Safety Comparison of High-Intensity Atorvastatin vs. High-Intensity Rosuvastatin

Safety Comparison of High-Intensity Atorvastatin vs. High-Intensity Rosuvastatin
Emily Hulke, PharmD, Goodrich Pharmacy

Background: The 2019 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on the Prevention of Cardiovascular Disease recommend high-intensity statin therapy for most patients with clinical ASCVD. Atorvastatin doses of 40 or 80 mg and rosuvastatin doses of 20 or 40mg are defined as high intensity statin therapies (decrease LDL cholesterol by 50% or more). Many randomized controlled trials support the efficacy of high-intensity statin therapy in reducing major cardiovascular events; however, guidelines do not identify differences in safety profiles between different statin agents and previous studies had not been powered to detect a difference in adverse reaction rates between high-intensity rosuvastatin and high-intensity atorvastatin. In 2011, the Veterans Health Administration switched formulary statin agents from rosuvastatin to atorvastatin because of significant cost savings, as rosuvastatin was still under patent at that time. 

Purpose: Determine if high-intensity atorvastatin is associated with an increased incidence of adverse drug reactions (ADRs) compared with high-intensity rosuvastatin in the Veteran population.

Study Design: Retrospective electronic database review was conducted at the James A. Haley Veterans’ Hospital (JAHVH) in the Greater Tampa Area. Patients with an active outpatient order for a high-intensity statin at JAHVH within the prespecified time frame time period were included: rosuvastatin 20-40 mg from January 2009 to November 2011 or atorvastatin 40-80 mg from May 2012 to June 2016. Patients were excluded if they had a documented ADR or allergy prior to the formulary switch or if they did not receive 1 refill of high intensity statin therapy at any time within the study time frame. The primary endpoint was any documented ADR to statin therapy. Secondary endpoints included rates of abnormal liver function tests  (LFTs), elevated creatine kinase (CK) levels, and statin-associated muscle symptoms (SAMSs) in patients on high intensity atorvastatin compared to high intensity rosuvastatin. ADRs were identified from documented ADRs within the allergy/ADR package in VistA, the electronic health record used by the VA. Adverse muscle reactions including SAMSs, muscle pain, and rhabdomyolysis were identified using ICD-9 or ICD-10 for myalgia or rhabdomyolysis. LFT and CK elevations were identified using laboratory values during the study period. 

Results: A total of 10,017 patients were identified to be on high-intensity statin therapy in the prespecified time frame with 5,852 patients in the atorvastatin group, 4,165 in the rosuvastatin group, and 1,920 patients in both groups due to the formulary change. A statistically significant difference was found in the primary objective of overall ADRs between the atorvastatin and rosuvastatin groups (4.59% vs 2.91%, P<0.05). A higher rate of SAMSs was documented for atorvastatin vs rosuvastatin (1.14% vs. 0.50%, P<0.05). A total of 3.99% of patients in the atorvastatin group had LFTs greater than 3X upper limit of normal compared to 1.39% in the rosuvastatin group (P<0.005). No significant difference was noted between groups for CK elevations. Patients were on therapy for an average of 274 days in the atorvastatin group and 669 days in the rosuvastatin group prior to having a documented ADR. In a subgroup analysis, ADRswere noted to be higher in the atorvastatin 80 mg group (7.22%) than the 40 mg group (4.09%) (P<0.05). ADRswere found to be higher in the rosuvastatin 20 mg group compared to the 40 mg group (3.35 vs. 1.09%, P<0.05). No differences in ADRs were found between the atorvastatin 40 mg group and the rosuvastatin 20 mg group, however there was a significant difference between the atorvastatin 80 mg group and rosuvastatin 40 mg group (7.22% vs. 1.09%, P<0.05). 

Conclusions: This observational study suggests that high intensity atorvastatin is linked to an increased incidence of overall ADRs, specifically statin-associated muscle symptoms and LFT elevations, compared with high intensity rosuvastatin in the Veteran population (4.59% vs. 2.91%). These differences were found to be more prominent in a subgroup analysis comparing atorvastatin 80 mg vs. rosuvastatin 40 mg. Additionally, patients were on rosuvastatin 2.5 times longer than patients on atorvastatin prior to the development of an ADR. 

Key Point: In this study, high-intensity atorvastatin was linked to an increased incidence of overall ADRs when compared with high-intensity rosuvastatin in the Veteran population. The results of this study may be used to promote awareness of the suggested safety differences between high-intensity statin therapies. 


  1. Stein B, Ward T, Hale G, Lyver E. Safety of high-intensity statins in the veteran population: atorvastatin 40 to 80 mg compared with rosuvastatin 20 to 40 mg. Ann Pharmacother. 2019: 1-9.