Diabetes mellitus and other cardiovascular risk factors in lower-extremity peripheral artery disease versus coronary artery disease: an analysis of 1,121,359 cases from the nationwide databases

The current study, based on analysis of data from nationwide procedural databases, describes comparative features of symptomatic LE-PAD and CAD warranting revascularization. As summarized by the C statistics for heterogeneity, patient profiles were not identical, but rather quite different between LE-PAD and CAD, especially between CLI and ACS. Given that currently major and familiar cardiovascular diseases in clinical practice are CAD rather than LE-PAD [16], a clearer understanding of the distinctive features of LE-PAD would be promoted by the current comparative analysis of LE-PAD versus CAD.

Compared to CAD, diabetes mellitus was more prevalent in LE-PAD, especially in CLI. As reported previously, diabetes mellitus increases the risk of lower-limb amputation [17, 18]. The high prevalence of diabetes mellitus in LE-PAD, especially in CLI, would confirm its high population attributable fraction for the limb prognosis. Other remarkable differences between CVDs included advanced age and end-stage renal disease on dialysis, both of which were again more frequently seen in LE-PAD. Diabetes mellitus, advanced age, and end-stage renal disease on dialysis are often recognized as major risk factors of perioperative morbidity in clinical practice [19‐23]. Compared to PCI, lower-extremity EVT was likely targeted at a generally higher-risk population. Note that the prevalence of cardiovascular risk factors was different among CVDs even after stratification by age, indicating that their inter-CVD difference was not solely attributable to the difference in age distribution. The apparently lowered prevalence of end-stage renal disease on dialysis after adjustment for the inter-institution variability would simply come from the fact that patients on dialysis likely undergo interventions at a facility with a dialysis center. The comorbidity is clinically so closely linked with the institutional feature that the adjustment for the institution variable would statistically attenuate its prevalence.

In addition to the overall prevalence of cardiovascular risk factors, inter-CVD differences were observed in their clustering (Fig. 2). For example, the clustering of diabetes mellitus and end-stage renal disease on dialysis was more marked in an ACS population than in a CLI population, whereas the overall prevalence of these two cardiovascular risk factors per se was much higher in a CLI population. These findings suggest that differences in overall prevalence of cardiovascular risk factors between CVDs would not have any relationships with those in their clustering. Clinical guidelines have recommended cardiovascular risk management in LE-PAD patients, sometimes based on evidence shown in CAD patients, to cover scanty evidence in the field of LE-PAD [1, 2, 6, 7]. However, beneficial effects of an intervention to a cardiovascular risk factor would potentially vary according to the coexistence of another cardiovascular risk factor [8‐12]. Furthermore, the efficacy and safety of some medications for a cardiovascular risk factor would be influenced by the coexistence of another cardiovascular risk factor, especially end-stage renal disease [24, 25]. The different cardiovascular risk clustering suggests that beneficial effects of the cardiovascular risk management including administration of certain medications in LE-PAD patients might be different from those expected from the studies in CAD patients.

The current analysis on patient profiles clarified another two features. First, patient profiles further varied with the vascular territory of LE-PAD (i.e., aortoiliac, femoropopliteal, and below-the-knee), even in the same clinical phenotypes (i.e., intermittent claudication or CLI). The association between treated vascular territories and patient profile in LE-PAD undergoing EVT was already reported [26, 27]. Those reports, however, did not divide LE-PAD into intermittent claudication and CLI. Given that below-the-knee revascularization is usually performed for CLI [28], treated vascular territories are expected to be strongly confounded by clinical phenotypes of LE-PAD. The current study, in which intermittent claudication and CLI were analyzed separately, successfully validated the previous findings that diabetes mellitus and end-stage renal disease on dialysis were associated with more distal arterial lesions, whereas smoking and dyslipidemia were associated with more proximal lesions, and that male versus female sex was related to aortoiliac and below-the-knee versus femoropopliteal lesions. On the other hand, some findings were not consistent with the previous reports [26, 27]: CLI with below-the-knee lesions had younger age and lower prevalence of hypertension than that with femoropopliteal lesions. Lower prevalence of hypertension was also seen in intermittent claudication with aortoiliac versus femoropopliteal lesions. The inconsistency might have come from our stratification by the clinical phenotypes, and our much larger sample size.

Second, younger patients were in general more likely exposed to cardiovascular risk factors than older patients in the LE-PAD population. When discussing the clinical impact of LE-PAD in the ageing society, some are apt to assume that cardiovascular risk factors are highly prevalent among seniors with LE-PAD [29]. The assumption would presumably lie on a general recognition that the risk of developing cardiovascular risk factors is commonly increased by age in a general population. The current findings might be paradoxical in this sense, but would be simply explained by the fact that, whereas age is a major promoter of atherosclerosis, the development of atherosclerosis (or vascular aging) is accelerated by cardiovascular risk factors. Patients with accumulated cardiovascular risk factors will develop LE-PAD earlier (i.e., at younger age), whereas those with fewer will develop the disease later (i.e., at older age). This would explain why age had an inverse correlation with the exposure to cardiovascular risk factors in the LE-PAD population.

One should note that the aim of this cross-sectional study was to compare clinical profile between an LE-PAD population and a CAD population, and not to assess risk factors of developing the CVDs and their prediction. The current findings of different clinical profiles might be suggestive of different developmental mechanisms between LE-PAD and CAD; however, the current study was only a cross-sectional and observational one, and underlying pathogeneses remained unrevealed. For example, we found the inter-CVD differences in prevalence and clustering of cardiovascular risk factors with adjustment for age. However, these findings only demonstrated the cross-sectional associations, and did not mean that the time course of development was adjusted. There still remained a possibility that ageing would be intermediating these apparent disparate findings, when one focuses on developmental mechanisms of the diseases. Moreover, the observed difference in clinical profile between CVDs might be biased and explained by other unmeasured confounders. Future studies are needed to uncover the underlying mechanisms of the differences between the CVDs.

The study had some other limitations. First, the J-PCI and J-EVT collect limited information regarding treated lesions and clinical profile. The databases included the data on whether individual cardiovascular risk factors were present or not, but not any biological data indicating their severity, such as blood pressure, serum lipids levels, plasma glucose levels, and serum creatinine levels to estimate glomerular filtration rate, all of which were previously reported to be associated with the risk of CVDs [30‐33]. Neither were data on treatments or medications included. Furthermore, data on complications related to cardiovascular risk factors [34, 35], detailed severity of CVDs (e.g., foot infection in CLI [18]), and pathological lesion characteristics [36, 37] were also unavailable, and therefore their potential impact on inter-CVD differences remained to be explored. Second, smoking was only assessed by the definition as any history of smoking within the past 1 year, and the data were not available on smoking status otherwise defined (e.g., current smoking defined by present or prior smoking during the last 3 years) or quantitative measurements of smoking exposure. Third, the registries did not collect data on which diagnostic criteria of respective cardiovascular risk factors patients met. For example, although plasma glucose levels 2 h after a 75-g oral glucose tolerance test were included in the definition of diabetes mellitus, how many patients were really defined as diabetes mellitus by this criterion was unknown. Similarly, hypercholesterolemia and hypertriglyceridemia were not distinguished in dyslipidemia, although these two entities would not have the same effect in LE-PAD and CAD. Fourth, data were not available on arterial lesions coexisting but not indicated for revascularization. Fifth, the current study analyzed PCI and EVT cases in Japan. It remained unknown to what extent regional or racial differences would influence the findings [38]. Sixth, the current study analyzed cases undergoing percutaneous intervention, and did not target those undergoing open bypass surgery or those undergoing primary amputation. Clinical profiles might be different between the two revascularization procedures, although recent clinical studies have shown that major patient backgrounds are not so largely different between them in clinical practice [39, 40]. On the other hand, previous studies suggested that patient attributes would be different between LE-PAD patients undergoing revascularization and those undergoing primary amputation [41]. Future studies in other countries will be needed to validate the current findings.