Interventions to Improve Adherence to Cardiovascular Medication: What About Gender Differences? A Systematic Literature Review

Figures & data

Figure 1 Flowchart of study inclusion.

Abbreviations: CVD, cardiovascular disease; RCT, randomized controlled trial; CCT, clinical controlled trial.

Table 1 Characteristics of Studies Describing Interventions for Which Subgroup Analyses are Performed to Investigate Gender Differences in Intervention Effects

Author, Publication Year, Country	Study Design	Study Population	Type, Setting and Aim of Intervention	Intervention Description
Interventions WITH gender-specific Intervention Effect
Choudry, 2018, USA ^Citation31	Cluster RCT	4078 patients with suboptimal control of hyperlipidemia, hypertension, or diabetes, and being non-adherent to prescribed treatment. Intervention group: n=2038 (♀ n=924) Control group: n=2040 (♀ n=917)	Type: multicomponent; Telephone counseling, text messaging and pillboxes, mailed progress reports Setting: Clinical pharmacy in primary care Aim: improve medication adherence among patients with hypertension, hyperlipidemia, or diabetes	A trained clinical pharmacist conducted an individually tailored telephone consultation, during which potential adherence barriers or other factors that may contribute to poor disease control were discussed as well as the patient’s readiness to modify behaviors. Patient and pharmacist together composed a plan to improve adherence and disease control, using. strategies that included text messages, pillboxes, and mailed progress reports.
Kooy, 2013, The Netherlands ^Citation34	RCT	381 patients who had started statins at least one year prior to inclusion and were non-adherent (refill rate between 50-80%) in preceding year. Intervention group 1: n=130 (♀ n=69) Intervention group 2: n=123 (♀ n=70) Control group: n=128 (♀ n=74)	Type: multicomponent; electronic reminder device (ERD) with or without counseling Setting: Community pharmacy Aim: improve adherence and persistence to statin treatment	Two intervention groups: 1) ERD and non-adherence counseling in which the pharmacist provided feedback on patients’ previous drug dispensing data, discussed reasons for non-adherence, provided information about the benefits of statin use. 2) ERD only. Patients received the ERD by mail with user instructions.
Interventions WITHOUT gender-specific intervention effect
Derose, 2013 USA ^Citation25	RCT	5,216 new statin users . Intervention group: n=2,606 (♀ 51,0%) Control group: n=2,610 (♀ 50,1%)	Type: single component; automated telephone call and messaging Setting: direct messaging to members of Kaiser Permanente Southern California (health plan) Aim: decrease primary nonadherence to statins	Patients received an automated telephone call 1 to 2 weeks after the prescription date. A personalized message provided them with information on the benefits of the therapy and encouraged them to fill the prescription. Patients who still did not fill their prescription a week after the telephone call were sent a letter signed by their prescriber.
Eussen, 2010 The Netherlands ^Citation26	RCT	899 new statins users. Intervention group: n=439 (♀ n=232) Control group: n=460 (♀ n=230)	Type: single component; counseling Setting: community pharmacy Aim: improve adherence to statin therapy, especially in the first months after initiation.	Five individual counseling visits in the pharmacy, at first dispense, second dispense and dispenses at 3, 6, and 12 months. Counseling at first dispense included education about the medication and the importance of adherence. Patients were given a written summary of the verbal information. At second dispense, patients were asked about their experience (incl. potential barriers to adherence). The association between adherence and lipid levels was discussed to encourage patients to adhere.
Patel, 2015 Australia ^Citation27	RCT	623 patients with an established CVD or an estimated five-year CVD risk of ≥15% with indications for antiplatelet, statin and ≥2 blood pressure lowering drugs. Intervention group: n=311 (♀ n=114) Control group: n=312 (♀ n=117)	Type: single component; polypill-based strategy Setting: general practice Aim: improve adherence to CVD medication	Patients used a polypill (fixed-dose combination) containing aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and either atenolol 50 mg (version 1) or hydrochlorothiazide 12.5 mg (version 2). The control group used separate medications and doses as prescribed by their doctor.
Schulz, 2019 Germany ^Citation32	RCT	237 patients of ≥60 years with chronic heart failure (CHF), treated with a diuretic, hospitalized for HF within the last 12 months or with increased B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide concentrations. Intervention group: n=110 (♀ n=42) Control group: n=127 (♀ n=49)	Type: multicomponent; medication review, (bi-) weekly dosing aids and counseling Setting: community pharmacy Aim: improve adherence for three heart failure medication classes in elderly patients with CHF.	A medication review was conducted to generate a medication plan. Patients received a weekly dosing aid and printout of the plan. (Bi-)weekly pharmacy visits thereafter during which the plan was updated (if necessary), dosing aids were supplied, medication counselling was given, and the physician was contacted (if necessary).
Selak, 2014 New Zealand ^Citation28	RCT	513 adults with an established CVD or an estimated five-year CVD risk of ≥15% recommended for treatment with antiplatelet, statin, and ≥2 blood pressure lowering drugs. Intervention group: n=256 (♀ n=99) Control group: n=257 (♀ n=88)	Type: single component; polypill-based strategy Setting: general practice Aim: improve adherence to CVD medication	Patients used a polypill (fixed-dose combination) containing aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and either atenolol 50 mg (version 1) or hydrochlorothiazide 12.5 mg (version 2). The control group used separate medications and doses as prescribed by their doctor.
Vollmer, 2014 USA ^Citation29	Pragmatic clinical trial	21,752 participants, ≥40 years, with diabetes mellitus and/or CVD who were suboptimally adherent (<90%) to a statin or ACEI and ARBs and (over)due for a refill. Intervention group 1: n=7,247 (♀ 46.5%) Intervention group 2: n=7,250 (♀ 47.1%) Control group: n=7,255 (♀ 47.3%)	Type: single component; automated reminder Setting: direct communication to patients Aim: improve adherence to statins, or ACEI and ARBs.	Two intervention groups using interactive voice recognition (IVR) calls: (1) IVR group received automated phone calls when they were (over)due for a refill. (2) IVR+ group received the same phone calls, plus a personalized reminder letter, a live outreach call, EMR-based feedback to their primary care provider, and additional mailed materials.
Wald, 2014 UK ^Citation30	RCT	301 patients taking blood pressure and/or lipid-lowering medications. Intervention group: n=150 (♀ n=68) Control group: n=151 (♀ n=70)	Type: single component; text messaging Setting: direct communication to patients Aim: improve adherence to blood pressure and/or lipid-lowering treatment	Daily text messages for 2 weeks, on alternate days for 2 weeks and once weekly for 22 weeks. Patients were asked to respond whether they had taken their medication, whether the text reminded them, and the reason if they had not taken their medication.
Ineffective Interventions (neither a gender-neutral nor a gender-specific intervention effect)
Blackburn, 2016 Canada ^Citation35	Cluster RCT	1,906 new statins users. Intervention group: n=907 (♀ n=447) Control group: n=999 (♀ n=431)	Type: single component; counseling Setting: community pharmacy Aim: prevent nonadherence during the first year of statin use	Two brief screening questions: 1) “How long have you been taking this medication?” 2) (example) “Are you having any difficulties or concerns with this new medication?” Pharmacists were challenged to personalize the second screening question.
Volpp, 2017 USA ^Citation33	RCT	1,503 patients surviving acute myocardial Infarction (AMI), were prescribed at least 2 of the 4 medications (statin, aspirin, β-blocker, antiplatelet agent). Intervention group: n=1000 (♀ n=343) Control group: n=503 (♀ n=190)	Type: multicomponent; electronic reminder, lottery incentive and social support Setting: direct communication to patients Aim: improve adherence to CVD medication in patients surviving AMI	Use of electronic pill bottles, combined with daily incentives and social support (enlisting a friend or family member who would be notified if medication was missed, access to social work resources, a staff engagement advisor to provide close monitoring, feedback, and adherence reinforcement) .

Abbreviations: RCT, randomized controlled trial; CVD, cardiovascular disease; ♀, female.

Table 2 Adherence Outcomes and Measurement and Intervention Effects, Including Gender-Specific Results

Author, Publication Year, country	Adherence Outcomes, Measurement and Stage	Overall Intervention Effects	Gender-specific Intervention Effects
Interventions WITH gender-specific Intervention Effect
Choudry, 2018 USA ^Citation31	Method: prescription claims data Primary outcome: PDC over 12 months using the “average of averages” approach. Stage of adherence: implementation	Mean PDC: - Intervention group: 46.2% (SD: 33.9) - Control group: 42.1% (SD: 33.8). The intervention resulted in a 4.7% (95% CI 3.0-6.4) improvement in adherence.	The intervention was more effective in men than women. For men in the intervention group, mean adherence was 48.5 (SD: 33.8) versus 42.5 (SD: 33.7) for men in the control group. For women, the mean adherence was 43.3 (SD: 33.8) and 41.5 (33.8) for those in the intervention and control group respectively. The interaction was significant at p=.03.
Kooy, 2013 The Netherlands ^Citation34	Method: pharmacy refill data Primary outcome: PDC calculated by dividing the total days’ supply by the number of days of study participation (=360 days) (PDC360). PDC360 was analyzed as a continuous and a dichotomous measure with cut-off <80% for non-adherence. Secondary outcome: occurrence of discontinuation defined as >182 consecutive days of the 360 days uncovered. Stage of adherence: implementation and discontinuation (persistence)	Median PDC360: - Counseling + ERD group: 90.0% (76.8-98.3) - ERD group: 91.0% (76.0–99.0) - Control group: 87.5% (75.0–99.0). Using 80% cut-off: - Counseling + ERD group: 69.2% - ERD group: 72.4% - Control group: 64.8% Discontinuation: - Counseling + ERD group: 6.2% - ERD group: 5.7% - Control group: 9.4% None of the differences were significant.	Gender was a significant effect-modifier (p<.10) in the group of patients using oral antidiabetics and/or platelet aggregation inhibitors. Women in the ERD group were more likely to be adherent to statin treatment compared to women in the control group: OR: 8.26 (95% CI 2.20-31.0), p=.002 (model adjusted for refill adherence in 12 months before index date and use of beta-blocking agents or calcium channel blocker; unadjusted OR 5.58 (95% CI 1.79-17.40)
Effective Interventions WITHOUT Gender-specific Intervention Effect
Derose, 2013 USA ^Citation25	Method: electronic health records and pharmacy records Primary outcome: dispense of a statin between the first telephone call (day 0) and up to 2 weeks after expected delivery of the letter. Stage of adherence: initiation	Significant difference in the proportion of participants who were dispensed a statin (p<.001): - Intervention group: 42.3% - Control group: 26.0% The relative risk for adherence in the intervention vs control group was 1.63 (95% CI 1.50-1.76)) The odds ratio for adherence in the intervention group vs control group was 2.08 (95% CI 1.85-2.35).	Intervention effects were examined by sex using regression interaction terms, but no significant interaction was found. Female vs. male: OR 1.01 (95% CI 0.90-1.14), p=.86
Eussen, 2010 The Netherlands ^Citation26	Method: Electronic pharmacy dispensing records Primary outcome: discontinuation of statin treatment 12 months after start, defined as failing to refill the statin within 90 days or 1 time the theoretical duration. Secondary outcome: discontinuation rates 6 months after statin initiation, and the Medication Possession Ratio (MPR) calculated as the sum of the days’ statin supply dispensed divided by the therapy length. Stage of adherence: discontinuation (persistence)	Significant difference in discontinuation of statin therapy within 6 months of initiation (p=.026): - intervention group: 47 (11%) patients discontinued - control group: 72 (16%) patients discontinued. The intervention group had a significantly lower 6-month discontinuation rate than the control group (HR 0.66 (95% CI 0.46-0.96)). The 12-month discontinuation rate did not differ between the groups (HR 0.84 (95% CI 0.65-1.10)). The intervention group was more likely to persist with treatment compared to the control group (OR 1.52 (95% CI 1.04-2.17)). The median MPR was 99.5% (96.9-100%) in the intervention group and 99.2% (95.6-100%) in the control group (p=.14).	A treatment-by-subgroup interaction term was added to the Cox proportional hazard model to test whether different subgroups (sex was one) had different risks. Although females seemed to gain more benefit from receiving the intervention, the difference in intervention effect was not statistically significant.
Patel, 2015 Australia ^Citation27	Method: self-reported medication use assessed at each monthly visit Primary outcomes: self-reported use combination treatment (antiplatelet, statin and ≥2 BP lowering therapies for ≥4 of the previous 7 days) at study end. Secondary outcomes: self-reported use of combination treatment at 12 months; combination treatment prescriptions at study end. Stage of adherence: implementation and discontinuation (persistence)	Significant difference at study end in the use of combination treatment: 70.1% in the intervention group versus 46.9% in the control group (RR 1.49 (95% CI 1.30-1.72); p<.0001). Higher prescription rate of combination treatment at study end in the intervention group compared to the control group (RR 1.54 (95% CI 1.36-1.74); p<.001).	Pre-specified subgroups, one for sex. Use of combination treatment: female RR versus male RR: 1.56 (95% CI 1.22-2.00) versus 1.46 (95% CI 1.23-1.73), p=.64
Schulz, 2019 Germany ^Citation32	Method: pharmacy claims data Primary outcome: PDC, calculated as the number of days covered divided by the total number of days (365 days) Secondary outcome: the proportion of patients classified as adherent (mean PDC≥80%) for each drug class.. Stage of adherence: implementation	PDC for three HF medication classes improved in the intervention group compared to the control group (mean difference 5.7% (95% CI 1.6–9.8), p=.007). The proportion of adherent patients w was 86% in the intervention group versus 69% in the control group, a difference of 17% points (OR 2.7, 95% CI 1.3–5.7, p<.01).	No significant interactions were found for subgroups (including sex).
Selak, 2014 New Zealand ^Citation28	Method: self-reported medication use Primary outcomes: self-reported adherence (use of antiplatelet, statin, and ≥2 blood pressure lowering drugs) at 12 months. Stage of adherence: implementation	Self-reported adherence at 12 months was higher in the intervention group compared with the control group (81% vs 46%, RR 1.75 (95% CI 1.52-2.03), p<.001). National dispensing claims data for fixed dose combination versus usual care (79% vs. 47%, p<.001) showed close concordance with the self-reported adherence.	Pre-specified subgroups (one for sex) showed no effect.
Vollmer, 2014 Hawaii and USA ^Citation29	Method: pharmacy dispensing data Primary outcome: modified version of the PDC (mPDC), including the whole follow-up period as the denominator time frame. Stage of adherence: implementation	Statin adherence: - IVR group vs. control group: +2.2% (95% CI 1.1-3.4), p=.000 - IVR+ group vs. control group: +3.0% (95% CI, 1.9-4.2), p=.000. Proportion of adherent patients (>0.8): - IVR group vs. control group: OR 1.14 (95%CI 1.05-1.24), p=.002 - IVR+ group vs. control group: OR 1.16 (95% CI 1.06-1.26), p=.000. ACEI/ARB adherence: - IVR group vs. control group +1.6% (95% CI 0.2-2.9), p=.022 - IVR+ group vs. control group: +3.7% (95% CI 2.3-5.0), p=.000 Proportion of adherent patients (>0.8): - IVR group vs. control group: OR 1.12 (95% CI 1.02-1.23), p=.014 - IVR+ group vs. control group: OR 1.21 (95% CI 1.10-1.32), p=.000	The differences generally persisted across subgroups, amongst which sex.
Wald, 2014 UK ^Citation30	Method: personal enquiry at clinic visits or failing that, electronic prescription records. Primary outcome: medication use at 6 months exceeding 80%. Secondary outcomes: (i) proportion of patients continuing their medication regardless of the number of days missed; (ii) proportion of patients continuing their medication taking >80% of their prescribed regimen. Stage of adherence: implementation and discontinuation (persistence)	Stopped their medication or continued to take <80% at 6 months: - intervention group: 9% - control group: 25% An improvement in adherence of 16% (95% CI 7%–24%), p<.001.	No significant interactions were found for subgroups (including sex).
Ineffective Interventions (neither a gender-neutral nor a gender-specific intervention effect)
Blackburn, 2016 Canada ^Citation35	Method: prescription medication claims Primary outcome: PDC defined as the sum of days supplied for statin medications divided by the number of days of follow-up with max of 1 year. Secondary outcomes: percentage of new statins users with PDC ≥80%, and the percentage stopping all statin dispensations within 3 months of the first dispensation. Stage of adherence: implementation and discontinuation (persistence)	All pharmacies, primary analysis: Mean statin adherence: - Intervention group: 71.6% (SD: 33) - Control group: 70.9% (SD: 33); unadjusted p=.64 Percentage of patients with PDC ≥80%:: - Intervention group: 57.3% - Control group 55.9%; unadjusted p=.51 Percentage of non-persistent patients: - Intervention group: 9.4% - Control group 8.3%; unadjusted p=.41. Differences remained non-significant after multivariable adjustment. Pharmacies stratified according to protocol compliance (low-medium-high): High protocol compliance pharmacies showed higher adherence compared with control pharmacies (β = .056, (95% CI 0.010–0.101), p=.01). Percentage of patients with PDC ≥80%was significantly higher in pharmacies with high protocol compliance compared with control(OR 1.32 (95% CI 1.08–1.61), p<.01).	Subgroup based on sex exhibited results consistent with the primary analysis. (Data not shown)
Volpp, 2017 USA ^Citation33	Method: medical insurance claims data Primary outcome: time until first vascular readmission. Secondary outcomes: PDC for the 12-month study period for medications other than aspirin. Three definitions for adherence were used: (1) strict definition assumed that patients were prescribed all 3 drugs for the entire study period; (2) intermediate definition assumed that patients had been prescribed a medication for the entire study period if they ever filled that medication after discharge; (3) relaxed definition assumed that patients were prescribed medication from first fill until the end of study period. Adherence was achieved if a participant was covered by all 3 medication classes on a given day. Stage of adherence: implementation	No differences in PDC between the control and intervention groups, - using the strict definition (control=0.42, intervention=0.46; difference=0.04; 95% CI −0.01-0.09; p=.10) - using the relaxed definition (control=0.63, intervention=0.66; difference=0.03; 95% CI −0.02-0.08; p=.19). No significant differences between the 2 groups for adherence to individual drug classes.	Subgroup analyses were performed (amongst which sex). No significant differences were found for subgroups.

Abbreviations: RCT, randomized controlled trial; CVD, cardiovascular disease; ♀, female.

Table 3 Risk of Bias of Included Studies Determined with the Cochrane Collaboration Tool for Assessing Risk of Bias. Seven Domains of Bias Were Scored Low (Green Dot), High (Red Dot) or Unclear Risk (Yellow Dot)

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