By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A meta-analysis on published literature and a disproportionality analysis using Food and Drug Administration data found that statin use was associated with the occurrence of daptomycin-induced musculoskeletal adverse events. In most cases, statin use should be discontinued while patients are on daptomycin.
SOURCE: Chuma M, Nakamoto A, Bando T, et al. Association between statin use and daptomycin-related musculoskeletal adverse events: A mixed approach combining a meta-analysis and a disproportionality analysis. Clin Infect Dis 2022;75:1416-1422.
Daptomycin causes elevation of creatine phosphokinase (CPK) and muscle injury in approximately 2% to 13% of patients, with prolonged therapy increasing the risk. The manufacturer recommends that CPK levels be monitored weekly while on daptomycin and that statin therapy be discontinued to prevent the development of musculoskeletal adverse events (MAEs). However, the use of statins with daptomycin is controversial, with some studies showing concurrent use was associated with higher MAEs, while others did not. There also is evidence that discontinuing statin therapy may lead to worse cardiac, neurological, and survival outcomes in patients with an acute myocardial infarction or stroke. Therefore, Chuma and colleagues sought to determine whether the combination of a statin with daptomycin increases the risk for MAEs with an improved study design that implemented two separate methodologies.
The study first included a meta-analysis with studies on the effects of statin use on daptomycin-induced MAEs. Next, the investigators performed a disproportionality analysis using the U.S. Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS), which is a large database of adverse events related to drugs. A disproportionality analysis is a quick and inexpensive method that, with some important precautions, is able to give valuable information on adverse drug reactions and drug safety.1 The relationship between the dose of daptomycin and MAEs was evaluated in cases that reported the dose, body weight, and dosing interval.
Seven studies were included in the meta-analysis, including six cohort studies and one case control study. The definition of MAEs based on CPK varied among the studies. There was a high risk of bias in four of the seven studies due to confounding variables that were not included in the analysis and in two of the seven studies due to incomplete outcome data. Rhabdomyolysis was found in 17/276 (6.2%) patients in the daptomycin group and 9/69 (13%) in the daptomycin plus statin group. The incidence of rhabdomyolysis in the daptomycin plus statin group was significantly greater than in the daptomycin alone group (odds ratio [OR], 3.83; 95% confidence interval [CI], 1.43-10.26). Of the eight statins evaluated, rosuvastatin had the highest incidence of myopathy (OR, 7.28; 95% CI, 4.68-11.32) and rhabdomyolysis (OR, 7.73; 95% CI, 4.94-12.10) when combined with daptomycin.
The disproportionality analysis found the incidence of MAEs was not affected by the dose of daptomycin (> 8 mg/kg/d vs.< 8 mg/kg/d). The rate of patients developing myopathy (223/5,486, 19.42%) and rhabdomyolysis (201/5,486, 17.99%) was significantly greater in patients on both statins and daptomycin compared to those on daptomycin alone (myopathy 81/417, 4.06%; rhabdomyolysis 75/417, 3.66%; P < 0.001).
COMMENTARY
This study provides compelling evidence that there is a significant association between statin use and daptomycin-induced MAEs. The authors chose a robust design that incorporated two different methodologies, a meta-analysis and a disproportionality analysis, and both resulted in the same findings. It is difficult to conduct a randomized clinical trial (RCT) to investigate adverse events that occur from drug-drug interactions. Thus, the mixed approach was able to overcome this methodological obstacle. The mechanism underlying the effect of statins on daptomycin-induced MAEs is unknown and warrants further investigation, along with its occurrence in different patient populations.
There are some limitations to the study. First, no relationship between daptomycin dose and MAEs was observed, which is contrary to previous studies that showed higher daptomycin doses increase the risk for MAEs. One explanation may be that the dose effect may vary in different patient populations. Second, none of the studies in the meta-analysis was an RCT and most had a high risk of bias. Third, it is possible (albeit unlikely) that the MAEs reported in the FAERS data were due to another etiology besides statin use with daptomycin. Finally, the generalizability of the results is uncertain, although it is consistent with previously reported studies and seems scientifically credible.
Should statins be discontinued for patients on daptomycin? In my opinion, the answer is yes, with a caveat. Patients who experience an acute cardiovascular event (i.e., myocardial infarction or stroke) shortly before or during treatment with daptomycin should continue on a statin given their risk for worse outcomes. In these rare cases, careful monitoring of CPK levels (i.e., weekly) should be performed. For the vast majority of others, holding statin therapy while on daptomycin seems like an appropriate and reasonable decision based on the preponderance of scientific evidence.
REFERENCE
- Montastruc J-L, Sommet A, Bagheri H, Lapeyre-Mestre M. Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database. Br J Clin Pharmacol 2011;72:905-908.
