At what level of creatine phosphokinase (CPK) elevation should statins (HMG-CoA reductase inhibitors) be discontinued?

From the Guidelines

Statins should be stopped when creatine phosphokinase (CPK) levels exceed 10 times the upper limit of normal (ULN) or if the patient is experiencing severe muscle symptoms, as recommended by the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol 1. For asymptomatic patients with CPK elevations between 3-5 times ULN, close monitoring may be appropriate while continuing the statin at the same or reduced dose. If a patient develops muscle symptoms (myalgia, weakness) with any CPK elevation, statin therapy should be temporarily discontinued and the patient reassessed. After CPK levels normalize, rechallenge with the same statin at a lower dose or an alternative statin (such as rosuvastatin or pravastatin, which are less likely to cause myopathy) may be considered. Some key points to consider when managing statin-associated muscle symptoms include:

• Identifying potential predisposing factors for statin-associated side effects before initiation of treatment 1
• Reassessing and rechallenging to achieve a maximal LDL-C lowering by modified dosing regimen, an alternate statin or in combination with nonstatin therapy 1
• Measuring creatine kinase levels in individuals with severe statin-associated muscle symptoms, objective muscle weakness, and measuring liver transaminases if there are symptoms suggesting hepatotoxicity 1
• Considering RCT proven nonstatin therapy that is likely to provide net clinical benefit in patients at increased ASCVD risk with severe statin-associated muscle symptoms or recurrent statin-associated muscle symptoms despite appropriate statin rechallenge 1

From the FDA Drug Label

Discontinue atorvastatin calcium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected The FDA drug label does not specify the exact level of CPK elevation at which statins should be stopped, only that they should be discontinued if CK levels are markedly elevated.

• The decision to stop statins due to CPK elevation should be made on a case-by-case basis, considering the individual patient's risk factors and clinical presentation.
• It is recommended to discontinue atorvastatin calcium tablets if myopathy is diagnosed or suspected, regardless of the CPK level 2.

From the Research

Statin Therapy and CPK Elevation

• The decision to stop statins due to CPK elevation is complex and depends on various factors, including the level of CPK elevation, symptoms, and individual patient risk factors 3, 4, 5.
• A study published in 2009 found that patients with high CPK levels (>or=250 but <2500 IU/L) can tolerate statins well without developing myalgia-myositis, suggesting that high pretreatment CPK should not be an impediment to starting or continuing statins 3.
• However, another study published in 2018 reported a case of rhabdomyolysis with severe acute kidney injury and normal CPK levels, highlighting that CPK alone may not be a sensitive marker for rhabdomyolysis-induced AKI in some cases 6.
• A 2020 review of statin-associated muscle symptoms noted that myalgia with CK elevation is the most common presentation, and that the mechanism of muscle injury involves statin accumulation, muscle fragility, and genetic susceptibility 4.
• A 2021 study found that PCSK9 inhibitors can be a safe and effective treatment for hyperlipidemia in patients with markedly elevated CPK levels, with 92% of patients demonstrating a reduction in CPK of >50% after treatment initiation 7.
• A 2014 cohort study identified clinical risk factors associated with myotoxicity in statin users, including concomitant prescribing of CYP3A4-interacting drugs, rosuvastatin use, and larger daily doses of other statin types 5.

CPK Elevation Thresholds

• The study published in 2009 suggested that CPK levels >or=250 but <2500 IU/L are not a contraindication to statin therapy 3.
• The 2014 cohort study found that CPK concentrations above four times the upper limit of normal (ULN) were associated with an increased risk of rhabdomyolysis and myotoxicity 5.
• The 2021 study included patients with CPK levels >1,000 U/L, with a median value of 3,687 U/L, and found that PCSK9 inhibitors can be effective in reducing CPK levels in these patients 7.

Clinical Considerations

• The decision to stop statins due to CPK elevation should be individualized, taking into account the patient's overall risk profile, symptoms, and response to treatment 3, 4, 5.
• Regular monitoring of CPK levels and clinical assessment for muscle symptoms are essential for early detection and management of myotoxicity 3, 5.
• Alternative lipid-lowering therapies, such as PCSK9 inhibitors, may be considered for patients with markedly elevated CPK levels or those who experience myotoxicity with statin therapy 7.