Effect of Concomitant 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor Therapy on Creatine Phosphokinase Levels and Mortality Among Patients Receiving Daptomycin: Retrospective Cohort Study

Daptomycin is an antibiotic used to treat complicated infections caused by aerobic Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) [1]. The use of this agent has somewhat been limited by its toxicity profile, specifically the potential to cause elevations in creatine phosphokinase (CPK) [1]. This is a meaningful outcome as CPK elevation may be indicative of skeletal muscle toxicity and, in extreme circumstances, life-threatening conditions such as rhabdomyolysis [2].

The potential to cause elevations in CPK may be enhanced when daptomycin exposure is altered (e.g., higher doses or diminished creatinine clearance) [3] or when used in combination with other agents that also increase CPK [1]. Among medications known to elevate CPK, HMG-CoA reductase inhibitors (statins) are commonly used [4]. The prescribing information for daptomycin specifically recommends discontinuing statin therapy during receipt of daptomycin [1]. However, the literature supporting this recommendation is sparse, and there has not been a thorough assessment to determine if there is an increased frequency of CPK elevations between statin recipients and non-recipients receiving daptomycin.

The primary objective of this study was to compare the incidence of CPK elevation between recipients and non-recipients of statins receiving daptomycin. The secondary objective was to assess the relationship between concomitant statin therapy and mortality.

There were 350 patients who received daptomycin at a VISN-2 facility. There were 117 patients that were excluded because they did not receive daptomycin for ≥48 h or did not have a CPK level measurement taken while on therapy. Among the 233 patients that met inclusion criteria, 180 received daptomycin alone and 53 received daptomycin while receiving a statin.

The demographics and clinical characteristics of the study population are displayed in Table 1. Overall, the majority of these baseline characteristics were similar between the two groups. Mean ± standard deviation (SD) age was higher (p = 0.02) for statin recipients (69.7 ± 9.8) than non-recipients (65.1 ± 13.0). Mean ± SD APACHE-II scores were also higher (p = 0.04) in statin recipients (13.9 ± 7.3) than non-recipients (11.6 ± 6.8). Patients with a higher degree of renal dysfunction at baseline were more likely to receive daptomycin while receiving a statin. With regard to daptomycin use, there were no statistically significant differences observed in dose and duration of daptomycin therapy between groups. The frequency of concomitant medication use associated with CPK elevations did not differ significantly (p = 0.15) between statin users (20.8%) and non-users (12.8%). No patients were receiving phenothiazines, chloroquine or hydroxychloroquine.

Hypertension, congestive heart failure, renal disease and diabetes were observed more frequently among statin recipients than non-recipients. The indications for daptomycin use had comparable distributions between statin users and non-users and daptomycin was most commonly being used to treat bacteremia and skin and skin structure infections. The most frequently used statin was simvastatin (58.5%), followed by atorvastatin (17.0%), pravastatin (13.2%) and rosuvastatin (11.3%). No patients received lovastatin, fluvastatin or pitavastatin.

Study outcomes are described in Table 2. Elevations in CPK levels were observed in a total of five patients (2.1%). Among these five patients, 3/53 (5.7%) patients received daptomycin while receiving a statin, and 2/180 (1.1%) received daptomycin alone (p = 0.08). No effect modification was observed by use of other concomitant medications known to increase CPK values. In the time-to-event analyses, there was no significant difference in CPK elevation over time between statin recipients and non-recipients (p = 0.14). All patients that had a CPK elevation had a normal baseline CPK value. Baseline creatinine clearance also did not affect the development of CPK elevations. Of patients with creatinine clearances ≥30 mL/min, 2.2% experienced a CPK elevation versus 2.0% of patients with creatinine clearances <30 mL/min. The comparison of CPK elevations between patients who received daptomycin while receiving a statin and daptomycin alone, within each of these creatinine clearance strata, did not differ significantly (Breslow–Day test p value = 0.47). Although not statistically significant (p = 0.17), a higher frequency of death was observed for patients who did not receive concomitant statin therapy (17.2%) versus those who were on statin therapy (9.4%).

We performed a retrospective cohort study of Veterans’ Affairs patients that received daptomycin therapy to assess the relationship between concomitant statin therapy and CPK elevation. We observed no significant difference in the frequency of CPK elevation between statin recipients and non-recipients. Among patients with a creatinine clearance >30 mL/min (same type of patients studied in registration trial [7] and Bhavnani et al. [3]), there was a lower incidence (2.2%) of CPK elevation observed than previously reported in the literature [8‐10], irrespective of whether daptomycin was given with or without a statin. Bhavnani et al. examined the probability of CPK elevations in patients who received daptomycin without a statin and determined the predicted probability of a CPK elevation to be between 3.73% and 19.5% (at doses ranging from 4 to 12 mg/kg/day) [3]. It is interesting to note that the median (IQR) daptomycin dose in our study was 6.0 (5.5–6.3) mg/kg and is similar to the actual dose (6 mg/kg) administered to patients in the bacteremia/endocarditis registration trial [7] and the simulations performed by Bhavnani et al. [3]. The lower frequency of CPK elevations may denote competing risks or an etiology that involves varying contributions of exposure, severity of illness and other clinical factors.

The results of our study are generally consistent with recently published data regarding lack of a statistically significant relationship between CPK elevations and concomitant use of daptomycin and statin therapy [2, 8‐10]. Parra-Ruiz et al. reported an 8% occurrence of CPK elevation with the combination of high-dose (>6 mg/kg/day) daptomycin and statin therapy, and a 10% occurrence of CPK elevation in patients receiving daptomycin only [6]. While the point estimates are higher than those in our analysis, the comparison resulting in no difference between the two treatment groups is largely consistent.

Our study suggests that the incidence of CPK elevation may be less frequent than previously reported. This is an interesting finding given that the population studied included patients that received care at a VISN-2 facility. The Veterans’ Affairs population is primarily made up of patients with a larger distribution of comorbidities than the general population [11]. Given their underlying health status, this is a population that one would expect to have a higher frequency of CPK elevations [12]. These findings have important implications for utilization of daptomycin since it may not be as toxic as previously perceived, regardless of whether used concomitantly with statin therapy. Future studies should assess the risk of CPK elevation in non-VA Medical Center settings where the volume of comorbidities is less pronounced.

Although not found to be statistically significant, daptomycin patients receiving a concomitant statin had a lower frequency of death versus statin non-recipients. These findings among daptomycin recipients are consistent with other retrospective studies that have shown beneficial effects with statin use in bacteremia, including reduction in all-cause mortality and bacteremia-related death [13, 14]. Given the lack of relationship between statin use and CPK elevation and the effect on mortality, the recommendations surrounding the concomitant statin use may warrant further investigation for daptomycin recipients.

Some considerations should be taken into account when interpreting these findings. First, only five CPK elevation events were observed and power may have been an issue indicating that a larger study needs to be performed. However, we evaluated all patients that received daptomycin since FDA approval in VISN-2. Over 500 patients would have been required to demonstrate a statistically significant difference in the small effect size (5.7% versus 1.1%) observed in our study and this was not feasible given daptomycin usage in VISN-2. Due to the very low number of events, we were unable to perform multivariate analysis to assess if statin therapy is independently associated with CPK elevation. Second, we were unable to discriminate the CPK risk associated with individual statins because the majority of patients were on the VA formulary agent, simvastatin, during the study period. Third, some patients who did not receive statin therapy while receiving daptomycin had previous exposure to statins. It is unclear whether previous exposure would affect the risk of developing a CPK elevation. Future studies should discern whether this is an important predictor. Fourth, this study was performed among patients receiving care at VISN-2 facilities. External validity may be an issue in populations with a different distribution of comorbidities and gender. Finally, none of the CPK events occurred in patients on hemodialysis. This is an important point to consider because these patients are likely to have altered drug exposure and potentially have a higher probability of achieving troughs in excess of 24.3 µg/mL, the threshold associated with an elevated risk of CPK elevations [3]. Given that this trough target was derived from patients enrolled in registration trials of daptomycin, future studies should evaluate if this trough threshold is applicable to the general population of patients using daptomycin and if the threshold differs by use of concomitant statin therapy, hemodialysis and other clinical factors that may modify daptomycin exposure.

In summary, the incidence of CPK elevation did not significantly differ with or without concomitant statin therapy among patients receiving daptomycin. Previous recommendations to avoid this combination should be revisited given these findings. Future studies should examine this relationship in larger populations with more heterogeneous statin usage and attempt to quantify the risk of CPK elevation with individual statins.