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

Abstract

Objective

Drug interactions are a common cause of morbidity and mortality and may require prompt discontinuation of therapeutic regimens due to harmful side effects. Patients with acute coronary syndromes are likely to be prescribed multiple medications that are metabolized through the cytochrome P450 system, increasing the probability for drug interaction. Atorvastatin and simvastatin are both well known to interact with the oral P2Y12 agent ticagrelor. The purpose of this paper is to describe the interaction of ticagrelor with rosuvastatin leading to rhabdomyolysis, which is less clearly defined in the literature.

Method

We report a case of a 74-year-old male who presented with bilateral lower extremity weakness and difficulty ambulating for one month after being prescribed ticagrelor for a drug eluting stent, in the setting of already being on rosuvastatin. His clinical picture and laboratory findings were consistent with a diagnosis of rhabdomyolysis. His medications were adjusted to a regimen of clopidogrel and alirocumab. One month later, he returned to his baseline status.

Results

The mechanism of interaction between rosuvastatin and ticagrelor appears to be multifactorial. It may be caused by CYP450-mediated metabolism from a small amount of crossover between isoenzymes. Ticagrelor may also cause acute kidney injury, increasing the concentration of rosuvastatin. Other mechanisms of interaction include genetic differences in the organic anion transporter polypeptides and transportation through p-glycoprotein.

Conclusion

Future pharmacokinetic studies are warranted to better understand the interaction.

Introduction

In the United States, side effects of properly prescribed drugs are estimated to cause 1.9 million hospitalizations per year, contributing to national morbidity and mortality. ¹ One of the most commonly prescribed drug classes are statins, used after large clinical trials established their effectiveness in the primary and secondary prevention of coronary artery disease (CAD). ²

Muscle symptoms, ranging from myalgias to myonecrosis and frank rhabdomyolysis, are the most notorious side effect of statins. While frank rhabdomyolysis occurs in 0.1% of statin-treated patients, some degree of myopathy occurs in nearly 10% to 25% of patients, ³ making this adverse event a frequent complaint encountered by clinicians.

Oral P2Y12 agents, on the other hand, are commonly indicated for dual antiplatelet therapy with aspirin after acute coronary syndromes (ACS), resulting in significant numbers of patients on a combination regimen of a statin and P2Y12 agent. While there is some heightened awareness of the potential for drug-drug interaction (DDI), specifically between ticagrelor and atorvastatin or simvastatin causing rhabdomyolysis based on their common cytochrome P450 (CYP) metabolism,^3,4 the true prevalence is unknown.

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. ¹ , ⁷

Since myopathy can lead to immobility or falls, and rhabdomyolysis can result in advanced and long-term kidney injury or even death, the astute clinician should still be vigilant in actively monitoring a patient on this drug combination. Here, we report a case of rhabdomyolysis in the setting of rosuvastatin and ticagrelor in order to add to the current body of knowledge for this clinically significant DDI, with the hope that we can continue to build evidence for improved safety guidelines and action.

Case Presentation

A 74-year-old white man (93 kg) presented to the hospital with bilateral lower extremity weakness and difficulty ambulating for 1 month. The patient had been discharged 1 month ago after admission for non-ST-elevation myocardial infarction (NSTEMI). A drug-eluting stent (DES) was placed at that time. His past medical history was significant for hypertension, hyperlipidemia, and CAD with a remote DES. Prior to his hospitalization for NSTEMI, the patient had been on appropriate goal-directed medical therapy for multiple years (including rosuvastatin 40 mg daily, ezetimibe 10 mg daily, aspirin 81 mg daily, and clopidogrel 75 mg daily). During his prior hospitalization, clopidogrel was changed to ticagrelor, as his ACS occurred while compliant with clopidogrel therapy. On the day of the latest admission, the patient fell, was unable to stand, and called 911. Review of symptoms was also notable for decreased urination over the same time period. The patient’s home medications at the time of hospital admission were ticagrelor 90 mg twice daily, aspirin 81 mg daily, rosuvastatin 40 mg daily, ezetimibe 10 mg daily, lisinopril 5 mg every other day, metoprolol succinate 50 mg daily, verapamil 120 mg daily, tamsulosin 0.4 mg daily, dutasteride 0.5 mg daily, colchicine 0.6 mg every other day, and gabapentin 600 mg nightly.

Physical exam was notable for bilateral lower extremity muscle tenderness and oliguria. Laboratory work-up revealed evidence of acute renal failure, with a serum creatinine (Scr) of 14.99 mg/dL (increased from 1.33 mg/dL 1 month prior), and increased aminotransferase enzymes of an aspartate aminotransferase (AST) 876 U/L and alanine aminotransferase (ALT) 382 U/L (increased from 138 and 70 U/L 1 month prior, respectively). The patient’s creatinine phosphokinase (CPK) level peaked at 39 849 U/L, which led to a diagnosis of rhabdomyolysis, a syndrome of muscle necrosis where intracellular muscle components like myoglobin are released into circulation.

In our search for an etiology, the patient denied trauma, prolonged immobilization, extreme physical exertion, illicit drug or alcohol abuse, signs of infection, over-the-counter or herbal supplement use, or toxic exposures. However, given the temporal development of rhabdomyolysis after initiation of ticagrelor, as well as a few case reports described in the literature of ticagrelor-associated rhabdomyolysis, ticagrelor was changed back to clopidogrel. The patient’s cardiologist was on board with this decision. Ezetimibe, rosuvastatin, colchicine, and lisinopril were also held. The patient was admitted to the medical intensive care unit. He was treated with intravenous fluids (lactated ringers 150 mL/hr for 5 days), a strategy initially derived from studies of traumatic crush injuries which showed that diluting the circulating concentration of myoglobin with intravenous fluids decreases intratubular cast formation and washes out any partially obstructing intratubular casts that have already formed, resulting in reduced renal injury. ⁸ The patient was also treated with sodium bicarbonate (150 mEQ at 100 mL/hr for 1 day) in an attempt to raise urine pH, with the overall goal of preventing the precipitation into intratubular casts of myoglobin with Tamm-Horsfall protein, again reducing lasting renal injury. ⁸ Finally, the patient was treated with coenzyme Q10 (200 mg orally every 8 hours for 2 days) based on the theory that sarcolemma injury in rhabdomyolysis may be due to mitochondrial dysfunction in the setting of reduced coenzyme Q10 levels.^2,3,9

Although the most likely diagnosis was felt to be medication-induced, autoimmune etiologies and myositis were also ruled out with a negative antinuclear antibody, anti-Jo-1 antibody, and myositis panel (that included ribonucleic protein, SSA 52, anti JO-1, nuclear helicase protein, PL-7, PL-12, P155/140, EJ, KU, small nuclear RNP antibody, signal recognition particle, OJ, SSA 60, fibrillarin, sumo activating enzyme, nuclear matrix protein-2, MDA5, and TIF-1 gamma antibodies). A 3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody was also negative.

With the described treatment, the patient’s aminotransferase abnormalities resolved, and creatinine and CPK decreased. Labs checked 45 days after initial presentation revealed ALT 12 U/L, AST 16 U/L, CPK 94 U/L, and creatinine 1.44 mg/dL. Given his inability to continue his ezetimibe and rosuvastatin, discussion occurred with the patient’s cardiologist about alternatives and the patient was started on alirocumab (150 mg subcutaneous every 2 weeks), a monoclonal antibody proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor approved as second-line treatment for hyperlipidemia. He was discharged to acute rehabilitation 2 weeks after presentation.

Discussion

Statins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, decrease synthesis of mevalonate, ¹⁰ lowering total cholesterol, low-density lipoprotein cholesterol, and triglycerides, and raising high-density lipoprotein cholesterol. ⁹ Despite their benefits across multiple randomized clinical trials (RCTs) in reducing all-cause mortality, CAD-related mortality, nonfatal myocardial infarction (MI), and cardiovascular hospitalizations across various populations,^11–14 statins are notorious for muscular side effects that range from mild myalgias to potentially fatal rhabdomyolysis. ³ In rhabdomyolysis, disruption of the sarcolemma causes release of toxic intracellular contents into the bloodstream, potentially causing renal failure or disseminated intravascular coagulation. ¹⁵ The mechanism of sarcolemma injury by statins is multifactorial. ¹⁶ One proposed mechanism is reduction of the cholesterol content of skeletal muscle cell membranes, leading to membrane destabilization and lysis.^2,10 This is reasonable in the context of existing case reports of clofibrate also causing elevated CPK levels and myalgias (in the absence of statins). ¹⁷ A second theory suggests that reduced coenzyme Q10 levels that occur with statin use result in mitochondrial dysfunction.^2,3,9 Imbalances in cell degradation, repair, and intracellular protein signaling are also implicated.^3,9 Rosuvastatin, considered the most potent statin,^18–20 is more likely to cause rhabdomyolysis than atorvastatin, simvastatin, or pravastatin.^3,21 Other factors increasing the risk of statin-induced rhabdomyolysis include statin dose, age, female gender, low body mass index, and untreated or uncontrolled hypothyroidism.^1,3,4,22

On the contrary, ticagrelor, a direct-acting oral antiplatelet drug approved in 2011,^1,3 is not known to cause myotoxicity. Compared to clopidogrel, ticagrelor does not require metabolic activation, so its effects are more predictable and consistent across patients. ³ Its first metabolite, AR-C124910XX, also has antiplatelet properties.^3,23 The 2009 Platelet Inhibition and Patient Outcomes (PLATO) trial directly compared ticagrelor with clopidogrel in head-to-head fashion and showed that ticagrelor significantly decreased the composite endpoint of death from vascular cause, MI, or stroke in ACS patients (hazard ratio, 0.84; 95% confidence interval [CI], 0.77-0.92; P < .001). There was no increase in major bleeding (11.6% in the ticagrelor group, 11.2% in the clopidogrel group; P = .43). ²⁴ Subsequently, guidelines from European Society of Cardiology (ESC), European Association of Cardio-Thoracic Surgery (EACTS), AHA, and American College of Cardiology (ACC) recommend ticagrelor and aspirin therapy for prevention of stent thrombosis and medical management after ACS.^3,4

Up to the beginning of 2018, there were eight published case reports describing a clinically significant DDI in which the combination of ticagrelor with rosuvastatin resulted in rhabdomyolysis. ⁷ The time-course of drug exposure, development of rhabdomyolysis, and resolution of acute illness in these patients also supported an interaction. ²⁵ In the case reported by Vrkic Kirhmajer et al, the patient’s rhabdomyolysis did not resolve despite immediate discontinuation of rosuvastatin (and amiodarone). Only upon review of 2 case reports in the literature was ticagrelor discontinued on hospital day 7, resulting in normalization of CPK and complete recovery. ⁷ In a case reported by Park et al, ²¹ all of the patient’s home medications (including rosuvastatin) were discontinued upon hospital admission, except ticagrelor and aspirin. However, the patient’s rhabdomyolysis only resolved upon changing ticagrelor to clopidogrel on hospital day 6. Finally, van Vuren et al reported a patient with rhabdomyolysis on rosuvastatin, ezetimibe, and ticagrelor. The patient had been using rosuvastatin and ezetimibe for 6 years without side effects. Ticagrelor was initiated a month prior after MI. Upon hospital presentation, rosuvastatin was immediately discontinued; however, rhabdomyolysis only resolved when ticagrelor was stopped (along with ezetimibe and omeprazole) on hospital day 4. The authors noted that upon retrospective chart review, the patient’s glomerular filtration rate (GFR) had decreased from 60 to 52 mL/min 1 week after ticagrelor initiation. ²⁶

Possible Mechanisms of DDI

Cytochrome P450–Mediated Metabolism

Ticagrelor is metabolized through (and weakly inhibits) cytochrome P450 3A4 and 3A5 isoenzymes,^3,10,23 the former of which also metabolizes simvastatin and atorvastatin. ³ Pharmacokinetic studies between ticagrelor and simvastatin or atorvastatin expectedly show an increased exposure to both statins (and their metabolites) by up to 67% and 56%, respectively (while showing no change in ticagrelor exposure). ²⁷ Based on these data, there is heightened awareness of the potential for atorvastatin or simvastatin-induced rhabdomyolysis with ticagrelor, and product information for ticagrelor recommends a maximal concurrent simvastatin dose of 40 mg daily. ⁴

The combination of ticagrelor and rosuvastatin, on the other hand, is generally thought to be safe, since rosuvastatin is metabolized through CYP2C9. ³ However, some small amount of crossover between CYP isoenzymes occurs. An in vitro study of human liver microsomes showed that ticagrelor moderately inhibited CYP2C9, ²⁸ which would theoretically increase exposure to rosuvastatin. However, in a separate in vivo study of 23 healthy volunteers receiving a CYP2C9 substrate with ticagrelor, the results were not replicated. ²⁹ Rosuvastatin is also in small part metabolized by CYP3A4 and CYP1A2, 2C19, 2D6, and 2E1. ³ Given the presumed lack of clinical contribution of these pathways, both products’ SmPC do not list interactions. ⁷ However, unlike atorvastatin and simvastatin, no direct comparative pharmokinetic study has been performed between rosuvastatin and ticagrelor; ³ therefore, the true extent of the interaction is unknown. ³

Ticagrelor-Induced Acute Kidney Injury

Another mechanism of DDI that likely contributed to our case was ticagrelor-induced acute kidney injury (AKI) increasing rosuvastatin exposure and thereby increasing risk of rhabdomyolysis. Rosuvastatin is dosed depending on creatinine clearance (CrCl): if less than 60 mL/min, doses over 40 mg daily of rosuvastatin are contraindicated. For a CrCl less than 30 mL/min, rosuvastatin is entirely contraindicated since its plasma concentration may increase threefold in this setting. ²⁶ Ticagrelor, on the other hand, may affect renal function by prolonging the half-life of adenosine, which vasoconstricts the afferent renal arteriole, reducing renal blood flow and possibly medication clearance. ⁷ The PLATO trial documented significantly worse renal function in patients taking ticagrelor compared to clopidogrel. ¹ Scr increased by 30% in 25.5% of patients receiving ticagrelor; 8.3% of those patients experienced increased creatinine by more than 50%. ²⁶ Increase in Scr was most pronounced in patients over the age of 75, receiving concurrent angiotensin receptor inhibitors, and with preexisting renal impairment. ⁷ Consistent with these results, a 2012 study looked at a different renal function biomarker, cystatin C, in PLATO patients. Cystatin C levels are entirely dependent on GFR. The study found that cystatin C levels were higher in ticagrelor-treated patients compared to those treated with clopidogrel. ³⁰

Despite this, there is no recommended dose adjustment of ticagrelor for patients with preexisting renal dysfunction.^3,23 There is also no recommended dose adjustment for patients also on rosuvastatin or angiotensin receptor inhibitors, or those over the age of 75. One reason is that ticagrelor is mainly excreted by hepatic (rather than renal) metabolism. ⁷ Ticagrelor and its active metabolite are only found in the urine in concentrations less than 1% the original dose. ⁷ Also, despite the increases in Scr with ticagrelor, overall serious renal-related adverse events did not differ between ticagrelor and clopidogrel patients in the PLATO trial. This is even mentioned on the FDA package insert for ticagrelor. ¹ However, 70% of patients in the PLATO trial predominantly used simvastatin and atorvastatin, rather than rosuvastatin. ³¹ Complicating the picture further, chronic kidney disease (CKD) patients with GFR less than 60 mL/min benefit more from ticagrelor than clopidogrel. In this population, ticagrelor was associated with significantly fewer deaths from vascular causes, MI, and stroke, with a similar safety profile as clopidogrel (17.3% vs 22%).^1,3 Ticagrelor was also associated with a greater absolute risk reduction in patients with CKD compared to patients with normal renal function (7.9% vs 89%). ¹ Interestingly, DiNicolantonio and Serebruany suggest in their 2013 editorial that the “remarkable and yet unexplained” mortality benefit of ticagrelor in PLATO may have been due to increased serum concentrations of CYP3A4-metabolized statins, ³¹ though they do not mention the possibility of ticagrelor-induced AKI also causing increased serum concentration of the CYP2C9-metabolized rosuvastatin.

Genetic Differences in Organic Anion Transporter Polypeptides

A second mechanism of DDI between ticagrelor and rosuvastatin that may contribute to risk of rhabdomyolysis is genetic differences in organic anion transporter polypeptides (OATPs), encoded by the gene SLCO. ³ OATP1B1, OATP1B3, and OATP1A2 are involved in the metabolism of all statins to varying degrees. ³ Varenhorst et al conducted a genome-wide association study (GWAS) of PLATO trial patients to determine the role of OATPs in the metabolism of ticagrelor and its active metabolite. They showed serum concentrations were influenced by some single-nucleotide polymorphisms (SNPs) of SLCO1B1. ³²

Transportation by P-Glycoprotein

Another polypeptide, P-glycoprotein (P-gp, also known as multidrug resistance-1 [MDR-1]), may also have a role. P-gp is a transmembrane channel encoded by the ABCB1 gene and expressed in intestinal epithelium where it pumps toxins or drugs back into the intestinal lumen. ³ Ticagrelor is transported by, and weakly inhibits, P-gp. ³ Verhulst et al ³³ conducted a study with human tubular cells and a different P-gp inhibitor, vinblastine. In their experiment, net rosuvastatin secretory flux was reduced in the presence of vinblastine by approximately 30%, resulting in a concomitant intracellular rosuvastatin concentration rise (7.8 ± 0.2 vs 2.8 ± 0.1 μM; P < .05). ³³ Supporting this, various ABCB1 gene polymorphisms and haplotypes have been shown to cause varying rosuvastatin pharmacokinetics in 12 healthy Chinese volunteers. ³⁴ However, in another study with 10 volunteers, ABCB1 haplotype was unrelated to interindividual variability in rosuvastatin pharmacokinetics; ³⁵ therefore, more investigation is required.

Conclusion

This DDI is more than plausible. In fact, the November 2018 World Health Organization (WHO) Pharmaceuticals Newsletter stated that the cases in VigiBase (the WHO global database of individual case reports) “support the signal of an interaction between ticagrelor and rosuvastatin, especially in high-risk patients.” ¹⁵ Using the Drug Interaction Probably Scale (DIPS), this is a “possible” interaction. ³⁶ Steps can, and must, be taken for further safety.

Current barriers include the perceived safety of this drug combination, given the lack of awareness of other mechanisms of DDI aside from CYP metabolism. There is a need for a formal pharmacokinetic study between the 2 drugs. Both the FDA package inserts and SmPC are without interactions or warnings. Finally, there are no dose recommendations for ticagrelor for those with preexisting renal dysfunction, on concomitant rosuvastatin or angiotensin receptors inhibitors, or those above the age of 75, representing the highest risk cohorts.

Although there are no current guidelines on managing this DDI, if a provider is concerned, in addition to managing any acute process, the provider should reach out to the prescribing cardiologist or primary care physician in to discuss alternative antiplatelet or lipid-lowering agents. Otherwise, prevention and anticipation of remain key. The European Medicines Agency SmPC recommends checking renal function 1 month after initiation of ticagrelor, especially in high-risk patients.^1,26 However, in many of the published case reports, patients’ creatinine was not checked at this time point, ¹⁵ again calling for greater awareness of, and compliance with, this recommendation. Furthermore, our case, along with the case reported by van Vuren et al, indicates 1 month may be too long. Checking creatinine earlier and more frequently may help with prevention of rhabdomyolysis in susceptible individuals. Finally, in the future, genetic profile testing of candidate patients should be considered, as there is sufficient data that gene SNPs and haplotypes influence interindividual pharmacokinetics, and therefore susceptibility to negative clinical outcomes, including rhabdomyolysis. ⁷