Adherence with cardiovascular medications and the outcomes in patients with coronary arterial disease: “Real‐world” evidence

Abstract Background Cardiovascular medications are vital for the secondary prevention of coronary arterial disease (CAD). However, the effect of cardiovascular medication may depend on the optimal adherence of the patients. This meta‐analysis aims to determine the magnitude of adherence to vascular medications that influences the absolute and relative risks (RRs) of mortality in patients with CAD in real‐world settings. Methods The Cochrane Library, PubMed, and EMBASE databases were searched through March 1, 2022. Prospective studies reporting association as RR and 95% confidence interval between cardiovascular medication adherence and any cardiovascular events and/or all‐cause mortality in patients with CAD were included. A one‐stage robust error meta‐regression method was used to summarize the dose‐specific relationships. Results A total of 18 studies were included. There is a significant inverse linear association between cardiovascular medication adherence and cardiovascular events (p nonlinearity = .68) or mortality (p nonlinearity = .82). The exposure‐effect analysis showed that an improvement of 20% cardiovascular medication adherence was associated with 8% or 12% lower risk of any cardiovascular events or mortality, respectively. In subgroup analysis, the benefit was observed in adherence of stain (RR: 0.90, for cardiovascular events, RR: 0.85, for mortality), angiotensin‐converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB)(RR: 0.90, for mortality), and antiplatelet agent (RR: 0.89 for mortality) but not in beta‐blocker (RR: 0.90, p = .14, for cardiovascular events, RR: 0.97, p = .32 for mortality). Estimated absolute differences per 1 million individuals per year for mortality associated with 20% improvement were 175 cases for statin, 129 cases for antiplatelet, and 117 cases for ACEI/ARB. Conclusion Evidence from the real word showed poor adherence to vascular medications contributes to a considerable proportion of all cardiovascular disease events and mortality in patients with CAD.


| INTRODUCTION
Coronary arterial disease (CAD) is a highly prevalent disease, associated with increased costs, morbidity, and mortality. 1 Cardiovascular medications, such as angiotensin-converting enzyme inhibitos (ACEI)/angiotensin II receptor blockers (ARB), beta-blockers, antiplatelet agents, and statins, remain the most common medical interventions worldwide for the prevention of CAD. [2][3][4] Although their beneficial effects have been established in the primary and secondary prevention of cardiovascular diseases (CVDs), their effort in real-world settings is inferior to that seen in random control trials (RCT), and this has been partly attributed to poor medication adherence. According to a recent study, almost 31% of myocardial infarction (MI) patients are no longer persistent with their prescribed medications by 6 months. 5 A meta-analysis that included 1 978 919 patients showed that only 60% of patients were adherence to their cardiovascular medications. Additionally, compared with good adherence, the risk of cardiovascular events or mortality in those with poor adherence increased by 20% or 35%, respectively. 6 A systematic evaluation of the association between cardiovascular medication adherence and the outcomes in patients with CAD is of significance for understanding the role of medication adherence in secondary prevention. Furthermore, a quantitative analysis of adherence and their outcomes could provide more detailed guidelines and education information for patients with cardiovascular medication to have better outcomes (e.g., cardiovascular events and mortality). However, the quantitative association between cardiovascular medication adherence and long-term outcomes in patients with CAD remains to be determined.
Moreover, considering well-designed RCTs might not reflect the actual adherence level or effectiveness of medication therapy in the "real" community. 7 We conducted an exposure-effect meta-analysis based on prospective observational studies to (i) quantitatively investigate the relationship between adherence to cardiovascular medication and outcomes in patients with CAD in real-world settings and (ii) estimate the future absolute risk for cardiovascular events or mortality for suboptimum adherence to cardiovascular medication.

| METHODS
We conducted this meta-analysis according to preferred reporting items for systematic reviews and meta-analyses guidelines 8 (Supporting Information: Table 1). All prospective studies (cohort, nested case-control), reporting data about medication adherence (statin, antiplatelet agents, ACEI/ARB, and beta-blockers) and any cardiovascular (defined as any fatal or nonfatal coronary heart disease) events, or allcause death were considered eligible for the systematic review. A comprehensive literature search was performed using Cochrane Library, PubMed, and Embase databases, up to March 1, 2022. Two researchers (Chen Chen and Xiaoqing Li) independently worked in the whole process of this meta-analysis from the literature search and selection to data analysis. Supporting Information: Table S2 provides a detailed description of the search strategy. All discrepancies were resolved through discussion with each other or through consultation with a third reviewer (Yuhao Su).
We used a robust error meta-regression method 9 for the exposure-effect analysis of cardiovascular medication adherence and any cardiovascular events and all-cause death. All statistical analyses were undertaken using Stata software (version 14.0; Stata Corp LP). Assessment of the quality of the included studies was performed using the Newcastle-Ottawa quality assessment scale (NOS), with a score over 6 defined as high quality. 10 Full details of the literature search strategy, study selection criteria, quality assessment, and statistical analysis have been reported in Supporting Information: Methods. This study has been registered with PROSPERO (international prospective register of systematic reviews)-registration number-CRD42019116748.

| Study characteristics and quality
Detailed characteristics of the included studies are presented in and three were nested case-control. Seven were from North America (US and Canada); three were from Asia, and eight were from Europe.
The reporting quality of the included articles was high. All included studies obtained a NOS of ≥7 points (Supporting Information: Table S3).

| Medication adherence and all-cause death
Fifteen 11-20,23,25-28 studies with available data on all-cause mortality outcomes. Statin adherence was the most commonly studied (n = 13).
There were five studies that assessed the ACEI/ARB drugs, eight assessed beta-blockers, and 3 assessed antiplatelets, respectively. The association between good adherence and mortality persisted in almost all subgroup analyses defined by age, region, follow-up times, and other covariates (Supporting Information: Table S4).

| Medication adherence and any CVD events
Among six studies 19 with no evidence of heterogeneity ( Figure 3). In the nonlinear model, an inverse association was found between cardiovascular medication adherence and CVD events (Figure 3).
In subgroup analysis, there was also evidence of a linear association between statin (p nonlinearity = .64) and beta-blockers (p nonlinearity = . 48

| Sensitivity analyses and publication bias
The omission of any single study did not significantly alter the pooled RRs. There was no statistical evidence of publication bias (Supporting Information: Figure S1).

| DISCUSSION
To the best of our knowledge, this is the first meta-analysis that quantitively analyzes the effect of cardiovascular medication adherence on outcomes among patients with CAD in a real-world setting. This meta-analysis strengthens and extends the understanding of the positive impact of cardiovascular medication adherence on secondary prevention among people with CAD, further supporting the notion that improved cardiovascular medication adherence was associated with better outcomes in patients with CAD.
Medication adherence has been defined as the extent to which a patient takes medications as prescribed by their healthcare providers. 30 In clinical practice, medication nonadherence is one of the main factors that reduce the effectiveness of drug therapies. 31 However, a previous study reported that almost 40% of the patients who initiated the use of ACEIs/ARBs, beta-blockers, or statins following hospitalization for MI became nonadherent during the first treatment year. 32 Moreover, many patients seemed to do so already during the first 6 months. 5 Therefore, better adherence to cardiovascular treatment should be highlighted in the clinical secondary prevention in patients with CAD.
We subsequently found the inverse association between cardiovascular medication adherence and outcomes in patients with CAD risk was found. A 20% improvement in cardiovascular medication adherence was associated with an 8% reduction in cardiovascular case risk. In addition, this cardiovascular event risk reduction would be translated into a reduction of all-cause mortality (decreased by 12%). However, this benefit was not observed in good beta-blocker adherence. This reason might be the majority of the included sample were patients with post-MI. Recently, several studies reported that beta-blocker might have no benefit on post-AMI patients without heart failure or ventricular dysfunction (so-called reperfusion era). 33,34 Actually, the evidence of benefits associated with beta-blocker use is mostly from trials predating the advent of F I G U R E 2 Dose-response analysis (linear and nonlinear) of cardiovascular medication adherence and all-cause death. The solid line and the dashed lines represent the estimated relative risk and the 95% confidence interval, respectively. CVD, cardiovascular disease.
F I G U R E 3 Dose-response relationship (linear and nonlinear) of cardiovascular medication adherence and cardiovascular events. The solid line and the dashed lines represent the estimated relative risk and the 95% confidence interval, respectively. CVD, cardiovascular disease.
| 1225 the era of early revascularization. 35 A meta-analysis of randomized clinical trials also showed that beta-blocker use has no mortality benefit for patients without heart failure. 36 Another study also showed patients adherent to ACE inhibitors/ARBs and statins only had similar mortality rates as those adherents to ACE inhibitors/ARBs and statins and beta-blocker, 17  In general, the impact of age on "statin adherence" in the Some authors have raised the idea of "it is not too late to improve statin adherence" among patients whether they were adherent to statin therapy pre-AMI. 14 We also suggest clinicians should emphasize this idea in health propaganda education when patients discharging from the hospital. Besides, poor adherence was affected by lots of factors (i.e., sex, age, race). 45 Another simple method to solve this problem is to develop predictive screen models to better identify at-risk for nonadherence patients prospectively. On the other hand, we suggest physicians pay more attention to these patients with a high-risk factor of nonadherence (e.g., older, depression, cognitive dysfunction). 46 however, because of data-type restriction, the exposure-effect analysis was not available.

| CONCLUSION
In summary, poor adherence is dose-dependently associated with significantly increased risk of cardiovascular events and all-cause mortality in patients with CAD. Cardiovascular medication adherence should be a target for quality improvement interventions to maximize the outcomes of secondary prevention of CAD.

AUTHOR CONTRIBUTIONS
Kui Hong was responsible for the entire project and revised the draft.
Chen Chen and Xiaoqing Li performed the systematic literature review and drafted the first version of the manuscript. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

ACKNOWLEDGMENT
This study was supported by grants from the National Natural Science Foundation of China (31971041).