In this study, disproportionality analysis revealed that Alirocumab may correlate with the neurocognitive disorder due to the presenting positive signal, while the total PCSK9 inhibitors and Evolocumab presented a negative signal with a weak correlation. From the report system, we retrieved 77 neurocognitive disorder outcome events which should pay more attention to the clinic, including primary and long-term hospitalization (7.79%), disability (3.90%) and life-threatening (1.30%). In addition, the origin of reports was summarized to accumulate more adverse event information of PCSK9 inhibitors in the real world.
Disproportionality signal can help to establish a new potentially causal association between PCSK9 inhibitors and neurocognitive disorder. Alirocumab was highly associated with the neurocognitive disorder, but Evolocumab was not related. This result is consistent with the finding obtained in two previous RCTs. The ODYSSEY LONG TERM trial indicated that Alirocumab caused a higher ratio of neurocognitive disorder occurrence than placebo. Another prospective study assessed the cognitive function of the patients, EBBINGHAUS trial concluded that there was no significant difference between the Evolocumab and placebo. In two large meta-analyses, Khan et al. (2016) and Lipinski et al. (2015) found that there was an increased occurrence of neurocognitive disorder after the usage of PCSK9 inhibitors[5, 19]. Although their result further supports the idea that there is a signal toward PCSK9 inhibitors associated with the neurocognitive disorder, they did not identify which PCSK9 inhibitor existed the potential relation with neurocognitive impairment. Our study is distinguishing from the anterior RCTs and meta-analysis study because we had comprehensively applied the pharmacovigilance study method to detect the drug-event signal. Thus, a larger amount of data can be obtained to reveal the hidden relationship between the adverse event and PCSK9 inhibitors. For example, the meta-analysis conducted by Lipinski et al. enrolled 17 RCTs, 13,083 patients participated, whereas, this study included 12,198,404 reports, which is much more than these four mentioned studies. Consequently, the sufficient real-world datasets can transform into valuable evidence to improve the insight of the medication effect.
However, there would be a concern that the signal of the Alirocumab report was a false positive. Alirocumab may not have any association with the neurocognitive disorder as Karatasakis A. et al. studied it. Their finding was based on a meta-analysis, which involved 21 RCTs including 42,668 patients who participated in analyzing neurocognitive adverse events. Some potential biases may lead to an alpha error in our study. For example, PCSK9 inhibitors were exclusively prescribed for very-high risk ASCVD patients for managing their LDL-C level, which caused the channelling bias. In addition, the notoriety bias was existed, because some stimulating reports were raised after the FDA had issued the surveillance. With the existence of the above bias, evaluating the false positive signal by a single study is impossible. But it can motivate the healthcare professionals to pay more attention to monitoring the neurocognitive dysfunction among the patients who received Alirocumab. The follow-up data and cognitive evaluation report are vital sources for case analysis then assessing the false positive signal. Moreover, the negative disproportion signal should not be interpreted as a safety endorsement[16, 17]. Although the signal of Evolocumab is negative, it cannot infer that neurocognitive disorder is unassociated with Evolocumab. Since disproportion analysis is only used for adverse signal detection and prioritization, it cannot identify the risk and mechanism of medicine. Therefore, establishing the causality of neurocognitive disorder and PCSK9 inhibitors should require more comprehensive evidence. Recent research proposed the mechanism that the neurocognitive adverse event may pose by sustained low LDL-C levels. While the treatment effect of PCSK9 inhibitor can promote the above process, thus neurocognitive dysfunction becomes the potential adverse event[12, 20]. Based on this mechanism and the disproportional analysis, it is necessary to keep vigilant for the usage of PCSK9 inhibitors in the clinic and record the effect. The collected data would further prove the causality of PCSK9 inhibitor and neurocognitive disorder.
From the traits of the report, neurocognitive adverse events occurred after a period of using PCSK9 inhibitors. We found that neurocognitive related events occurred among 5 patients within one year. This result matched those observed from Koren et al. They reviewed the OSLER-1 trial including 12,251 patients, and 8 patients presented neurocognitive disorder in the first year after using Evolocumab. However, data related to the onset time of Alirocumab have remained absent because many RCTs did not demonstrate the detailed information of adverse event onset time. Although the sample size of onset time was limited in this study, we still calculated the median for analysis, however, less valuable information was obtained. By analyzing the age of the patient provides, we find that the neurocognitive disorder was concentrated in the age of 45 to 64 patients. Normally, dementia would occur among the patient who is over 65 years old, except the Frontotemporal dementia because it can induce onset earlier[7, 22]. In addition, around 60% of reports were submitted by the healthcare professionals, the source of data was reliable. These reports may relate with the PCSK9 inhibition, but it lacks the follow-up data or the subsequent report. For example, whether the patients recovered after withdrawing the PCSK9 inhibitors. Therefore, it still requires more evidence.
Since PCSK9 inhibitor is pricy for patients, the potential adverse event possibly leads to the increasing of therapy cost, then patient life-quality would decrease. A systematic review concludes that although adverse events associated with PCSK9 inhibitors were rare in most outcome studies and RCTs, the severe events were still existing. Another research based on the real-world experience inferred that although the adverse effect did not interfere with the usage of PCSK9 inhibitors since it was rare, Gurgoze MT. et al. pointed out that balancing the long-term benefits and potential adverse events is a critical process. The rare adverse events should not be neglected, but the real-world data of PCSK9 inhibitors was limited. Thus, it is vital to collect more evidence of adverse events associated with PCSK9 inhibitor[24–26]. Here, we therefore advocate performing more drug pharmacovigilance programs for PCSK9 inhibitors, consequently, the awareness of those serious adverse effects among patients and clinicians will be enhanced, which is also beneficial for the patient to remain safe and reduce medical costs.
As real-world study is developed for post-approved drug surveillance, it performs differently from the RCTs in reflecting the real clinical treatment, especially for drug safety assessment[27, 28]. Since the real-world data is based on clinical observation, some rare but important clinical features can preserve as supplementary evidence to the pharmacovigilance study. Besides, real-world evidence also helps to provide a practical and persuasive clinical suggestions for healthcare professionals.
Although the recognition of the potential of big data analytics is rising, its application in pharmacovigilance research is still emerging. FAERS database might be a useful tool for pharmaceutical companies to collect related efficacy and safety information because the preserved data size and worldwide coverage of this database are conducive to provide robust evidence for the conduction of spontaneous reporting data analysis. Moreover, the substantial volume of data contributes to real-world study, in terms of saving the research cost and time compared with the RCTs[29, 30].
Data mining of the FAERS database can obtain the previously unknown, but clinically important drug and adverse events associations. Since the valuable information comes from the raw data, the application of data mining technology is vital for the pharmacovigilance study. Establishing the association between the drug and adverse event is a complex process, the connection requires deep investigation, such as the inducement mechanism. A disproportional signal is a symbol to guild the researchers to find out the new objective. With the comprehensive and multifaceted study, drug safety can be reached to a higher level.
There were several limitations in this study. First, the subjectivity is the main factor in drug-related adverse event research. As the FDA did not require the reporters should be an expert or professionals in pharmacovigilance activities, the quality of the adverse reports is particularly different. There might contain underreported or submitted with false and incomplete information. Second, the worldwide coverage of the FAERS may become a two-edged sword. It provides a substantial sample size, but the different reporting culture from different countries is another major source of heterogeneity, which affects the quality of the reports as well. Third, the causal relationship between medication and the adverse event may not consistent, because the report lacks relative evidence. Furthermore, the spontaneous reporting system cannot quantitatively measure the signals of neurocognitive disorder base on the total number of adverse reactions. It also cannot calculate the exact incidence of potential adverse events, the main reason is the spontaneous reporting system has insufficient exposure data, which corresponds to the denominator of incidence. Despite the above limitation, the FAERS database is still a reliable source of real-world data for the disproportional signal study. In the future pharmacovigilance study, the analysis for causality of PCSK9 inhibitor and neurocognitive disorder should together with clinical follow-up and cognitive function evaluation.