Ticagrelor and Statin Interaction Induces Rhabdomyolysis and Acute Renal Failure: Case reports and Scoping Review

Abstract

Ever since evidence about the increased risk of stent thrombosis with drug eluting stents (DES) surfaced in 2005, the Food and Drug Administration (FDA) has recommended the use of dual antiplatelet therapy (aspirin with P2Y12 inhibitor) following DES placement. The PLATO trial demonstrated lower mortality rates with the use of Ticagrelor when compared to clopidogrel (9.8% vs. 11.7%, p<0.001) when treating patients with acute coronary syndrome. Given their pleiotropic benefits, statins are today the second most prescribed drug in the United States and often co-prescribed with Ticagrelor. FDA's post market surveillance of Ticagrelor use along with statins in post-myocardial infarction care is now revealing novel and serious adverse events. We present two cases of rhabdomyolysis and acute renal failure (ARF) which develop while the patients were on statins and Ticagrelor. Case 1: A 66-year-old female presented with bilateral thigh pain for 3 days. One month prior to presentation, she was managed for non-ST segment elevation myocardial infarction (NSTEMI) and had been started on aspirin, ticagrelor and simvastatin. Laboratory values revealed creatinine kinase (CK) level at 40,000 U/L and creatinine 3.2 mg/dL suggesting rhabdomyolysis and ARF. Case 2: A 63-year-old male presented with generalized body aches and fatigue for 4 days. He had sustained STEMI two months before and received two drug eluting stents (DES) and aspirin, ticagrelor and rosuvastatin had been initiated. CK was 380,000 U/L and creatinine 7.94 mg/dL suggesting rhabdomyolysis and ARF. Both patients presented with rhabdomyolysis and acute renal failure within weeks after ticagrelor and statin were commenced. A review of the literature indicated that 11 similar cases of ticagrelor-induced ARF and rhabdomyolysis had been reported. Ticagrelor competes with statins when metabolized by cytochrome P450 (CYP) 3A4 leading to statin retention, leading to major adverse effects like rhabdomyolysis and acute renal failure. Our review is intended to alert clinicians about this important drug interaction.

Acute kidney injury and rhabdomyolysis due to ticagrelor and rosuvastatin

“…19 A review of the literature revealed that rosuvastatin was the most common statin used with ticagrelor in patients who developed rhabdomyolysis. 20 It also showed that most statins were being taken at a high-intensity dose (such as rosuvastatin 20 or 40 mg), which is similar to this case in which Ms. Y was taking rosuvastatin at the high-intensity dose of 20 mg orally daily. Unlike this case, the vast majority of patients in the literature were taking an ACE inhibitor or an ARB, while Ms. Y was not.…”

“…The case was also different in that the time from initiation of ticagrelor and a statin to the development of rhabdomyolysis was approximately 4 months, whereas previous cases reported onsets of around a few weeks to 2 months. 20 This delayed onset of rhabdomyolysis and acute renal failure is a unique aspect of this case that may be explained by the absence of an ACE inhibitor or ARB, which potentially caused less decline in renal function, and therefore, less impairment of rosuvastatin elimination.…”

“…Awareness of this issue needs to be raised within the medical community so appropriate measures for prevention can be implemented. One such measure may be to avoid high-intensity statin therapy with rosuvastatin in patients on ticagrelor, as the vast majority of cases in the literature including the case mentioned above involved a high-intensity statin dose 20. This would be especially pertinent in older adult patients who are already at increased risk for statin toxicity due to diminished renal and/or hepatic function.…”

“…One such measure may be to avoid high-intensity statin therapy with rosuvastatin in patients on ticagrelor, as the vast majority of cases in the literature including the case mentioned above involved a high-intensity statin dose. 20 This would be especially pertinent in older adult patients who are already at increased risk for statin toxicity due to diminished renal and/or hepatic function. However, in patients with a compelling indication for high-intensity statin therapy, such as those with established atherosclerotic cardiovascular disease who are 75 years of age or younger, it may be more appropriate to consider an alternative P2Y12-inihibitor, such as clopidogrel or consider the use of atorvastatin at high-intensity doses.…”

The Interaction Between Rosuvastatin and Ticagrelor Leading to Rhabdomyolysis: A Case Report and Narrative Review

“…The interaction between rosuvastatin and ticagrelor, in particular, has not received due attention. Despite a recent literature review revealing 11 cases of a major DDI between statins and ticagrelor resulting in rhabdomyolysis and renal failure, with rosuvastatin being the most commonly used statin, 5 the 2016 Scientific Statement from the American Heart Association (AHA) ("Recommendations for Management of Clinically Significant Drug-Drug Interactions with Statins and Select Agents Used in Patients with Cardiovascular Disease") still did not list this interaction among the 49 listed. 6 Additionally, there are no dose adjustment recommendations for those on ticagrelor and rosuvastatin, and both the Food and Drug Administration (FDA) package inserts and Summary of Product Characteristics (SmPC) are without interactions or warnings.…”