Patient perspectives on statin intolerance, attribution of the nocebo effect and use of N=1-interventions: a qualitative focus group study.

Statin Intolerance and Noncompliance: An Empiric Approach

BackgroundThe ‘placebo effect’ and ‘nocebo effect’ are phenomena whereby beneficial (placebo) or adverse (nocebo) effects result from the expectation that an inert substance will relieve or cause a particular symptom. These terms are often inappropriately applied to effects experienced on drug therapy. Quantifying the magnitude of placebo and nocebo effects in clinical trials is problematic because it requires a ‘no treatment’ arm. To overcome the difficulties associated with measuring the nocebo effect, and the fact that its definition refers to inert compounds, rather than drugs, we introduce the concept of ‘drucebo’ (a combination of DRUg and plaCEBO or noCEBO) to relate to beneficial or adverse effects of a drug, which result from expectation and are not pharmacologically caused by the drug. As an initial application of the concept, we have estimated the contribution of the drucebo effect to statin discontinuation and statin‐induced muscle symptoms by performing a systematic review of randomized controlled trial of statin therapy.MethodsThis preferred reporting items for systematic reviews and meta‐analysis‐compliant systematic review was prospectively registered in PROSPERO (CRD42017082700). We searched PubMed and Cochrane Central from inception until 3 January 2018 using a search strategy designed to detect studies including the concepts (Statins AND Placebo AND muscle pain). We included studies that allowed us to quantify the drucebo effect for adverse muscle symptoms of statins by (i) comparing reported rates of muscle symptoms in blinded and unblinded phases of randomized controlled trials and (ii) comparing rates of muscle symptoms at baseline and during blinded therapy in trials that included patients with objectively confirmed statin intolerance at baseline. Extraction was performed by two researchers with disagreements settled by a third reviewer.ResultsFive studies allowed the estimation of the drucebo effect. All trials demonstrated an excess of side effects under open‐label conditions. The contribution of the drucebo effect to statin‐associated muscle pain ranged between 38% and 78%. The heterogeneity of study methods, outcomes, and reporting did not allow for quantitative synthesis (meta‐analysis) of the results.ConclusionsThe drucebo effect may be useful in evaluating the safety and efficacy of medicines. Diagnosis of the drucebo effect in patients presenting with statin intolerance will allow restoration of life‐prolonging lipid‐lowering therapy. Our study was limited by heterogeneity of included studies and lack of access to individual patient data. Further studies are necessary to better understand risk factors for and clinical management of the drucebo effect.

The ability of statins to reduce the morbidity and mortality of cardiovascular disease has ensured that they are among the most prescribed drugs in modern medicine. Unfortunately, most patients who start taking statins will end up stopping them, most commonly due to side effects. Confusingly, however, in blinded placebo-controlled trials, side effects appear no more common in those taking statins than those taking placebo. One possible explanation is that ever-present background symptoms are being falsely attributed to statins. However, another explanation is the nocebo effect, where the act of just taking a tablet (even a placebo) causes genuine side effects in patients. Two recent randomized placebo-controlled personalized (N-of-1) trials have been reported: StatinWise and SAMSON. In these trials, each participant was randomized to multiple periods of statin and placebo, with regular symptom burden assessments. Together, these trials support the existence of a significant nocebo effect from taking statins. Possibly even more importantly, they demonstrate the ability of personalized trials to inform and empower patients: up to half of the patients in these trials were able to successfully restart statins after taking part, despite previously having been statin intolerant. StatinWise and SAMSON have raised public awareness of the nocebo effect in statin intolerance. However, they also demonstrate a potential role for the personalized design outside of clinical trials. If taking part in these personalized experiments allows half of our patients to successfully restart life-saving medications, maybe we should be able to prescribe personalized experiments to our patients in the clinical setting?

Background: Dealing with statin intolerance represents a major clinical challenge. Controlled clinical trials suggest that a large percentage of statin intolerance may be due to a “nocebo effect”, wherein adverse reactions are linked to pill ingestion irrespective of actual pill content (e.g., SAMSON trial). We tested whether statin intolerance was associated with intolerance to other medications in a large real-world experience. We hypothesized that statin intolerance would be associated with multiple drug intolerances. Methods: We searched Intermountain Healthcare medical records between January 2002 and February 2021 for patients (pts) with a listed intolerance or allergy to 1 or more statins. We compared these to a control group of randomly selected pts not exposed to statins but taking one or more other oral medications. A second control group included all patients taking and tolerating statin therapy. We compared the number of recorded drug allergies/intolerances in the statin intolerant group with those in the 2 control groups. Results: Characteristics of patients in the 3 groups are shown in the Table. On average, statin intolerant patients had 3.64 additional listed drug allergies/intolerances (beyond statins), compared to 1.31 in non-statin exposed controls and 1.81 in the statin tolerant population (both p<.001). Conclusion: In this large real-world experience, statin intolerance was strongly associated with intolerance to multiple other medications. Although some patients may have a true intolerance to multiple medications, including statins, patients with multiple drug intolerances may also suffer from a generalized nocebo effect. In either case, noting a patient’s tendency toward multiple drug intolerances can alert clinicians to an increased intolerance risk when initiating a statin and can lead to preemptive medical and educational interventions aimed at reducing this risk.

Background: Despite proven efficacy and safety of statins for use in dyslipidemia patients, a significant proportion of patients report intolerance to statins leading to treatment discontinuation. In 2014, the National Lipid Association (NLA) Statin Intolerance (SI) Panel recognized a pressing need to better understand patient-centric experience of SI. We believe combining a clinical perspective with patient experience of SI provides a comprehensive view on management of SI. Objective: This abstract describes clinician’s perspective of SI and patients’ presentation of SI in clinical practice. Methods: Experts were identified based on publications in the CV and SI research area. Interviews were conducted with health care professionals with known expertise and practice experience in evaluating and treating patients with SI. Interviewers were trained to follow the open-ended, semi-structured guide. The experts summarized their professional background, defined and described characteristics of SI, and their current management of SI in clinical practice. Additionally, targeted probes by the interviewers obtained information pertinent to research questions not spontaneously reported by experts. Following the completion of coding, data were pooled and qualitatively analyzed for common themes. Results: Four physicians and one nurse practitioner participated in the interviews and reported that they had been treating patients for a range of 19-29 years. Each of the experts provided a unique definition of SI, and four (80.0%) reported that SI is different than experiencing side effects from statins. A total of 13 characteristics reflecting the patient experience with SI were identified from the expert perspective: muscle symptoms (muscle pain (n=5; 100%), muscle weakness (n=4; 80%), muscle cramps (n=1; 20%), fatigue (n=1; 20%)), CNS symptoms (forgetfulness (n=2; 40%), headache(n=1; 20%)), or GI symptoms (i.e.- (n=1; 20%), burping, constipation, diarrhea, gas, indigestion, reflux, or upset stomach ). Experts displayed common approaches to the management of SI patients, including changing the type of statin the patient was receiving, usually at a lower dose, and using alternative treatments either alone or in combination with a statin (n=5; 100%). Regardless of the strategies used for managing SI patients, four experts (80.0%) indicated that they encouraged their patients to continue using statins despite experiences of intolerance. Conclusions: This study reports the opinions of 5 experts with varying backgrounds concluding that SI is multi-faceted and primarily characterized in the context of muscle pain and weakness which is best assessed from the perspective of the patient. These results, in concert with results from a literature review and patient interviews, will inform a comprehensive and patient-centric understanding of SI and a measure to assess this phenomenon.

BackgroundSwitching to biosimilars is an effective and safe practice in treating inflammatory diseases; however, a nocebo effect may arise as a result of the way in which the switch is communicated to a given patient.ObjectiveWe aimed to design a gaming-based digital educational tool (including a discussion algorithm) to support the training of health care professionals in efficiently communicating the switch to biosimilars, minimizing the generation of a nocebo effect and thus serving as an implementation strategy for the recommended switch.MethodsThe tool was developed based on interviews and focus group discussions with key stakeholders, both patients and health care professionals. Messages likely to either generate trust or to trigger a nocebo effect were generated on the basis of the interviews and focus group discussions.ResultsA total 7 clinicians and 4 nurses specializing in rheumatology, gastroenterology, and dermatology, with balanced levels of responsibility and experience, as well as balance between geographic regions, participated in the structured direct interviews and provided a list of arguments they commonly used, or saw used, to justify the switching, and objections given by the patients they attended. Patients with immune-mediated inflammatory diseases who were taking biologic drugs with (n=4) and without (n=5) experience in switching attended the focus groups and interviews. Major topics of discussion were the reason for the change, the nature of biosimilars, and their quality, safety, efficacy, and cost. Based on these discussions, a list of objections and of potential arguments was produced. Patients and health care professionals rated the arguments for their potential to evoke trust or a nocebo effect. Two sets of arguments, related to savings and sustainability, showed discrepant ratings between patients and health care professionals. Objections and arguments were organized by categories and incorporated into the tool as algorithms. The educators then developed additional arguments (with inadequate answers) to complement the valid ones worked on in the focus groups. The tool was then developed as a collection of clinical situations or vignettes that appear randomly to the user, who then has to choose an argument to counteract the given objections. After each interaction, the tool provides feedback. The tool was further supported by accredited medical training on biosimilars and switching.ConclusionsWe have developed a digital training tool to improve communication on switching to biosimilars in the clinic and prevent a nocebo effect based on broad and in-depth experiences of patients and health care professionals. The validation of this implementation strategy is ongoing.

The management of low-density lipoprotein cholesterol (LDL-C) levels is a central strategy for the prevention of atherosclerotic cardiovascular disease. Current United States (2018 American Heart Association/American College of Cardiology/Multisociety) and European (2019 European Society of Cardiology/European Atherosclerosis Society) guidelines endorse statin therapy as the first-line therapy for pharmacologic LDL-C lowering. However, in clinical practice up to 30% of patients report partial or complete intolerance to statin therapy. While the nocebo effect with statins is well described, perceived statin intolerance prevents many patients from achieving LDL-C thresholds associated with clinical benefit. Bempedoic acid is a novel, oral, non-statin lipid-l owering therapy that works by inhibiting adenosine triphosphate-citrate lyase, an enzymatic reaction upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the hepatic cholesterol synthesis pathway. Bempedoic acid confers reduction in LDL-C of ~18% on background statin therapy,~21% in patients with statin intolerance, and ~38% when given in fixed-dose combination with ezetimibe. The CLEAR Outcomes trial, which enrolled high-risk primary and secondary prevention patients with reported statin intolerance and LDL-C levels ≥100 mg/dL, showed that bempedoic acid compared with placebo reduced 4-component major adverse cardiovascular events (MACE) by 13% (hazard ratio 0.87, 95% confidence interval 0.79-0.96). Bempedoic acid also reduced 3-component MACE by 15%, myocardial infarction by 23% and coronary revascularization by 19%. The benefit was even greater in the primary prevention cohort (hazard ratio 0.70, 95% confidence interval 0.55-0.89) for 4-component MACE. Bempedoic acid was associated with increases in uric acid levels and cholelithiasis, but numerically fewer events of myalgia and new-onset diabetes. These findings confirm that bempedoic acid is an effective approach to reduce cardiovascular outcomes in high-risk patients with statin intolerance who require further reduction in LDL-C.

The nocebo effect in the context of statin intolerance

Statins are highly effective therapies for reducing low-density lipoprotein cholesterol and preventing cardiovascular events. However, many patients taking statins experience statin-associated muscle symptoms. In the current manuscript, we review algorithms to define statin intolerance and approaches to optimize cardiovascular risk reduction and reduce the nocebo effect among individuals reporting statin-associated muscle pain. Patients with statin intolerance have a higher cardiovascular event risk. These data underscore the need to apply clinical strategies that improve treatment utilization and adherence of patients experiencing statin-related side effects. Recent data have shown that the nocebo effect is frequent with statin therapy. This may be explained by the high frequency of muscle symptoms in the general population and media misinformation. When statins even at a low dosage are not tolerated other therapies can be used such as fibrate, ezetimibe nutraceuticals and antiPCSK9 antibodies. Recent data have identified other alternative therapeutic strategies such as bempedoic acid. There are multiple strategies for the management of statin-intolerance, both pharmacological and nonpharmacological. Patient involvement in the justification of statin treatment indication and therapeutic choice is the first step to overcome misbelief and reduce nocebo effect.

Does Googling lead to statin intolerance?

Introduction and purpose of review: Statins are widely used drugs in the prevention of cardiovascular diseases, yet many patients experience side effects of statin use, mainly muscle symptoms, such as myopathy, which often lead to discontinuation of treatment. The aim of this literature review is to assess the role of the nocebo effect in reported muscle symptoms and its impact on statin discontinuation in patients with cardiovascular diseases. Methods: The review analysed the results of several studies, including key publications such as the N-of-1 trial by Wood et al.[1] and the work of Collins et al.[2] on the safety and efficacy of statin therapy. The review covered articles published between 2000 and 2023 that examined the impact of the nocebo effect on statin discontinuation[3-10]. Results: The collected data indicate that the nocebo effect plays a significant role in the reported muscle symptoms during statin use. The study by Wood et al.[1] showed no significant differences in reported symptoms between the groups taking statins, placebo, or receiving no treatment, suggesting that a substantial portion of the symptoms results from the nocebo effect. Similar findings were obtained in the study conducted by the StatinWISE group[4], where patients taking statins and placebo reported a comparable frequency of muscle symptoms. An analysis conducted by Collins et al.[2] indicates that the actual incidence of myopathy associated with statin therapy is much lower than commonly reported. Conclusions: The nocebo effect significantly influences the perceived adverse effects of statins, which may lead to the unjustified discontinuation of these drugs by patients with cardiovascular diseases. Further research is needed to better understand the psychological mechanisms affecting statin tolerance and to develop educational and clinical strategies aimed at minimizing the nocebo effect and improving long-term adherence to therapy.

Barrett's esophagus is a premalignant condition in the lower part of the esophagus, caused by gastroesophageal reflux disease. Previous studies found that having a Barrett's esophagus is associated with a significant decrease of health-related quality of life (HRQOL). Over the past decade, a considerable amount of literature has been published on the development of endoscopic treatment for (early) neoplasia in Barrett's esophagus. Though, currently very little is known about the impact of those endoscopic treatments on HRQOL from the perspective of patients. In this study, we aim to assess the factors influencing HRQOL according to Barrett's esophagus patients. By using a qualitative focus group design, patients with nondysplastic Barrett's esophagus and patients with a history of endoscopic treatment for Barrett's dysplasia were included. Data were analysed following the conventional content analyses approach. A total of 34 patients participated in the four focus group sessions. Experiencing symptoms was valued as the most important factor in both groups. Other factors identified as important HRQOL influencers were: use of medication, fear of cancer and trust in physicians and endoscopic procedures. In general, Barrett's esophagus patients experienced a good HRQOL, with a minimal emotional burden from the diagnosis of Barrett's esophagus. Most influencing factor on HRQOL was: experiencing reflux and dyspepsia symptoms. This study underlines the importance of adequate gastroesophageal reflux treatment and providing information to Barrett's esophagus patients, tailored to their personal needs.

BackgroundDespite important improvements in pharmacological care for patients with rheumatoid arthritis (RA), many patients with RA need additional care to achieve and maintain an optimal level of functioning (1). Delivery...

Background: The primary purpose of this study was to assess perceived burdens and benefits of participating in implementation research among staff employed in resource-constrained healthcare settings. Another objective was to use findings to generate considerations for engaging staff in research across different phases of implementation research. Methods: This qualitative focus group and consensus building study involved researchers affiliated with the National Cancer Institute Implementation Science Centers in Cancer Control program and nine Community Health Centers (CHCs) in Massachusetts. Six focus groups (n = 3 with CHC staff; n = 3 with researchers) assessed barriers and facilitators to staff participation in implementation research. During consensus discussions, we used findings to develop considerations for engaging staff as participants and partners throughout phases of implementation research. Results: Sixteen researchers and 14 staff participated in separate focus groups; nine researchers and seven staff participated in separate consensus discussions. Themes emerged across participant groups in three domains: (1) influences on research participation; (2) research burdens and benefits; and (3) ways to facilitate staff participation in research. Practical considerations included: (a) aligning research with organizational and staff values and priorities; (b) applying user-centered design to research methods; (c) building organizational and individual research capacity; and (d) offering equitable incentives for staff participation. Conclusions: Engaging staff as participants and partners across different phases of implementation research requires knowledge about what contributes to research burden and benefits and addressing context-specific burdens and benefits.

• Discontinuing statin therapy results in increased cardiovascular risk. • The nocebo effect is a common reason for perceived statin intolerance. • Statin intolerance is much less commonly reported in clinical trials than in clinical practice, suggesting that patient education and other safeguards employed in clinical trials are important to include in clinical practice. • Several strategies are available that can enable continuation of statin therapy in patients who are truly statin-intolerant.