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

Abstract

A drug-drug interaction (DDI) is a pharmacokinetic or pharmacological influence of 1 medication on another that differs from the known or anticipated effects of each agent alone.1 A DDI may result in a change in either drug efficacy or drug toxicity for 1 or both of the interacting medications.2 Pharmacokinetic DDIs result in altered absorption, distribution, metabolism, or excretion of a medication. A pharmacodynamic DDI occurs when 1 medication modifies the pharmacological effect of another in an additive, a synergistic, or an antagonistic fashion.It is estimated that ≈2.8% of hospital admissions occur as a direct result of DDIs. 3 However, the actual incidence of hospitalization secondary to clinically significant DDIs is likely to be highly underestimated because medication-related issues are more commonly reported as adverse drug reactions. Complex underlying disease states also may make recognizing a DDI more challenging, further contributing to a lower reported incidence. The overall clinical impact of a DDI can range from mild to life-threatening. Therefore, not all DDIs require a modification in therapy. The variability in the clinical significance of a DDI depends on both medication-specific and patient-specific factors. Medication-specific factors include the individual pharmacokinetic characteristics of each medication implicated in the DDI (eg, binding affinity, half-life [t 1/2 ]), dose of the medications, serum concentrations, timing and sequence of administration, and duration of therapy. Patient-specific factors include age, sex, lifestyle, genetic polymorphisms causing differences in enzyme expression or activity, and disease impairment affecting drug metabolism (eg, hepatic or renal impairment, cardiac failure) or predisposition to differences in efficacy or safety (eg, statin intolerance in patients with a history of myopathy). Clinically significant DDIs are usually preventable. To optimize patient safety, healthcare providers must have an understanding of the mechanisms, magnitude, and potential consequences of any given DDI. Interpreting this information will assist clinicians in the safe prescribing of medications and permits careful consideration of the benefits and risks of concomitant medications.Statins reduce morbidity and mortality in patients with known atherosclerotic cardiovascular disease (ASCVD) and in many primary prevention patients.4-9 Current guidelines recommend high-intensity statin therapy in all patients with ASCVD age ≤75 years and moderate-to high-intensity statin therapy in patients with ASCVD and age >75 years, diabetes mellitus, and familial hypercholesterolemia and in primary prevention patients with 10-year ASCVD risk ≥7.5%.10 Given the important role of statins in patients with ASCVD and those at high ASCVD risk, combination therapy with statins and other cardiovascular medications is highly likely, and potentially significant DDIs must be considered in patients treated with statins.Another important aspect of prescribing medications in combination is evalu...

Statins and the risk of bleeding in patients taking dabigatran

“…The pharmacokinetic properties of NOACs have little variation among patients, and this simplifies the long-term therapeutic management of patients with NVAF, especially elderly patients presenting with multiple morbidities and polypharmacy. 25 The results of our study support the view that statin use in patients with AF could provide additional benefits. 16 Polypharmacy among NOAC users may increase the plasma levels anticoagulants, and thereby increase the risk of bleeding.…”

Severe Rhabdomyolysis due to Presumed Drug Interactions between Atorvastatin with Amlodipine and Ticagrelor

“…Dose adjustment is not required to prevent bleeding excluding severe hepatic impairment irrespective of age, gender, ethnicity, or renal impairment [9]. There is a minor increase in the myotoxic effect of atorvastatin when combined with ticagrelor, with area under concentration (AUC) curve 1.4-fold increase, while simvastatin AUC is increased 2-3-fold [10]. Ticagrelor is a known weak inhibitor of the CYP3A enzymes and P-glycoprotein, with the risk of drug interactions with other drugs affected by these pathways considered to be low [9, 11].…”

“…Ticagrelor is a known weak inhibitor of the CYP3A enzymes and P-glycoprotein, with the risk of drug interactions with other drugs affected by these pathways considered to be low [9, 11]. The latest American Heart Association (AHA) recommendation from 2016 for using the atorvastatin and ticagrelor is that the “combination is reasonable” [10]. While others have suggested that the interaction between ticagrelor and statins metabolised via CYP3A4 may have provided an added benefit in the primary ticagrelor registration study [12], the interaction may have clinical implications from a safety point of view also [6].…”

“…Although this is considered a minor risk in young healthy volunteers [9], such a combination with a large dose of atorvastatin was sufficient to cause extensive rhabdomyolysis in our patient. Further, the latest guideline from the AHA has classified ticagrelor as low risk drug interaction for myotoxicity when coadministered with atorvastatin and has recommended that no dose alteration is required [10]. …”

Statin-related myopathies

“…Cardiovascular drugs are of course likely to be prescribed long term, whereas most antimicrobial agents are used only briefly; arguably in the latter situation, the statin could be temporarily withheld if there is no alternative antibiotic. Cardiovascular drugs such as amlodipine can be used safely if the dose of statin is restricted (eg, simvastatin restricted to maximum dose of 20 mg with amlodipine) 21. Besides these two major drug groups, many other drugs may precipitate rhabdomyolysis through cytochrome p450 inhibition;23 these include ciclosporin, which is fairly often used in association with statins (eg, for immune suppression following kidney transplantation in a diabetic).

Some commonly prescribed drugs that may precipitate rhabdomyolysis when coprescribed with statins (for comprehensive reviews, see Wiggins et al and Hylton et al 21 22)

Fibrates

Gemfibrozil

Cardiovascular drugs

Amiodarone

Amlodipine

Diltiazem

Verapamil

Antimicrobials

Azole antifungal agents

Macrolides (eg, erythromycin, clarithromycin)

Ciprofloxacin

Others

Ciclosporin

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