The burden of major adverse cardiac events in patients with coronary artery disease

Coronary artery disease (CAD) is a major health problem worldwide including Taiwan, and it is expected to be the leading cause of death by 2020 [1‐3]. With advances in both coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI), mortality from CAD has significantly decreased [4]. Moreover, PCI or PCI with stenting and CABG were associated with a long-term safety profile and improving patient outcomes [5, 6]. However, the poor prognosis and high cost of medical care for patients with CAD impose a considerable burden on both their families and society. Therefore, identifying risk factors that affect the prognosis of patients undergoing revascularization is necessary.

Major adverse cardiac events (MACE) are important causes of morbidity and mortality in CAD patients undergoing PCI. The detection and treatment of the risk factors for MACE are critical to improve health and longevity. As expected, the traditional risk factors (e.g. age, sex, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, systolic blood pressure, and smoking) [7] for CAD are associated with disease progression. Using Intravascular ultrasound monitoring of changes in atheroma burden in 3,473 patients, Chhatriwalla et al. demonstrated that the patients with a very low LDL level (≤70 mg/dL) and normal systolic blood pressure (SBP) (≤120 mmHg) had the slowest CAD progression [8]. In addition, in patients with LDL levels ≤70 mg/dL, progression of native coronary atherosclerotic disease was associated with the presence of residual risk factors including high baseline glucose levels, increased level of triglycerides, and small decrease in apolipoprotein B [9]. Previous study also reported that baseline diabetes was the strongest significant cardiovascular disease-related factor for disease progression [10]. Therefore, the purpose of this study was to evaluate whether baseline risk factors such as demographic and clinical characteristics, lipid levels, inflammation, triple vessel disease, stent implantation, anemia, diabetes mellitus (DM), hypertension, and chronic kidney disease (CKD) were associated with the development of MACE in patients with CAD receiving PCI. The results could be important in increasing physicians’ awareness on the importance of regular baseline risk factors screening when caring for patients with CAD.

Among 1,644 consecutive CAD patients, 124 were excluded due to the following reasons: four patients refused to join the study after PCI, six patients had no significant stenosis of the culprit lesion (<50%), one hundred and one with coronary artery bypass graft surgery, and 13 patients could not be provided complete information regarding demographic history, mini nutritional assessment, and medication treatment. The final study population included 1,520 patients (654 with ACS and 866 with elective PCI patients; Fig. 1). Of the 1,520 patients, 1,107 (72.8%) men and 413 (27.2%) women, mean age of patients is 69 ± 12 years (range, 30 to 99 years). 582 (38.3%) had DM, 949 (62.4%) had hyperlipidemia, and 1,092 (71.8%) had hypertension (Tables 1 and 2).

The goal of this study was to determine the predictors of MACE in Chinese patients with CAD who underwent PCI and/or stenting. Of the 1,520 consecutive patients evaluated, the incidence of MACE was 36.7% after a median duration of 23 months (interquartile range: 5–55 months) of follow-up. Triple vessel disease, stent implantation, hypertension, and eGFR or uric acid all contributed to the risk of a MACE between ACS and elective PCI patients. To the best of our knowledge, this study is the first observational clinical study to identify the independent risk factors for adverse cardiac events in a Chinese cohort of patients, who have distinct differences in presentation from those in western countries [17].

In addition to the most common predictors of MACE in CAD patients such as age [18], female gender [19], hypertension, number of stents placed [19‐21], chronic heart failure [20], eGFR [22, 23], anemia [24], HDL- cholesterol [25], and hs-CRP [26], the development of MACE in our population was further determined by triple vessel disease, stent implantation, hypertension, and eGFR or uric acid. Furthermore, we found that triple vessel disease, stent implantation, hypertension, and eGFR predicted the development of MACE in multivariate analysis, with an AUC of 0.655 in ACS patients, and triple vessel disease, stent implantation, hypertension, and uric acid predicted the development of MACE in multivariate analysis, with an AUC of 0.678 in elective PCI patients. In addition, consistent with several previous reports [19, 20] but in contrast to others [26‐28], in the present study, DM did not predict the development of a MACE in our patients. Previous studies investigating the impact of DM on clinical outcomes yielded inconsistent results, which likely reflect differences in clinical diagnosis [29‐31].

In the current study the levels of eGFR at baseline were inversely associated with the development of MACE in ACS patients, so a low eGFR may have higher risk of MACE, which is consistent with other studies where a lower eGFR was associated with the risk of death, cardiovascular events, and hospitalization [32, 33]. The mechanisms that underlie the association between renal dysfunction and CAD have not been elucidated fully. Previous studies have shown that renal dysfunction is associated with low-grade inflammation and activation of the sympathetic nervous system or the rennin-angiotensinaldosterone system [34‐36]. Foley et al. demonstrated that calcium-phosphate production and oxidative stress were shown to promote renal dysfunction [37]. Muntner et al. showed that apolipoprotein A1 levels are decreased and levels of homocysteine, lipoprotein (a), fibrinogen, and CRP are increased among patients with CKD [38]. These factors above could also contribute to the pathogenesis of atherosclerosis. Herzog and colleagues also described pressure overload, volume overload, and CKD associated non-hemodynamic factors that have enhanced CKD to alter the myocardium [39]. Renal insufficiency is an independent risk factor for cardiovascular outcomes and in-hospital and late mortality [40, 41]. Increased uremic toxins such as total indoxyl sulfate and p-cresylsulphate may be involved in the pathogenesis of coronary atherosclerosis, prolonged QTc interval, left ventricular systolic dysfunction, and elevated risk of MACE in CAD patients with low estimated glomerular filtration rate, and it is considered a coronary heart disease risk equivalent [42‐46]. In addition, we found that uric acid was an independent risk factor for developing a MACE in elective PCI patients. Previous clinical investigations have demonstrated that hyperuricemia is an independent predictor of mortality in patients with cardiovascular disease [47‐49]. Uric acid is the final oxidation product of purine catabolism in humans. It is formed from the breakdown of adenosine and guanine. When the purine breakdown products xanthine and hypoxanthine are converted to uric acid through the enzymatic action of xanthine oxidase, molecular oxygen is reduced and the free radical superoxide is generated. Oxygen-free radicals are postulated to play a key role in vascular injury in cardiovascular and kidney disease. George et al. suggested that uric acid was harm to endothelial function leading to cause of cardiovascular disease because uric acid levels may act as a marker of xanthine oxidase activity [50]. Previous studies have also shown that uric acid has directly contributed proliferative, proinflammatory, and proatherogenic effects on human vascular smooth muscle cells and endothelial cells through upregulate CRP, an active component in the inflammatory process, which can lead to both hypertension and vascular disease [51‐53]. Taken together, these findings highlight the clinical and public health importance of chronic renal insufficiency and hyperuricemia.

In this study, we found that hypertension was an independent risk factor for developing a MACE not only in ACS patients but also in elective PCI patients. This is consistent with reports in which a history of hypertension was one of the risk factors for a MACE [21, 54]. Madan et al. enrolled 9,494 patients and found that hypertension was an independent predictor of adverse cardiac events after PCI [20]. In the other hand, chronic hypertension is also one of the important cardiovascular risk factors for development of atherosclerosis [55] and an increased incidence of CAD [56], CKD [57], peripheral vascular disease [58], and cerebrovascular disease [59]. Moreover, hypertension is also known as an important risk factor for myocardial infarction, stroke, heart failure, and cardiovascular death [60, 61]. The relation between hypertension and myocardial infarction could be explained underscoring two key factors: (1) common risk factors, such as sympathetic hyperactivity, insulin resistance, vasoactive substances (i.e., angiotensin II), and genetic risk profiles and (2) hypertension is a risk factor of atherosclerosis, which contributes to progression of myocardial infarction [62]. Genetic risk factors such as gene polymorphisms of the angiotensinogen-converting enzyme and of the renin-angiotensin-aldosterone system, could cause myocardial infarction, hypertension, and cardiovascular complications [63, 64]. Furthermore, in hypertensive patients, a hyperactivity of sympathetic tone which causes sympathetic vasoconstriction on glucose extraction in skeletal muscle, beta-adrenergic receptor-mediated insulin resistance, and vascular rarefaction; may contribute atherosclerosis by worsening insulin resistance. Previous study suggested that sympathetic hyperactivity itself also contributes higher risk of coronary spasm, coronary thrombosis, and sudden death [65].

Besides the classical risk factors, others risk factors may also influence the development of MACE [20]. In the present study, we also found that triple vessel disease and stent implantation were associated with the development of MACE. Studies by Chow et al. and de Waha et al. both reported that the severity of CAD and multivessel CAD not only predicted all-cause mortality but also were high-risk factors for adverse clinical outcomes [66, 67]. The higher morbidity and mortality are seen in ST-segment elevation myocardial infarction patients with multi-vessel CAD. The mechanism is multifactorial, including total ischemic burden, the presence of diffuse atherosclerosis as a harbinger of plaque instability, and impaired contractility of non-infarct zones in the presence of multiple obstructive stenosis [68]. Interestingly, in our study, the stent implantation was found to be a surrogate marker of MACE. When we further subgrouped our study subjects according to their stent implantation status, the results found that patients with stent implantation had higher rates of triple vessel disease and hyperlipidemia; higher BMI, HbA1C, total cholesterol, LDL-cholesterol, hs-CRP, and white blood cell count than those without stent implantation patients. Hyperlipidemia and obesity are recognized as a risk factor for CAD and coronary mortality [69, 70]. Furthermore, several reports have suggested that delayed arterial healing and vessel remodeling due to chronic inflammation have been reported as reasons for the high rates of very late stent thrombosis with drug-eluting stent [71‐75]. Previously, studies have indicated that this reduction in restenosis might have been obtained at the expense of a higher incidence of stent thrombosis that links stent implantation and adverse cardiac events such as recurrent myocardial infarction or death [76, 77]. Hence, we think multifactorial occurrence, including triple vessel disease, hyperlipidemia, higher BMI, HbA1C, and inflammation response that promote the association of stent implantation with the MACE in our study [66, 67, 69, 70, 75, 78]. In addition, there was no statistically significant difference in rate of MACE among 4 operators in the present study. This indicated that operators issue did not affect the finding of stent implantation association with MACE.

There are several limitations to this study. First, the results may be skewed by procedural preferences and the patients seen at our institution. Second, we did not assess several complications that are common after PCI such as contrast nephropathy and access-site vascular complications. Third, we did not examine the relationship between operator procedure volume and cardiac complications. Four, this is an observational study in only one centre. Hence, further work is required to confirm these findings in populations of different races and these exploratory results should be confirmed in a larger study and other centre. Finally, although the current model has been validated for the contemporary practice of PCI, further advances in PCI techniques and technology may reduce the discriminatory ability and predictive accuracy of the model. Thus, the model may need to be recalibrated in the future.

The present study indicates that having triple vessel disease, stent implantation, hypertension, and eGFR or uric acid levels independently predicted the development of MACE in patients with CAD after long-term follow-up. We suggest that uric acid, eGFR, and blood pressure should be closely monitored in patients with CAD.