Acute coronary syndrome (ACS) constitutes an important public health challenge that imposes an economic burden worldwide, causing almost 50% of deaths related to coronary heart disease (CHD) [1]. Accurately stratifying risk is of great value in the clinical treatment of acute and chronic CHD. Nevertheless, current predictive models for identifying potential poor prognosis in patients with ACS, including the global registry of acute coronary events (GRACE) scoring scale, do not consider coronary artery and noncoronary lesions.

Peripheral arterial disease (PAD) represents a non-coronary sign of atherosclerosis, which often coexists with coronary artery disease (CAD) and cerebrovascular disease [2, 3]. More than 40% CAD cases also show concurrent PAD, imposing an important burden of cardiovascular events and increasing overall mortality [4]. Individuals with combined CAD and PAD administered coronary revascularization show elevated rates of perioperative and long-term complications in comparison with patients without PAD [5]. Studies have confirmed that PAD cases administered percutaneous coronary intervention (PCI) have an elevated rate of major adverse cardiovascular events (MACEs) in comparison with non-PAD cases, with PAD independently and significantly predicting death [6, 7].

However, the prognostic potential of PAD in ACS cases administered PCI is unknown. Additionally, reports evaluating whether PAD addition improves the GRACE scale are scarce. Therefore, this work aimed to determine the potential of PAD in predicting prognosis in patients with ACS following PCI, and to investigate whether PAD improves the predictive potential of the GRACE risk scoring system.

This study evaluated PAD’s predictive power for adverse outcomes in ACS cases after PCI. The results indicated that MACE incidence was markedly elevated in PAD cases in comparison with non-PAD cases. After adjustment for potential confounders, PAD remained strongly correlated with poor prognosis. Additionally, PAD addition markedly enhanced the predictive capability of the GRACE system for MACEs.

PAD has been detected in 5% to 20% of CAD cases [9, 10, 11, 12, 13, 14, 15]. In an early study including 10,440 patients undergoing PCI, symptomatic PAD was found in 18.9% of patients [9]. In another early trial reported by the Northern New England Cardiovascular Disease Study Group, 13.4% of individuals with multivessel disease administered either PCI or CABG were considered PAD cases [10]. However, PAD prevalence rates in CAD cases were much lower in several recent reports. In the multicenter e-ULTIMASTER registry including 37,198 PCI patients, PAD was found at 6.7% [11]. Another recent report based on a single-center prospective PCI registry including 25,690 PCI patients found that PAD occurred in 6.3% of the cases [12]. The falling trend of PAD was documented by a nationally representative study of 4.6 million individuals in the UK [16], which found an astonishing 15% reduction in the standardized PAD incidence between 2006 and 2015, possibly due to early identification and treatment. Of the ACS patients administered PCI in this study, 10.4% had PAD, which is within the previously reported range but higher than the prevalence rates in recent reports. A possible explanation for prevalence variability could be differences in study populations, regions, and diagnostic criteria. We only included ACS cases administered PCI, who had higher odds of having comorbidities compared with stable CAD patients. Other studies only examined PAD patients with a prior history or current symptoms [13, 14]. In contrast, we also included asymptomatic patients with positive ultrasound findings, who are easily missed but have similar risk profiles for morbidity and mortality as those with symptoms [17].

Consistent with previous studies [9, 10, 11, 12, 13, 14, 15], we found that PAD conferred higher risk profiles and worse clinical outcomes. PAD patients were older, had elevated prevalence rates of cardiovascular risk factors and higher SYNTAX scores, but lower odds of achieving complete revascularization. Meanwhile, the proportion of smoking is lower in PAD patients than that in those without PAD. The exact reason is not known. One possible reason is that only the information of current smoking was collected in our registry dataset. Most of PAD patients in our study were diagnosed previously. It is possible that a substantial number of smokers had quitted smoking after the diagnosis of PAD, and were not indicated as ‘current smoker’. Furthermore, in this study, the utilization rate of DCB was relatively high. This study is based on a cohort dataset which represent the real-world clinical situation. There are interventional cardiologists who prefer DCB to stenting under certain situations, especially for treatment of small vessels, in-stent restenosis or bifurcation lesions. The proportion of PCI with in-stent restenosis in PAD patients was significantly higher than that in patients without PAD (24.0% vs. 10.0%, p 0.001, Table 1), which could partly explain the higher rate of DCB use in PAD patients.

Previous studies consistently indicated independent associations between PAD and enhanced risk of mortality and cardiovascular events in several clinical settings, including in patients with prior MI [18], undergoing PCI or CABG [9, 10, 11, 12, 13, 14, 15], or post-ACS [19, 20]. In a joint database of post-ACS patients in 4 trials, the incidence of MACEs in PAD cases was 1.6 fold that of those without PAD20. In recent reports assessing patients undergoing PCI, PAD was consistently reported to independently predict MACEs and death, with hazard ratios varying between 1.3 and 2.0 [9, 10, 11, 12, 13, 14]. In this work, only ACS cases administered PCI were included. Our results confirmed previous findings and demonstrated that PAD patients had markedly elevated incidence rates of MACEs and individual MACE components compared with those without PAD. The association between PAD and increased risk of MACE in ACS patients after PCI is complex. The worse clinical outcomes related to PAD could not be completely attributed to differences in risk profiles. After adjusting for all comorbidities and angiographic indexes, PAD still independently predicted a worse clinical outcome, which conferred a 73.5% increase in MACE risk. Patients with PAD are more likely to have older age, more concomitant disorders, more complex lesions, and higher SYNTAX score, which are all relevant to worse clinical outcomes. Another possible explanation is that the higher atherosclerotic burden of PAD patients may be relevant to those risk factors which are not routinely measured, such as genetic background, increased inflammatory state, or higher level of cytokines.

Surprisingly, few reports have considered PAD a risk factor in predictive models. In the Dual Antiplatelet Therapy (DAPT) trial, although PAD was predictive of both the expected decrease of ischaemic events as well as the expected elevation of bleeding events with continued thienopyridine therapy beyond 12 months after PCI, it was not included in the DAPT score because the strengths of the associations were similar for both endpoints [21]. The GRACE score based on clinical indexes at discharge constitutes a potent predictive factor of short-term and long-term prognosis following ACS [22, 23, 24] and provides a more accurate risk assessment for patients admitted and discharged from hospital with integral parameters including age, systolic blood pressure, pulse, blood creatinine, Killip classification at presentation, cardiac arrest at admission, elevated markers of myocardial necrosis and ST-segment changes. Although TIMI is simpler to calculate, its identification accuracy is not as good as that of the GRACE score. Studies in China have shown that the GRACE score has better predictive value than the TIMI score for the prognosis of patients with acute non-ST-segment elevation myocardial infarction [25]. However, not all the validated predictive factors decreasing prognosis are included in the GRACE scale. As shown above, PAD addition further improved the predictive capability of the GRACE system for MACEs, albeit the improvement was small in magnitude (C-statistic 0.610 vs. 0.587). It may not be easy to improve such models including potent indexes as the GRACE scale. To deal with this anomaly, IDI and NRI were devised to evaluate reclassification with new molecular markers or variables [26, 27]. In this study, a significant improvement in net reclassification was obtained by using these two matrices after PAD addition to the GRACE score. These findings suggest this novel risk-prediction model might have high accuracy in predicting the outcome of ACS patients undergoing PCI in clinical practice.

As PAD has relatively low diagnosis cost and is a modifiable disease, the current study highlights the potential significance of early identification and treatment in this specific population. Given that PAD increases the risk of cardiovascular events, whether routine extremity ultrasound screening in ACS patients could help detect asymptomatic PAD and improve prognosis warrants further investigation by randomized trials.

Unfortunately, this study had several limitations. Firstly, the current study was a small-sample single-center observational trial. Secondly, ultrasound was not routinely applied for all patients. Some patients without symptoms or a previous history might be missed. Thirdly, three quarters of the ACS patients included in this study were UA, which may not reflect well on patients with acute myocardial infarction. Finally, treatment strategies for PAD, including medications or peripheral revascularization, were not considered in the current analyses, which might affect prognosis in PAD patients.

In ACS cases administered PCI, PAD independently predicted worse clinical outcomes. PAD addition could improve the performance of the GRACE risk score for MACEs. Further investigations are warranted to clarify the underpinning mechanism and to develop potential therapeutic strategies that would minimize such risk.

ACS, acute coronary syndrome; CHD, coronary heart disease; GRACE, global registry of acute coronary events; PAD, peripheral artery disease; CAD, coronary artery disease; PCI, percutaneous coronary intervention; MACE, major adverse cardiovascular event; UA, unstable angina; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction; CABG, coronary artery bypass grafting; FBG, fasting blood glucose; hs-CRP, high-sensitivity C-reactive protein; BP, blood pressure; T2DM, type 2 diabetes mellitus; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; MI, myocardial infarction; HR, hazard ratio; CI, confidence interval; NRI, net reclassification improvement; IDI, integrated discrimination improvement; SYNTAX, synergy between percutaneous coronary intervention with taxus and cardiac surgery; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.

The datasets used in the current study are available from the corresponding author upon reasonable request.

YJZ and XTM performed the study design. YHX analyzed data and drafted the manuscript. XTM, KNH, YJC, ZJW and FG contributed to study conception and data collection, analysis and interpretation. All authors contributed to the revision of the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The trial followed the Declaration of Helsinki and had approval from the Institutional Review Board of Beijing Anzhen Hospital, Capital Medical University (Approval ID: ChiCTR1800017417). Each participant provided written informed consent.

Not applicable.

The current study was funded by grants from the National Key Research and Development Program of China [No. 2022YFC3602500] and the Youth Fund Project of National Natural Science Foundation of China [No. 82200405].

The authors declare no conflict of interest.