Are ACE inhibitors not as ace as we thought?

ACE inhibitors and related drugs known as angiotensin receptor antagonists (ARAs or “sartans”) are the second most frequently prescribed medicines in UK clinical practice, only just lagging behind statins in the popularity stakes, and their use is steadily increasing. They are widely considered as cardiovascular “wonder drugs”, and are used to treat common conditions such as high blood pressure, heart disease and kidney problems, especially in people with diabetes. This use is supported by a substantial evidence base, from numerous large international clinical trials with inspiring names such as HOPE and PROGRESS.

However, many clinicians, particularly those based in acute medical receiving or nephrology units, will be aware of anecdotal evidence suggesting these medicines may contribute to sudden deteriorations in kidney function, otherwise known as acute kidney injury. This condition places a substantial burden on health services and patients alike, with significant costs associated with hospitalisation and utilisation of critical care services, potential long-term adverse effects on kidney function, and considerable mortality, the latter as high as 25 per cent according to some estimates. Furthermore, in contrast to other common acute illnesses such as myocardial infarction, the incidence of acute kidney injury, is steadily rising. However, to date, the size of any association between the use of ACE inhibitors and ARAs, and hospital admission for acute kidney injury, is unknown.

We examined this issue by conducting a GP practice-level analysis comparing the admission rates for acute kidney injury in all English hospitals (from Hospital Episode Statistics data) with the prescribing rates for ACE inhibitors and ARAs (using national ePACT data). The work is described in the journal PLOS One. From 2007/8 to 2010/11, there was a 52 per cent increase in acute kidney injury admissions. During this same period of time, there was an increase in the number of prescriptions for ACE inhibitors and ARAs issued by GP surgeries by 16 per cent.

A clear association was observed between the increase in prescriptions and the increase in hospital admissions. Indeed, based on our models, we estimate that 1636 hospital admissions with acute kidney injury could potentially have been avoided if the prescribing rate had remained at the 2007/8 levels – that’s around one in seven of the additional cases.

So does this mean ACE inhibitors (and ARAs) are not all they are cracked up to be? Well, there is no doubting the wealth of evidence to support their use, and our study is not able to tell how many additional patients received benefit as a result of increased use of these medicines. In addition, the sudden deterioration in renal function is often triggered by an acute illness, such as diarrhoea and vomiting, and it’s not possible from this work to say whether or not these drugs were the direct cause of acute kidney injury. Nevertheless, the use of these drugs in clinical practice may not reflect their use in carefully conducted clinical trials. For example, in the real world, patients may be older, or have other co-morbidities, or take additional medications. Exclusion criteria, rigidly adhered to in randomised trials, are generally forgotten about when medicines enter routine practice. So the risk-benefit ratio of these drugs may not necessarily be as favourable as previously thought, and may be an important contributing factor to the spiralling cases of acute kidney injury being observed at the front door of many hospitals.

Further work to examine the patient-level association is now being undertaken as part of a Wellcome fellowship by our co-author Laurie Tomlinson, and will hopefully further improve our understanding of the competing risks and benefits of these specific medicines, as well as the role of factors that may trigger acute kidney injury in the first place. It also emphasises the need to ensure these drugs are used appropriately, in line with current clinical guidance. In particular, clinicians and patients alike need to be aware of recommendations by organisations such as the National Institute for Health and Care Excellence (NICE) advocating caution when those prescribed these medicines develop concurrent illnesses, as biochemical monitoring may be indicated and temporary cessation of treatment may sometimes be appropriate.

More generally, this study highlights to me the importance of improving our understanding of the risks and benefits of drugs more generally in the actual clinical environment, away from the faux setting of clinical trials.

Read the paper at


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