richard Crawley
Cardiology Registrar
Portsmouth Hospitals NHS Trust

Dr Richard Crawley (Portsmouth Hospitals NHS Trust)

Dr Richard Crawley (Portsmouth Hospitals NHS Trust)

 

Clinical Articles, Lead Article

Atrial fibrillation and CKD

Guidelines suggest that renal function should be assessed in anyone with new AF, particularly in those with bleeding episodes, when considering oral anticoagulation (OAC). Impairment in renal function is included as part of several bleeding risk scores (e.g.HAS-BLED) and anticoagulation may be ruled out in those with high scores. Whilst monitoring AF patients on OACs, renal function should be checked regularly, and whilst safe in moderate and moderate-to-severe CKD (eGFR >15), dose adjustment should be considered for those on non-vitamin K novel oral anticoagulation (NOACs).

Dr Ami Banerjee (University College London)

Dr Ami Banerjee (University College London)

Around 20% of patients in trials with the four NOACS had renal dysfunction, but no studies included patients with end-stage renal disease. It also appears that in clinical practice there is reluctance throughout Europe to give renally impaired patients the full drug dose, and that a lower dose is given even in patients with mild kidney impairment. Despite that, data from The Health Improvement Network (THIN) database, a national GP prescribers’ database, showed that in the UK there is greater prescribing of NOACs in moderate and moderate to severe renal failure than warfarin.

A recently published meta-analysis of four randomised controlled trials (RCTs) compared efficacy and safety (major bleeding) of NOACs versus warfarin in over 58,000 patients, including data on renal function.2 It showed that use of NOACs was associated with a reduced risk of stroke, systemic embolism and major bleeding compared to warfarin in individuals with mild or moderate renal impairment, suggesting a favourable risk profile for these agents in patients with renal disease. However, there is very little data regarding the use of NOACs in end-stage renal disease, and the severe end of the spectrum appears to be neglected. At this time, there are no RCTs assessing OACs in haemodialysis patients or following kidney transplantation, nor studies of NOACs in those with severe CKD (i.e. a creatinine clearance <25-30ml/min). This severe end of the CKD spectrum needs to be addressed in the future.

References

1. Kirchhof P, Benussi S, Kotecha D, et al. (The Task force for the Management of Atrial Fibrillation of the European Society of Cardiology). ESC 2016 European Society of Cardiology Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;117:1-90. http://dx.doi.org/10.1093/eurheartj/ehw210

2. Munoz F, Gharacholou SM, Munger TM, et al. Meta-analysis of renal function on the safety and efficacy of novel oral anticoagulants for atrial fibrillation. Am J Cardiol 2016;17:69-75. http://dx.doi.org/10.1016/j.amjcard.2015.09.046

 

Clinical Articles, Lead Article

Targeting uric acid

This, therefore, begs two questions:

  • Firstly, does uric acid directly cause vascular endothelial damage, contributing to acute renal dysfunction – thereby increasing the risk of cardiovascular disease?
  • Secondly, does uric acid increase the risk of hypertension, chronic kidney disease and diabetes mellitus – which, in turn, increases the risk of cardiovascular problems?
Professor Austin Stack (University Hospital, Limerick, Ireland)

Professor Austin Stack (University Hospital, Limerick, Ireland)

An increase in serum uric acid is thought to result in a proportional fall in nitric oxide levels by decreasing its production. Certainly, animal studies artificially inducing hyperuricaemia have resulted in endothelial damage, and this is separate to the damage caused by reactive oxygen species (ROS) produced by xanthine oxidase.2

In humans, there have been several studies to suggest that in those with major cardiovascular co-morbidities such as hypertension, type 2 diabetes and chronic kidney disease, higher levels of serum uric acid have also been found. This previously was thought to be a result of renovascular damage and nephrosclerosis,3 but more recent studies have shown hyperuricaemia to be a predictor of onset. This risk of comorbidity has been seen to be significantly higher in the higher quartiles of uric acid concentration, suggesting a further direct correlation.

What then can be done? Is there a role for xanthine oxidase inhibitors such as allopurinol? Certainly, evidence from a study looking at adolescent hypertension suggested that taking allopurinol for only four weeks was enough to significantly reduce blood pressure in two thirds of the participants.4 Despite the encouraging results, this small study had many limitations. Further studies in humans have suggested that allopurinol use slows deterioration in renal function, and that contributes to a reduced risk of cardiovascular events.5 Professor Stack highlighted though that no large randomised control trials have yet demonstrated the beneficial effects of allopurinol in reducing cardiovascular risk, and perhaps it is time for us to focus on uric acid – a forgotten risk factor.

References

1. Stack AG, Hanley A, Casserly LF et al. Independent and conjoint associations with gout and hyperuricaemia with total and cardiovascular mortality. Q J Med 2013;106:647–58. http://dx.doi.org/10.1093/qjmed/hct083

2. Khosla UM, Zharikov S, Finch JL et al. Hyperuricaemic induces endothelial dysfunction. Kidney Int 2005;67:1739–742. http://dx.doi.org/10.1111/j.1523-1755.2005.00273.x

3. Messerli FH, Frohlich ED, Dreslinski GR et al. Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Ann Intern Med 1980; 93:817–21.

4. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: A randomized trial. JAMA 2008;300:924–32. http://dx.doi.org/10.1001/jama.300.8.924

5. Goicoechea M, García de Vinuesa S, Verdalles U et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. CJASN 2010;5:1388–93. http://dx.doi.org/10.2215/CJN.01580210

 

Clinical Articles, Lead Article

SGLT-2 inhibitors: a game changer?

SGLT-2 inhibitors, such as empagliflozin, are thought to reduce the level of glucose reabsorption at the nephron, resulting in higher urinary glucose concentrations.1 However, no direct link has previously been shown between lowering serum glucose levels and cardiovascular risk. EMPA-REG has sought to investigate this issue, and the implications of this trial are certainly exciting for those working in both diabetes and cardiology.

Evidence published last year suggests an overwhelming benefit of empagliflozin in preventing cardiovascular disease in comparison to placebo.2 Although there was no difference in the incidence of stroke or myocardial infarction, there was evidence suggesting significantly lower rates of death from cardiovascular causes and lower rates of hospitalisation for symptoms associated with heart failure. Interestingly, the large population recruited already had evidence of cardiovascular disease, and a relative risk reduction of 38% for further cardiovascular events in such a high risk population is impressive.

Another major finding from this trial is the safety of empagliflozin in the long term. There were slight increased risks of genital and urinary tract infections, but no obvious deterioration in renal function. Given the safety and efficacy in reducing serum glucose and HbA1c levels, even in those with CKD Stage II & III,3 it is likely that SGLT-2 inhibitors would be particularly useful in patients with multiple co-morbidities, where other more diabetic medications come into trouble.

What’s more, there is increasing evidence from EMPA-REG to suggest that empagliflozin has a diuretic effect from increased glucose excretion, and this may be the reason for the improved outcomes in chronic heart failure patients, particularly lower rates of hospitalisation from symptoms.

References

1. Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res 2015;12: 78–89. http://dx.doi.org/10.1177/1479164114561992

2. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med 2015;373: 2117–28. http://dx.doi.org/10.1056/NEJMoa1504720

3. Barnett AH, Mithal A, Manassie J et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. LanDia 2014;2:369–84. http://dx.doi.org/10.1016/S2213-8587(13)70208-0

 

Clinical Articles, Lead Article

Novel functional imaging techniques

Blood-oxygen-level dependent imaging (BOLD) works off of the basis that both oxygenated and deoxygenated haemoglobin are both weakly magnetic. The spin of both molecules can alter the signal and this has been useful in renal imaging – particularly identifying the loss of capillary beds in renal artery stenosis. Arterial spin labelling takes this further with real-time perfusion images – for example, demonstrating differences in the perfusion of both renal cortex and medulla. This has the potential to demonstrate both areas damaged by acute tubular injury. From a cardiac perspective, it also has the potential to be an extremely sensitive functional assessment of perfusion damage in myocardial ischaemia.

Dr Aghogho Odudu (University of Manchester)

Dr Aghogho Odudu (University of Manchester)

In non-ischaemic cardiomyopathies, it is thought that myocardial fibrosis is the primary underlying cause. This change in extracellular matrix remodelling increases the risk of diastolic heart failure and arrhythmias.1 Areas of specific regional myocardial scarring seen in cardiac ischaemia have a far slower washout time with regards to gadolinium-enhancement and, as such, are seen as an increased signal intensity. Diffuse fibrosis is more difficult to establish, and post-contrast T1 cardiac MR mapping has a role in identifying this. Consequently, T1 mapping is far more effective in detecting pathologies, such as dilated cardiomyopathy. 2 This technique may soon be used also in renal imaging – in particular for characterising the scarring seen in (CKD) kidney disease and end-stage renal failure.

References

1. Ling LH, Kistler PM, Ellims AH et al. Diffuse ventricular fibrosis in atrial fibrillation: noninvasive evaluation and relationships with aging and systolic dysfunction. J Am Coll Cardiol 2012;60: 2402–08. http://dx.doi.org/10.1016/j.jacc.2012.07.065

2. Iles L, Pfluger H, Phrommintikul A et al. Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol 2008;52:1574–80. http://dx.doi.org/10.1016/j.jacc.2008.06.049

 

Clinical Articles, Featured

News from the Heart Rhythm Congress 2016

Dr Rahul Mukherjee (Guys and St Thomas's Hospital)

Dr Rahul Mukherjee (Guys and St Thomas' Hospital)

 

Clinical Articles, Lead Article

Healthcare costs and innovative solutions for arrhythmia care

Professor Richard Schilling

Professor Richard Schilling (Barts Health NHS Trust, London)

Professor Schilling emphasised the need to reduce variation in practice – for example the standardisation of ablation procedures for persistent atrial fibrillation (AF) (pulmonary vein isolation only as per the evidence from the STAR-AF II trial) thereby reducing procedure times and fluoroscopy dose. The need to get greater value from technology was addressed as well as encouragement of patient leadership. Finally, a call for open audit was made to drive innovation and improvement, and challenge us to learn from colleagues about best practice.

Dr Aaisha Opel (London) discussed data during an oral abstract presentation on the use of day case cryoablation for paroxysmal AF in the district general hospital setting. She noted that if performed by experienced operators in high volume centres, this was a safe and effective treatment strategy. Work of this nature will take on increasing significance if the demand for AF ablation increases. The catheter ablation vs. anti-arrhythmic drug therapy for AF (CABANA) trial is due to report next year on whether catheter ablation is superior to drug therapy in reducing a composite of total mortality, disabling stroke, serious bleeding or cardiac arrest. A positive outcome is likely to increase the demand for AF ablation.

Professor Silvia Priori (University of Pavia, Italy) described an exciting approach using gene therapy to treat inherited arrhythmia syndromes. Her work involved a mouse model of catecholaminergic polymorphic ventricular tachycardia (CPVT) and used the delivery of miRNA via an adenovirus vector to silence the mutant gene, reduce mutant transcripts and break the arrhythmogenic substrate. The pre-clinical studies appeared promising and may represent an alternative approach to treat inherited cardiac arrhythmias.

 

Clinical Articles, Lead Article

Improving outcomes from VT ablation

ManistyCharlotte

Dr Charlotte Manisty (Bart’s Health NHS Trust, London)

Dr Manisty presented a vision that one day, these developments in imaging could lead to an ability to identify VT circuits in 3D based on patterns of scar at different levels of tissue. Such information may be able to guide the electrophysiologist in improving success rates from catheter ablation (currently around 40–50% of patients have a recurrence of VT after an initial ablation procedure within one year).

 

Clinical Articles, Lead Article

NOACs: translating latest clinical and cardioversion data into practice

Dr Ian Menown (Craigavon Cardiac Centre, Northern Ireland) described the evidence base for the use of NOACs for anticoagulation in AF, including the findings of the ENGAGE-AF (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation) trial comparing the use of edoxaban vs. warfarin for AF. He noted the 20% reduction in major bleeding and reduced cardiovascular mortality seen in the secondary end-points of the trial.

Dr Ian Menown (Craigavon Cardiac Centre)

Dr Ian Menown (Craigavon Cardiac Centre)

The challenges faced in adequately anticoagulating a patient undergoing DC cardioversion are all too familiar to arrhythmia specialists. Contemporary guidelines recommend >3 weeks of therapeutic anticoagulation prior to elective DC cardioversion. Achieving and maintaining a stable INR with warfarin can often be challenging and can frequently lead to the cancellation or postponement of cardioversion.  In this context, Dr David Jones (Royal Brompton & Harefield NHS Trust, London) discussed the results from the recently published ENSURE-AF (Edoxaban vs. Warfarin in Subjects Undergoing Cardioversion of Atrial Fibrillation) trial where edoxaban was demonstrated to be a safe and effective alternative to warfarin in patients needing anticoagulation prior to elective DC cardioversion.

It was noted that adherence to edoxaban was very high in the trial setting. The study also included many patients with a low CHADSVasc score (0 or 1) likely representing a real world population. Although the trial was the largest randomised controlled trial (RCT) for a NOAC in the setting of DC cardioversion, the efficacy and safety event rates were low in both arms. The net clinical outcome was numerically lower but not statistically different in the edoxaban and enoxaparin/warfarin arm. Despite this, the ENSURE-AF trial suggests that patients needing anticoagulation prior to DC cardioversion may indeed benefit from edoxaban. Further work is needed to assess whether use of transoesophageal echocardiography can further reduce stroke risk and the minimal/optimal ‘run in’ period for NOAC anticoagulation (is three weeks enough/too long?).

Dr Menown provided important insights into deciding which anticoagulants should be used for different patients. While noting that due to different trial populations in the major NOAC trials, direct comparisons are difficult to make but various clinical factors and patient preference can help guide NOAC choice. The ROCKET-AF (rivaroxaban) and ENGAGE-AF (edoxaban) trials had a larger proportion of patients with higher CHADS2 score than RE-LY (dabigatran) and ARISTOTLE (apixaban). In network meta-analyses, edoxaban was favoured for major bleeding vs. dabigatran and rivaroxaban whilst having similar efficacy for prevention of stroke compared to other NOACs.

Based on this and other data, the speakers noted that in patients with a high bleeding risk, edoxaban or apixaban may be a better option compared to other anticoagulants. In patients with a high risk of ischaemic stroke but a low bleeding risk, dabigatran 150 mg may be a better option. In patients with renal impairment, apixaban, low-dose edoxaban or low dose rivaroxaban may be a better option. Taking into account patient surveys, patients tended to prefer rivaroxaban and edoxaban with their once daily regimens.

 

Clinical Articles, Lead Article

Young Investigator Award

Dr Ahmed Merghani (St George’s Hospital, London)

Dr Ahmed Merghani (St George’s Hospital, London)

Cardiac MRI was then performed to assess the underlying substrate for these arrhythmias; overall 16% of male veteran athletes had mid-myocardial or epicardial scarring whilst 40% had subendocardial scar (suggestive of an ischaemic aetiology). A cardiac CT was then performed alongside a calcium score. Intriguingly, male veteran athletes had significantly higher incidences of luminal stenosis >50% and >2 vessel involvement with coronary disease. A moderate amount of exercise appeared protective (in terms of calcium score) compared to no exercise and extreme exercise. The moderators praised the design and quality of the study whilst also noting that it raised further questions regarding screening of endurance athletes >40 years age.

 
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