**5. Interventions to improve adherence and clinical outcomes**

Given multiple factors influencing medication adherence in CVD, interventions addressing these factors to improve adherence have received rising interest (**Table 3**). They were classified partly or wholly into several categories of intervention: patient education, behavioral interventions, using reminder tools, cost reduction, and financial aid, using a healthcare team, and using fixed-dose therapy (polypill). Multifaceted interventions appeared more effective than single ones [63, 64]. This can partly be explained by the multifaceted nature of factors influencing medication adherence. Due to differences in healthcare resources and patient characteristics between high- and middle- or low-income countries, the interventions should be appropriately adapted to the local context. As most effective interventions on adherence improvement demand greater resources, the healthcare system needs to be supported. In waiting for support, some simple strategies for improving adherence to CVD medication were proposed (**Table 4**) [8]. An initial intervention might not be effective when applied in other settings. Thus, the healthcare team should continuously assess the effectiveness and feasibility of the intervention.

#### **5.1 Patient education**

The mode and frequency of the delivery of educational material may impact its effectiveness. Providing a few episodes of educational mails and/or phone calls did not improve adherence to secondary prevention medications in patients with MI (OR 1.03, 95% CI 0.77–1.36) [65] or with obstructive coronary artery disease (mail only vs. usual care, OR 0.98, 95% CI 0.81–1.19; mail and phone call vs. routine care, OR 0.99, 95% CI 0.82–1.20) [80]. However, tailored and interactive educational programs



*Abbreviations: ACEIs/ARBs, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers; ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; LDLc, low-density lipoprotein cholesterol; NA, not available; OR, odds ratio; RCT, randomized controlled trial; RR, risk ratio; SBP, systolic blood pressure; SMS, short message service; STS, structured telephone support.*

#### **Table 3.**

*Interventions that may improve medication adherence and clinical outcomes in CVD.*


#### **Table 4.**

*Strategies for improving medication adherence in CVD.*

with reinforcements improved CVD medication adherence. Earlier and more regular health checks with clinicians have improved adherence to cardiovascular medications [43, 81]. Intensive follow-up phone calls and regular consultations with cardiologists for patients with ACS were associated with higher adherence (58% intervention vs. 40% control, *P* < 0.001) and lower MACEs (19% intervention vs. 29% control, *P* < 0.001) at 36 months follow-up [67]. Face-to-face education by a nurse also significantly improved adherence to statin therapy (*P* < 0.01) and significantly lowered LDLc levels for primary prevention (2.66 vs. 3.00 mmol/l, *P* = 0.024) [68].

Regular educational information formats besides in-person also indicated an improvement in medication adherence. Both web-based and counselor-delivered formats improved adherence to medications in moderate-to-high risk patients with coronary heart disease (18% improvement in the web-based group and 21% improvement in the counselor group) [69]. Structured text messages and phone calls regularly made by a nurse positively affected medication adherence (78.9% message vs. 81.4% call vs. 69.5% control, *P* = 0.011) and reduced mortality or readmission (50.4% message vs. 41.3% call vs. 36.5% control, both *P* < 0.05) in patients hospitalized for acute HF [48]. A series of educational phone calls from nurses over 9 months improved

12-month medication adherence to dual antiplatelet therapy among patients with recent drug-eluting stent placement (87.2% call vs. 43.1% control (*P* < 0.001)) [72].

Patient education might improve medication adherence in CVD patients who do not fully understand the severity of their disease and the benefits of cardiovascular medication(s). The educational programs with reinforcements have improved adherence in most studies.

#### **5.2 Behavioral interventions**

A meta-analysis evaluating the impact of motivational interviewing over a year demonstrated a modest increase in medication adherence in patients with stroke (pooled RR 1.13, 95% CI 1.01–1.28) [70]. Promising results were again demonstrated in another RCT in which motivational interviewing improved both adherence (OR 1.91, 95% CI 1.19–3.05) and reduced rates of uncontrolled SBP (OR 0.62, 95% CI 0.50–0.78) compared with the control group [78]. Other counseling techniques such as providing patient feedback regarding medication adherence and enhancing family involvement showed a beneficial but negligible effect on medication adherence [82, 83].

Improving patient motivation and behaviors has not shown significant improvements in adherence outcomes. These interventions should be tailored to patients who are less motivated to take medication.

#### **5.3 Reminder tools**

Mobile phone-delivered interventions seemed to increase adherence to medication prescribed for the primary prevention of CVD, according to a Cochrane review of 14 trials with 25,633 randomized participants. Trials of BP self-monitoring with mobile phone telemedicine support modest benefits. One trial reported modest reductions in LDLc but no benefits for BP [84]. In a randomized trial of 5216 initiators of statin, those who received automated phone calls had significantly increased adherence (42.3% intervention vs. 26.0% control; absolute difference = 16.3%, *P* < 0.001; RR 1.63, 95% CI 1.50–1.76) [73]. Utilizing text message reminders also improved medication adherence in CVD in recent meta-analyses [85, 86].

Smartphone apps providing reminder alerts, adherence reports, and optional peer support significantly improved medication adherence (between-group difference 0.4; 95% CI 0.1–0.7, *P* = 0.01). However, this difference in adherence did not produce a significant difference in BP control between the groups (between-group difference −0.5, 95% CI −3.7–2.7, *P* = 0.78) [87]. A smartphone app integrating education, automatic reminder, and patient engagement strategies improved medication adherence among elderly patients with atrial fibrillation. Approximately 78% (14/18) of the patients in the high-adherence group at baseline remained in the same state, 45% (24/53) of the patients in the medium-adherence group at baseline moved to the highadherence group, and 72% (18/25) of the patients in the low-adherence group moved to either the medium- or high-adherence group [75]. A meta-analysis of nineRCTs evaluating the impact of apps on medication adherence showed an improvement in SBP, DBP, total cholesterol, and LDLc levels in the intervention arm. Apps have an acceptable degree of usability, yet the app characteristics conferring usability and effectiveness are ill defined [88].

Mobile phone calls, text messages, and applications can improve adherence and clinical outcomes. Patients who often forget to take medications and use technology can try these techniques.
