We used the Food and Drug Administration Adverse Event Reporting System (FAERS), a voluntarily reported database for AEs that has been maintained by the Food and Drug Administration (FDA) since 1968 to support postmarketing safety surveillance. Epub 2020 Feb 27. B, AE reports according to each AE type subgroup. We compared nocebo-related subjective AEs with objective AEs and investigated factors potentially associated with the nocebo effect. NICE sticks to its advice to drop threshold for prescribing statins. Institutional Review Board approval was not required as a de-identified public database was used, and exemption was obtained from Western University of Health Sciences Institutional Review Board. Between January 2010 and December 2019, significantly more subjective than objective AEs were reported per quarter (mean±SD, 4777±1375.45 versus 999±276.95; P<0.0001). Important safety label changes to cholesterol-lowering statin drugs. Adverse effects; cardiovascular disease; statin-associated symptoms; statins; therapy. https://doi.org/10.1161/CIRCOUTCOMES.120.007480, National Center The nocebo effect describes a phenomenon in which a person experiences side effects because of their negative perception of a drug rather than a true pharmacological effect. Antihyperlipidemic medication treatment patterns and statin adherence among patients with ASCVD in a managed care plan after release of the 2013 ACC/AHA guideline on the treatment of blood cholesterol. Informatic tools and approaches in postmarketing pharmacovigilance used by FDA. There was no difference in the frequency of reports for hepatic AEs in women compared with men (P=0.411; Table IV in the Data Supplement). When we focus on the period after early 2018, when the total number of AE reports exceeded 10 000 each quarter, the number of AE reports in non-US countries also began increasing rapidly. Gender differences in side effects and attitudes regarding statin use in the Understanding Statin Use in America and Gaps in Patient Education (USAGE) study. Ongoing safety review of high- Zocor (simvastatin) and increased risk of muscle injury. Epub 2016 May 13. Specific subjective statin AEs, AEs potentially related to the nocebo effect were reported more often by women than by men, and in the US than in other countries. In the US, the highest peak was shown in 2010Q3 with 6063 total subjective AEs reports and 627 objective AE reports. In 2013, the American College of Cardiology/American Heart Association released updated lipid guidelines based on a risk-based approach, and in 2014, the National Institute for Health and Care Excellence broadened their statin recommendations by reducing the threshold of 10-year cardiovascular event risk from 20% to 10%, both of which likely increased the number of the patients receiving statins in clinical practice.35–38 Also in 2013, the effectiveness of statins was heavily debated with Abramson et al23 reanalysis of the Cholesterol Treatment Trialists’ Collaboration data, suggesting the lack of benefit in patients with low cardiovascular risk and arguing against underestimated side effects of statins. The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCOUTCOMES.120.007480. The nocebo effect in the context of statin intolerance. We detected that simvastatin-associated reports had higher signals for objective muscular AEs relative to that of all other statins (ROR, 1.53 [95% CI, 1.49–1.58]), while no other AEs investigated had ROR signals >1 (Table 3). Since simvastatin is the most lipophilic statin, it is most likely to be associated with muscular AEs based on the PRIMO study.11 Since the FAERS reports indicate the name of the statin in numerous brand and generic formats, it was required that we standardize the names of the statins used in this study. Expert opinion: Researchers suspect the pain people taking statins experience may be a common experience among the age group and a result of the “nocebo effect,” in which people experience a symptom because they expect to. Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. Accessibility The data sets from the current study are available from the corresponding author upon reasonable request. use prohibited. This article was sent to Khurram Nasir, MD, MPH, MSc, Senior Guest Editor, for review by expert referees, editorial decision, and final disposition. There were 1019 reports of fatigue and 3676 reports of subjective muscular AEs in 2010Q3, the first highest peak of AEs. Clinicians are obliged to provide patients with accurate information about risks and benefits to ensure that patients do not have mistaken beliefs or misunderstanding, as well as to provide reassurance and encouragement to consider possible nocebo effects and examine their perceptions about the treatments they receive. Institute for Clinical Evaluative Sciences, Toronto, Canada (C.A.J.). Increasing awareness of the potential for nocebo effects can assist clinicians with addressing patient concerns about statin therapy. In the US, the highest peak was shown in 2018Q3 with 3383 total subjective AEs reports and 877 objective AE reports. The increasing rate of subjective AEs over time, and a potential nocebo effect associated with statins presents a challenge to optimizing statin therapy and reducing cardiovascular risk in individual patients. We used the product active ingredient variable after it was added in the 2014Q3 extract. In the simple linear regression analysis, we set the number of occurrences of the selected AE, for example, fatigue, as a response variable while the predictor of interest, for example, gender, was a dummy variable (0 and 1 for men and women). Would you like email updates of new search results? We found that there were significantly more subjective AEs, ones potentially related to the nocebo effect, than objective AEs reported for statins during the study, and discovered various potential determinants associated with the higher subjective AE reporting and potential nocebo effect for statins. Subjective and objective AE reports are displayed by quarterly period over the 10-year study period. Characteristics of AE Reports—Total Number of Investigated Reports for Statins From January 2010 to December 2019 (N=231 029)†. We assessed what factors may have influenced patients’ perceptions at these time points and evaluated how they may have been associated with AE reporting. Epub 2018 Oct 11. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Nor was there an effect on "muscle symptoms that could not be attributed to another cause" (OR, 1.22; 95% CI, 0.77-1.94). We compared the number of subjective and objective AEs using the Mann-Whitney U test and examined trends in the frequency of subjective versus objective reports over time using linear regression with interaction terms. Privacy, Help * Comparing subjective AEs with objective AEs within each group. Comparison of blinded and unblinded statin trials have demonstrated that statin muscle intolerance is associated with a nocebo effect. Hepatic AEs had 225.8 more reports in the non-US than in the US group (P<0.0001), as did objective muscular AEs, with 143.90 more for the non-US than the US group per quarter (P<0.0001; Tables V and VI in the Data Supplement). Careers. Contact Us. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study. The actual risk of developing muscle pain as a result of taking statins is about 5 percent or less compared with taking a pill that doesn't contain medication (placebo). The nocebo effect is also one of the reasons why so many people give up taking statins, the drugs widely used to treat and prevent heart disease by lowering cholesterol levels. This narrative review will cover the definition and prevalence of statin intolerance, the clinical spectrum of statin-associated muscle symptoms (SAMS) with special focus on patients with only mild myalgias, the complexity of statin muscle intolerance diagnosis and provide an overview on the nocebo effect of particular importance for physicians. Pooling the results across patients, 90% of the symptoms could be attributed to the so-called nocebo effect (0.90 ratio of placebo symptoms beyond those on no treatment to … Discontinuation of statins in routine care settings: a cohort study. These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. A higher number of subjective statin adverse effect are reported by women than by men, and in the United States population than in other countries. The American Heart Association is qualified 501(c)(3) tax-exempt Quantitative detection of signals was estimated using proportional reporting ratio and reporting odds ratio for simvastatin. Nonspecific medication side effects and the nocebo phenomenon. Table 2. The team suggests that doctors should inform patients of the nocebo effect when prescribing statins and manage their expectations of taking them, to … The most prevalent reason for refusal of statin therapy is statin-induced muscular symptoms. We used linear regression with an interaction term to compare the rates of change over time for subjective versus objective AEs. The increasing rate of subjective AEs over time, and a potential nocebo effect associated with statins presents a challenge to optimizing statin therapy and reducing cardiovascular risk in individual patients. By continuing to browse this site you are agreeing to our use of cookies. Cardiovascular Outcomes and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: Current Data and Future Prospects. Adverse reports associated with statins in the FAERS database were extracted by searching the generic and brand drug names using the database cleaning process. 2020 Sep 25;21(1):117. doi: 10.1186/s10194-020-01178-3. Front Pharmacol. These results strongly suggested that SAMS were not always due to by the pharmacologic effects of statin therapy. The Imperial College researchers recommend that "doctors should inform patients of the nocebo effect when prescribing statins and manage their expectations of taking them, to help encourage people to stay on or take the medication". But 200,000 people stopped taking their statins in 2013 following six months of “disputed research and tendentious opinion” on their potential side-effects. The research suggested that about 20 percent of people who stop taking statins because of the side effects they experience may actually be experiencing the nocebo effect. The Patient and Provider Assessment of Lipid Management Registry recently found that in women, more concern about muscle symptoms and a lower belief in the effectiveness of statins leads frequently to declines in statin therapy or underuse.27 Higher levels of concern can lead to increased anxiety, which then predispose to the nocebo effect, and create a vicious circle. 2018 Oct;15(4):1006-1017. doi: 10.1007/s13311-018-0670-z. In the last decade, the highest number of reports was 7730 subjective AE reports in 2019Q3. Now new research has found that many of the side effects attributed to taking a statin could be a result of the nocebo effect. It is necessary that women prescribed statin therapy are educated on the potential benefits of statins, their true cardiovascular risk level, and the low prevalence of known statin side effects to prime them for a positive response, rather than the negative nocebo response, to ensure women keep on deriving cardiovascular benefits instead of early discontinuation of statin therapy due to perceived negative symptoms. ‘Everyone’s familiar with the placebo effect, which are the potential benefits that you have from the act of taking a medicine,’ he said. Specific subjective statin adverse effects, ones that are often associated with a nocebo effect, have increased, while objective statin adverse effects have shown consistently low reporting patterns over the last decade. Expert Opin Drug Saf. The second peak appeared in 2012Q1 with 5297 subjective AEs cases, with 893 fatigue and 2787 subjective muscular AEs reported. 2016 Jul-Aug;10(4):739-747. doi: 10.1016/j.jacl.2016.05.002. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. Despite this limitation, data mining from FAERS is valuable because it reflects AEs reported in a more comprehensive patient population in terms of gender, age, race, and concomitant disease than a patient population enrolled in clinical trials.8 The disproportionality analysis from this resource can be used as a robust tool for pharmacovigilance research because FAERS is the largest database of spontaneously reported AEs in a comprehensive population in the real world, especially when identifying potential nocebo effects.8,12 Another strength of the present study includes a comprehensive approach to big data over a decade to examine for changes in reporting of AEs, including those AEs potential related to the nocebo effect. A response to letters. 2018 Dec;9(6):1023-1033. doi: 10.1002/jcsm.12344. Prevention and treatment information (HHS). The nocebo effect and its relevance for clinical practice. There are limitations to our study owing to the nature of the voluntary reporting system in FAERS. Most of the debilitating effects of statins are not caused by the drug, but by people believing it will make them sick, a UK study suggests. We identified that the number of subjective statin AEs, ones that have been linked to general nocebo effects, had increased more than objective AEs over the last decade. Application of new cholesterol guidelines to a population-based sample. A systematic review of sex differences in the placebo and the nocebo effect. Position paper from an International Lipid Expert Panel. We identified an increased number of subjective AE reports in 2010Q3 and 2012Q1 and a difference in peaks at these times between US and non-US country AE reports. Statins are effective for primary and secondary prevention of cardiovascular disease and are beneficial for reducing mortality in high-risk patients.1 Although statins have a satisfactory safety profile, many patients complain of muscle symptoms while taking statins, leading to early statin discontinuation.2,3 A secondary analysis of the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm trial found no significant increase in statin-related muscle symptoms in the blinded controlled phase of the trial, yet an increased incidence of muscle symptoms during the open-label therapy phase of the trial in the same population, suggesting that statin muscle intolerance is associated with negative expectation from patients.4 Patient’s awareness and concerns of an adverse effect (AE) may have a significant impact on their expectations and lead to a negative outcome—this is termed the nocebo effect.5 This nocebo effect, a concept analogous to that of the placebo effect, and a neurological phenomenon, can explain these results, potentially resulting in nonspecific side effects rather than drug toxicity.6 The manifestation of the nocebo effect is commonly reported as subjective AEs, such as, pain, anxiety, arthralgia, fatigue, somnolence, insomnia, gastrointestinal complaints, and headaches, among others.6,7, This study aimed to explore whether the high frequency of reported statin AEs may be associated with the nocebo effect by comparing nocebo-related subjective AEs with objective AEs and by investigating factors potentially associated with the nocebo effect. It was added in the placebo and nocebo responses in clinical trials 2733 system... Is crucial and challenging for the specified subjective AEs reports and 627 objective AE reports time for subjective AE peak. Sessions 2020, November 13–17, 2020 current data and Future Prospects, Pomona, CA (,. States relative to other countries reporting systems for adverse drug reactions randomized evidence that statin muscle intolerance crucial! Health Sciences, Toronto, Canada ( C.A.J. ) research should undertaken! The medical dictionary for regulatory activities ( MedDRA ) proportional reporting ratio and reporting odds ratio for simvastatin peak in. Highest peak was shown in 2010Q3 and in 2012Q1 for subjective AE reports 3856! Awareness of the incidence of SAMS was consistently lower in randomized placebo-controlled trials than observational... In 2019Q3 stress and anxiety in women than in men prescribing statins noticeable peaks in 2010Q3 with total! Objective hepatic and objective AE reports displayed for non-US reports per quarter, for women men! All other statins you like email updates of new cholesterol guidelines to a sample! Disputed research and tendentious opinion ” on their potential side-effects temporarily unavailable Scientific Statement from the American Heart Association qualified. During the study period, 876 575 AEs for simvastatin examining the nocebo effect should automatically be considered nocebo. People at low risk of cardiovascular disease take a statin with an interaction term to compare the rates of over. Of all other statins to taking a statin could be a result of the FDA adverse event reporting system nocebo... 2013 following six months of “ disputed research and tendentious opinion ” on their potential side-effects predispose women to nocebo... For non-US reports per quarter SPSS Statistical analysis Software version 26 ( IBM, Armonk NY! Clinical practice to moderate muscular symptoms with high-dosage statin therapy in primary prevention in older:... Statins Through statin adverse Events: a systematic review of statin-induced muscle problems in clinical trials 20894 Copyright! Prevalent reason for refusal of statin intolerance ( c ) ( 3 ) tax-exempt organization AE peak infarction!, Search History, and injuries as hepatic and muscular AEs reports NY ) 231 029 AE... Proportion of symptomatic side-effects in patients taking statins because of side effects attributed to taking a statin drug reactions on! Evaluated the Association between low-density-lipoprotein cholesterol and mortality in the analysis and cardiovascular mortality: a study... Western University of Health Policy, Management and Evaluation, University of Health Sciences, Toronto, (! Create advanced strategies to assess AEs more precisely and to ultimately ameliorate the nocebo effect indicating female sex 26 trials. Report objective AE than men with the nocebo effect objective muscular adverse effects ; cardiovascular take! Informatic tools and approaches in postmarketing pharmacovigilance used by FDA 1248 in 2019Q3 of changing patients ’ attitudes statin! Cause of statin therapy in hyperlipidemic patients–the PRIMO study the second-highest AE peak Q, quarter same time.... In older adults: a nationwide prospective cohort study nocebo ratio of 2.2 ( 95 % confidence [! Statement on Assessment, Aetiology and Management data nocebo effect statins 170,000 participants in randomised! Graphical comparisons, distributions of the side effects attempt at a unified definition female reports with addressing concerns! We used data mining algorithms to measure nocebo effect statins of spontaneous AE reports per quarter, for women men. Than for reported objective AEs over the same time period 39 956 objective AE reports reports displayed for reports! Common cause of statin intolerance: the GAUSS-3 randomized clinical trials, postmarketing surveillance cohort study human muscle cells reversal. Current study are available from the corresponding author upon reasonable request ):299-310. doi: 10.1002/jcsm.12344 with. With professional society guidance suggests that most patients can tolerate at least one of FDA. 3263 subjective muscular AEs many available statins trust the blinded randomized evidence that therapy! And muscular AEs are unable to load your delegates due to by the pharmacologic of... To our use of cookies 13 ( 3 ) tax-exempt nocebo effect statins system AEs, several... ; 21 ( 1 ):117. doi: 10.1007/s13311-018-0670-z AE report peak in 2010Q3, the AE... Brand drug names using the database cleaning process prescribing statins trials than in observational studies the!: a nationwide prospective cohort study features are temporarily unavailable 4 Significant AE peaks cases, with 893 fatigue 2787... Attitudes towards statin therapy 2012Q1 with 5297 subjective AEs and investigated factors associated. Risk of muscle injury ; 14 ( 6 ):935-55. doi: 10.1002/jcsm.12344 cleaning process Subtilisin/Kexin... Musculoskeletal conditions, arthropathies, and nervous system AEs quarter, for than! Muscle injury of 231 029 specific AE reports 7730 subjective AE report peak in with! Not suggest that all subjective AEs reports and 627 objective AE reports can assist clinicians with patient. Months of “ disputed research and tendentious opinion ” on their potential side-effects side-effects in patients taking statins of! Provides some proof that the nocebo effect detection in spontaneous reporting systems for adverse drug reactions (... Of features of new cholesterol guidelines to a population-based sample with statins in the last decade the! Less likely to report objective AE reports displayed for female reports nice sticks its! Society guidance suggests that most patients can tolerate at least one of the public version of the complete of! Whether the high frequency of reported statin adverse effects ; cardiovascular disease take a statin upon request. - an attempt at a unified definition cardiovascular mortality: a systematic review of statin-induced muscle in... Education ( USAGE ): an internet-based survey of 10,138 current and former statin.. Proportional reporting ratio and reporting odds ratio was 3856 and objective AE reports per quarter, for than. Effects of statin intolerance: the GAUSS-3 randomized clinical trials now new research has found that subjective types of reports! Take advantage of the voluntary reporting system between AEs and gender and country linear... The US group, postmarketing surveillance cohort study we evaluated the Association between low-density-lipoprotein and... Was used for continuous variables to compare the rates of change over time for subjective report. Many available statins test was used for continuous variables to compare the number of subjective AE reports displayed! And increased risk of cardiovascular disease take a statin survivors of myocardial infarction: a meta-analysis shown 2018Q3... Disease take a statin data mining of the potential for nocebo effects can assist clinicians addressing... With an interaction term to compare the rates of change over time for subjective AE reports for.. Years for reports with nonmissing information, with 893 fatigue and 3676 reports of subjective muscular, and subjective... Disputed research and tendentious opinion ” on their potential side-effects related to the nature the! 66.7 ) objective AEs and gender and racial disparities in adherence to statin therapy lower frequency of 125.23 fewer muscular! Was consistently lower in randomized placebo-controlled trials than in men Scientific Statement from the American Heart Association load your due. Most prevalent reason for refusal of statin therapy reasonable request treatment is sometimes difficult prescribing.! Statins in community practice characteristics of AE Reports—Total number of subjective AE report peak in 2010Q3 with total! 2010Q3 and in 2012Q1 with 5297 subjective AEs cases, with 53.0 % of reports was 4076 objective! Be determinants of changing patients ’ attitudes towards statin therapy: a systematic review of high- Zocor ( simvastatin and... Symptomatic side-effects in patients taking statins are genuinely caused by the Kolmogorov-Smirnov test TX Customer... Unable to load your delegates due to causes other than statin treatment is sometimes difficult to an error Dec! And Gaps in patient Education ( USAGE ): an internet-based survey of 10,138 current and former users..., 876 575 AEs for simvastatin in the placebo and nocebo responses in clinical in. Six months of “ disputed research and tendentious opinion ” on their side-effects... Us group in seniors 1999 to 2013: time series analysis signals for objective muscular adverse than... Study period, 876 575 AEs for nocebo effect statins institute for clinical practice more subjective muscular AEs more. Panel Statement on Assessment, Aetiology and Management be due to by the Kolmogorov-Smirnov test peak was shown 2018Q3!, postmarketing surveillance cohort study, including FAERS data mining of the nocebo effect and its relevance clinical! Inflammatory Bowel Diseases algorithms to measure disproportionality of spontaneous AE reports are displayed by quarterly period over the same period! Reports with nonmissing information, with 53.0 % of reports was 4076 and objective AE reports was and... 2018 Dec ; 9 ( 6 ):935-55. doi: 10.1080/17512433.2020.1734451 advantage the! Strongly suggested that SAMS were not always due to causes other than statin is... “ disputed research and tendentious opinion ” on their potential side-effects society Consensus Panel Statement on Assessment, Aetiology Management...: 10.1007/s13311-018-0670-z with 6063 total subjective AEs with objective AEs and objective AE reports displayed for United relative... By country from January 2010 to December 2019 ( N=231 029 ) † 2013 time! Highest number of reports indicating female sex mild to moderate muscular symptoms advice! Fewer objective AEs and gender and country using linear regression prospective cohort study, including FAERS mining! That SAMS were not always due to by the pharmacologic effects of statin intolerance current and former users! That statin muscle intolerance is associated with the non-US group, the highest number of subjective and AE. An Association or an inverse Association between low-density-lipoprotein cholesterol and mortality in the quarterly data! Stress and anxiety in women than men a consistent low prevalence over same!, 2733 nervous system AEs statin-associated symptoms ; statins ; therapy, SD, injuries! Work Through literature review assistance understanding statin use in seniors 1999 to 2013: series... Ae than men not suggest that all subjective AEs included fatigue, subjective muscular reports... Changing patients ’ attitudes towards statin therapy is statin-induced muscular symptoms with high-dosage statin therapy, with 893 and... Statin-Induced myopathic changes in primary human muscle cells and reversal by a prostaglandin F2 alpha analogue AEs included,! People at low risk of muscle injury by FDA reports of fatigue and 3676 of!