Acute kidney injury – Any three of metformin, NSAID, ACEI/ ARB, or diuretics

This hot topic considers the impact of the triple whammy where any three of metformin, an ACEI (angiotensin-converting enzyme inhibitor), ARB (angiotensin II receptor blocker), NSAID (non-steroidal anti-inflammatory drug) and a diuretic are prescribed.

The purpose of this hot topic is to ensure that if they are prescribed in combination they are prescribed safely and appropriately.²⁹²

ACEI/ARB may be essential for some individuals, particularly those with severe left ventricular systolic dysfunction.

ACEI/ARB and diuretics are commonly prescribed together, for example the management of heart failure or secondary prevention of cardiovascular disease (CVD). ACEI/ARB, with or without diuretics, are associated with an increased risk of acute kidney injury (AKI); the addition of NSAID significantly increases this risk; combining ACEI and ARB also significantly increases risk.

Due to the increased risk of lactic acidosis metformin should be prescribed with caution to people, with reduced renal function, if taking concomitant nephrotoxic drugs, or older adults.

Metformin

The blood glucose-lowering effects of metformin may be enhanced by:

• ACEI

The blood glucose-lowering effects of metformin may be antagonised by:

• diuretics (thiazide and related, and loop)

NSAIDs

Joint pain is the most frequently cited reason for prescribing NSAIDs to individuals taking ACEI/ARBs with diuretics. Before prescribing an NSAID consider if an alternative option would be more appropriate. For example,

• exercise and physical activity can contribute to a reduced need for medicines in osteoarthritis
• in osteoarthritis the first-line medicines are paracetamol and/or topical analgesia, e.g. diclofenac and ibuprofen gels/sprays or capsaicin cream
• intra-articular injections of corticosteroids can be a useful alternative to oral NSAID for osteoarthritic flares in some individuals
• a weak opioid, such as codeine, may be required for some, if pain is ongoing or severe, for short-term use only and with regular review
• for those with gout, corticosteroids may be a safer option than NSAIDs for the treatment of acute flares when starting treatment with allopurinol, if colchicine is not tolerated.

Where possible, NSAIDs should be stopped. If an NSAID is essential, then the shortest possible course should be used, and renal function reassessed regularly.

ACEI/ARBs and other renin-angiotensin modifying agents can exacerbate AKI by reducing the kidney’s ability to adapt to changes in perfusion pressure.²⁹⁴

Diuretics or other antihypertensives increase the risk of hypovolaemia/hypotension/ hyperkalaemia.²⁹⁵

Risk factors for triple whammy-induced AKI are similar to other forms of kidney injury and include:²⁹²

• chronic kidney disease (CKD) eGFR less than 60 ml/min/1.73m²
• older age, e.g. over 75 years
• volume depletion due to, e.g. vomiting, diarrhoea, sepsis or low fluid intake
• diabetes
• heart failure
• liver disease

The combination of any three or more of metformin, NSAIDs, ACEI/ARBs or diuretic is a very high-risk combination - stop if you can, starting with NSAIDs.

All these medicines are associated with risk of renal impairment. Concurrent use of three or more of these drugs is likely to create a significant cumulative risk of AKI.

Also consider other medications that the individual may be taking that are nephrotoxic, e.g. aminoglycoside antibiotics, and iodinated contrast agents.²⁹⁶

NSAIDs do not need to be stopped gradually, but alternative analgesia may need to be in place to support the individual. Discuss Medication Sick Day Guidance with them and ensure that people taking the triple whammy combination, or the double whammy combination, know to avoid over the counter (OTC) products that contain NSAIDs, and use alternative analgesics.

Supporting people who do not or cannot reduce/stop

There are no guidelines for monitoring patients taking metformin, ACEI/ARB, a diuretic and an NSAID. A pragmatic approach is to take a baseline measurement of the persons:

• body weight
• blood pressure
• serum creatinine and electrolytes
• HbA1c

A baseline measurement of serum creatinine is essential as it may be required later to diagnose AKI. Serum potassium may increase with the use of ACEI/ARB or NSAIDs, particularly as renal function declines, or decreases with volume depletion.

A follow-up assessment, with repeat weight, blood pressure, serum creatinine and electrolytes, within the first month of treatment may also be beneficial, due to the increased risk of AKI during this period. More frequent monitoring is required if they become acutely unwell.

Discuss Medication Sick Day Guidance and ensure that those taking the triple whammy combination, or the double whammy combination, know to avoid OTC products that contain NSAIDs using alternative analgesics and seek advice.

Specific areas/situations where medication may need to be introduced or increased

Medication does not need to be introduced, but need to ensure that there is avoidance of the prescribing cascade where additional medication needs to be added in to counteract the effects of the combinations below:

• ACEI/ARB, a diuretic and an NSAID: antihypertensives and diuretics may be less effective if they are concurrently prescribed with an NSAID²⁹⁷
• when NSAIDs are taken with an ACEI/ARB, the blood pressure lowering effect of the ACEI/ARB is decreased
• when NSAIDs are taken with a diuretic, the effect of the diuretic is reduced, and any heart failure may be exacerbated
• there is an increased risk of cardiovascular events associated with all NSAIDs; a risk that is higher in older adults due to their increased baseline risk of a cardiovascular event.

Polypharmacy: Manage Medicines website and app

Does the person understand the outcomes of the review, including risk and benefits?

• By stopping the NSAID, the risk of AKI, and the additional negative effects of the interaction with ACEI/ARB and/or diuretic are reduced.

Is therapy tailored to the individual?

• Maintain a good fluid intake to avoid volume depletion, particularly if feeling unwell or in hot weather
• Discuss Medication Sick Day Guidance. If the individual becomes acutely unwell whilst taking the triple whammy combination, e.g. with vomiting or diarrhoea, advise them to:
  • Stop taking the NSAID and use an alternative analgesic for pain relief or fever if required, e.g. paracetamol

Agree the plan

• Ensure that the individual understands the importance of taking alternative analgesia to NSAIDs
• Avoid inadvertently taking additional NSAIDs. Educate about the different types (oral and topical) and brand names of NSAIDs that are available, e.g. ensure that they know that Nurofen® and ibuprofen are the same medicine, and that diclofenac and naproxen are also NSAIDs

• self-management/support tools
• decision aids

Medication Sick Day Guidance

National Therapeutic Indicators (NTIs) use prescription data in specific areas to provide a measure of prescribing activity for comparison across NHS Boards, Health and Social Care Partnerships (HSCPs), GP clusters and GP practices.

NTIs are available to view online.

NTIs benchmark prescribing across set parameters and are presented in a variety of ways. Examining variation over time can indicate where improvements in prescribing can be made. The indicator detail provides further information and suggested actions.

Indicators for this hot topic include:

• Number of people aged 65 years and over co-prescribed an NSAID and ACE inhibitor/angiotensin receptor blocker and diuretic, as a percentage of all people aged 65 years and over prescribed an ACE inhibitor/angiotensin receptor blocker and diuretic. See the chart below.
• Number of people co-prescribed an NSAID and ACE inhibitor/angiotensin receptor blocker and metformin, as a percentage of all people prescribed an ACE inhibitor/angiotensin receptor blocker and metformin

Number of people co-prescribed an NSAID and ACE inhibitor/angiotensin receptor blocker and diuretic, as a percentage of all people prescribed an ACE inhibitor/angiotensin receptor blocker and diuretic

(Click on image to enlarge)