ACE inhibitor use may be linked to kidney failure

"Blood pressure drugs…could raise the risk of potentially deadly kidney problems," the Daily Mail warns. Researchers have looked at whether there is an association between the prescribing patterns for these drugs and hospital admissions for kidney problems.

They were specifically interested in the relationship between two widely used antihypertensive drugs (ACE inhibitors and angiotensin-II receptor antagonists) and hospital admissions for kidney failure.

Kidney failure (now known as acute kidney injury, or AKI) is when the kidneys suddenly lose the ability to filter waste products from the blood and balance fluids in the body. It leads to a range of serious and potentially fatal symptoms.

The study found that in the four years up to 2010, English hospitals saw a 52% increase in admissions for AKI. During the same period there was a 16% increase in prescriptions for ACE inhibitors and related drugs. They estimate that up to 15% of these increased admissions – one in seven cases – could be as a result of increased prescriptions for these drugs.

The study does not show that the admissions were because of the number of these prescriptions, and only shows an association. The study also contained no information about individual patients and why they were taking the drugs. Some of the conditions these drugs are prescribed for are themselves a risk factor for AKI.

Patients prescribed these drugs should not stop taking them unless advised to do so by their doctor. Left untreated, high blood pressure could trigger a heart attack or stroke.

Where did the story come from?

The study was carried out by researchers from the University of Cambridge, the Institute of Public Health in Cambridge, Cambridge University Hospitals NHS Foundation Trust, and the North Bristol NHS Trust.

It was part-funded by the Cambridge Biomedical Research Centre and the British Heart Foundation, and was published in the peer-reviewed journal PLoS ONE. PloS ONE is an open access journal, so the study is free to read online or download.

The study was covered reasonably well by the Daily Mail and The Daily Telegraph. While the headlines were a little alarmist, the actual reporting was appropriate and responsible.

The Mail included comments from independent experts and advice that patients should not stop taking the drugs, and The Daily Telegraph reported that the link was not proven.

What kind of research was this?

This was an observational ecological study looking at whether hospital admission rates for acute kidney injury (AKI) are associated with an increase in the prescribing rates of two drugs called ACE inhibitors (ACE-Is) and angiotensin-II receptor antagonists (ARAs).

This type of study looks for associations between the occurrence of disease and exposure to known or suspected causes. But the unit of observation was at the level of a GP practice rather than the individual patient. This lack of individual detail could have failed to account for a number of other factors.

The authors point out that AKI is associated with the risk of death and leads to prolonged hospital stays and a possible decline in long-term kidney function. Although concerns have been raised in the past about links between AKI and the use of ACE inhibitors and ARAs in some patients, the size of the problem is unknown.

These are the second most commonly prescribed drugs by GPs in England, accounting for 6% of all prescriptions, and are used for a number of conditions, including high blood pressure, chronic kidney disease and heart failure.

What did the research involve?

The researchers compared admission rates to English hospitals for AKI with prescribing rates for ACE inhibitors and ARAs during the period 2007-8 to 2010-11.

The researchers used an NHS database to obtain the number of ACE inhibitor and ARA prescriptions from all general practices in England during the study period. They controlled for differences in age and sex demographics of general practice populations in their prescribing rates.

They obtained the number of patients admitted to hospital with AKI using a national database. For the main analysis, the international code classifying AKI (N17 in the ICD-10 system) needed to be present as the primary diagnosis for any episode within seven days of the date of admission.

In their statistical analysis, the researchers matched the NHS prescribing data to the number of hospital admissions for AKI at the general practice level. The data combined four one-year periods starting on April 1 2007. They used a recognised statistical method to model the number of admissions for AKI occurring in each practice for each of the four years from 2007.

To ensure the robustness of their findings, the researchers performed a number of sensitivity analyses. For example, they examined whether their results could be affected by improvements in the thoroughness of clinical coding for AKI over time, and whether including admissions for unspecified kidney failure, which is coded differently, affected their findings.

What were the basic results?

The researchers found that from 2007-8 to 2010-11 in England:

• AKI admission rates increased from 0.38 to 0.57 per 1,000 patients (51.6% increase)
• annual ACE-I/ARA prescribing rates increased by 0.032 from 0.202 per 1,000 patients to 0.234 (15.8% increase)
• there was strong evidence that increases in practice-level prescribing of ACE-I/ARA over the study period were associated with an increase in AKI admission rates
• the increase in prescribing seen in a typical practice corresponded to an increase in admissions of approximately 5.1%
• they predict that 1,636 (95% confidence interval [CI] 1,540-1,780) AKI admissions would have been avoided if prescribing rates for ACE-Is and ARAs had remained at the 2007-8 level – this is equivalent to 14.8% of the total increase in AKI admissions

How did the researchers interpret the results?

The researchers say that up to 15% of the increase in AKI admissions in England over a four-year time period is potentially attributable to the increased prescribing of ACE inhibitors and ARAs.

They argue that better understanding of individual risk factors for AKI associated with ACE inhibitors and ARAs is needed to reduce the potential harms associated with these important and commonly prescribed medications.

Their analysis, they say, "throws uncertainty on the balance of benefits and risks associated with use of these drugs".

Conclusion

ACE inhibitors and ARAs are recognised as a potential risk factor for AKI in some patients. This particular study has tried to estimate the possible size of the problem, but its findings should be viewed with some caution. As the authors point out:

• some of the conditions these drugs are prescribed for are themselves a risk factor for AKI
• changes in hospital coding and better recognition of AKI could explain the rise in admissions
• an ageing population leads to both increased prescribing of these drugs and an increased risk for AKI
• increased use of these drugs may be a marker for increased use of other drugs known to cause kidney injury, such as diuretics and non-steroidal anti-inflammatories
• findings are limited by the lack of information about individual patients

Further research is required on this important topic undertaken at the level of individual patients rather than GP practices.

It is important that you do not stop taking any prescribed medication for high blood pressure, chronic kidney disease or heart failure without first consulting your GP. Doing so could lead to a sudden worsening of your symptoms.