The impact of age on the implementation of evidence-based medications in patients with coronary artery disease and its prognostic significance: a retrospective cohort study

After 30 years of rapid economic growth, China is facing the dual pressures of chronic non-communicable diseases and an ageing population [1, 2]. Elderly patients frequently have complications from various cardiovascular disease risk factors, such as hypertension, hyperlipidaemia, and diabetes, which are independently associated with cardiovascular events and deaths in patients with coronary artery disease (CAD) [3‐5]. Studies have shown that CAD is the most common disease in people over 65 years of age and that 83% of patients who die of ischaemic heart disease are older than 65 years [3]. Current treatment for CAD have entered the era of evidence-based medications (EBMs), and the clinical diagnosis and treatment are implemented following the standard of care listed in the guidelines [6‐9]. However, the current guidelines were established based on studies that did not take age factors into full account; in addition, many studies completely excluded elderly patients due to safety considerations [10‐12]. Furthermore, when treating elderly patients, clinicians have more concerns for the therapeutic window and the possibility of side effects due to elderly patients’ unique physiological characteristics [13]. Therefore, current guidelines might have significant limitations regarding clinical compliance among elderly CAD patients. These limitations have not been adequately studied among CAD patients in China.

By analysing a single-centre cohort of 2830 CAD patients, this study explored the association of EBM compliance in CAD patients in different age groups and the risk of long-term death.

A total of 2830 patients with CAD were included in the study. The the average age and its SD were 64.62 ± 10.54 years, and 20.3% of the patients were male. A total of 850 (30.0%) patients are younger than 60 years old, 1490 (52.6%) were in the range of 60 to 75 years old and 491(17.3%) were over 75 years old. The distribution of baseline data is shown in Table 1. The clinical features of the patients showed certain differences between groups. Older patients have a lower proportion of dyslipidaemia, and higher proportion of hypertension, diabetes mellitus and heart failure (p < 0.001). The percentage of patients diagnosed with non-ST segment elevation myocardial infarction (NSTEMI) had a higher trending proportion (Fig. 1).

The average follow up was 30.25 ± 11.89 months. A total of 270 cases of all-cause death occurred (mortality, 9.5%, 95% CI: 8.5%–10.7%), including 150 cases of cardiovascular death (cardiovascular mortality, 5.3%, 95% CI, 4.5%–6.2%). The survival curve of patients older than 75 years old had a significantly higher risk of all-cause death (panel A) and cardiovascular death (panel B) than the group ranging from 60 to 75 years old and the group younger than 60 years old (mortality, Group 3 vs. Group 1: 18.7% vs. 4.1%, p < 0.001; Group 2 vs. Group 1: 9.6% vs. 4.1%, p < 0.001; cardiovascular mortality, Group 3 vs. Group 1: 10.3% vs. 2.7%, p < 0.001; Group 2 vs. Group 1: 5.1% vs. 2.7%, p < 0.001) (Fig. 2).

Approximately 92.2% of CAD patients were discharged with aspirin, 86.4% with aspirin and clopidogrel, 66.22% with beta-blockers, 56.6% with ACE inhibitors, 89.1% with statins, and 36% with the combination of aspirin, clopidogrel, beta-blockers, ACE inhibitors, and statins. The medicine proportion of ere different in all groups. In the group 2 and 3, the proportion of EBMs prescribed at discharge is significantly lower than the younger but ACEIs or ARBs is opposite. (asprin, dual-antiplatelet, and beta-blockers: all p for tends < 0.001; and statins: p = 0.023) (Fig. 3). Meanwhile, we analysed the combined use of beta-blockers, statins, and ACEIs or ARBs among the EBMs (Fig. 4). The percentage of patients over 75 years old using no EBMs was significantly higher than the percentages in the other 2 groups (7.7% vs. 4.6% vs. 2.2%,p for trend < 0.05) (Fig. 4).

In multivariate Cox’s proportional hazards regression model analyses each kind of EBMs (beta-blockers, statins, and ACEIs or ARBs) alone was considered an important modifiable protective factor of both all-cause death and CV death in patients ranged from 60 to 75 years old or over 75 years old (Table 2). For ACEI or ARB use, Group 3 and 2 benefit more than Group 1 regarding to all-cause death and CV death (all-cause death: Group 1: HR = 0.89, 95% CI, 0.44–1.80; Group 2: HR =0.48, 95% CI, 0.34–0.68; Group 3: HR =0.54, 95% CI, 0.35–0.84; CV death: Group 1: HR = 0.54, 95% CI, 0.22–1.34; Group 2: HR =0.42, 95% CI, 0.26–0.68; Group 3: HR =0.45, 95% CI, 0.25–0.83). In the unadjusted Cox’s proportional hazards regression model analysis of the patients after propensity score matching, we obtained constant results with the adjusted analysis of patients before propensity score matching (Table 2). The combination of EBM use resulted in a greater reduction in the risk of all-cause death even in patients older than 75 years. Meanwhile, similar results were observed in the analysis of CV death (Table 3).

This study found that elderly patients had complications with more cardiovascular disease risk factors and had higher all-cause death and cardiovascular events. However, the proportion of elderly patients receiving EBMs was lower than that of younger patients. Patients who had higher compliance with EBMs exhibited a lower risk of death.

Age is an important risk factor for poor prognosis in patients with CAD [15]. On one hand, with increases in age and organ ageing, the capacity to survive cardiovascular events declines; on the other hand, due to concerns regarding drug tolerance and side effects, elderly patients often receive insufficiently effective drugs, resulting in poor prognosis [16‐19]. Previous studies have shown that complications or dysfunctions of liver and kidney limit the use of statins and ACEI/ ARB drugs [17, 18]. Concerns regarding the risk of bleeding and gastrointestinal discomfort limit the use of aspirin in elderly patients [20, 21]. Similar with previous foreign reports [3, 22, 23], our study suggests that EBM compliance among Chinese patients with CAD is notably inadequate.

The reasons for inadequate compliance with EBMs for elderly patients are not clearly elucidated. Based on previous studies, we speculate that the inadequate compliance might be caused by the following reasons. (1) Due to organ dysfunction, elderly patients had concerns about drug side effects. For example, due to high risk of cerebral haemorrhage and gastrointestinal bleeding, elderly patients had more concerns about the risk of bleeding associated with anti-platelet drugs, especially double antiplatelet therapy [21, 24]; due to liver and renal dysfunction, elderly patients had major concerns about statin-induced liver injury and ACEI/ARB-induced renal damage [25‐27]; and due to conduction dysfunction and high incidence of chronic obstructive pulmonary disease (COPD), elderly patients had concerns that a beta-blocker would aggravate slow arrhythmia and wheezing [28, 29]. (2) Elderly patients had poor tolerance for drugs. Elderly patients had a narrow therapeutic window, with the minimum effective concentration being very close to the minimum toxic concentration [30]. (3) The physical conditions of elderly patients is frequently changing. CAD is a chronic disease, and the long-term compliance with EBMs requires complicated medication dose adjustment and maintenance [13]. (4) Elderly patients often suffered from multiple diseases and therefore bear high medication costs [31]. (5) Elderly patients had decreased memory and limited social support, negatively affecting long-term medication compliance [32]. The above factors not only led to low EBM compliance among the elderly patients but also discouraged physicians from prescribing EBMs to elderly CAD patients. However, the available evidence does not show that elderly CAD patients should reduce the use of EBMs [33‐35]. Two meta-analyses showed that statin use in elderly patients over 65 years of age was able to reduce the risk of all-cause mortality by 22%, coronary-related deaths by 30%, myocardial infarction by 26% and revascularization by 30% [36, 37]. Another meta-analysis showed that the use of an ACEI or ARB in elderly patients with cardiovascular disease may increase the risk of vascular oedema, hypotension, and renal impairment, but cautious use could still reduce the risk of all-cause death, cardiac death, myocardial infarction, heart failure, and other clinical events [38]. Soumerai et al. found that the risk of death was 14% lower in elderly patients with acute myocardial infarction who were treated with beta-blockers at discharge, which was consistent with the results of randomized controlled trials of young and low-risk populations [39]. The results of the present study also showed that a higher degree of EBM compliance corresponded to better prognosis, suggesting that elderly CAD patients should also adhere to the guidelines and EBMs.

Several limitations of this study should be addressed. First, the registry made it difficult to completely avoid selection bias and confounding factors including information of activity of daily livings. In current study, the prescription rate of ACEI/ARBs was higher in those aged 60–75 and > 75 than those aged < 60, which was a converse trend to other EBMs. The possible explain was that ACEI/ARBs was not only an EBMs for ACS, but also used as an antihypertensive agents. Elderly CAD patients were complicated more hypertension than younger patients, and had more chance to take ACEI/ARBs. After excluding the patients with hypertension, the prescription rate of ACEI/ARBs were equal in three groups of different ages. (see Additional files 2) Second, the samples in this single-centre study were subject to geographical restrictions, which affected their representativeness and generalization. Third, patients older than 80 years old are thought to be more insufficient in EBM use than younger patients [40, 41]. We conducted analysis on patients older than 80 but the group sizes (n = 155) was too small to obtain an adequate statistical power. (see Additional files 3 and 4) Finally, this study focused on four types of medications, antiplatelet drugs, statin, beta-blocker and ACEI/ARB. The effects of other medications were not studied. In conclusion, caution must be taken when analysing the results of this study. However, attention should be paid to the insufficient use of EBMs and its potential impact on prognosis in elderly patients with CAD. High-quality research reports are needed to provide more clinical evidence and experience in the use of EBMs in elderly patients with CAD.

Elderly patients with CAD had higher risk of cardiovascular disease but had a lower degree of compliance with EBMs usage to prevent cardiovascular events. Elderly CAD patients, similar to younger CAD patients, could also receive more clinical benefits by strictly adhering to the use of EBMs. Therefore, EBMs should also be actively promoted for elderly CAD patients.