The area of lipid testing warrants a lot of attention nowadays, not least because of the inherent cost and time taken for same. 

A recent article in the British Journal of General Practice¹ stated that there has been a 10-fold increase in lipid testing over the past 20 years. Much of this may be patient-driven. 

Alarmingly, the article states that the proportion of lipid testing for monitoring has risen from 28-61% in the past 10 years. This puts an increased strain on laboratory services and GPs need solid guidelines to know when to retest in terms of monitoring. Hepatotoxicity is a well-known side-effect of statin medication and, therefore, liver function testing (LFT) is often carried out in conjunction with lipid profile monitoring.

Hepatotoxicity is rare, dose-dependent and usually reversible when it occurs as a side-effect of statin medication. Liver failure due to statin use occurs in 1/1,000,000 person years of treatment.²

The objective of the research is to set out guidelines in relation to LFT monitoring within the cohort of patients who are prescribed statin medication.

Study setting

The practice setting is a busy rural practice with six doctors (three full-time, two part-time and one GP registrar) and three practice nurses. All clinical staff performed phlebotomy for monitoring and there was no protocol in place in relation to monitoring.

Aims

• To identify clear guidelines in relation to liver function testing after a patient is commenced on a statin
• To raise awareness among the doctors and nurses of the practice regarding the new guidelines
• To implement the guidelines in our practice.

In the US the Food and Drug Administration (FDA) has recently announced that routine LFT monitoring for patients on statin medication costs > $3 billion/year. 

The FDA points out that statins can increase liver enzymes but the rise is usually transient and liver failure is extremely rare in patients taking statins, therefore, the FDA no longer recommends routine monitoring. The FDA recommends LFTs before commencing statins and then again if the patient is symptomatic.³

The NICE clinical guidelines (published May 2008) state that LFT should be performed at the outset of commencing an agent, again after 12 weeks and again after 12 months and also after any dose change. 

We decided to use the NICE guidelines as the standard which the GPs should aim to achieve in our practice. NICE confirms that if the alanine transaminase (ALT) and aspartate transaminase (AST) are < 3 times the upper limit of normal, the statin can be continued. If LFTs are normal at 12 months, they are not required to be repeated for monitoring purposes.

An asymptomatic increase in aminotransferase levels, generally less than three times the upper limit of normal range, is relatively common in patients receiving statins. It is dose-dependent and often regresses even though treatment continues. A significant increase in aminotransferase levels is very rare in patients receiving statins.⁴

The best available evidence supports the use of the NICE guidelines. The acceptable standard for the purpose of my audit was that the patient on statin medication had LFT performed:

• Three months prior to commencing statin or two months after commencing statin
• After 10-16 weeks of statin therapy
• After 10-14 months of statin therapy
• Within eight weeks after dose change.

A search of HEALTHone identified 947 patients were prescribed a statin in the past five years. Patients in the following groups were excluded for the purposes of this audit:

• Patients who had been commenced on statin therapy during a hospital admission or in OPD
• Patients who had been commenced on statin therapy within the past 12 months
• Patients who joined the practice within the past five years who had been commenced on statin therapy at the time of joining the practice
• Patients with hepatic disease (hepatitis, alcoholic liver disease) who were having transaminase levels monitored for reasons other than statin-related hepatotoxicity monitoring.

Once these exclusions were applied, 81 patients were identified.

Comparing performance with criteria:

• 10 met NICE criteria
• 26 had LFTs checked at time of commencing statin
• 47 had continued LFT monitoring > 12 months (normal at 12 months)
• 11 had statin stopped while LFT raised < 3 upper limit normal
• 14 never had LFTs checked after commencing statin.

The standards were not met. Not enough patients had scheduled LFT monitoring at outset, three months and at 12 months. There were too many LFTs carried out after 12 months of statin therapy, even though LFTs were normal at 12 months.

Reasons for standards not being met:

• Lack of awareness of NICE clinical guidelines
• Lack of practice protocol regarding blood tests
• No instant callback or reminder system on computer
• Patients not informed re: schedule of blood tests when commencing statin.

Making improvements

A practice meeting was held to discuss the audit results. It was agreed that changes and the following recommendations were made:

• All patients who are commencing statin medication will be informed of the schedule of blood testing for liver function monitoring at outset
• There will be written information in each clinical room regarding the new protocol
• All new practice staff to familiarise themselves with the new phlebotomy schedule
• No LFT monitoring to be performed if LFTs normal after 12 months of statin therapy unless there was a dose change
• Reminders to be flagged in patients charts on commencing statin medication by doctor prescribing the medication re: blood testing schedule
• The audit cycle will be followed by re-auditing in six months.

Closing the loop: re-auditing

A second cycle of the audit was carried out six months later. Due to time constraints, it was decided to focus on the cohort of patients who had commenced statin medication following the implementation of the new protocol. 

Patients who had newly commenced statin medication in the practice in the six months following the audit were selected (n = 22). Of these 17 patients had LFTs performed at outset (four weeks before or after commencing statin) and 13 patients had LFTs checked at three months (eight to 16 weeks after commencing statin). We were unable to follow up patients for a period beyond this but it is hoped that the audit may be repeated in one year.

Discussion

We have found that many patients have their statin stopped/dose reduced or changed to an alternative statin when LFTs are not raised > 3 times the upper limit of normal. This may cause unnecessary anxiety to the patient in many instances.

One of the main outcomes of this audit was the potential for savings to be made. 

In a busy rural practice, one less blood test means one less appointment, one less patient sitting in the waiting room, one less bottle for labelling, one less form to be filled, one less telephone call to be made with results, less time spent interpreting results, less patient anxiety re: possibly normal/abnormal results.

We contacted Dr Ned Barrett, consultant clinical biochemist at the Mid-Western Regional Hospital in Limerick. He informed us that when performing LFT for monitoring, it is not necessary to analyse the full panel that includes: aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT) and total bilirubin. ALT and AST are the most important markers of hepatotoxicity.

Many patients in this audit had their statin stopped when GGT or bilirubin alone were raised.

• LFT panel = €4.36
• ALT = 96c
• AST = 95c.

The current NICE guidelines apply the ‘fire and forget’ strategy when a patient is newly commenced on statin medication for primary prevention. Patients are commenced on generic simvastatin 40mg and their lipid profile is never re-checked. For secondary prevention or for audit purposes, lipid levels are repeated after about 12 weeks’ treatment with a statin.

They are benefitting from the non cholesterol-related effects such as restoring/improving endothelial function and anti-inflammatory properties.

The total cholesterol figure is not as important as it once may have been. LFTs are rechecked in accordance to 2008 guidelines. This provides scope for further savings. This is an interesting point for future monitoring.  

References

1. Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Lipid modification, NICE Clinical Guidelines, 2008
2. Law M, Rudnicka AR. Statin safety: a systemic review. Am J Cardiol 2006; 97 (8A): 52C-60C
3. Prescriber’s letter 2012; 19 (5)
4. Cadranel JF, Seddik M, Loric S, Jeanne S. Statins hepatoxicity and monitoring. Presse Med 2009; 38(5): 717-725