The American Heart Association (AHA) released recommendations for managing potential statin drug-drug interactions with other therapies in patients with cardiovascular disease (CVD). This scientific statement was published in Circulation.

According to the AHA writing committee, the 2 most common pharmacokinetic drug-drug interactions that involve statins are those mediated by the cytochrome P-450 (CYP450) enzyme system and permeability glycoprotein. These drug-drug interactions could alter low-density lipoprotein cholesterol reductions or increase the risk of muscle-related toxicity.

Drug-drug interactions were analyzed based on data from clinical trials, case reports, prescribing information, and pharmacokinetic studies, and included the following:


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  • Nonstatin lipid-lowering agents (eg, fibric acid derivatives,  gemfibrozil, fenofibrate/fenofibric acid)
  • Calcium-channel blockers (eg, diltiazem, verapamil, amlodipine)
  • Antiarrhythmic agents (eg, amiodarone, dronedarone, digoxin)
  • Antianginal agents (eg, ranolazine)
  • Anticoagulants (eg, warfarin)
  • Antiplatelet agents (eg, ticagrelor)
  • Vasopressin receptor antagonists (eg, conivaptan)
  • Immunosuppressive agents (eg, cyclosporine and tacrolimus)
  • Heart failure medications (eg, ivabradine and sacubitril/valsartan)

For the first set of drug-drug interactions, the authors found that the combination of gemfibrozil with lovastatin, prevastatin, and simvastatin was “potentially harmful and should be avoided.” However, the combination of gemfibrozil with atorvastatin, pitvastatin, and rosuvastatin may be considered if necessary, as the interaction produced only a minor increase in statin concentrations. Additionally, since fluvastatin does not interact with gemfibrozil, it can be used without dose limitations. The combination of fenofibrate/fenofibric acid with any statin is also reasonable when indicated.

Amlodipine presents little clinical concern when used in combination with lovastatin, simvastatin, or other statins. Diltiazem and atorvastatin combination therapy is also reasonable when necessary, as well as verapamil with lovastatin or simvastatin. Interactions were only of moderate intensity.

The combination of antiarrhythmic agents amiodarone and dronedarone with most statins is reasonable, as is digoxin coadministration with any statin when clinically indicated.  Combining ranolazine with rosuvastatin, atorvastatin, pitavastatin, fluvastatin, and prevastatin is acceptable, and combination therapy with simvastatin or lovastatin may also be considered.

When warfarin is either coadministered or used in combination therapy with statins, there is no clinically significant increase in statin exposure. However, the international normalized ratio (INR) should be monitored closely after initiation or dose change.

Coadministration of ticagrelor and atorvastatin produces only a minor increase in statin exposure; however, if ticagrelor is used in combination with simvastatin and lovastatin, doses should not exceed 40 mg/d. Pravastatin, fluvastatin, pitavastatin, and rosuvastatin do not require dosing restrictions.

The vasopressin receptor antagonist conivaptan should be avoided in combination with lovastatin or simvastatin. However, atorvastatin, pravastatin, fluvastatin, rosuvastatin, or pitavastatin may be considered in combination with conivaptan when clinically indicated. Likewise, cyclosporine, everolimus, or sirolimus in combination with lovastatin, simvastatin, and pitavastatin may be harmful and should be avoided. Combining tacrolimus with lovastatin, simvastatin, or pitavastatin also presents concern. However, combining cyclosporine, everolimus, or sirolimus with rosuvastatin, atorvastatin, fluvastatin, or pravastatin may be considered.

In patients with heart failure, coadministration of ivabradine with statins is reasonable when indicated. Sacubitril/valsartan may also be considered with statins at lower doses (eg, atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) due to potential interactions mediated by OATP (organic anion-transporting polyprotein) and OAT.

“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 [drug-drug interactions] can be identified early, evaluated, and managed appropriately by implementing dose adjustments, changing to a safer statin medication, or discontinuing when needed,” the authors wrote.

They concluded that clinicians should be mindful of adverse effects, dose limits, and monitoring parameters associated with these drug-drug interactions to minimize toxicity in patients.

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Disclosures: Dr Lanfear reports receiving research funding from Novartis, Janssen, and Amgen. Dr Morris reports serving as a consultant for AstraZeneca, Amgen, and Sanofi/Regeneron. Dr Kulik reports receiving research funding from Pfizer and AstraZeneca. Dr Schwartz reports receiving research funding from Sanofi, Resverlogix, The Medicines Company, Roche, and Cerenis.

Reference

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 of Functional Genomics and Translational Biology. 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;134. doi:10.11161/CIRC.00000000000000456 [Epub ahead of print].