ticagrelor and Rhabdomyolysis

We present 3 patients diagnosed with rhabdomyolysis 1-6 months after the initiation of concomitant rosuvastatin and ticagrelor medication. A literature review and Food and Drug Administration adverse event reporting system revealed >40 reports of rhabdomyolysis during concomitant ticagrelor and rosuvastatin, including 3 with a fatal outcome. We show that ticagrelor inhibits breast cancer resistance protein-, organic anion transporting polypeptide (OATP) 1B1-, 1B3- and 2B1-mediated transport of rosuvastatin in vitro with half-maximal unbound inhibitory concentrations of 0.36, 4.13, 7.5 and 3.26 μM, respectively. A static drug interaction model predicted that ticagrelor may inhibit intestinal breast cancer resistance protein and thus increase rosuvastatin plasma exposure 2.1-fold, whereas the OATP-mediated hepatic uptake of rosuvastatin should not be inhibited due to relatively low portal ticagrelor concentrations. Taken together, concomitant use of ticagrelor with rosuvastatin may increase the systemic exposure to rosuvastatin and the risk of rosuvastatin-induced rhabdomyolysis. Further studies are warranted to investigate the potential pharmacokinetic interaction between ticagrelor and rosuvastatin in humans.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Breast Neoplasms; Drug Interactions; Female; Humans; Neoplasm Proteins; Organic Anion Transporters; Rhabdomyolysis; Rosuvastatin Calcium; Ticagrelor; United States

Up to the beginning of 2018, a total of eight cases describing rare but clinically important drug interactions between rosuvastatin and ticagrelor which resulted in rhabdomyolysis have been noted in the Global World Health Organization (WHO) adverse drug reaction (ADR) database (VigiBase) as well as in available literature. There are several possible factors which could contribute to the onset of rhabdomyolysis: old age, initially excessive rosuvastatin dose, drug-drug interactions (DDI) on metabolic enzymes (CYPs and UGTs) and drug transporter levels (ABCB1, ABCG2, OATP1B1) and pharmacogenetic predisposition. We reviewed all available cases plus the case of an 87-year-old female Croatian/Caucasian patient who developed rhabdomyolysis following concomitant treatment with rosuvastatin and ticagrelor. The results of the pharmacogenetic analysis indicated that the patient was a carrier of inactivating alleles CYP2C9*1/*3, CYP3A4*1/*22, CYP3A5*3/*3, CYP2D6*1/*4, UGT1A1*28/*28, UGT2B7 -161C/T, ABCB1 3435C/T and ABCB1 1237C/T which could have added to the interactions not only between ticagrelor and rosuvastatin but also other concomitantly prescribed medicines, such as amiodarone and proton pump inhibitors. In this case report, the possible multifactorial causes for rhabdomyolysis following concomitant use of rosuvastatin and ticagrelor such as old age, polypharmacy, renal impairment, along with pharmacogenetics will be discussed.

Topics: Age Factors; Aged; Aged, 80 and over; Drug Interactions; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Male; Middle Aged; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Platelet Aggregation Inhibitors; Polypharmacy; Predictive Value of Tests; Renal Insufficiency, Chronic; Rhabdomyolysis; Risk Factors; Rosuvastatin Calcium; Ticagrelor

The introduction of ticagrelor, one of the first directly-acting oral antiplatelet drugs, provided new possibilities in the prevention of thrombotic events in patients with acute coronary syndromes (ACS). Current guidelines recommend ticagrelor in dual antiplatelet therapy with aspirin over clopidogrel for prevention of stent thrombosis in patients with ACS. Moreover, in the management of ACS, lipid-lowering treatment with high-intensity statin therapy is advised for secondary prevention of cardiovascular events over the long term. Despite the apparent advantages of combined antiplatelet and lipid-lowering treatments, a possible interaction between statins and ticagrelor may lead to myopathy and rhabdomyolysis. In this review, relevant information was gathered on the ticagrelor-statin interaction that might lead to this life-threatening condition. This review focuses on the most widely used statins-simvastatin, atorvastatin, and rosuvastatin. Possible mechanisms of this interaction are discussed, including CYP3A4 isoenzymes, organic anion transporter polypeptide (OATPs), P-glycoprotein and glucuronidation. PubMed database was searched for relevant case reports and all data gathered from the introduction of ticagrelor to March 2018 are presented and discussed. In summary, co-administration of statins and ticagrelor was found to be relatively safe in routinely prescribed doses. However, caution should be exercised, especially in elder populations.

Topics: Acute Coronary Syndrome; Drug Interactions; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscular Diseases; Platelet Aggregation Inhibitors; Rhabdomyolysis; Risk; Thrombosis; Ticagrelor

Topics: Acute Kidney Injury; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rhabdomyolysis; Rosuvastatin Calcium; Ticagrelor

Topics: Acute Kidney Injury; Administration, Oral; Aged, 80 and over; Coronary Artery Disease; Diagnosis, Differential; Female; Humans; Nausea; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Rhabdomyolysis; Ticagrelor; Vomiting

BACKGROUND Following acute coronary intervention in cardiology patients, the combined medical therapy with the platelet inhibitory drug ticagrelor and a statin medication (e.g., simvastatin) is recommended according to international guidelines. Yet combined therapeutic regimens have the potential of pharmacological interaction with both ticagrelor and simvastatin being metabolized by CYP3A4. Rhabdomyolysis is a known side-effect of statin therapy and combined therapy increases the susceptibility to this complication. CASE REPORT A 72-year-old patient presented to our Emergency Department with typical signs of rhabdomyolysis consisting of muscular cramps and pain in both legs and a significant elevation of creatinine kinase (CK). Five months prior to this presentation, he had been hospitalized due to acute coronary syndrome followed by a coronary intervention of a high-grade left anterior descending artery stenosis. His long-term medication included simvastatin 20 mg daily, which he had taken for several years, and ticagrelor, which had been added to his medication following coronary intervention. The patient showed fast recovery of symptoms and rapid normalization of CK levels upon treatment change from ticagrelor to clopidogrel with a paused statin administration. CONCLUSIONS The combined use of ticagrelor with low dose simvastatin poses a risk for rhabdomyolysis even in patients with normal kidney function. Patients treated with ticagrelor might require changes in statin therapy and dose adjustments in order to avoid pharmacological interactions and higher risk for adverse effects.

Topics: Adenosine; Aged; Creatine Kinase; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Rhabdomyolysis; Ticagrelor

Topics: Adenosine; Aged; Humans; Male; Myocardial Ischemia; Purinergic P2Y Receptor Antagonists; Rhabdomyolysis; Ticagrelor

Renal function deterioration is a rather frequent side effect of ticagrelor; this is especially so in patients over the age of 75, with pre-existent mild renal failure and/or taking an angiotensin receptor inhibitor. We describe a patient in whom deterioration of renal function due to ticagrelor led to a rise in serum concentration of rosuvastatin which resulted in rhabdomyolysis. The presented case emphasises the importance to check renal function routinely before and one month after starting ticagrelor and to screen carefully for possible interactions with other drugs.

Topics: Acute Kidney Injury; Adenosine; Aged; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Rhabdomyolysis; Rosuvastatin Calcium; Ticagrelor