AHA Provides Guidance on Drug-Drug Interactions With Statins and CVD Medications

The American Heart Association (AHA) has released a new scientific statement for managing clinically significant drug-drug interactions in patients who are prescribed statins and other agents used in the treatment of cardiovascular disease, including antiarrhythmic agents, calcium-channel blockers, warfarin, and other lipid-lowering medications, such as fibrates.

The AHA also makes recommendations on managing potential drug-drug interactions with statin therapy and ticagrelor (Brilinta, AstraZeneca), a commonly prescribed antiplatelet agent for patients with acute coronary syndromes. With ticagrelor, the AHA recommends limiting the dose of lovastatin and simvastatin to 40 mg daily but states there is no need to limit the dose of atorvastatin, as there is only a minor increase in systemic statin exposure when the drugs are used in combination.  

“In general, statins, like a lot of drugs, when used by themselves are generally well tolerated by most patients,” Barbara Wiggins, PharmD (Medical University of South Carolina, Charleston, SC), chair of the AHA writing committee, told TCTMD. “But when you have to combine medications, there is always the potential for an interaction to occur. And because statins are so widely prescribed, and because many of these patients have underlying cardiovascular issues, there is a lot of potential for interactions with cardiovascular drugs when they are prescribed concomitantly.”

Michael Miller, MD (University of Maryland Medical Center, Baltimore, MD), who was not part of the writing committee, agreed. He noted that while statins are safe drugs by and large, with proven cardiovascular benefits, there are potential drug-drug interactions that may pose an increased risk of side effects with statin treatment. “This may be especially prominent among the elderly taking multiple medications with some degree of renal and/or hepatic impairment,” he told TCTMD.

Stephen Kopecky, MD (Mayo Clinic, Rochester, MN), also said statins are generally safe medications, but he noted that the new AHA statement is a good reminder of the vast number of agents that have the potential to interact with statin therapy. “It’s so hard to know all this on the tip of your fingers,” he said. “These are very commonly used drugs and internists, general practitioners, and nurse practitioners, and so on, just don’t do this all the time. . . . It’s very difficult to keep abreast of all of this.”

Gemfibrozil Not Recommended, Not Always Avoided

In the new statement, which was published online today in Circulation, the AHA provides recommendations for statin-treated patients who might also require additional nonstatin lipid-lowering therapy, such as fibrates. When the coadministration of statins and fibrates is needed, fenofibrate or fenofibric acid is preferred over gemfibrozil, but if gemfibrozil must be used, lovastatin and pravastatin should be avoided. Coadministration with atorvastatin, pitavastatin, and rosuvastatin is “acceptable” if clinically needed, given that these drugs have less of an interaction with gemfibrozil than the other statins.

In the 2013 clinical guidelines for the treatment of cholesterol, the American College of Cardiology and AHA also state that combination therapy with a statin and gemfibrozil should be avoided because of the possibility of muscle-related toxicity.

To TCTMD, Wiggins said that while fenofibrate/fenofibric acid is preferred, the issue is that gemfibrozil is a relatively inexpensive fibrate. “If insurance doesn’t cover it, or say patients can’t tolerate fenofibrate, you have somewhat limited options over what you can prescribe for a patient who might need a fibric acid derivative,” she explained. “Gemfibrozil becomes the default.” Given the significant interaction, the new AHA statement provides guidance for physicians with patients “who fall outside the masses” and who still need additional lipid-lowering. The recommendations are a means to optimize therapy while minimizing the risk of adverse events, said Wiggins.

The experts also provide guidance on the use of the antianginal agent ranolazine (Ranexa, Gilead), noting that the coadministration with rosuvastatin, atorvastatin, pitavastatin, fluvastatin, and pravastatin can be considered if needed but the dose of simvastatin and lovastatin should not exceed 20 mg.

For Wiggins and colleagues, there is evidence of a minor or moderate increase in statin exposure when the calcium-channel blockers amlodipine, diltiazem, and verapamil are used with lovastatin and simvastatin, but not the other statins. With diltiazem and verapamil, low-dose lovastatin (20 mg/day) and simvastatin (10 mg/day) are recommended, but a non-CYP3A4-metabolized statin is preferred (fluvastatin, pitavastatin, pravastatin, or rosuvastatin).

Kopecky, who was not part of the writing committee, told TCTMD that if a patient needs a calcium-channel blocker, such as amlodipine or diltiazem, they will switch them off lovastatin or simvastatin before starting therapy. “Fortunately, atorvastatin is generic now so that helps a lot,” he said. Rosuvastatin will soon be available as a generic statin shortly, which will also help in this setting, said Kopecky.  

Use of warfarin with statin therapy is considered relatively safe, with the AHA noting there is no clinically significant increase in statin exposure with the coadministration of warfarin. They do recommended monitoring the international normalized ratio “more closely” after starting statin therapy or when the dose is altered.

To TCTMD, Miller said medications metabolized through CYP3A4 include not only calcium-channel blockers and warfarin but also some antidepressants (eg, trazodone), HIV antiviral medications, and antifungal agents, such as ketoconazole. “If a patient is receiving any of these medications, I would select a statin less likely to incite a negative drug-drug interaction,” he said. Miller added that he has good success with pitavastatin as it is not metabolized through CYP3A4 and has insignificant metabolism through CYP2C9, making it safe in patients with HIV or renal dysfunction.

Antiarrhythmic Agents and Heart Failure Drugs

The AHA also provide recommendations on the use of antiarrhythmic agents amiodarone, dronedarone, and digoxin, including dialing back the dose of lovastatin and simvastatin when amiodarone is used (maximum 40 and 20 mg/day, respectively, although higher doses can be used if signs of muscle toxicity are monitored closely). For simvastatin and lovastatin, 10 mg/day is the recommended dose with dronedarone.

Wiggins noted that statins are also used in heart-transplant patients—the International Society of Heart and Lung Transplantation recommends statins 1 to 2 weeks after transplantation—so they provided direction on the concomitant use of cyclosporine, everolimus, sirolimus, or tacrolimus. Combination therapy with lovastatin, simvastatin, and pitavastatin is considered “potentially harmful” and should be avoided, but rosuvastatin, atorvastatin, fluvastatin, or pravastatin can be considered, albeit with dose restrictions.

The AHA also provides guidance on the use of the new heart-failure therapy sacubitril/valsartan (Entresto, Novartis), a combination of a neprilysin inhibitor with an angiotensin receptor blocker. There is a potential for drug-drug interactions with atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin so lower doses of the statin should be considered, state the experts.

“Our whole objective is to provide some insight into the specifics of the drug interactions with statins and cardiovascular agents,” Wiggins said. “When you look at prescriber labeling, it will either tell you not to give it, or to limit the dose, that sort of thing. But we also know there are going to be patients who are going to maybe need more.” The new recommendations will help physicians maximize therapy, if needed, while minimizing the risk of adverse events, she said.