Statin-related adverse events a nocebo effect?
Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase
Statin use has been associated with increased rates of adverse events (AEs) and symptomatic side-effects, including muscle pain and weakness. This withdraws many patients from statin therapy [1,2]. However, this increase in AEs is mainly derived from observational studies, in which patients were neither randomized nor blinded, whereas double-blind randomized controlled trials did not show such results, as different types of AEs were generally similar between patients in these studies [3-6]. The absence of AEs has been explained by the statin not being sufficiently specific or sensitive [1,7].
In this study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) data of the Lipid-Lowering Arm (LLA) had been used to assess the effect of blinded (1998-2002, median follow-up 3.3yrs) and unblinded (2002-2005, median follow-up 2.3yrs) therapy on AEs in the same individuals. Four AEs of interests (AEOIs) were prespecified: muscle-related side-effects, erectile dysfunction, sleep disturbance and cognitive impairment. In ASCOT-LLA, 5101 patients were blinded to atorvastatin, of which 3364 were assigned to atorvastatin in the extension phase again and 1608 were assigned to non-use of atorvastatin. On the other hand, 5079 were placebo-treated, of which 3045 were assigned to atorvastatin and 1882 were assigned to non-use in the extension phase.
- In total, 60 612 distinct AEs occurred.
- In the blinded randomized phase, definite or probably muscle-related AEOIs were reported in 298 statin- and 283 placebo-treated patients (HR 1.03, 95% CI 0.88-1.21, P=0.72), erectile dysfunction in 272 statin- and 302 placebo-treated patients (HR 0.88, 95% CI 0.75-1.04, P=0.13) and sleep disturbance in 149 statin- and 210 placebo-treated patients (HR 0.69, 95% CI 0.56-0.85, P=0.0005). As too few cases of cognitive impairment were reported, analyses were not statistically reliable regarding this AE (31 vs 32, HR 0.94, 95% CI 0.57-1.54, P=0.81).
- Findings were similar in sensitivity analyses based on only definite AEOIs or when more possible AEOIs were included.
- Regarding other AEs, renal and urinary disorders occurred more among patients on atorvastatin (HR 1.23, 95% CI 1.08-1.41, P=0.002).
- In the non-blinded non-randomized phase, overall less AEOIs were reported compared to the blinded phase. However, muscle-related AEOIs were reported more often in statin users than non-users (HR 1.41, 95% CI 1.10-1.79, P=0.006), which proportional excess was similar between atorvastatin- or placebo-assigned patients of blinded phase (P interaction=0.63).
- There was no significance difference of other prespecified AEs between statin-users and non-statin-users in non-blinded phase (erectile dysfunction HR 0.89, 95% CI 0.66-1.20, P=0.44, sleep disturbance HR 0.87, 95% CI 0.63-1.20, P=0.40, cognitive impairment HR 0.59, 95% CI 0.34-1.02, P=0.06). Findings were similar in sensitivity analyses.
- When non-blinded comparisons were adjusted for baseline age, sex, race, smoking, diabetes, left ventricular hypertrophy, total cholesterol and systolic blood pressure, HRs were minimally affected. For muscle-related AEs, HR changed to 1.43 (95% CI 1.12-1.83).
- Regarding other AEs in unblinded phase, only musculoskeletal and connective tissue disorders (HR 1.17, 95%C CI 1.06-1.29, P=0.001) and blood and lymphatic system disorders (HR 1.40, 95% CI 1.04-1.88, P=0.03) occurred more often among statin users.
In the blinded randomized phase of the ASCOT-LLA trial, the number of muscle-related AEs were comparable between statin-treated and placebo-treated patients. However, these AEs were significantly more often reported when these same patients knew that they were taking a statin during the extended non-blinded non-randomized phase. This observation is consistent with a nocebo effect, whereby subjective AEs are probably a result of a treatment thought that causes some particular side-effects. These data suggest that muscle-related AEOIs are not causally related to statin-use and therefore, the benefits of statins in reducing cardiovascular events should override concerns about reports of side-effects.