Therapeutic Substitution From Atorvastatin to Simvastatin: Impact on LDL Control

AJPB® Translating Evidence-Based Research Into Value-Based Decisions®March/April 2015
Volume 7
Issue 2

Evaluation of a therapeutic substitution from atorvastatin to simvastatin on low-density lipoprotein control, and assessment of program participation rates for a commercially insured population.

Use of generic drugs is an important tool in controlling healthcare costs. Switching patients from branded agents to generic therapeutic alternatives reduces pharmacy costs and has become a common cost control method. Lipid-lowering agents have been targeted for therapeutic substitution due both to their high cost to patients and payers1 and to the similarity of action among drugs within the statin class. However, questions have been raised about whether a switch from brand Lipitor (atorvastatin) to generic simvastatin would provide equal level of control of low-density lipoprotein (LDL) cholesterol. Therapeutic substitution programs for these agents are only appropriate if outcomes are comparable and clinical objectives are met.

Lipid levels and cardiovascular outcomes are directly related to statin dosing.2-4 The potency (lipid-lowering capacity/mg) of statins varies, so comparisons between agents requires the use of equipotent doses. Dose-response trials support the inference of equivalence between low-dose (10 mg to 20 mg) atorvastatin and mid-dose (20 mg to 40 mg) simvastatin to reduce LDL cholesterol levels.5-7

Previous studies of statin switches have demonstrated LDL outcomes consistent with this dose-response relationship. Statin interchange programs that decreased the average equipotent dose found unfavorable patient outcomes.8-10 From an analysis of prescription claims, Hess and colleagues observed that 38% of atorvastatin-to-simvastatin changes were to lower-potency doses, suggesting that greater caution is necessary for these interchanges.11 Several switch programs resulting in higher average equipotent doses documented superior lipid control, but applicability of these studies is limited because they involved switching to or from cerivastatin (Baycol), which was withdrawn from the market in August 2001.12,13

The studies that have investigated equipotent switches or comparisons have been insufficient to resolve outstanding questions. An observational trial described differences in outcomes between equipotent doses of atorvastatin and simvastatin but did not measure or control for lipid levels.14 A small audit of atorvastatin-to-simvastatin switches (n = 70) in the United Kingdom demonstrated substantial cost savings and did not demonstrate a significant impact on lipid control.15

Our research was conducted to evaluate the equivalence of lipid control (as measured by LDL serum levels) through retrospective observation of a commercially insured population that chose, for financial reasons, to interchange medications through a therapeutic substitution program. This study observed and evaluated the impact of a therapeutic substitution program from low-dose atorvastatin to simvastatin on lipid control. We hypothesized that patients switching to simvastatin would exhibit lipid control comparable to that achieved by equipotent atorvastatin therapy.

This study was reviewed and approved by Massachusetts General Hospital’s Institutional Review Board under protocol number 2008P001583. Subject records were deidentified and the study qualified for and was granted a waiver to informed consent.



The Massachusetts General Physicians Organization (MGPO) is a multi-specialty medical group consisting of more than 2000 physicians practicing at a large tertiary urban academic medical center.

Program Design

The MGPO implemented a therapeutic substitution program in 2007 as part of its efforts to address rising healthcare costs. This program, known as “Switch To,” assisted physicians in offering their patients access to lower-cost medications. The program was conducted as a standard-of-care medical management intervention, so design choices prioritized operational concerns over considerations related to subsequent research questions. The MGPO—in consultation with clinical experts—selected drugs with therapeutic alternatives that could be used to achieve comparable clinical outcomes at lower cost to patients and the health system. An interchange from atorvastatin 10 mg to simvastatin 20 mg was among the first suitable interchanges identified for the Switch To program, and is the focus of the current analysis. The program aimed to address patients prescribed atorvastatin before the introduction of generic mid-potency statins (pravastatin and simvastatin) to the US market in 2006.

Patients taking brand atorvastatin were identified from pharmacy claims from 3 large commercial payers made available to the program through existing pay-for-performance agreements. Contractual limitations prevented investigators from using claims to assess related issues such as drug costs or adherence. Patients who had claims for simvastatin before their current

atorvastatin therapy were excluded out of concern that it might signify a prior treatment failure. Pharmacy claims and health records were used to identify the predominant prescriber for each patient’s atorvastatin.

The predominant prescriber, most frequently the patient’s primary care physician, was invited by the program manager to review their patients in a secure Web tool and indicate which patients should be offered a switch to simvastatin. If the prescriber approved the change, 3 attempts were made to contact patients by phone, inviting them to switch. Letters were sent to patients who were not reached by phone, with instructions on how to opt out of switching. If the patient agreed to the switch by phone or did not opt out of the switch after a mailing, the program worked with the prescriber, the electronic medical record (EMR), and the patient’s pharmacy to effect the switch. After a switch, the program sent confirmation notices to patients and prescribers to support follow-up labs, and performed population-level surveillance for quality assurance purposes.

The study is a retrospective review of patient participation in the Switch To program and their subsequent lipid control. Patients identified by the Switch To program for having pharmacy claims for atorvastatin 10 mg and having at least 1 recorded LDL result before and after the intervention period met the inclusion criteria. Patients were excluded from the analysis if their physician requested an alternate simvastatin dosing regimen. Also excluded were patients whom the program recorded as switching to simvastatin, but whose medical records indicated that they did not switch, or switched back to atorvastatin.

Demographics and lipid lab results were obtained from the EMR, and the EMR information was combined with pharmacy insurance claims information to evaluate previous and current medication use. The Switch To program recorded outreach efforts and physician and patient responses, though neither physicians nor patients were asked to explain the reasoning underlying their decisions.

The change between average pre-intervention and average post intervention LDL levels was the primary outcome of interest. Average LDL levels were calculated from the subjects’ medical records, during periods when the patients were taking atorvastatin or simvastatin. We were also interested in the participation rates at each stage of the program to quantify the effectiveness of the Switch To program.


The pre- and post intervention periods were defined relative to the date that the patient switched medications, or by the last contact with the program for patients who did not switch. Pre-intervention LDL results were included in the patient’s average if they were: 1) within 2 years of this date, and 2) at least 6 weeks after the first recorded prescription in the EMR for atorvastatin. The long potential evaluation period was used because the program reached patients at various times in relation to their regular office visits—there was some reasonable likelihood that very recent lab values were not available. Patients without a recorded atorvastatin start date in the EMR, but with atorvastatin claims, were evaluated based on lab results occurring within 180 days before the switch or last contact date. The post intervention LDL average was based on results obtained at least 6 weeks after a switch, or immediately after the last contact date until the last available data. LDL values were included without regard to fasting since the patient’s fasting status was not reliably recorded, and studies demonstrate that fasting and nonfasting LDL levels are similar.16,17 We described the Switch To program performance characteristics using descriptive statistics.

Statistical Analysis

All statistical analyses were performed using SAS statistical software, version 9.3 (SAS Institute, Cary, North Carolina). The hypothesis and normally distributed predictors were evaluated using a t test for significance, with alpha 0.05. Median income by zip code was non-normally distributed and was therefore evaluated for differences using a Wilcoxon rank-sum test. Switchers and nonswitchers did not differ with respect to observed pretreatment factors, nor did those factors predict participation; therefore, propensity scoring was not appropriate.


We identified 1687 patients from commercial pharmacy claims who filled at least 1 prescription for 10 mg atorvastatin. Of the 1687 patients, 1312 patients had lipid lab results available before and after the program intervention. Four patients who were switched by the program to nonequivalent doses were removed from this analysis, and 28 patients for whom EMR medication records disagreed with program records were also removed, leaving 1280 evaluable patients.

Of the 1280 cases meeting inclusion criteria, physicians responded regarding 1261 patients, encompassing 98.5% of the identified patients (


). Physicians chose to enroll 68% of the patients they reviewed. Among enrolled patients, the program reached 533 patients by phone, with 115 (21.6%) of those electing to switch. Letters were sent to 304 patients not reached by phone; these letters informed patients that they would be switched and provided instructions on how to avoid switching by opting out. Nonresponse to the opt-out letters led to 101 (33.2%) patients being switched.

The patient group that switched and the group that did not switch had similar demographics by age, race, and median income by zip code (

Table 1

). Patients who switched were disproportionately male (P = .003). Patients who switched had an average of 2.04 (SD = 1.02) LDL values before the switch, 0.16 (SD = 0.37) LDL values excluded during the switch, and 2.12 (SD = 1.07) LDL values after the switch. Nonswitchers averaged LDL results of 2.33 (SD = 1.27) before contact and 2.55 (SD = 1.36) after. On average, pre-treatment labs among switchers occurred 363.4 (SD = 207.0) days before the intervention date, and 332.4 (SD = 205.4) days after the switch. Switchers’ labs occurred an average of 349.1 (SD = 210.1) days before intervention date, and 382.3 (SD = 225.5) days after.

Over the evaluation period, LDL control declined, illustrated by rising LDL levels in both groups (

Table 2

). The small increase in LDL in both groups was not statistically significantly different for switchers and nonswitchers (P = .144).


The purpose of this study was to investigate the impact on lipid control of a therapeutic substitution from atorvastatin 10 mg to equipotent simvastatin 20 mg. While the average LDL levels of both switchers and nonswitchers increased, there was no statistically significant difference between patients who switched to simvastatin 20 mg and those who remained on atorvastatin 10 mg. We observed a 16.9% switch rate using our therapeutic substitution program.

The finding that use of equipotent doses of generic and brand statin did not produce statistically significant differences in lipid control suggests that statin therapeutic substitution programs are a clinically appropriate option to control pharmacy costs. The difference in mean LDL measurements between switchers and nonswitchers of 2.36 mg/dL was judged to be clinically insignificant.

The decline in the LDL control of both groups was concerning. A partial explanation for the decline in LDL control may relate to the long evaluation period. The unfavorable trend may indicate that patients require escalating doses to maintain control, or that patients are not adequately continuing with the prescribed doses. We did not have access to pharmacy claims data post intervention, so we could not evaluate the impacts of adherence and persistence on LDL control. Thus, even if patients were fully adherent, it is possible that their doctors did not adjust the medications in response to persistently elevated LDL levels. This study was not designed to address this issue, so no data were generated that would explain the upward drift in both groups.

Our therapeutic substitution program resulted in a 16.9% effective switch rate. In the context of an optional program for prescribers and patients, we consider these results to be moderately effective. The program achieved a high physician response rate, which demonstrates a potential benefit to conducting pharmacy management within the prescribers’ organization. Working within the prescribers’ institution enabled the program to integrate multiple insurers’ patients into a single effort and streamline messaging and response with frontline providers. Operating within the prescribers’ organization also helped ensure that the clinical experts involved in creating the program had credibility with the participating providers.

The program experienced considerable difficulties reaching patients by phone, despite up to 3 attempts for each patient. There was a substantially different patient participation rate depending on whether they were reached by phone or by letter. Calls and mailings also used different default choices: phone calls invited patients to opt in to switching, while letters required patients to opt out if they wanted to avoid the interchange. Unfortunately, we could not distinguish between the impact of the communication medium and the impact of differing default choices.

The differing participation rates between patients who had to act to opt in by phone and those who were automatically enrolled by letter and had to act to opt out illustrates choice architecture, which theorizes that the way choices are presented to decision makers influences the choices they select.18 There were 2 aspects of choice architecture at work: first, the media used were letter versus phone; second, the default choices were opt in versus opt out. Since both properties were changed together, we could not distinguish between the 2 effects, but this aspect of choice architecture merits further investigation. Amid increasing pressure to control costs while attempting to preserve patient autonomy, healthcare management interventions may increasingly base their intervention designs on principles of choice architecture. Measuring these influences will be necessary to ensure that healthcare providers use choice architecture in an ethical manner, thus empowering patients with meaningful choices.

Since the Switch To program, the American College of Cardiology (ACC) and American Heart Association (AHA) released updated guidelines.19 Within the ACC / AHA guidelines, atorvastatin 10 mg and simvastatin 20 mg are classified as moderate-intensity therapy. The updated guidelines preferentially recommend considering high-intensity statin treatment, but also describe a role for moderate-intensity therapy. To contrast the guidelines with this study, the guidelines recommend when to use moderate-intensity statins, while this study examines agent selection after a decision to treat with moderate intensity statins is made.


Our analysis was limited by data availability and the observational nature of the inquiry. We were unable to obtain additional pharmacy claims data that would have allowed evaluation of adherence and persistence metrics. We only included analysis switches that were facilitated by the therapeutic substitution program, but some patients switched therapies with their physician outside the formal program. As patients were not randomly assigned to treatment groups, our analysis was limited to observational methods. While switchers and nonswitchers were similar with respect to observed factors, we cannot rule out the possibility of unobserved confounders. This study found no evidence to support the proposition that observable factors meaningfully predict program participation, but such factors would be of interest if they could be identified.

A greater understanding of why physicians declined to enroll patients or why patients declined to switch is also of interest, but this information was not collected by the program. Some physicians informally reported that they didn’t enroll patients due to prior use of simvastatin that the available data failed to identify. A few prescribers shared concerns about having staff reaching out to their patients, or about the therapeutic equivalence of the switch. The program’s callers reported that the most common reason patients cited for not switching was interest in discussing the interchange with their doctor first.

Subsequent Switch To Programs

The Switch To program continued, addressing other brand-to-generic therapeutic substitution opportunities. The program subsequently offered a switch from atorvastatin 20 mg to simvastatin 40 mg, but did not address higher doses. Further large efforts included a switch from brand proton pump inhibitors to generic omeprazole and from brand nasal steroids to generic fluticasone.


This analysis supports the assertion that there is an appropriate role for therapeutic substitution programs to contain costs while achieving equivalent patient management. Of interest in the current drive toward accountable care organizations, the findings also demonstrate that very high provider participation rates can be achieved by programs initiated by the provider’s own system and leadership. These results raise questions about decision inertia among providers and patients and the power of default choices, which warrants further study. Finally, the unfavorable trend in LDL control suggests further investigation into prescription adherence and persistence.

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