FormalPara Key Summary Points

Why carry out this study?

The lipid-lowering efficacy of atorvastatin is well studied in clinical trials, yet many patients fail to meet their prescribed low-density lipoprotein-cholesterol (LDL-C) goals when atorvastatin is taken in a real-world setting.

The availability of atorvastatin as a generic formulation has facilitated widespread prescribing, increasing the need to understand medication-taking behavior of patients in the non-clinical setting.

The aim of this review was to identify literature that discussed: (1) patient adherence/persistence to atorvastatin in the real-world setting and the impact of adherence on lipid and efficacy outcomes; and (2) the influence of generic atorvastatin utilization on adherence/persistence and efficacy outcomes.

What was learned from the study?

Adherence to atorvastatin remains suboptimal; patients fail to achieve their LDL-C goals, leading to increased risk of cardiovascular events.

Adherence may be impacted by switching between generic and branded atorvastatin, but further long-term studies are required to confirm the real impact of generic atorvastatin usage on medication-taking behaviors.

Several gaps in the literature exist regarding factors responsible for poor adherence to atorvastatin and their impact on efficacy outcomes, and further studies and training initiatives are required to resolve these issues.

Introduction

Atorvastatin was first introduced to the market in 1996 and has been approved by regulatory agencies for use as a moderate-to-high intensity statin therapy (10–80 mg/day, respectively). The lipid-lowering efficacy of atorvastatin is well established, and patients receiving 10–80 mg/day generally experience dose-dependent reductions in low-density lipoprotein cholesterol (LDL-C) and total cholesterol, and small reductions in triglycerides [1, 2]. In addition, the long-term benefit and safety of atorvastatin for lowering cardiovascular (CV) risk have been demonstrated in > 80,000 patients across 11 CV clinical outcomes trials for both primary- and secondary-prevention patients, with and without comorbidities [3,4,5,6,7,8,9,10,11,12,13]. The landmark Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA) trial was terminated early after hypertensive patients with at least three additional CV risk factors demonstrated a 36% reduction in non-fatal myocardial infarction (MI) and fatal coronary heart disease (CHD) when atorvastatin (10 mg) was added to blood pressure-lowering regimens, versus patients receiving placebo [7]. Similarly, the Collaborative Atorvastatin Diabetes Study (CARDS) in patients with dyslipidemia and type 2 diabetes was terminated approximately 2 years early because patients treated with atorvastatin (10 mg) experienced a 37% reduction in the incidence of major CV events compared with those treated with placebo [11]. The benefits of more intensive atorvastatin therapy were later demonstrated in studies such as the Treatment to New Targets (TNT) study, where patients with clinical evidence of CHD receiving 80 mg atorvastatin experienced a 25% reduction in major CV events versus those receiving 10 mg atorvastatin [4]. Collectively, outcomes data have contributed to the development of clinical management guidelines for cardiovascular disease (CVD) [14,15,16] and resulted in > 400 subsequent clinical trials, accruing over 250 million patient-years of experience.

The patent for branded atorvastatin expired globally in November 2011, although the generic formulation was available as early as 2008 in South Korea [17]. Generic products are approved on the premise that they contain the same active compound as the branded product, their inactive ingredients are safe, they are pharmacokinetically bioequivalent (i.e. equivalent rate and extent of exposure) and they display no significant differences in efficacy or safety, when administered at the same dose under the same conditions as branded drugs [18]. Generic products are deemed bioequivalent if the mean (and 95% confidence intervals) of maximum serum concentration (Cmax) and/or area under the curve (AUC) are contained within 80 to 125% range of the proprietary values [18]. The most commonly prescribed statins, namely atorvastatin, rosuvastatin and simvastatin, are all now available as generic products. It has been shown that the availability of generic statins directly influences prescription trends [19,20,21,22]. For example, in the UK, branded atorvastatin was the most prescribed statin formulation but was outcompeted by generic simvastatin introduced to the market in 2003, in accordance with National Institute for Health and Care Excellence (NICE) guidelines recommending usage of the statins with the lowest cost and highest efficacy [21]. With expiration of the global patent for branded atorvastatin and marketing of its generic formulation with cheaper acquisition costs, atorvastatin once again became the most frequently prescribed statin by healthcare professionals [21]. Similarly, in the USA and Korea, the availability of generic atorvastatin led to widespread prescribing [19, 22], and atorvastatin has remained the most frequently prescribed lipid-lowering drug worldwide.

The Problem of Adherence

‘Adherence’ is a crucial factor associated with gaining full therapeutic benefit from a medication regimen [23]. Patients are enrolled into randomized controlled trials (RCTs) under strict inclusion/exclusion criteria, and they remain closely monitored by medical staff responsible for ensuring protocol adherence. With a focus on outcomes, RCTs do not always report adherence (only 85% according to some reports [24]), and investigators often utilize different adherence assessments, which may preclude comparison between RCTs and/or with real-world observations [24, 25]. The 2016 European guidelines on CVD prevention recommend an LDL-C target of < 70 mg/dL for very high-risk patients, < 100 mg/dL for high-risk patients and < 115 mg/dL for remaining patients [26]. However, the EUROASPIRE V (2016–2017) survey that used these guidelines found that most patients had LDL-C levels ≥ 1.8 mmol/L (≥ 70 mg/dL) and that more than one-third (37%) had LDL-C levels ≥ 2.5 mmol/L (≥ 100 mg/dL), despite being classified as very high risk, 1 year after acute MI and/or acute myocardial ischemia [27]. Decades of clinical evidence with statin therapy is now available in electronic databases, enabling researchers to link real-world adherence with efficacy and outcomes [28, 29]. As such, there is now potential to determine the impact of non-adherence with atorvastatin therapy in the real-world setting by studying these reports.

The aim of this targeted review of the literature was to identify studies that report patient adherence to atorvastatin therapy in the real-world setting (i.e. non-clinical trial). Specifically, we sought to investigate reported barriers to LDL-C goal attainment and how adherence to atorvastatin therapy has been related to efficacy outcomes, in an attempt to better understand medication-taking behavior of patients prescribed atorvastatin. Specifically, in the advent of widespread prescribing of generic atorvastatin, we sought evidence reporting the impact that generic atorvastatin has had on adherence and (where available) other efficacy outcomes.

Methods

Targeted literature searches of the PubMed (www.ncbi.nlm.nih.gov/pubmed) database were performed, with a focus on the years following the introduction of generic atorvastatin (1 January 2009 to 1 January 2020). A search of available meeting abstracts was also conducted using the Web of Science (http://apps.webofknowledge.com/) database. Meeting abstract data were only available from the Web of Science database from 2010 onwards; therefore searches were conducted between 1 January 2010 and 1 January 2020. The patent for atorvastatin expired globally in November 2011, although some countries did produce generic products prior to this date (as early as March 2008 in South Korea). These date ranges selected for our targeted searches aimed to cover the period just before and after global patent expiration.

Relevant publications and congress materials were identified using a combination of key search terms in different strings (atorvastatin; Lipitor; adherence; compliance; persistence; generic; brand; cardiovascular outcome or event; low-density lipoprotein cholesterol/LDL/lipid; mortality; treatment satisfaction). Relevant literature was supplemented by the inclusion of published evidence identified from screening of the reference lists of identified literature at the time of publication. Literature from these targeted searches was first assessed for relevance in order to provide context for the background of the narrative review. Targeted searches were also carried out to specifically identify literature discussing adherence with branded versus generic atorvastatin. Titles and abstracts of all literature were screened. These articles were then taken forward for full-text screening to confirm relevance. Literature that focused on prescription trends, switching to a different statin (non-atorvastatin) therapy, genetic conditions, atorvastatin use in children or health economic outcomes were not included.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Defining Medication Adherence

Medication adherence and compliance have historically been used synonymously to describe ‘the extent to which the patient follows medical instructions’ [30]; however, in 2003 the World Health Organization expanded this definition to incorporate dietary and lifestyle factors, and to further distinguish adherence from compliance by emphasizing that agreement to the recommendations is required by the patient [30, 31]. Medication persistence refers to the duration of medication use, from initiation to discontinuation, for the prescribed duration [32]. These terms are used by medical professionals and other healthcare providers to give a comparative ‘guide’ to assess whether patients are taking their medication as prescribed. Although different methods for assessing adherence and persistence are still used in the medical literature [33,34,35,36] (see Electronic Supplementary Material [ESM] Table S1), taking medication in accordance with 100% of the prescribed regimen is rarely achieved in the real-world setting [30, 37]. Consequently, patients will not receive the full therapeutic benefit from their medications, which in CVD means they remain at higher risk for major CV events than if they took their medications as prescribed [38].

Atorvastatin: Real-world Adherence, LDL-C Goal Attainment and Outcomes

While the efficacy of atorvastatin has been demonstrated in several RCTs and meta-analyses [3,4,5,6,7,8,9,10,11,12,13, 39, 40], LDL-C goal attainment remains inadequate in a real-world setting [41,42,43,44,45,46,47,48,49,50,51,52,53,54]. For example, a cross-sectional, observational study of 1849 outpatients from across Croatia who were receiving statins reported that although nearly half of patients were taking atorvastatin (43%), LDL-C goal attainment was low (39%), especially among those at high CV risk (37%) [51]. The authors also reported that adherence was suboptimal overall, with only 35% of patients compliant with > 70% of their prescribed dose and just half (51%) being fully compliant [51].

Observations from the IDEAL study demonstrate how poor adherence to atorvastatin may be linked to increased CV risk. Although conducted in the clinical trial arena, IDEAL was a non-blinded, open-label study of atorvastatin (80 mg/day) versus simvastatin (40 mg/day), the results of which demonstrated high patient adherence (total study medication exposure as a percentage of follow-up time) of 89%, and a low discontinuation rate (14%) [5]. However, a subanalysis of IDEAL that adjusted for categorical adherence (above and below 80%, within each treatment arm) and censoring of the first occurrence of a CV event demonstrated a significant lowering of CV risk by 6% in patients with > 80% adherence [52].

Primary- and secondary-prevention patients have been compared to determine if a previous history of CV events drives better adherence in a real-world setting [53, 54]. For example, an analysis of 94,287 patients with dyslipidemia demonstrated that approximately 50% of patients were non-persistent with atorvastatin after the first year of treatment, with CV events occurring in approximately 2 and 9% of primary- and secondary-prevention patients, respectively [53]. Across both cohorts, patients who remained ‘adherent’ with their medication (taking a relatively conservative ≥ 60% proportion of days covered [PDC; ESM Table S1] in the year after initiation) were significantly less likely to experience CV events versus non-adherent patients, and the relative risk was 8% lower for secondry-prevention patients [53]. Similarly, a study of 500 patients newly prescribed atorvastatin found that those with a prior CV event or history of diabetes were significantly more adherent and persistent throughout the 6-month study period compared with patients without a history of comorbidities [54]. These results are consistent with observations from studies of other statins which demonstrate that secondary-prevention patients appear to appreciate the importance of managing CVD risk and are more likely to be adherent and persistent to these measures after experiencing CVD complications, as reviewed elsewhere [55]. There is a clear need to fully understand factors associated with poor adherence in order to help optimize adherence and CV risk factor management [56]. More recently, in an era where generic formulations have contributed to the increased utilization of statins [21], the influence of cheaper, generic statins on patients’ medication-taking behavior has become an additional consideration. Therefore, we specifically sought out literature that compared adherence and efficacy outcomes following use and/or switching to generic or non-generic atorvastatin therapy.

Comparing Adherence and Persistence with Branded Versus Generic Atorvastatin

Studies of adherence among patients prescribed atorvastatin have demonstrated that the switch from branded to generic atorvastatin had a mixed impact on adherence [57,58,59,60,61]. For example, a 6-month retrospective study analyzed adherence in 3417 patients on statin therapy (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) who switched from a branded to a generic formulation [57]. Patients with a medication possession ratio (MPR; ESM Table S1) ≥ 80% were considered to be ‘adherent.’ Of those who switched from a branded to generic formulation, the majority (52.3% [n = 1786/3417]) switched from branded to generic atorvastatin. While this study did not record adherence data for each specific type of statin, combined data showed that adherence was below optimal for one in four statin users who switched from branded to generic formulations (75.4% with MPR ≥ 80%) [57]. Many factors were identified that affected adherence, such as previous compliance with statin therapy [57].

Studies of patients who switched from branded to generic atorvastatin have also shown that switching may change patients’ adherence [57,58,59,60,61] (Table 1). For example, an 18-month non-interventional real-world study conducted in Greece by Tsioufis et al. compared the adherence of patients who continued taking branded atorvastatin with those who switched to generic atorvastatin [58]. In this study, patients remaining on branded atorvastatin therapy were more persistent than those switched to generic atorvastatin (76.4 vs. 90.1%; p = 0.1627) and significantly more adherent using both PDC (73.0 vs. 79.1; p < 0.001) and the Morisky Medication Adherence Scale-4 (MMAS-4; 73.7 vs. 26.3%; p < 0.001), although adherence remained suboptimal (< 80% across both the PDC and MMAS-4) (Table 1; ESM Table S1) [58]. Conversely, a shorter observational study (180 days) by Mano et al. in Japanese patients showed higher adherence, albeit non-significant (92.2 vs. 89.4%; p = 0.058) and persistence (75.6 vs. 67.3%; p = 0.097) in patients who switched to generic atorvastatin [59] (Table 1). Mano et al. also reported a higher overall adherence in both cohorts than seen in the longer-term study by Tsioufis et al. It appears that the first 180 days of follow-up is the most critical period in determining whether patients become non-adherent or discontinue treatment [62, 63], which reflects the observation that patient adherence decreases as time progresses [23]. Why switching to a generic medication could impact adherence and/or persistence may be a consequence of changes to medication appearance (tablet color, shape and packaging) throughout treatment, leading to patient confusion [64]. Therefore, it is important to consider how adherence is impacted in patients who were not switched, but rather initiated on either branded or generic atorvastatin [60, 61] (Table 1). Results from a Korean study utilizing insurance claims data of 747 patients showed that those who were newly prescribed generic atorvastatin had a significantly lower coverage ratio than those prescribed branded atorvastatin (Table 1) [61]. These results are consistent with those from another study of Spanish patients who were prescribed either a branded or generic statin, and further highlighted the impact of poor adherence with a generic formulation on lipid and CV outcomes [65].

Table 1 Studies reporting data on adherence, persistence or compliance in patients taking branded or generic atorvastatin
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Comparing Efficacy and Safety Observations with Branded Versus Generic Atorvastatin

Our literature searches identified studies reporting patient adherence and persistence with branded or generic atorvastatin, but these rarely included data on changes in lipid levels [2, 66, 67] (Table 2). Two observational studies provided lipid data for patients who switched from branded to generic atorvastatin over a period of 1–3 months, with the authors reporting no significant difference in LDL-C or triglyceride levels after switching to generic atorvastatin (Table 2) [2, 67].

Table 2 Studies reporting lipid outcomes in patients taking branded or generic atorvastatin
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While it is not clear why adverse events (AEs) may occur upon switching in some patients, differences in excipients may cause adverse reactions [68]. Four RCTs comparing branded versus generic atorvastatin reported myalgia as an AE, with a slightly higher prevalence in the generic cohort, although no formal analyses were conducted [69,70,71,72]. Historically, patients may report concerns around AEs as a factor impacting adherence [73], although we did not identify any studies that included patient perspectives of generic versus branded atorvastatin. The so-called ‘nocebo’ effect may negatively impact how patients or physicians perceive branded or generic treatment. In a non-blinded extension phase of the ASCOT-LLA trial, wherein patients knew they were receiving atorvastatin, trialists observed increased reporting of muscle-related AEs versus when patients were in the blinded phase and did not know if they were receiving a placebo or statin therapy [74]. The authors attributed this to the nocebo effect, as during the blinded phase of ASCOT-LLA, muscle symptoms, as well as other AEs such as sleep disturbance, cognitive impairment and erectile dysfunction, were reported at a similar rate in both the placebo and atorvastatin arm [74]. The nocebo effect has also been documented in patients who switch from other branded to generic medications, resulting in reduced effectiveness and increased reported AEs as a consequence of a negative bias toward generic products [75, 76].

When looking at longer-term outcomes, a single study by Jackevicius et al. [60] that enrolled patients aged ≥ 65 years with acute coronary syndrome and prescribed either branded or generic atorvastatin upon discharge from hospital showed that both cohorts remained adherent with their medications, with an identical MPR of 88.4% [60] (Table 1). Patients taking branded or generic atorvastatin had an equivalent rate of MI/angina (17.7% for both), heart failure (6.3 vs. 6.6%), stroke (1.6 vs. 1.9%) or overall mortality (11.6%), which might be anticipated given the similar MPR [60]. No other articles were identified that monitored the long-term CV outcomes of branded versus generic atorvastatin. However, similar to the conclusions drawn by Jackevicius et al., a study by Corrao et al. [77] that followed 13,799 patients newly prescribed generic or branded simvastatin showed no difference in persistence or CV outcomes over a 3-year period. It has been shown that patients are more likely to adhere to their statin treatment regimen following a cardiac event [56, 78, 79] and that statin patients following an MI are approximately 10% more adherent than primary treatment patients [80].

What Evidence is Needed to Help Improve Adherence in the Real-World Setting: Gaps in the Literature

In this review we highlight that many barriers to adherence occur throughout the initiation, execution and persistence stages of treatment [30, 81, 82]. These factors have been reviewed extensively elsewhere and have been broadly characterized into five interacting factors [30]: patient-related (lifestyle, perceptions), socio-economic (demographics, costs, family, country, conflict), therapy-related (side effects, treatment regimen/concomitant medications, type of statin [formulation, branded, generic], dose), condition-related (disabilities, disease severity, comorbidities, access to treatment) and healthcare-related factors (patient interactions, physician perceptions of therapy effectiveness, clinical inertia) [23, 30, 55, 83, 84].

However, we also highlight a paucity of data directly comparing real-world adherence with atorvastatin to longer-term lipid and CV outcomes and, in addition, whether the introduction and use of generic formulations has impacted CV morbidity and mortality. The conclusions reported here are drawn from mixed sources depending on available studies, but we highlight a number of gaps in the literature that could be addressed by future studies in this area (Table 3).

Table 3 Barriers to adherence with atorvastatin therapy: gaps in the current literature
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The literature on outcomes in patients who initiated or switched between branded atorvastatin and its generic version was also sparse; instead, we frequently found studies focusing on therapeutic substitution (switching between different types of statin) [85,86,87,88,89,90,91,92,93,94]. Studies that saw improved adherence with switching therapies highlighted associations with increasing age, prior CVD and polypharmacy, with the authors suggesting that patients who are switched may receive more attention at the pharmacy [95]. In patients initiated on generic statins, lower out-of-pocket expenses have been associated with improved adherence and persistence [88, 96]. Conversely, variability in excipients and co-payment effects are potential hurdles to compliance upon switching statin therapy [65]. Real-world observational studies are needed which monitor adherence and persistence alongside lipid outcomes and therapeutic goal attainment, but also factor in these barriers to adherence (Table 3).

How Can Healthcare Providers Work to Improve Adherence in the Real-World Setting? Practical Advice for Improving Statin Therapy Adherence

Although physicians are aware of the importance of treatment optimization, additional factors more specific to lipid-lowering therapies should be considered. For example, patients with dyslipidemia do not have immediate ‘feedback’ to recognize/feel improvements in their condition associated with lipid-lowering therapy. This lack of perceived benefit may negatively impact adherence [63, 97]; therefore, a blood test and follow-up assessment are required to confirm if patients are taking medications as prescribed [16]. Subsequent appointments may be needed to further allow healthcare providers to consult patients about their medication adherence and to discuss reasons for non-adherence, all of which require active benefit on the part of both patient and prescriber. A patient–physician interaction provides the physician with an opportunity to consider changes to the treatment regimen (e.g. up-titration, concomitant therapy, monitoring of AEs) or, if needed, to provide further support (e.g. counseling, reminders, support group sessions, involving family) to ensure adherence to achieve recommended treatment targets [16, 98]. The relationship between patient and physician should be based on both verbal and non-verbal communication (‘body language’) aimed at increasing patient understanding of their disease and the risks and benefits of the chosen treatment [99]. Mutual collaboration between patient and healthcare provider can not only reduce the risks of non-adherence, but also improve patient satisfaction with therapy and, ultimately, patients’ healthcare outcomes [99]. Healthcare providers should also consider the demographics of their patients. For instance, while statins are increasingly used in some children (aged > 10 years), particularly those with genetic lipid disorders [100], limited data are available on adherence in this patient population. Considerations of age-appropriate formulations, weight-appropriate dosing, acceptability, palatability and the role of their parents/carers are critical for improving adherence in the pediatric population, and further studies are required to understand their influence with real-world statin usage [101, 102]. This trust is especially important for statin patients, as chronic medication regimens, fear of AEs and polypharmacy are all factors linked to poor adherence [103].

Patient perceptions also influence adherence to statins and are intrinsically tied to treatment-related factors [23, 30, 83]. Studies are needed that link patient’s perception and preference with their statin formulation to adherence. When focusing on generic versus branded atorvastatin therapy, we were unable to identify any studies that included a survey of patient preferences or perceptions of their atorvastatin medication (i.e. perceived benefit or need) (Table 3). In this review of the literature, only a single study by Tsioufis et al. was identified that reported both atorvastatin adherence and treatment satisfaction data [58]. In this study of 190 patients from Greece, the authors report that global patient satisfaction and perceived effectiveness, measured by the Treatment Satisfaction Questionnaire for Medication (TSQM), in those who did not switch to generic atorvastatin was significantly higher versus those who switched (mean score 68 vs. 58, respectively; p < 0.001) [58]. These observations support the association between patient treatment satisfaction and greater treatment adherence/persistence, an association that has been noted in other non-atorvastatin studies [104, 105]. While most physicians discuss statin treatment with their patients, those patients who discontinue have reported being less satisfied with these discussions [106]. Thus, poor adherence as a consequence of patient perceptions is also closely tied to interactions with their physician and may be compounded by a non-perceived benefit and/or medical distrust [83]. On balance, it remains unclear whether the prescription of generic or branded atorvastatin influences adherence in a real-world setting. Studies investigating patient perceptions would help physicians understand this patient-related barrier to adherence with atorvastatin therapy (Table 3).

Conclusions

Adherence to atorvastatin remains suboptimal in the real-world setting, and the introduction of generic formulations adds further complexity to the multifaceted issues around poor adherence. There are clear gaps in the literature concerning the factors responsible for poor adherence and their impact on efficacy outcomes, including data on cost, long-term usage, patient perspectives and polypharmacy. Furthermore, we highlight a paucity of real-world data from comparisons between initiation with branded or generic atorvastatin and the impact on adherence/persistence and lipid/CV outcomes. However, healthcare providers should consider the potential impact on adherence of switching patients between branded and generic medications. Targeted education initiatives and additional research are still needed with the aim to improve adherence to atorvastatin in the clinical setting.