The highly anticipated 14th Annual Scientific Meeting of the Cardiorenal Forum was held at The King’s Fund, London, on 4th October 2019. The focus of the meeting was integrating care between specialities in cardiorenal medicine and it attracted a high number of attendees across multiple specialities and the wider multidisciplinary team. Expert speakers ensured the meeting was packed with interesting thought-provoking talks, generating interactive discussion throughout the day. Dr Helena Edwards reports on the meeting’s highlights.
The complexity of today’s population with diabetes
The opening talk of the meeting was given by Dr Peter Winocour (East and North Hertfordshire NHS Trust). He discussed the complexity and multi-morbidity seen in our increasing population with diabetes, who commonly present with both chronic kidney disease (CKD) and cardiovascular disease (CVD). Ageing and obesity amplify both diabetes and CKD, often co-existing. Furthermore, CVD outcomes are magnified when diabetes and CKD co-exist. Vogel B et al.1 showed the risk of major adverse cardiovascular events (MACE) in patients undergoing percutaneous coronary intervention to be significantly increased in CKD patients with diabetes, regardless of their syntax score, a tool used to score complexity of coronary artery disease.
It is important to note that the spectrum of diabetic kidney disease exists beyond the traditional diabetic nephropathy model of albuminuria in the presence of retinopathy. Only 40–50% of patients with proven diabetic nephropathy have retinopathy, previously thought to be 100%. It is necessary to distinguish these patient groups due to the risk profiles attached. The complications associated with kidney disease will happen earlier if the underlying cause is diabetes, particularly in those with the traditional diabetic nephropathy presentation.
Moving forward, holistic care is essential for all patients with diabetes and we can refer to the 15 pillars of care recommended by Dr Winocour.2 Beyond diabetes and obesity, we need to consider multiple other factors such as anaemia, bone health, sick day rules and managing patients with an increased risk of hospital admission.
An update on SGLT2 inhibitors
SGLT2 inhibitors have been the feature of many recent trials and discussions both in renal disease and CVD. These were a key theme of discussion at this year’s meeting. Professor David Lappin (National University of Ireland, Galway) started the conversation, presenting the results of the CREDENCE (Canaglifozin and Renal Outcomes in Type 2 Diabetes and Nephropathy) trial published earlier this year.3
Diabetic kidney disease is the commonest cause of end-stage renal disease in the UK and yet proven therapeutic options remain limited with renin-angiotensin-aldosterone blockade being the main standard of care. The positive results from SGLT2 inhibition seen in EMPA-REG, CANVAS and DECLARE prompted a primary study looking at renal outcomes, of which CREDENCE is the first and only published trial currently. The trial enrolled 4,401 patients with type 2 diabetes and evidence of diabetic kidney disease with impaired renal function (estimated glomerular filtration rate [eGFR] of 30–90 ml/min) and proteinuria. Patients were randomised to receive either canagliflozin or placebo on a background of optimised standard of care. Canagliflozin led to a 30% relative risk reduction in the primary outcome, a composite of doubling of serum creatinine, end-stage renal disease and death from renal or cardiovascular cause. This equated to a number needed to treat for the primary outcome of 22, with the benefits seen as early as 12 months after initiation of treatment.
With the compelling data from the CREDENCE trial, the US Food and Drug Administration has recently updated their guidelines and awarded a license to canagliflozin for renoprotection in patients with type 2 diabetes patients with an eGFR > 45 ml/min. The position in the UK remains that SGLT2 inhibitors are licensed for use as a second-line oral hypoglycaemic agent only for patients with an eGFR > 60 ml/min. It is anticipated by many, however, that these guidelines are likely to be updated in the light of the newer evidence. Many attendees at the meeting would advocate their use now, after careful discussion with the patient. An important point highlighted by Professor Lappin was that an early initial drop in renal function is seen in SGLT2 inhibition, similarly to that seen with renin-angiotensin-aldosterone system (RAAS) blockade.
Another study with a SGLT2 inhibitor – the DAPA-HF (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction) trial – is also causing much excitement.4 Dr Geraint Morton (Portsmouth Hospitals NHS Trust) presented the results in the cardiology trials update session. DAPA-HF enrolled 4,744 patients who had symptomatic heart failure and an ejection fraction of less than 40%. The trial was consistent with previous studies, showing that dapagliflozin treatment led to a 26% relative risk reduction in the primary outcome of hospitalisation for heart failure and death. An interesting point from this trial was that 58% of patients did not have diabetes. The subgroup analysis showed that all groups benefited regardless of whether or not they had diabetes. Perhaps we need to change our thought process on SGLT2 inhibitors to that of a cardiovascular and renoprotective drug that also lowers blood glucose.
The vulnerable patient – treating CVD in the patient with diabetes
Professor Julian Halcox (Swansea University Medical School, and Swansea Bay University Health Board) discussed the vulnerable patient with diabetes to conclude the first session of the morning. Diabetes leads to widespread changes causing alterations in the blood, plaques and myocardium of patients. Vulnerable plaques are more widespread and lipid-rich, and the myocardium is metabolically disturbed. Risk-factor modification using a multifactorial and multidisciplinary integrated approach can have significant impact, which was well demonstrated in the Steno-2 (Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes) study.5
Professor Halcox presented a helpful summary of the existing evidence and his current practice, with recommendations for individual risk factor management. Optimal blood pressure (BP) targets continue to be an ongoing dilemma with contrasting results from trials, such as SPRINT and ACCORD-BP, and variations across national and international guidelines. The National Institute for Health and Care Excellence (NICE) gives clear recommendations of a BP target of <140/90 mmHg, with a more intensive target of <130/80 mmHg in patients with diabetes and end-organ damage.6 The European Society of Cardiology (ESC) guidance recommends aiming for a systolic BP of between 120–130 mmHg and a diastolic BP of 70–80 mmHg.7 Professor Halcox acknowledges this can be a challenge and, in his practice, aims for a target of <140/80 mmHg, with a 130 mmHg systolic BP where possible, using angiotensin-converting enzyme (ACE) inhibitors and calcium-channel blockers as first-line agents.
Lipoproteins are the fundamental building block of atherosclerotic lesions. High-intensity statin therapy has a wealth of evidence supporting its use and we are comfortable in this as one of the commonest drug classes prescribed to our patients. However, beyond statins, we are now seeing additional agents with beneficial results. Ezetimibe, one of the more well-known agents, was shown to have a small but statistically significant impact on reducing MACE when used in addition to standard statin therapy in patients with acute coronary syndrome. Both PCSK9 monoclonal antibodies and fenofibrates have also shown benefit. The current ESC guidelines recommend the addition of ezetimibe to statin therapy if the target low-density lipoprotein (LDL) cholesterol is not reached. The LDL-cholesterol target is ambitious at <1.4 mmol/L in very high-risk patients, which include those with significant CKD, established atherosclerotic CVD or diabetes with target end-organ damage. Furthermore, in patients with persistently high LDL-cholesterol on statin and ezetimibe combination therapy, PCSK9 inhibitors should be considered. This is likely to have a cost implication if fully adhered to.
Frailty – a sense of vulnerability and lack of physiological reserve
The British Geriatrics Society Cardiovascular Forum Lecture, delivered by Dr Nigel Beckett (Guy’s & St Thomas’ NHS Foundation Trust, London), discussed the effective management of frailty. With an ageing population, the complexity of our patients is increasing year on year.
The multi-morbid patient is defined as one having two or more long-term health conditions – this covers the majority (54%) of the UK population over the age of 65 years. Some 78% of patients with hypertension will have another health condition and therefore be classed as multi-morbid. Despite this, the majority of clinical guidelines are disease specific and do not consider a holistic approach.
Multi-morbidity is not frailty, he said, but there is an interaction between them. Dr Beckett commented that there is no internationally agreed definition for frailty. He described a helpful way to view frailty as a sense of vulnerability, with a lack of physiological reserve. This vulnerability can lead to a sudden change in health status after only a minor illness with a substantial impact on the functionality and length of recovery, which may not be to the pre-existing baseline.
There are multiple models that can be used to help identify frailty in patients – for example, the Fried frailty phenotype criteria, which define frailty by the presence of three or more from the following clinical features:
- weakness
- slow walking speed
- unintentional weight loss
- exhaustion
- low physical activity.
A problem that can be encountered when considering the phenotype is the assumption that a thin patient must be frail. Looking at the association between body mass index (BMI) and frailty, this follows a U-shaped curve with patients with a high BMI also being at risk. Furthermore, the concept of sarcopenic obesity is becoming increasingly recognised, where muscles are filled with fat stranding.
A simple tool that all health professionals can use to identify frailty is that of gait speed; a cut-off of walking <0.8 m/s is highly likely to trigger for frailty. This can be measured easily in a clinical setting by timing how long it takes your patient to walk four metres. This test has been used in multiple settings including in those with hypertension, heart failure and haemodialysis, and is a good predictor of poor outcome, irrespective of the underlying health condition. When we consider the impact of frailty and multi-morbidity, this is further highlighted in data published from the Mayo Clinic, which looked at outcome after primary coronary intervention (PCI).8 This has shown a shift in the cause of death in patients over 80 years post-PCI from cardiac to non-cardiac causes.
The evidence base for managing frail patients is limited and requires clinical judgment. Frail patients tend to benefit from interventions that will give symptomatic relief. These are often those that take a less invasive approach, such as closer monitoring and optimising the patient pre- and post-procedure. We should focus on three key interventions for frailty:
- exercise
- dietary optimisation
- managing polypharmacy.
When mobile patients are admitted to hospital, 75% will remain in bed. The greatest impact of this is seen in the frail population. Moving forward, in addition to dealing with frailty, we must also look at how resilience and robustness can be maintained to avoid it. Dr Beckett’s hope for the future is that older people will be living with frailty as a long-term health condition successfully managed by timely intervention, self-management and personalised care.
Understanding the pathogenesis of diabetic heart disease
Professor Gerry McCann (University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Unit) presented the British Heart Foundation Lecture on advances in our understanding of diabetic cardiomyopathy. Heart failure is emerging as the most common and deadly vascular complications of type 2 diabetes. It has been well recognised since the Framingham heart study that type 2 diabetes is an independent risk factor for heart failure.9 The development of heart failure is independent of age, gender, dyslipidaemia, hypertension, coronary artery disease and end-stage renal disease. Furthermore, there is very little evidence that improving glycaemic control improves your risk. With optimal risk factor modification, patients with diabetes still have a 2.5-fold increased risk of developing heart failure.
Professor McCann provides a strong case for us to change our mindset and consider all our patients with type 2 diabetes to be at risk of heart failure, with certain groups at highest risk including the younger population and those of South Asian ethnicity.
There are several potential mechanisms of cell injury leading to diabetic cardiomyopathy, with metabolic abnormalities leading to both structural and functional myocardial changes. It has been observed in the current UK Biobank study10 and replicated in Professor McCann’s smaller cohort that patients with diabetes, despite often having a higher BMI, have smaller hearts with more concentric remodelling. A raised BMI is often associated with left atrial enlargement but this appears not to occur in patients with diabetes. This could be related to advanced glycation end products making the atria stiffer.
Professor McCann presented results from a pilot study looking at 20 young patients with type 2 diabetes with 10 lean control patients and 10 obese control patients. Patients with obesity and diabetes had more concentric remodelling as seen in other trials. Furthermore, the ability of the heart to relax during diastole was markedly impaired and there was a trend towards a reduction in systolic strain, which is an early measure of systolic impairment before the ejection fraction falls. Aortic stiffness was noted to predict concentric remodelling, independent of the patient’s BP. This may become a potential target for intervention in the future, to reverse aortic stiffness before it becomes irreversible.
We now have a greater understanding of the characteristics in asymptomatic diabetic heart disease with concentric left ventricular remodelling, diastolic dysfunction, and aortic stiffness being key. Other features that have also been identified, primarily using imaging techniques, are increased myocardial triglycerides, impaired energetics and reduced blood flow. The PREDICT study is currently ongoing with recruitment from primary care of patients with type 2 diabetes with no clinical evidence of cardiac disease. This study may assist us in understanding what reversible factors are involved and enable development of a clinical risk score to screen patients. Another important question raised is whether remission of type 2 diabetes can also lead to regression of the cardiac abnormalities seen, which is being studied in the DIASTOLIC study.
An update of pregnancy in cardiorenal disease
Dr Kate Bramham (King’s College London) presented an update on pregnancy in cardiorenal disease. One of the main issues we are currently facing is the older age of pregnant women. In developed countries, the number of first-time births to women over the age of 30 has tripled in the last two decades. Alongside this, the maternity care demographic has changed with chronic hypertension being the most common condition encountered in pregnancy. Multi-morbidity in pregnancy is increasing in prevalence and we are also seeing more complex patients, including those with congenital heart disease and advanced CKD. There has been a recent trend of increasing maternal death rates in the UK, with cardiac disease remaining the most common cause.
Pre-pregnancy counselling and planning is recommended for all women with a chronic health condition including hypertension, CVD or renal disease. This is not yet a commissioned or widespread practice in the UK. Aspirin is recommended for all women with hypertension, CKD or CVD. The dose of this should be either 75 mg or 150 mg once daily, with no clear consensus currently on the optimal dose. It is important to discuss this with patients clearly, as although common in UK clinical practice, it remains an unlicensed indication.
The NICE Hypertension in Pregnancy guidelines have recently been updated and advise stopping ACE inhibitors and angiotensin receptor blockers (ARBs) when patients become pregnant.11 There had previously been concern raised regarding the safety of ACE inhibitors in the first trimester. A large population study has now demonstrated there was no increased risk of congenital heart defects in infants exposed to ACE inhibitor in utero.12 Interestingly, there was an increased risk with other antihypertensives. It seems to be the factors that lead to a woman needing an ACE inhibitor or other antihypertensive agent, which increase the foetal risks rather than the drugs themselves. For patients with proteinuria, Dr Bramham recommends optimising the dose of ACE inhibition pre-pregnancy in order to control both the proteinuria and BP. Drugs should be stopped after conception, as uncontrolled hypertension and proteinuria are the biggest factors affecting the pregnancy outcome.
Acknowledgements
The Cardiorenal Forum would like to thank the following companies for their generous support of the 2019 meeting: A Menarini Farmaceutica Internazionale SRL, AstraZeneca, Bayer, MSD, Napp, Novo Nordisk, Pharmacosmos, Sanofi, Vifor Pharma and Vifor Fresenius Medical Care Renal Pharma.
It also thanks the British Society for Heart Failure, The Renal Association and The Irish Nephrology Society for their endorsement of the 2019 meeting.
Save the dates
Join up for a Cardiorenal Forum webinar ‘Intravenous iron in heart failure’, to be held on Thursday 27th February 2020. The webinar is free for healthcare professionals. Further information can be obtained at: https://cardiorenalforum.com/Webinar_programme_2020.php
Next year’s 15th Annual Scientific Meeting of the Cardiorenal Forum will take place on Friday 9th October 2020 in London. Further information can be obtained from www.cardiorenalforum.com as it becomes available.
Helena Edwards
Renal Registrar
Portsmouth Hospitals NHS Trust, Southsea
[email protected]
References
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