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The American Journal of Managed Care September 2017
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Evaluation of a Packaging Approach to Improve Cholesterol Medication Adherence
Hayden B. Bosworth, PhD; Jamie N. Brown, PharmD, BCPS; Susanne Danus, BS; Linda L. Sanders, MPH; Felicia McCant, MSSW; Leah L. Zullig, PhD; and Maren K. Olsen, PhD
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Evaluation of a Packaging Approach to Improve Cholesterol Medication Adherence

Hayden B. Bosworth, PhD; Jamie N. Brown, PharmD, BCPS; Susanne Danus, BS; Linda L. Sanders, MPH; Felicia McCant, MSSW; Leah L. Zullig, PhD; and Maren K. Olsen, PhD
A 7.6% improvement in 12-month cholesterol refill was observed among US military veterans randomized to an adherence blister packaging intervention versus an education-only intervention.
Group differences in lipid levels over time were evaluated using general linear mixed model equations. Unconstrained models were initially run for each measure, and the mean baseline measures were compared between the adherence packaging intervention and education-only groups.11 When nonsignificant, the model was then constrained to make both groups equal at baseline. Dummy-coded variables for time at 6 and 12 months and interactions between time and randomization status were included in each model. An unstructured covariance matrix was selected to account for the correlation between repeated measures on the same subject. 

Group differences in self-reported adherence over time were evaluated using a generalized estimating equation with a logit link function and unstructured covariance matrix. As with the general linear mixed model, an unconstrained model was initially run, and when the baseline was found to be not significantly different between the 2 groups, a constrained model was used to obtain estimates.

Qualitative analyses were used to evaluate challenges and successes of the intervention. To formally evaluate the process of implementation of the adherence packaging intervention, we conducted a summative evaluation at 12 months. This was used to gather insights from patients who participated in the intervention program. We randomly selected participants to interview at 12 months and interviewed 10 individuals.


We sent 1117 recruitment letters and completed telephone screening on 708 individuals, which resulted in the identification of 321 eligible potential participants. Five individuals refused to participate at baseline and of the 240 patients who consented for the study, we randomized 120 to each arm and completed the baseline assessment. The sample was, on average, approximately 62 years of age and a majority of individuals were African American, male, married/cohabitating, and had completed 12 or more years of education (Table 1). Approximately 30% of participants had a low health literacy level and 20% reported financial strain. At baseline, 68% of the adherence packaging intervention group and 70% of the education-only group reported they had not been adherent with their cholesterol medication in the last month. However, refill rates were greater than 75% for both intervention and controls at baseline.


Median MPR at 12 months was greater than or equal to ≥0.99 for the adherence packaging group and 0.94 for the education-only group (P = .30). In terms of the dichotomous measure of MPR adherence, 54% of the adherence packaging intervention group were adherent with their refills over 12 months compared with 47% for the education-only group (Table 2). There was a 7.6% greater refill rate by the adherence packaging intervention arm than by the education-only arm (P = .24; 95% confidence interval [CI], –5% to 20%). 

Both arms reported improvement in self-reported adherence over the 12 months (Table 3). The difference in self-reported adherence by arm was not significant (odds ratio, 0.75; 95% CI, 0.47-1.19) (Table 3).

Clinical Outcomes

Decreases in LDL-C, HDL-C, and total cholesterol were observed for both the adherence packaging intervention arm and the education-only arm, but these differences were nonsignificant (Table 3). 

Evaluation of the Blister Package

Among a random subset of individuals who received the adherence packaging intervention and were asked to evaluate aspects of the blister packaging (n = 30), the ratings were high on a scale of 1-10: overall quality of the package (mean = 9.23; standard deviation [SD] = 1.59), ease of opening (mean = 8.43; SD = 2.33), dispensing the cholesterol medication (mean = 9.00; SD = 2.02), and served to help individual to remember if they already took their cholesterol medication (mean = 8.53; SD = 2.52). 


The 10 patients interviewed reported that the use of the blister packaging was beneficial and would recommend it to others, noting that the packaging kept the pills from breaking, kept them clean/uncontaminated, and provided a clear reminder of whether they had remembered to take the medication on a given day. Also, patients reported seeing when they were nearing the end of medication, which prompted them to re-order. Individuals also reported appreciating that their medication came in full tablets and that they did not having to worry about possible inaccuracies when splitting tablets.

Three of the 10 participants reported having difficulty in removing the inner medication card from the outer packaging component (American Society for Testing and Material child-resistant feature) and then removing the pill from the blister cavity; they felt they had to push hard and “fight” to remove it, citing arthritis/age as their reason. For some, adherence was more challenging if they used a pillbox for some medications and the calendar blister packaging for the statin medication. Patients liked the convenience of calendar blister packaging, but were not particularly receptive to potentially paying more for it; they felt a small increase might be acceptable but that it really should be about the same cost as standard packaging, or they would want to know the true price of packaging before making a determination. 


Given the number of individuals at risk for CVD and who have inadequately controlled cholesterol levels12 and poor refill rates of cholesterol-lowering medications, low-cost interventions that are potentially easy to administer, such as calendar blister packaging, may be useful, especially for those with particular challenges regarding forgetfulness. In the current study, there was a 7.6% improvement in refill rates of the adherence packaging intervention arm over the education-only arm (95% CI, –0.05 to 0.20). However, these improvements in refill rates did not translate to decreases in LDL-C, HDL-C, and total cholesterol. 

Our results are consistent with a recent meta-analysis, in which the overall mean weighted standardized difference effect size for 2-group comparisons was 0.593 (favoring treatment over control); this is consistent with the mean of 71% adherence for treatment subjects compared with 63% among control subjects.5 There are several reasons packaging interventions may be effective at improving medication adherence. Packaging interventions provide a mechanism for patients to self-monitor medication consumption. Difficulty remembering whether a certain dose had been consumed is an important aspect of forgetting medications—it is the most often patient-reported reason for nonadherence.13,14 Packaging also allows third parties, such as informal and home-visiting formal caregivers, to use the device to monitor doses taken or not taken.5 The cost differential of the blister packaging is closely related to volume and typically ranges from $0.10 to $0.25 more than traditional medication bottles.

A key strength of our study was in addressing the efficacy of this innovative prescription calendared blister packaging in a diverse patient population. Selected clinics serve a large African American population, which enabled the recruitment of a racially diverse sample. 


Although the specific definition of elevated LDL-C and the guidelines for CVD risk reduction continue to evolve, there is growing emphasis on the importance of statin therapy for individuals with high CVD risk.1 These changing definitions occurred while our study was ongoing—a potential limitation of the study. Despite this definitional change, nonadherence with statin therapy for elevated LDL-C remains a serious issue. 

An additional limitation is that during the study enrollment period, the VA National Formulary adjusted its coverage of rosuvastatin. Unless clinically contraindicated, patients prescribed rosuvastatin were converted to atorvastatin. Our study included patients prescribed rosuvastatin, not atorvastatin, potentially reducing the sampling pool of eligible patients. Providers could choose to keep patients on rosuvastatin despite it not being on the formulary. Systemwide conversion of all patients on rosuvastatin limited recruitment or created challenges during study participation. Second, some providers did not acknowledge the Research Clinical Warning (a marker indicating that the individual was participating in a trial) in the medical record. Thus, some providers changed their patients’ statin medications without notifying study personnel to see if the study could accommodate medication or dosage change. In addition, some providers separately ordered patients’ nonpackaged statin medication, leading to the potential for duplicate orders and confusion for the patient as to which medication they should be taking. Third, cholesterol management guidelines changed from a targeted LDL-C goal level to being on a recommended statin regimen. Fourth, the process for the adherence packaging intervention group to obtain their cholesterol medication may have been more onerous than for those in the education-only arm because adherence packaging patients were required to use a different phone number than the traditional refill number used for their other medications.


The findings of this study may have important clinical implications. Although the impact of the blister packaging seen in this study was less than we anticipated, blister packaging was well accepted. Its potential impact as a relatively inexpensive and highly scalable method for improving adherence should be further considered.

Author Affiliations: Center of Excellence for Health Services Research in Primary Care (HBB, SD, FM, LLZ, MKO), and Investigational Drug Service (JNB), Durham Veterans Affairs Medical Center, Durham, NC; Department of Medicine (HBB, LLS, LLZ), and Department of Psychiatry and School of Nursing (HBB), and Department of Biostatistics and Bioinformatics (MKO), Duke University, Durham, NC.

Source of Funding: This study was sponsored by a grant from WestRock (WRK) / MeadWestvaco (MWV; MWV XNV 21-158) and was approved by the Durham VA Medical Center Institutional Review Board ( registration number: NCT01744977). Dr Bosworth was supported by a research career scientist award from VA Health Service Research and Development (VA HSR&D 08-027). Dr Zullig (CDA 13-025) was supported by VA Health Services Research and Development Career Development Award.

Author Disclosures: Dr Bosworth has received grants from MeadWestVaco, now called Westrock, which co-funded this project, and has received honoraria from Genetech, Sanofi, CVS, Walgreens, Regeneron pharmaceuticals, CVS, Blue Cross/Blue Shield of Arkansas, Walgreens, and Johnson & Johnson. Dr Bosworth has received funding from Sanofi, Takeda, Improved Patient Outcomes. Dr Zullig has received grants from the VA for research on an unrelated subject. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. The views expressed in this article are those of the author(s) and do not necessarily represent the position or policy of Duke University, the US Department of Veterans Affairs, or the US government.

Authorship Information: Concept and design (HBB, JNB); acquisition of data (HBB, SD, LLS, FM); analysis and interpretation of data (HBB, LLS, MKO); drafting of the manuscript (HBB, SD, LLZ); critical revision of the manuscript for important intellectual content (HBB, JNB, SD, LLS, LLZ, MKO); statistical analysis (LLS, MKO); provision of patients or study materials (SD, FM); obtaining funding (HBB); administrative, technical, or logistic support (HBB, JNB, SD, FM, LLZ); and supervision (HBB, MKO). 

Address Correspondence to: Hayden B. Bosworth, PhD, Durham Veterans Affairs Medical Center, 411 W Chapel Hill St, Ste 600, Durham, NC 27701. E-mail: 

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