AHA Statement on Drug-Drug Interactions With Statins

Authors:
Wiggins BS, Saseen JJ, Page RL, et al., on behalf of the American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology; Council on Hypertension; Council on Quality of Care and Outcomes Research; and Council on Functional Genomics and Translational Biology.
Citation:
Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation 2016;Oct17:[Epub ahead of print].

The following are key points to remember from the American Heart Association Scientific Statement on Recommendations for Management of Clinically Significant Drug-Drug Interactions (DDIs) With Statins and Select Agents Used in Patients With Cardiovascular Disease (CVD):

  1. A DDI is a pharmacokinetic or pharmacological influence of one medication on another that differs from the known or anticipated effects of each agent alone.
  2. Pharmacokinetic DDIs result in altered absorption, distribution, metabolism, or excretion of a medication. A pharmacodynamic DDI occurs when one medication modifies the pharmacological effect of another in an additive, a synergistic, or an antagonistic fashion.
  3. Given the important role of statins in patients with atherosclerotic CVD (ASCVD) and those at high ASCVD risk, combination therapy with statins and other CV medications is highly likely, and potentially significant DDIs must be considered in patients treated with statins.
  4. When statin-fibrate combination therapy is indicated, fenofibrate or fenofibric acid is preferred because of a reduced incidence of DDIs compared with the gemfibrozil-statin combination. There are circumstances in which gemfibrozil may be the only available fibrate, cost may be a consideration, or fenofibrate may not be tolerated. Under any circumstance, the use of gemfibrozil should be avoided in combination with lovastatin, pravastatin, and simvastatin.
  5. Pharmacokinetic data suggest a minor increase in statin exposure with coadministration of amlodipine and lovastatin or simvastatin, and combination therapy may be considered. There is no evidence of significant interaction when amlodipine is coadministered with atorvastatin, pitavastatin, rosuvastatin, fluvastatin, and pravastatin, and combination therapy may be considered.
  6. Doses of simvastatin >10 mg/d and doses of lovastatin >20 mg/d when used with diltiazem or verapamil are not recommended. However, it should be noted that verapamil labeling recommends a higher dose limit of lovastatin of 40 mg/d when coadministered with verapamil. Caution should be exercised with statin-calcium channel blocker combination therapy in patients of various ethnic backgrounds, particularly those of Asian descent.
  7. Combination therapy with amiodarone and rosuvastatin, atorvastatin, pitavastatin, fluvastatin, or pravastatin is reasonable. When used in combination with amiodarone, the dose of lovastatin should not exceed 40 mg/d and the dose of simvastatin should not exceed 20 mg/d.
  8. Atorvastatin is the only statin that appears to be associated with a potential DDI when used in combination with digoxin. On the basis of the available data, patients on higher doses of atorvastatin may be at increased risk of digoxin toxicity, and closer monitoring for digoxin toxicity is recommended.
  9. Coadministration of ranolazine with rosuvastatin, atorvastatin, pitavastatin, fluvastatin, and pravastatin may be considered if clinically indicated. The dose of simvastatin should be limited to 20 mg daily when coprescribed with ranolazine, and doses above this limit are not recommended.
  10. Coadministration of ticagrelor and atorvastatin results in only a minor increase in statin systemic exposure and is reasonable for appropriate patients. When prescribed in combination with ticagrelor, the dose of simvastatin and lovastatin should not exceed 40 mg/d. The combination of conivaptan and lovastatin or simvastatin is potentially harmful and should be avoided.
  11. Combination therapy of cyclosporine, everolimus, or sirolimus with lovastatin, simvastatin, and pitavastatin is potentially harmful and should be avoided. The coadministration of tacrolimus and lovastatin, simvastatin, and pitavastatin is potentially harmful and should be avoided. The dose of atorvastatin >10 mg/d when coadministered with cyclosporine, tacrolimus, everolimus, or sirolimus is not recommended without close monitoring of creatinine kinase and signs or symptoms of muscle-related toxicity.
  12. The use of lovastatin, pitavastatin, and simvastatin should be avoided in patients receiving cyclosporine, tacrolimus, everolimus, or sirolimus as consistent with product labeling. Combination therapy of cyclosporine, everolimus, or sirolimus with lovastatin, simvastatin, and pitavastatin is potentially harmful and should be avoided.
  13. Coadministration of colchicine and rosuvastatin, fluvastatin, lovastatin, pitavastatin, and pravastatin is reasonable when clinically indicated. Dose reductions may be considered for atorvastatin, simvastatin, and lovastatin, given the potential for interactions mediated by both CYP3A4 and permeability glycoprotein (P-gp) pathways.
  14. Lower doses may be considered for atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin when administered with sacubitril/valsartan, given the potential for interactions mediated by organic anion-transporting polyprotein (OATP) and OAT.
  15. A review of all medications that statin-treated patients are taking should be done at each clinical encounter and during transitions of care within a health system so that DDIs can be identified early, evaluated, and managed appropriately by implementing doses adjustments, changing to a safer statin medication, or discontinuing when needed. A thorough understanding of the pharmacokinetics of statins and other select medications that are often prescribed in combination is paramount in ensuring patient safety.

Clinical Topics: Diabetes and Cardiometabolic Disease, Clinical Topic Collection: Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Amiodarone, Amlodipine, Atherosclerosis, Calcium Channel Blockers, Colchicine, Creatinine, Cyclosporine, Cytochrome P-450 CYP3A, Digoxin, Diltiazem, Drug Interactions, Dyslipidemias, Fenofibrate, Gemfibrozil, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lovastatin, Metabolic Syndrome X, P-Glycoprotein, Patient Safety, Polyproteins, Pravastatin, Primary Prevention, Pravastatin, Simvastatin, Verapamil


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