Impact of physician' and pharmacy staff supporting activities in usual care on patients' statin adherence.

AIMS: Little is known about usual care by physicians and pharmacy teams to support adherence to statins and whether the extent of this care is associated with adherence to statins. Objective of the study was to examine the relationship between the extent of adherence supporting activities of healthcare practitioners (HCPs) and patients' adherence to statins.
METHODS: Cross-sectional study in 48 pharmacies and affiliated physicians' practices, between September 3, 2014 and March 20, 2015. Patients visiting the pharmacy with a statin prescription from participating prescribers were invited to participate. Usual care to support adherence was assessed among HCPs with the Quality of Standard Care questionnaire about usual care activities to support adherence. Adherence to statins was assessed among patients with the MARS-5 questionnaire. The association between the extent of HCPs' adherence supporting activities and patients' adherence was examined by means of multilevel regression analysis.
RESULTS: 1,504 patients and 692 HCPs (209 physicians, 118 pharmacists and 365 pharmacy technicians) participated. No association was found between the extent of physicians' adherence supporting activities and patients' adherence to statins. The extent of adherence supporting activities by pharmacy teams in usual care was negatively associated with patients' adherence to statins (B coefficient -0.057 (95%CI: -0.112- -0.002).
CONCLUSIONS: This study suggests that there is no positive relationship between the extent of HCPs' adherence supporting activities in usual care and patients' adherence to statins. Other methods than questionnaires (e.g. electronic monitors (to assess adherence) and observations (to assess usual care) should be applied to confirm the results of this study.

Introduction

Statins are a proven therapy to lower serum cholesterol concentrations, reducing the long-term risk of ischaemic heart disease events by about 60% and stroke by 17% [1]. Despite these therapeutic advantages, medication adherence to statins (defined as the extent to which the patient’s medication taking behavior corresponds with the agreed recommendations from the healthcare provider) is suboptimal and varies between 32–77% [2-8].

Non-adherence to statin therapy has a negative impact on treatment outcomes. Patients with poor adherence to statins are at greater risk of cardiovascular events and hospitalization due to cardiovascular disease and cause avoidable high health care costs [9-15]. This makes improving medication adherence to statin therapy a key component of the treatment of hypercholesteremia [9, 16].

Adherence is multifactorial; “Health-system/Health-care team factors”, “Social/economic factors”, “Condition-related factors”, “Therapy-related factors” and “Patient-related factors” have been associated with/implicated in non-adherence [9]. Previous research on interventions to improve adherence to statins mainly focused on “patient-related factors”, however these studies yielded small inconsistent results, with a range of effect of these interventions from -3% up to 25% improvement of adherence [17-20]. Therefore, interventions that target other factors that can have impact on adherence might also be required, like relevant factors in the health-system/health-care [9]. Yet, evidence on the impact of health-system/health-care team factors on implementation adherence to statins is scarce. Insight into the association between relevant factors in the health system/health-care team and adherence is warranted.

Earlier studies demonstrated health system factors like continuity of care and complete treatment information are factors that are positively associated with adherence to drug treatment in chronic conditions as well as in statin use [16, 21, 22]. Furthermore, patients who experienced a higher quality of care and/or a higher degree of shared decision making had more knowledge of their illness, were more actively involved in their own treatment, were more confident in their communication with healthcare providers and had higher adherence rates [23, 24]. The aforementioned examples in literature are about the impact of the overall quality of care on adherence, whereas literature about the impact of the quality of care activities employed by individual healthcare practitioners (HCPs) is scarce. Based on the findings about the positive impact of the overall quality of care on adherence, it is also conceivable that quality of care activities, including usual care adherence support activities) of a single HCP, might positively influence patients’ medication adherence. Noteworthy, influencing the usual care of one single healthcare provider may affect the adherence of several patients, which makes interventions on HCP level potentially more impactful than interventions on patient level. Currently, no evidence is available about physicians’ and pharmacy staff’s’ usual care to support adherence to statins and how this care affects patients’ adherence.

The aim of this study is 1) to describe the nature and extent of adherence supporting activities provided in a usual care setting by physicians, pharmacists and pharmacy technicians; and 2) to examine the relation between the extent of adherence supporting activities of physicians, pharmacists and pharmacy technicians and adherence to statins. We hypothesized that increased HCPs’ usual care activities to support statin adherence have a positive impact on patients’ implementation adherence to statins.

Materials and methods

Study design and setting

This cross-sectional study was conducted between September 3, 2014 and March 20, 2015 in 48 Dutch pharmacies (44 community and 4 outpatient). The EMERGE (ESPACOMP Medication Adherence Reporting Guideline) was used as guidance in reporting this study [25]. The Medical Research Ethics Committee (MREC) of Arnhem- Nijmegen waived official ethical approval (file number: 2021–13158) and assessed the trial (including the verbal consent procedure) as not being subject to the Medical Research Involving Human Subjects Act (WMO).

Eligibility criteria and selection procedures

A pharmacy technician informed all patients with a prescription for a statin (prescribed by one of the included prescribers) and asked these patients to participate in the study. Patients were included only after verbal informed consent was obtained. Verbal consent was recorded per participant on one registration form per participating pharmacy. If patients did not wish to participate the pharmacy technician noted the reason on the registration form. The verbal informed consent procedure was a pragmatic choice, based on the assumption that completing the questionnaire was an implicit agreement of the patient to participate in the study and to achieve an efficient process at the pharmacy counter. For inclusion criteria, we refer to Huiskes et al. [26].

Measurements

Variables and data collection

Patient data were collected with a hardcopy questionnaire assessing socio-demographic characteristics, medication related information (duration statin use, prescriber) and patient’s adherence to statins (see measurement instruments). In this study implementation adherence (defined in the ABC taxonomy of medication adherence) was studied, as current statin users were included [27]. Patients were asked by the dispensing pharmacy technician to fill out the questionnaire in the pharmacy or to return the questionnaire by mail. HCPs’ socio-demographic characteristics and HCPs’ usual care to support adherence (see measurement instruments) to statins were assessed using a hardcopy questionnaire.

Outcomes

An inventory of the nature and extent of adherence supporting activities provided in a usual care setting by physicians, pharmacists and pharmacy technicians and the association between the extent of these HCPs’ adherence supporting activities and patients’ adherence to statins.

Measurement instruments

Usual care questionnaire. Usual care to support adherence to statins was assessed with a 47-item questionnaire about usual care activities to support adherence based on the Quality of Standard Care questionnaire as used by de Bruin et al., with modifications to assess usual care in patient care as described by Timmers et al. [28-30]. The list used by Timmers et al. was used in cancer care, so for use in this study the list was adapted to statin therapy by one of the researchers (BvdB). HCPs were asked to score the extent of their care activities they performed to support adherence in the majority of their patients the past six months a) when initiating statin therapy, b) during follow-up visits with patients that already used statins for a longer period and c) for their patients regardless of whether they used a statin. Four out of the 47 items were qualitative questions and 43 items could be answered with yes or no. Due to the quantitative character of this study the four qualitative questions were not included in the analysis. When the response to a quantitative question was answered with yes, the answer was awarded one point. The questions as presented to the HCPs are shown in Table 2. A sum score was calculated by summing the scores of each question, resulting in a sum score from 0 to 43. Furthermore, in order to create a better understanding of the nature and extent of the usual care activities, usual care activities were grouped to sub scales. Also for these sub scales sum scores were calculated. The sub scales were based on the coding taxonomy provided by the original author: knowledge, awareness, attitude, social influence, self-efficacy, intention formation, action control, facilitation, metascore [29]. A higher sum score indicates a higher quality of the level of usual care.

Table 2

Usual care to support adherence to statins as reported by physicians, pharmacists, pharmacy technicians & pharmacy team.

	Cat.	% yes phys. (n = 209)	% yes pharm (n = 118)	% yes pharm tech (n = 366)	%yes pharm team (n = 484)
Knowledge
1. Explain what cholesterol is and why raised cholesterol is undesirable	S	96	54	50	51
2. Discuss what a statin is and the mechanism of action	S	77	92	80	83
3.Hand out brochure or written information about statins	S	12	92	95	94
4. Discuss drug storage recommendations	S	3	35	41	39
5. Explain what to do if a dose is missed	S	22	34	44	42
6. Do you ask patients to repeat the received information in their own words regularly, to check whether the information is understood properly? (Refers to items:1;2;3;4;5;12;15;16;26;31;32;33)	S	18	19	21	21
7.Verbal explanation to the patient	S	94	99	98	98
8. Use of illustrative materials (pictures/charts/video)	S	14	4	3	3
9. Hand out written information	S	20	94	97	96
10. Refer patients to websites	S	38	8	7	7
11. Do you ask patients to repeat the received information in their own words regularly, to check whether the information is understood properly? (Refers to items:13;17;20;21;22;28;29;30)	S	19	17	19	18
Awareness
12. Discuss the consequences of non-adherence	S	49	50	48	49
13. Encourage patients to use a 7-day pillbox	S	47	36	37	37
14. Giving feedback about the effect of the statin using laboratory findings	F	95	18	10	12
Attitude
15. Explain that the patient doesn’t notice the effect of the statin but that the effect is evaluated by blood tests to check cholesterol levels	S	87	82	79	80
16. Discuss the importance of adherence	S	77	84	80	81
17. Encourage patients to be adherent	S	81	77	78	78
18. Ask the patient about non-practical problems with taking the medication as prescribed (unwilling to take medication, for example because of misunderstandings about taking medication)	F	56	36	35	35
19. In case of non-practical problems, propose solutions to solve these problems (for example discussing the necessity or concerns, referral to nurse practitioner)	F	67	70	61	63
Social influence
20. Involve partner and/or relatives in the treatment	S	30	21	15	16
Self efficacy
21. Encourage patients to plan ahead (for example for holidays or social activities)	S	19	16	26	23
22. Discuss potential barriers regarding adherence and possible ways to overcome them	S	41	42	26	30
23. Ask the patient if he/she is taking the medication as prescribed	F	79	67	69	68
24. Ask about practical problems with taking medication as prescribed (for example forgetting it or being unable to open the packaging)	F	29	41	34	36
25. In case of practical problems, discuss solutions with the patient to reduce these practical problems	F	56	84	81	82
Intention formation
26. Explain how often and how long the medication should be used	S	95	93	96	95
27. Develop and discuss a written individual dosing schedule	S	21	25	17	19
28. Write down patients’ dosing schedule (time, name of meds, number of doses)	S	22	41	39	39
Action control
29. Identify daily routines (like brushing teeth) and encourage patients to align the taking of medicines with their routines	S	36	35	39	38
30. Encourage patients to use alarm devices as a reminder for taking the medication	S	9	16	10	11
Facilitation
31. Discuss the common side effects of the drug	S	86	97	99	98
32. Discuss with the patient how to deal with side-effects	S	75	84	93	90
33. Monitor and/or discuss possible interactions with other drugs	S	63	98	99	99
34. Discuss the experienced positive effects of the treatment	F	47	38	38	38
35. Asking about (perceived) side-effects of the treatment	F	91	82	88	87
36. If patients experience side-effects, there is an active contribution to reduce these side-effects (sometimes by providing knowledge or adjusting the treatment)	F	93	92	81	84
37. Suggesting a new medication regimen in case patients feel their present regimen is too complex	F	72	84	59	65
38. Call the patient after the initiation of the drugs to ask about experiences	G	9	10	14	13
39. Give the patient a telephone number and tell who to contact in case of side-effects	G	23	25	25	25
40. Give the patient a telephone number and tell who to contact in case of problems with intake/medication adherence	G	19	15	21	20
41. Explain patients who to contact in case they would run out of medication	G	74	69	84	80
Metascore
42. Intensify the number of follow-up visits in case of (possible) treatment non-adherence	G	38	19	12	14
43. Refer patients to another health care provider for (co-)treatment (e.g., in case of side-effects)	G	35	60	47	50

S = when starting statin therapy; F = during follow-up visits; G = in general for their patients regardless of whether they used a statin.

Self-reported adherence to statins. The Medication Adherence Report Scale-5 (MARS-5) consists of five items, mainly addressing intentional non-adherence behavior (4 out of 5 items). The items are rated on a five-point Likert scale (from 1 (always) to 5 (never)), resulting in a summated score of 5–25 [31]. No standard cut-off point to define adherent versus nonadherent medication has been provided by the scale developers and it varies across studies [32]. In this study the MARS-5 cut-off scores of ≥ 23 and ≥ 24 to identify adherent patients are both reported, as these are cut-off points that are more often used and because adherence distributions found with the MARS-5 are often highly skewed [33-36].

Sample size and data analyses

Data analyses

Data were analyzed using STATA version 13. Descriptive statistics were provided using mean (± SD) or median (p25-p75) values depending on the (non-) parametric distribution of measured variables. P-values ≤0.05 were considered statistically significant.

The association between the extent of HCPs’ usual care activities (sum score of the Quality of Standard Care questionnaire) and the adherence (MARS-5 total score) of patients was subjected to multilevel linear regression analyses (see Huiskes et al. [26]). If a healthcare practitioner did not answer one or more items of the usual care questionnaire within the total of usual care activities or within a sub scale, then the respondent was considered as lacking for the calculation of the total sum score or the sum score of that sub scale.

Sample size

In this study a convenient sample of 1504 patients was included as described by Huiskes et al. in the methods section [26]. Based on a conservative estimation of one-third non adherent patients in this population, 501 non-adherent patients were expected. As eight independent variables were planned to be included in these multilevel regression analyses, 62 cases per independent variable were available, which means enough power is achieved, even taking into account the variance attributable to the group level (based on an alpha of 0.05, a beta of 0.8).

Results

Response rate

A total of 2229 patients visited the HCPs and were asked to participate in the study. Of these patients, 1504 (67.5%) agreed to participate and were included in this study (Table 1).

Table 1

Baseline characteristics patients and HCPs.

Parameter	Patient	Physician*	Pharmacists	Pharmacy technicians
	n = 1504	n = 209	n = 118
				n = 365
Gender (female) [n (%)]	675 (46.5)	94 (45)	71 (60.2)	353 (98.1)
Age (years) [mean (SD)]	66.8 (9.9)	49.5 (10.0)	36.9 (11.0)	39.7 (11.4)
Years of statin use [median (p25 p75)]	6 (3–10)	n/a	n/a	n/a
Years employed [median (p25 p75)]	n/a	19 (10–26)	10.3 (10.0)	16.2 (11.0)

*General practitioner 89.5%, general practitioner in training 1.0, cardiologist 2.9%, internist 1.9%, neurologist 0.5%, nurse practitioner 1.0%, practice assistant 2.9%, other 0.5%.

A total of 734 HCPs were asked to participate in the study, 692 (94.3%) of whom agreed to participate and were included. The response rates to the questionnaires per type of HCP were: 209 out of 225 (92.8%) physicians, 118 out of 119 (99.1%) pharmacists and 365 out of 390 (93.6%) pharmacy technicians. The following prescribers were included: general practitioner (89.5%), general practitioner in training (1.0%), cardiologist (2.9%), internist (1.9%), neurologist (0.5%), nurse practitioner (1.0%), nurse specialist in primary care (2.9%), others (0.5%). The mean (SD) number of patients per physician and pharmacy were 6,6 (SD± 5.0) and 31.1 (SD±15.0), respectively.

Patients’ adherence to statins

The median (p25-p75) MARS-5 score was 25 (24–25). A total of 1349/1483 (91%) and 1215/1483 (82%) of the patients were adherent to their statins using MARS-5 cut-off scores of ≥ 23 and ≥ 24 respectively.

HCPs’ usual care activities to support adherence to statins

HCPs’ (physicians, pharmacists and pharmacy technicians) usual care activities to support medication adherence to statins are reported in Table 2. The median usual care activities total scores ranged from 21–23 between the three subgroups (Table 3). The highest median sum scores (as percentage of the maximum sum score) were found on sub scales for attitude and facilitation (for all types of HCPs) and awareness (for physicians). The lowest median sum scores were found on sub scales for action control and social influence (for all HCPs) (Table 3).

Table 3

Median scores, interquartile ranges and median scores as percentage of the maximum score.

		Physicians		Pharmacists		Pharmacy technicians		Pharmacy team**
Sub scales*	Min—max	Median (p25—p75)	Median score as % of max score	Median (p25—p75)	Median score as % of max score	Median (p25—p75)	Median score as % of max score	Median (p25—p75)	Median score as % of max score
Knowledge	(0–11)	4 (3–5)	36	5 (4–7)	45	5 (4–7)	45	5 (4–7)	45
Awareness	(0–3)	2 (1–3)	67	1 (0–2)	33	1 (0–2)	33	1 (0–2)	33
Attitude	(0–5)	4 (3–5)	80	4 (3–5)	80	4 (3–4)	80	4 (3–4)	80
Social influence	(0–1)	0 (0–1)	0	0 (0–0)	0	0 (0–0)	0	0 (0–0)	0
Self efficacy	(0–5)	2 (1–3)	40	2 (1–4)	40	2 (1–3)	40	2 (1–3)	40
Intention formation	(0–3)	1 (1–2)	33	1 (1–2)	33	1 (1–2)	33	1 (1–2)	33
Action control	(0–2)	0 (0–1)	0	0 (0–1)	0	0 (0–1)	0	0 (0–1)	0
Facilitation	(0–11)	7 (5–8)	64	7 (6–8)	64	7 (6–8)	64	7 (6–8)	64
Meta-score	(0–2)	1 (0–1)	50	1 (0–1)	50	0 (0–1)	0	1 (0–1)	50
Sum score *	(0–43)	21 (16–26)	49	23 (18–27)	53	21 (17–26)	49	21.5 (18–26)	49

* Respondents were treated as a missing for calculation of the sum score if one or more items were missing. The number of missings was 21%.

** Pharmacy team is the combination of pharmacy technicians and pharmacists.

The top three most frequently reported usual care activities by physicians were: “Explain what cholesterol is and why raised cholesterol is undesirable“, “Explain how often and how long the medication should be used”, “Giving feedback about the effect of the statin using laboratory findings”. For pharmacy teams this consisted of: “Monitor and/or discuss possible interactions with other drugs”, “Discuss the common side effects of the drug “, “Verbal explanation about statins”(Table 2).

Association between the extent of HCPs’ adherence supporting activities and patients’ adherence to statins

The extent of adherence supporting activities by pharmacy teams in a usual care setting was negatively associated with patients’ adherence to statins (B coefficient -0.057 (95%CI: 0.112–0.002) (Table 4). No association was found between the extent of physicians’ adherence supporting activities and patients’ adherence to statins (Table 4).

Table 4

Multilevel regression analysis for the association between the extent of HCPs’ adherence supporting activities and patients’ adherence to statins, with controlling for the pharmacy level and physician level.

	Patients’ MARS-5 adherence scores
	B (95% CI) coefficient
Adherence supporting activities by physicians	0.085 (-0.010–0.027)
Adherence supporting activities by pharmacy teams	-0.057 (-0.112- -0.002) *

* p ≤ 0.05

Discussion

To our knowledge, this is the first study examining the level of usual care by HCPs to support adherence to statins and the impact of the level of usual care on patients’ adherence to statins. The results of this study did not confirm the hypothesis that there is a positive relationship between the extent of HCPs’ adherence supporting activities in usual care and patients’ implementation adherence to statins. The extent of usual care activities hardly differed between physicians, pharmacists and pharmacy technicians. The median sum scores on all sub scales of the Quality of Standard Care questionnaire were comparable for all HCPs, only on awareness physicians scored higher than pharmacy staff.

In this study the level of usual care to support adherence delivered by physicians is comparable and by pharmacists exceeded that reported by Timmers et al. (in patients using oral anti-cancer drugs) [30]. The latter might be explained by the fact that other HCPs than pharmacists (e.g. nurses) perform these activities (because of differences in setting and type of medication).

In our study, both pharmacists and physicians reported that half of the adherence supporting activities were performed and half were not. When HCPs coordinate their adherence supporting activities, this does not necessarily have to be a problem. This seems to be the case with respect to patient education to improve medication adherence: whereas doctors educate patients about the disease, the effect of the drug and treatment duration, pharmacy staff member tend to focus on adverse events, drug-drug interactions and storage conditions. Although doctors and pharmacy staff members seem to be synergistic with respect to education (sending information), neither doctors nor pharmacy staff members ask the patient about perceived barriers to take the medication as prescribed: patients’ knowledge about medication and non-practical barriers and practical barriers taking medication as prescribed are hardly inventoried by both physicians and pharmacy staff.

The extent of usual care of HCPs to support adherence to statins was not positively associated with patients’ adherence to statins. This in contrast with two meta-analyses on the quality of usual adherence care and medication adherence in patients infected with Human Immunodeficiency Virus (HIV) showing that a higher quality of self-reported usual care led to more patients being adherent to their medication [28, 29]. This might be explained by differences in type of medication, and design and setting (cross-sectional inventory of usual care in our study in one country versus retrospective inventory of usual care in usual care arms of trials in several countries). Furthermore, in HIV care often nurses are involved, which requires another role of pharmacists with respect to adherence support. Finally, adherence was measured differently, as in our study the MARS questionnaire was used and in the studies included in the meta-analyses by de Bruijn et al. (2009 and 2010) both self-reported adherence measures and Medication Event Monitoring System (MEMS) devices were used.

The lack of positive impact of usual care of both physicians and pharmacists to support adherence to statins on patients’ adherence to statins may be explained by conceptual differences (the extent of unintentional and intentional non-adherence aspects that are incorporated in the questionnaire) between the usual care activity questionnaire and the patient adherence measure (MARS-5). The Quality of Standard Care questionnaire is balanced with respect to the proportion of aspects related to unintentional and intentional non-adherence, whereas the MARS-5 questionnaire used in this study is predominantly focused on intentional non-adherence. Another explanation may be that the overall high MARS-scores might lead to ceiling effects, which may account for not finding a difference in adherence scores, as described in the strengths and limitations section.

Furthermore, HCPs with a patient population with low adherence rates to statins possibly feel a greater need to perform activities to support adherence to statins and consequently have higher scores on the usual care questionnaire. Alternatively, social desirability bias may have led to an overestimation of the level of usual care reported by pharmacy staff. In that case HCPs provide less activities to support adherence than they say they deliver, tentatively resulting in lower adherence rates and no (or weakly negative) association between the extent of adherence supporting activities and patients’ adherence. Participatory observations to assess the actually delivered extent of usual care activities to support adherence could be applied to overcome this.

The current findings should be interpreted in light of the strengths and limitations of our study. One of the strengths of this study concerns the large sample of patients and HCPs, as well as the high response rate, which increases the accuracy of the results. This study was furthermore carried out in a large number of practices across the Netherlands. This last aspect increases the generalizability (with respect to adherence supporting activities of HCPs to stimulate patients’ adherence to statins). The fact that the MARS-5 scores of patients using statins in this study were similar to those in another study and that 18% of patients are non-adherent to therapy (similar to the degree of non-adherence in other studies among Dutch patients taking statins), is a prove that a valid sample was included in the study and highlights generalizability [37-39].

However, this study does have its limitations. First of all, self-report questionnaires were the only means used in this study to measure adherence and the level of usual care. Questionnaires of this kind are subjective and therefore sensitive to social desirability bias. It is preferable for that reason to use a combination of methods when measuring adherence (e.g. self-report questionnaires, pill count, refill adherence, medication event monitoring systems and/or biochemical testing) and to observe the HCPs to inventory the level of usual care. If the extent of usual care delivered by a HCP is assessed by observation, it can be decided to observe each HCP once, or to observe all individual patient-provider interactions. Preferably all the individual patient-provider interactions are observed, as the usual care actually provided may depend on a specific patient and/or moment. Seeing that it is likely that adherent patients are more motivated to participate in a study of this kind (confirmed by slightly higher adherence rates in this study than in other studies), inclusion bias may have played a role [3, 8]. The chance that inclusion bias has affected the results, however, is reduced by that fact that the response rate of patients was high (67.5% of the selected patients agreed to participate in the study). Furthermore, we did not collect data on the indication for the use of statins. The extent to which patients perceive future risks and impact on the prognosis due to non-adherent behavior may differ between patient who use the statin for primary or secondary prevention. Therefore this kind of data should be collected and analyzed separately in future research. Another limitation of this study is that due to the cross-sectional design of the study, causality cannot be proven, as this should be investigated in a longitudinal and preferably randomized (to reduce confounding bias) design. Finally, due to a ceiling effect when using the MARS-5 and therefore little explained variance, no difference in adherence scores may be found.

This study provides an overview of usual care activities to support adherence to statins as reported by a large number of physicians, pharmacists and pharmacy technicians employed in a large number of practices in the Netherlands. Furthermore, the results of this study suggest that there is no positive relationship between the extent of HCPs’ adherence supporting activities in usual care and patients’ adherence to statins. Before trials are performed to improve adherence by intervening on HCPs, first more research with better techniques to objectify the level of usual care to support adherence and the impact on patients’ adherence is warranted. As only questionnaires were used in this study to examine the impact of usual care on adherence, further research in which other methods to measure adherence are used are recommended. Further research could furthermore be supplemented with observing the patient-provider interactions to inventory the level of usual care delivered by HCPs.

(XLSX)

Click here for additional data file.

28 Oct 2021

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Gianluigi Savarese

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that Table 2 may include questionnaire items that may have been previously published. The reproduction of previously published work has implications for the copyright that may apply to these publications. We would be grateful if you could clarify whether you have obtained permission from the original copyright holder to republish these items under a CC BY license. If you have not obtained permission to publish these items please remove them from your manuscript. You may wish to replace the text you have removed with relevant question numbers/ brief descriptions of each item; please be sure to include any relevant references and in-text citations.

3. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified : 1) whether the ethics committee approved the verbal/oral consent procedure, 2) why written consent could not be obtained, and 3) how verbal/oral consent was recorded. If your study included minors, please state whether you obtained consent from parents or guardians in these cases. If the need for consent was waived by the ethics committee, please include this information.

4. Thank you for stating the following in the Competing Interests section:

L. van Dijk has received grants for research not related to this study from TEVA and AstraZeneca

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf."

5. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this interesting analysis the authors assess the association between the level of usual care by HCPs to support adherence to statins and the association between the level of usual care on patients’ adherence to statins. The results did not confirm the authors’ initial hypothesis that there is a positive relationship between the extent of HCPs’ adherence supporting activities and patients’ adherence to statins, also interesting demonstrating a negative association between the level of usual activities among pharmacy teams and patients’ adherence. The study was cross-sectional and was based on questionnaires, i.e. adherence to usual measures was solely self-reported. This is a significant limitation that the authors acknowledge in the respective section of their manuscript.

Considering the journal’s criteria for publication, this study presents the results of original research, which has not been published elsewhere. The methods are described in detail and the analyses are performed to a high technical standard and described in sufficient detail. The conclusions are supported by the data and presented appropriately. The article is presented in an intelligible fashion and is written in standard English.

Based on this I find that the manuscript merits publication after minor revision of the following points:

1) Given the non-randomized design of the study the authors should discuss the highly likelihood that confounding could also explain their unexpected result

2) Page 8: “In this study the MARS-5 cut-off scores of ≥23 and ≥ 24 to identify adherent and non-adherent patients are both reported, as these are cut-off points that are more often used and because adherence”.

Consider omitting the phrase “and non-adherent”

3) Page 9, line 200: reference missing

4) Page 10, Table 1: simplify presentation by abiding to how data are presented based on the statistics section without repeating for each variable

5) Page 17, table 4: β coefficient for adherence supporting activities by pharmacy teams is not within 95%Cis. Please amend

Reviewer #2: The research paper “Impact of physician’ and pharmacy staff supporting activities in usual care on patients’ statin adherence” describes the results of a cross-sectional study that assessed the association between the extent of health care providers’ (HCP) activities aimed at improving adherence to statin therapy and patients’ self-reported adherence in a sample of 1,504 patients and 692 HCPs. Somewhat suprisingly, the results indicate that there is no positive association between HCP efforts to promote adherence and the actual adherence rate reported by the patients. The study is methodologically sound, and used validated measurement instruments and appropriate statistical analyses.

Major comments

1. When investigating the adherence to medications, it is praticularly important to provide details about the indications for their use, which may have an impact on patient’s adherence, because their behaviour may be influenced by the extent to which they perceive their future risks and the impact of treatment on the prognosis. This information is lacking from the manuscript. Could the authors provide description of the patient population and the proportion of patients with statins prescribed in primary vs. secondary prevention?

2. Along the same lines, were there any differences between patients receiving statins for primary prevention vs. secondary prevention?

3. Were there any individual aspects of HCP activities (e.g. knowledge, awareness, attitude etc) that were positively associated with patients’ adherence as those may be the activities further promoted in order to positively influence patients’ behaviour?

Minor comments

Spell out abbreviations at first appearance.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

26 Jan 2022

We would like to thank the editor and the reviewers for their careful and thorough reading of this manuscript and for the constructive suggestions that helped us to further improve it. This document provides a point by point response to each comment and highlights which adjustments were made.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Reply: thank you, we have adjusted the manuscript and file naming according to PLOS ONE’s style requirements.

2. We note that Table 2 may include questionnaire items that may have been previously published. The reproduction of previously published work has implications for the copyright that may apply to these publications. We would be grateful if you could clarify whether you have obtained permission from the original copyright holder to republish these items under a CC BY license. If you have not obtained permission to publish these items please remove them from your manuscript. You may wish to replace the text you have removed with relevant question numbers/ brief descriptions of each item; please be sure to include any relevant references and in-text citations.

Reply: Thank you for this remark. We have obtained permission from the original author to republish the original questionnaire items under a CC BY license. We have added the name of the original author in the methods section as follows:

Usual care to support adherence to statins was assessed with a 47-item questionnaire about usual care activities to support adherence based on the Quality of Standard Care questionnaire as used by de Bruin et al., with modifications to assess usual care in patient care as described by Timmers et al. (28-30). The latter was used in cancer care, so for use in this study the list was adapted to statin therapy by one of the researchers (BvdB).

3. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified : 1) whether the ethics committee approved the verbal/oral consent procedure, 2) why written consent could not be obtained, and 3) how verbal/oral consent was recorded. If your study included minors, please state whether you obtained consent from parents or guardians in these cases. If the need for consent was waived by the ethics committee, please include this information.

Reply: Thank you for this comment. We have added to the methods section that 1) the ethics committee approved the verbal consent procedure, 2) why verbal consent was obtained and 3) how verbal consent was recorded. We did not include minors in this study and the need for consent was not waived by the ethics committee.

We have added the following to the methods section with respect to 1) the ethics committee approved the verbal consent procedure:

The Medical Research Ethics Committee (MREC) of Arnhem- Nijmegen waived official ethical approval (file number: 2021-13158) and assessed the trial (including the verbal consent procedure) as not being subject to the Medical Research Involving Human Subjects Act (WMO).

And with respect to 2) why verbal consent was obtained and 3) how verbal consent was recorded:

A pharmacy technician informed all patients with a prescription for a statin (prescribed by one of the included prescribers) about the study and asked to these patients to participate. Patients were included only after verbal informed consent was obtained. Verbal consent was recorded per participant on one registration form per participating pharmacy. If patients did not wish to participate the pharmacy technician noted the reason on the registration form. The verbal informed consent procedure was a pragmatic choice, based on the assumption that completing the questionnaire was an implicit agreement of the patient to participate in the study and to achieve an efficient process at the pharmacy counter.

4. Thank you for stating the following in the Competing Interests section:

L. van Dijk has received grants for research not related to this study from TEVA and AstraZeneca

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf."

Reply: Thank you. We have added the statement to the competing interests section. We also updated our competing interests statement in the cover letter.

5. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Reply: Thank you for this comment. We have uploaded the anonymized data set as Supporting Information file. We also adjusted the Data Availability Statement in the manuscript.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this interesting analysis the authors assess the association between the level of usual care by HCPs to support adherence to statins and the association between the level of usual care on patients’ adherence to statins. The results did not confirm the authors’ initial hypothesis that there is a positive relationship between the extent of HCPs’ adherence supporting activities and patients’ adherence to statins, also interesting demonstrating a negative association between the level of usual activities among pharmacy teams and patients’ adherence. The study was cross-sectional and was based on questionnaires, i.e. adherence to usual measures was solely self-reported. This is a significant limitation that the authors acknowledge in the respective section of their manuscript.

Considering the journal’s criteria for publication, this study presents the results of original research, which has not been published elsewhere. The methods are described in detail and the analyses are performed to a high technical standard and described in sufficient detail. The conclusions are supported by the data and presented appropriately. The article is presented in an intelligible fashion and is written in standard English.

Based on this I find that the manuscript merits publication after minor revision of the following points:

1) Given the non-randomized design of the study the authors should discuss the highly likelihood that confounding could also explain their unexpected result

Reply: Thank you for this suggestion. We have added this to the discussion of the manuscript as follows:

Another limitation of this study is that due to the cross-sectional design of the study, causality cannot be proven, as this should be investigated in a longitudinal and preferably randomized (to reduce confounding bias) design.

2) Page 8: “In this study the MARS-5 cut-off scores of ≥23 and ≥ 24 to identify adherent and non-adherent patients are both reported, as these are cut-off points that are more often used and because adherence”.

Consider omitting the phrase “and non-adherent”

Reply: Thank you, we have removed the phrase “and non-adherent”.

3) Page 9, line 200: reference missing

Reply: Thank you, we have added the reference.

4) Page 10, Table 1: simplify presentation by abiding to how data are presented based on the statistics section without repeating for each variable

Reply: Thank you for this suggestion, we have adjusted Table 1 based on your input.

5) Page 17, table 4: β coefficient for adherence supporting activities by pharmacy teams is not within 95%Cis. Please amend

Reply: Thank you very much, we have added the minus signs that we unfortunately forgot.

Reviewer #2: The research paper “Impact of physician’ and pharmacy staff supporting activities in usual care on patients’ statin adherence” describes the results of a cross-sectional study that assessed the association between the extent of health care providers’ (HCP) activities aimed at improving adherence to statin therapy and patients’ self-reported adherence in a sample of 1,504 patients and 692 HCPs. Somewhat suprisingly, the results indicate that there is no positive association between HCP efforts to promote adherence and the actual adherence rate reported by the patients. The study is methodologically sound, and used validated measurement instruments and appropriate statistical analyses.

Major comments

1. When investigating the adherence to medications, it is praticularly important to provide details about the indications for their use, which may have an impact on patient’s adherence, because their behaviour may be influenced by the extent to which they perceive their future risks and the impact of treatment on the prognosis. This information is lacking from the manuscript. Could the authors provide description of the patient population and the proportion of patients with statins prescribed in primary vs. secondary prevention?

Reply: Thank you very much for this excellent comment. We fully agree that the medication taking behaviour of patients may be influenced by, besides practical barriers, the extent to which patients perceive their future risks and the impact of treatment on the prognosis (perceptual barriers). We also agree that these perceptual barriers in this population may be different for patients using their cholesterol-lowering medication for primary or secondary prevention and that consequently the extent of usual care to support statin adherence indeed may have different impact on the adherence of patients using statins for primary or secondary prevention. However, we did not collect this data, so unfortunately we will not be able to report this data. Future research has to be supplemented with this data. Therefore, based on your comments, we have added this point to the limitations section of the discussion:

Furthermore, we did not collect data on the indication for the use of statins. The extent to which patients perceive future risks and impact on the prognosis due to non-adherent behaviour may differ between patient who use the statin for primary or secondary prevention. Therefore this kind of data should be collected and analyzed separately in future research.

2. Along the same lines, were there any differences between patients receiving statins for primary prevention vs. secondary prevention?

Reply: Thank you, please see our answer to your first question.

3. Were there any individual aspects of HCP activities (e.g. knowledge, awareness, attitude etc) that were positively associated with patients’ adherence as those may be the activities further promoted in order to positively influence patients’ behaviour?

Reply: Thank you for this interesting question. Indeed we have performed an explorative analysis on the association of individual usual care items and patients’ statin adherence. See the results of this analysis in the table below. However, to avoid multiple testing, we did not include this analysis in our analysis plan and results.

Physicians Pharm Pharm Tech Pharm team

Domain Category Nr Question MARS B (95% CI) coefficient

Knowledge Start 1 Explain what cholesterol is and why raised cholesterol is undesirable -.462 (-.917 - -.007) -.403 (-.792 - -.014)

2 Discuss what a statin is and the mechanism of action

3 Hand out brochure or written information about statins

4 Discuss drug storage recommendations -.497 (-.895 - -.100)

5 Explain what to do if a dose is missed -.474 (-.920 - -.028) -.598 (-1.002 - -.194)

7 Verbal explanation to the patient

8 Use of illustrative materials (pictures/charts/video)

9 Hand out written information

10 Refer patients to websites -1.409 (-2.143 - -.675)

Awareness Start 12 Discuss the consequences of non-adherence

13 Encourage patients to use a 7-day pillbox

Follow-up 14 Giving feedback about the effect of the statin using laboratory findings .889 (.365 – 1.412) -2.627 (-4.967 - -.288) -1.314 (-2.483 - -.144)

Attitude Start 15 Explain that the patient doesn't notice the effect of the statin but that the effect is evaluated by blood tests to check cholesterol levels

16 Discuss the importance of adherence

17 Encourage patients to be adherent

Follow-up 18 Ask the patient about non-practical problems with taking the medication as prescribed (unwilling to take medication, for example because of misunderstandings about taking medication) -.533 (-.957 - -.109) -.507 (-.933 - -.080)

19 In case of non-practical problems, propose solutions to solve these problems (for example discussing the necessity or concerns, referral to nurse practitioner)

Social influence Start 20 Involve partner and/or relatives in the treatment

Self-efficacy Start 21 Encourage patients to plan ahead (for example for holidays or social activities) -.864 (-1.491 - -.238) -.876 (-1.497 - -.255)

22 Discuss potential barriers regarding adherence and possible ways to overcome them

Follow-up 23 Ask the patient if he/she is taking the medication as prescribed

24 Ask about practical problems with taking medication as prescribed (for example forgetting it or being unable to open the packaging) -.499 (-.959 - -.039)

25 In case of practical problems, discuss solutions with the patient to reduce these practical problems .242 (.018 - .467)

Intention formation Start 26 Explain how often and how long the medication should be used .520 (.064 - .977)

27 Develop and discuss a written individual dosing schedule -1.216 (-2.216 - -.217

28 Write down patients' dosing schedule (time, name of meds, number of doses) -.610 (-.978 - -.242) -.622 (-1.014 - -.230)

Action control Start 29 Identify daily routines (like brushing teeth) and encourage patients to align the taking of medicines with their routines

30 Encourage patients to use alarm devices as a reminder for taking the medication

Facilitation Start 31 Discuss the common side effects of the drug

32 Discuss with the patient how to deal with side-effects

33 Monitor and/or discuss possible interactions with other drugs

Follow-up 34 Discuss the experienced positive effects of the treatment -.218 (-.434 - -.002) -.508 (-.926 - -.091) -.462 (-.890 - -.035)

35 Asking about (perceived) side-effects of the treatment .433 (.068 - .799)

36 If patients experience side-effects, there is an active contribution to reduce these side-effects (sometimes by providing knowledge or adjusting the treatment) .650 (.237 – 1.064)

37 Suggesting a new medication regimen in case patients feel their present regimen is too complex

General 38 Call the patient after the initiation of the drugs to ask about experiences -1.205 (-2.344 - -.066)

39 Give the patient a telephone number and tell who to contact in case of side-effects -.710 (-1.234 - -.186) -.807 (-1.447 - -.167)

40 Give the patient a telephone number and tell who to contact in case of problems with intake/medication adherence -1.111 (-1.774 - -.449)

41 Explain patients who to contact in case they would run out of medication

Meta-score General 42 Intensify the number of follow-up visits in case of (possible) treatment non-adherence

43 Refer patients to another health care provider for (co-)treatment (e.g., in case of side-effects)

Minor comments

Spell out abbreviations at first appearance.

Reply: Thank you, we have spelled out abbreviations at first appearance now.

________________________________________

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

14 Feb 2022

Impact of physician’ and pharmacy staff supporting activities in usual care on patients’ statin adherence.

PONE-D-21-26245R1

Dear Dr. Huiskes,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Gianluigi Savarese

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have addressed all my initial coments in their revised manuscript. I have no further comments.

Reviewer #2: All my comments and suggestions have been adequately addressed. At this point I have no further questions for the authors.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

18 Feb 2022

PONE-D-21-26245R1

Impact of physician’ and pharmacy staff supporting activities in usual care on patients’ statin adherence.

Dear Dr. Huiskes:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Gianluigi Savarese

Academic Editor

PLOS ONE