**4. Medication adherence-related outcomes**

#### **4.1 Clinical outcomes**

Many observational studies have assessed the relationship between medication adherence and outcomes in CVD. Past evidence shows the broad impact of untreated or inadequately treated CVD ranging from major cardiovascular events (MACEs) to mortality. This might be caused by suboptimal adherence to effective medications. Nonadherence to statins in post-myocardial infarction (MI) patients was associated with up to 25% increased hazard of death [37]. In chronic coronary artery disease, nonadherence to cardioprotective medications (antihypertensive and antihypercholesterolemic medications) was associated with up to 40% increase in the risk of hospitalizations for cardiovascular events and up to 80% increase in the risk of death [38]. Conversely, optimal adherence was associated with significantly reducing cardiovascular events and mortality. A recent meta-analysis indicated that each incremental 20% increase in adherence level of cardiovascular medication reduced the risk of cardiovascular events by 9%, stroke by 16%, and all-cause mortality by 10% [39]. Several clinical studies highlighted the benefits of cardiovascular medications and the importance of adherence to prescribed medications to optimize health outcomes. This can raise awareness of the importance of medication adherence in CVD among clinicians, patients, healthcare insurers, and policymakers. The potential of overestimating the adverse outcomes of suboptimal adherence should be noted. Nonadherent patients are less likely to follow health recommendations (e.g. flu vaccination) and more likely to engage in harmful behaviors (e.g. smoking), impacting

health outcomes. Yet, these confounders can be minimized by (1) a well-designed study (i.e. using randomization, placebo, and double-blind) or (2) an appropriate statistical analysis. However, statistical analysis is less pronounced than study design, because a statistical analysis can be re-processed, but a poorly designed study can never be recovered. Medication adherence-related outcomes for specific diseases are detailed as follows:

## *4.1.1 Hypertension*

Suboptimal adherence to antihypertensive drugs was associated with multiple adverse cardiovascular events from acute to chronic conditions (e.g. chronic heart failure) to death [32]. Suboptimal medication adherence was also associated with various organ disorders, including chronic kidney disease, cognitive dysfunction, and dementia [32]. A study including 155,597 patients with hypertension showed that highly adherent patients (≥80% PDC with antihypertensive medication) had less than half the risk of experiencing a cardiovascular event compared with lower adherent ones over a median duration of 5.8 years (adjusted hazard ratio [aHR] 0.44; 95%CI 0.42–0.45) [40].

In elderly diabetic patients having multiple comorbidities, a retrospective cohort study found that ≥80% adherence to ACEIs/ARBs was not associated with BP < 140/90 mmHg in those ≥85 years (risk ratio [RR] 1.01, 95% CI 0.96–1.07) or with multiple comorbid diseases (e.g. RR = 1.04, 95% CI 0.99–1.08) [41]. Reasons for uncontrolled BP despite optimal adherence might be (1) age-related physiological changes and (2) pathological changes by comorbidities (e.g. chronic kidney disease).

## *4.1.2 Myocardial infarction (MI)*

Among post-MI patients, ≥80% adherence to both statins and ACEIs was associated with decreased risk of long-term MACEs (i.e. all-cause mortality, nonfatal MI hospitalization, stroke, or coronary revascularization) than <40% adherence (18.9% vs. 26.3%, HR 0.73, *P* = 0.0004) and 40–79% adherence (18.9% vs. 24.7%, HR 0.81; *P* = 0.02) at 2 years [42]. Another study across China in 4001 post-MI patients found that optimal adherence (≥90%) to cardiovascular medications was associated with a 39% reduction in the risk of 1-year cardiovascular events (aHR 0.61, 95% CI 0.49–0.77) [43].
