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Statins for Primary Prevention of Cardiovascular Disease

TO THE EDITOR: In their original research article, Yebyo and colleagues (1) performed a benefitharm balance modeling study to assess the expected 10-year risks above which statins provide net benefit for primary prevention of CVD. The results present higher risk thresholds for obtaining net benefit from statins than those advised in most current guidelines (1). However, a key limitation to the study emphasizes the need for cautious interpretation of their results and deserves further attention. The authors combined aggregated data from both randomized controlled trials (RCTs) and observational studies when estimating the benefits and harms of statins (1). However, there is a substantial discordance in rates of statin-related adverse events (AEs) between observational studies and RCTs, with much lower rates in the latter (2). Any result regarding statin-related AEs generated by observational studies should be interpreted with caution, because a causal relationship between statins and related AEs cannot be established. Patients recruited in observational studies are more likely to overreport AEs because of their awareness of and concerns about taking the medication, and nonspecific AEs could be falsely attributed to statin therapy (2). As clinical guidelines based predominantly on the existing evidence from RCTs are developed, the higher risk thresholds generated by Yebyo and colleagues can be attributed to the statistically significant harms of statins estimated in their study, including myopathy, renal and hepatic dysfunction, and cataracts, of which no excess risks have been shown in previous RCTs (13). The good safety profile of statins in RCTs further indicates that the purported AEs in observational studies may not be statin related. The nocebo effect suggested by a recent Lancet study may also partly explain the high AE rates in observational studies and clinical practice, which suggests that patients seem to perceive more AEs because of their negative expectations of statin treatment (4). Therefore, the statin-related harms in Yebyo and colleagues' study seem to be overestimated due to a large amount of observational data (1). This not only reduces the validity of their results but also brings a misleading message to both clinicians and patients. Given proven benefits of statins for primary prevention, an increased risk threshold for statin eligibility may impede appropriate use of statins in substantial numbers of people who may have a first CVD event that could otherwise have been prevented.