A Multidisciplinary Approach in Selecting Treatment Strategies in Patients with Aortic and Peripheral Artery Diseases

Abstract

Coronary artery disease (CAD) is the first leading cause of death worldwide, whereas ischemic stroke due to atherosclerosis of coronary and carotid arteries presents epidemiologically in a different ways among sexes. It ranks the second and the third leading cause of death among women and men globally. Noncoronary atherosclerosis also affects other arterial beds throughout the body, including the aorta and peripheral arteries. Atherosclerosis is a systemic disease affecting all arterial beds, but the progression of atherosclerosis in some arterial beds is triggered by the principal symptoms manifested in one bed and the subclinical course of atherosclerosis in others. There is a high probability of the presence of the so-called polyvascular disease defined as the simultaneous presence of clinically relevant atherosclerotic lesions in at least two arterial beds. It has been shown that patients with cerebral ischemic attacks have a 10-fold higher risk of acute myocardial infarction (AMI) or cardiac death within five years compared to a healthy population. About 35–50% of patients who have undergone carotid endarterectomy (CEA) have severe coronary artery lesions requiring surgical treatment.

1. Introduction

Coronary artery disease (CAD) is the first leading cause of death worldwide, whereas ischemic stroke due to atherosclerosis of coronary and carotid arteries presents epidemiologically in a different ways among sexes. It ranks the second and the third leading cause of death among women and men globally [1, 2]. Noncoronary atherosclerosis also affects other arterial beds throughout the body, including the aorta and peripheral arteries [3, 4]. Atherosclerosis is a systemic disease affecting all arterial beds, but the progression of atherosclerosis in some arterial beds is triggered by the principal symptoms manifested in one bed and the subclinical course of atherosclerosis in others. There is a high probability of the presence of the so-called polyvascular disease defined as the simultaneous presence of clinically relevant atherosclerotic lesions in at least two arterial beds. It has been shown that patients with cerebral ischemic attacks have a 10-fold higher risk of acute myocardial infarction (AMI) or cardiac death within five years compared to a healthy population [5]. About 35–50% of patients who have undergone carotid endarterectomy (CEA) have severe coronary artery lesions requiring surgical treatment [6, 7].

2. The incidence of coronary artery lesions in patients with atherosclerosis of the internal carotid arteries

About 87% of strokes are ischemic, of them 30% are caused by carotid artery atherosclerosis. Moreover, about 10–20% of ischemic strokes are caused by thromboembolism due to atherosclerotic lesions of the internal carotid artery (ICA), and their relative risk increases markedly with stenosis of over 75% [8, 9]. Thus, early detection of atherosclerotic lesions of the internal carotid artery is important for the prevention of ischemic stroke.

The prevalence of concomitant coronary artery disease in ischemic stroke patients varies from 18 to 38%, according to the previously published research [10, 11, 12, 13]. The European Society of Cardiology Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases reports the incidence of CAD in patients with ICA lesions of 39–61% and of 25 to 72% with the lesions of lower limb arteries (ABI < 0.90) [14].

Timely diagnosis and treatment of concomitant asymptomatic CAD in patients with significant carotid artery lesions can significantly improve the perioperative and long-term results as well as the overall survival rate [15].

Alekyan B.G. et al. assessed 693 patients with atherosclerotic lesions of the internal carotid artery and peripheral arteries admitted to the hospital for selective coronary angiography. A total of 202 (80.5%) patients with isolated atherosclerotic lesions of ICA had at least one coronary artery stenosis of over 50% and 44 (73.3%) patients showed combined atherosclerotic lesions of ICA and lower limb arteries [16].

It is important to note that the SAPPHIRE study is the only multicenter randomized controlled trial (RCT) comparing the results of carotid stenting and CEA in patients with a high surgical risk. The main inclusion criterion was the availability to perform target lesion revascularization, that is, the percutaneous intervention of the target lesion or bypass surgery of the target vessel. The high surgical risk was defined as clinically significant heart disease, severe lung disease, contralateral ICA occlusion or laryngeal nerve palsy, previous radical surgery or radiotherapy on the neck, restenosis after CEA, and age of patients over 80 years.

The SAPPHIRE findings strongly support the role of distal-protected CoC in high-risk patients. Compared with CEA, the rate of cumulative adverse events (death, stroke, ipsilateral stroke, MI) was low and did not differ significantly after 30 days, 1, and 3 years. There were 15 ipsilateral strokes in both groups during the 3-year follow-up. Of them 11 were registered in the carotid stenting group and 9 in the CEA group. Strokes were less frequent at day 30 and after 3 years in the carotid stenting group. The need for target lesion revascularization during the indicated follow-up period did not differ significantly (0.7 vs. 4.6%; p = 0.04). Cranial nerve palsy in the carotid stenting group and the CEA group was 0 and 5.3%, respectively (p = 0.003) [17].

Alekyan et al. assessed the in-hospital and long-term treatment results of 182 patients with combined coronary and ICA lesions admitted to the hospital in the period from 2017 to 2019. Depending on the treatment strategy, patients were divided into four groups: group 1—staged percutaneous coronary intervention (PCI) and ICA stenting (n = 57 (31.3%)), group 2—staged PCI and CEA (n = 99 (54.4%)), group 3—staged coronary artery bypass grafting (CABG) and ICA stenting (n = 9 (4.9%)), and group 4—simultaneous CABG and CEA (n = 17 (9.4%)). Groups 3 and 4 were excluded from the analysis due to the small number of patients. The in-hospital outcomes in groups 1 and 2 included one death in group 2 after CEA (0 vs. 0.4%, p = 0.44) and one myocardial infarction after PCI (0% vs. 0.4%, p = 0.44). There were one major and minor stroke in each group (p = 0.57). There was no significant difference in the in-hospital outcomes between both groups. The median follow-up was 24.5 months in 87.2% of patients. Twenty (12.8%) patients were lost to follow-up. The primary endpoint of major cardiovascular events occurred in 5 (3.6%) patients. There was one (0.7%) death in group 1. There were no strokes and myocardial infarctions in group 1 during the long-term follow-up. There were two (1.4%) deaths in group 2, one (0.7%) myocardial infarction, and one stroke (0.7%). Deaths from noncardiac and neurological causes were reported in two (1.7%) patients in group 1 and two (1.7%) in group 2. The analysis of the in-hospital and long-term results revealed no significant difference in the incidence of neurological events between the patients who underwent PCI + CEA (group 2) and PCI + ICA stenting (group 1). The individual approach to each patient by a multidisciplinary team, as well as the experience of the operating surgeons, enabled to minimize the possible adverse events [18].

The importance of preoperative diagnosis and revascularization of coronary artery lesions in patients with severe carotid artery lesions was reported by Illuminati et al. [19]. The RCT included 426 patients without prior angina and myocardial ischemic changes according to ECG and Echo-CG. All patients were referred to CEA. The patients were assigned to 2 groups: group A (n = 216) patients underwent coronary angiography and myocardial revascularization before CEA if necessary, and group B (n = 210) underwent only CEA. Significant coronary lesions were diagnosed in 68 (31.5%) patients in group A. Sixty-six patients underwent PCI, and 2 patients underwent simultaneous CEA and CABG. The mean follow-up period was 6.2 years. During the follow-up period, there were three (1.4%) MIs in group A, and 33 (15.7%) in group B (p < .001), 6 of which were fatal. At the same time, no myocardial infarctions were reported in group A at 30 days after CEA, whereas there were 9 MIs in group B (p = 0.01), one of which was fatal. The 6.1-year survival rate was 95.6 ± 3.2% in group A and 89.7 ± 3.7% in group B. This study proved that selective coronary angiography followed by myocardial revascularization prior to CEA in patients with asymptomatic coronary artery lesions is safe and can improve long-term survival and freedom from MI [19].

The findings suggest that carotid artery lesion is a predictor of adverse events in both cerebral and coronary circulations, which is a manifestation of systemic atherosclerosis.

Therefore, it is crucial to implement a systemic approach when treating patients with atherosclerosis to obtain adequate stratification of patients with cardiovascular risk factors, as well as to reduce the incidence of adverse events, improve quality of life, and prolong their survival [20].

3. The incidence of coronary artery disease in patients with chronic lower extremity ischemia

The American College of Cardiology and the American Heart Association (ACC/AHA) [21] were among the first to release in 2005 the guidelines on the management of patients with chronic lower limb ischemia. They relied on the previously published studies reporting a high risk of MI, acute impairment of cerebral blood flow, and death in patients with peripheral artery disease. Patients with combined coronary and peripheral artery disease have the risk of CAD-induced death varying from 2 to 6% per year. The risk of MI increases by 20–60% and CABG by 40% in this group of patients.

F.G. Fowkes as well as G.C. Leng et al. [22, 23] demonstrate the importance of outpatient examination for patients with chronic lower limb ischemia and emphasize that patients with asymptomatic (atypical) forms of claudication are more frequently diagnosed with CAD (95% CI 1.3–1.9).

The study by N. Savji et al. included 3.6 million people who underwent obligatory ultrasound examination to detect atherosclerosis of the lower limb arteries. The prevalence of peripheral artery disease was 3.7%. The proportion of patients with at least 2 affected arterial beds increases with age, from 0.04% between 40 and 50 years of age to 3.6% in the 81–90 years age group. Thus, the prevalence of CAD was 2% between 40 to 50 years of age, whereas at 81–90 years, it reached 22.3% (p < 0.0001) [24]. The risk of developing MI and CAD increases due to the progression of atherosclerosis [25]. The mortality associated with adverse cardiovascular events such as MI and CHF was higher in patients with chronic lower limb ischemia than in patients with CAD (5.35 vs. 4.52%) at one-year follow-up [25, 26].

During the last decade, many healthcare specialists all over the world have been dealing with the problem of determining a treatment algorithm for patients with chronic lower limb ischemia combined with CAD. Complex treatment of patients reduces the probability of CVD in patients with grade IIB chronic lower limb ischemia, improving the survival and quality of life of patients. The ARIC study [27] reported that male patients with peripheral artery disease were 4–5 times more often diagnosed with CHF compared to patients without arterial lesions of the lower extremities. The available literature indicates that a low ankle-brachial index (<0.9) is indicative of a high prevalence of CAD and CHF. It commonly reflects the presence of generalized atherosclerosis. The above-mentioned data suggest the necessity of preoperative examination of patients with polyvascular disease.

Over the past decade, the number of patients with chronic lower limb ischemia in Europe has increased by 23% [28]. By 2010, the cardiovascular mortality rate increased from 10 to 13 million compared with 1990 [28]. It is closely related to an increase in the prevalence of such risk factors as diabetes mellitus, arterial hypertension, tobacco smoking, and aging [28, 29].

Many studies have shown a high risk of CVD mortality (MI, STEMI) in patients with symptomatic or asymptomatic peripheral artery disease [30]. The ankle-brachial index less than 0.9 doubles the 10-year incidence of coronary events, mortality from cardiovascular events, and overall mortality [31]. About 20% of patients with chronic lower limb ischemia develop MI or CHF 5 years after disease progression with the mortality rate varying from 10 to 15% [32].

The randomized CARP study [33] included 510 patients with chronic lower limb ischemia. The stress test was performed in 74% of patients, and the remaining 26% were consulted by cardiologists. All patients were assigned to two groups: group 1 patients underwent coronary artery revascularization before elective vascular surgery (n = 258) and group 2 patients did not undergo coronary artery revascularization before elective vascular surgery (n = 252). Coronary angiography was recommended for patients with myocardial ischemia confirmed by the stress test. Patients with the controversial stress test results did not receive coronary angiography. In group 1, 141 (59%) and 99 (41%) patients underwent PCI and CABG, respectively, 8 (3%) patients required urgent vascular intervention, and 9 (3%) patients refused to undergo the intervention. CABG was canceled in one (0.1%) patient due to the development of CHF. The analysis of immediate results showed that 7 (5%) patients in group 1 developed MI after PCI, and 2 (1.4%) had fatal outcomes as a complication of myocardial revascularization. Seven (7.1%) of 99 patients developed MI after PCI and 2 (2.0%) had a fatal outcome. In group 2, where myocardial revascularization was not performed before elective vascular surgery (n = 252), nine (4%) patients underwent coronary artery revascularization in the perioperative period because of unstable angina. During the 30-day follow-up period after lower limb arterial revascularization, there were seven (3%) deaths in the myocardial revascularization group and eight deaths in the group without myocardial revascularization. In group 1, there were two (0.7%) deaths after emergent vascular surgery 7 days after PCI. Thus, a positive outcome from preoperative coronary revascularization was not proven. However, despite the relatively good statistical power of the CARP study, there are some specific limitations. G. Landesberg et al. believe that complete coronary artery revascularization could have prevented postoperative MI and improved survival rate in these patients [34]. Patients were selected for coronary angiography only with a positive stress test result, and patients without anginal complaints who were scheduled for vascular surgery were not screened for pain-free myocardial ischemia.

In 2019, Alekyan B.G. et al. reported that 80.4% of patients with chronic lower limb ischemia had at least one coronary artery lesion of more than 50% among 327 patients undergoing selective coronary angiography [16]. Thus, it can be assumed that in the CARP study a large proportion of patients was underdiagnosed. This argument is confirmed by nine (4%) out of 252 patients who did not undergo myocardial revascularization but required coronary intervention in the postoperative period due to unstable angina pectoris. Importantly, myocardial revascularization was performed in 21 (8%) patients in the long-term follow-up due to the episodes of tension angina [33].

The study of A. Raghunathan et al. reports that MI in 164 patients with chronic lower limb ischemia was the main cause of death. Perioperative MI was observed in 10 (12.4%) of 84 patients who underwent myocardial revascularization, whereas among those who did not undergo myocardial revascularization (n = 80) perioperative MI was defined in 18 (21.7%) patients. In the long-term period, one (1.2%) and two (2.4%) patients died, respectively. Importantly, 41 (25%) patients developed acute MI in the long-term follow-up [35].

A prospective randomized study by M. Monaco et al. with a study population of 208 patients with obstructive aortoiliac segment lesions and aortic aneurysms demonstrates a positive effect of coronary angiography and myocardial revascularization on long-term outcomes [36]. All the patients were divided into two groups. Group 1 (n = 103, 49.5%) patients underwent the stress test with the subsequent coronary angiography if required. Group 2 included 105 (50.4%) patients who underwent coronary angiography before vascular surgery. Forty-seven (45.6%) of 103 patients in group 1 who were referred to selective coronary angiography had positive stress test results. According to coronary angiography findings, significant coronary artery stenoses were detected in 46 (97.8%) patients. Myocardial revascularization was performed in 42 (91.3%) patients, among whom 1 (2.4%) died due to the cardiogenic shock. Three (7.1%) of 42 patients did not undergo vascular surgery and two (4.7%) patients refused to undergo it. Thirty-eight (90.5%) of 42 patients underwent elective lower extremity revascularization within 2 months. No fatal outcomes were recorded. The remaining 61 (59.2%) patients with a negative stress test result underwent elective vascular surgery without preoperative coronary angiography. There were five (8.2%) fatal outcomes from cardiovascular complications in this subgroup.

Sixty-five (61.9%) of 105 patients in group 2, who underwent coronarography, had significant coronary artery lesions. There were no complications associated with coronary angiography. Coronary artery revascularization was performed in 61 (93.8%) of them. The overall incidence of major cardiovascular complications in the in-hospital period, including cardiac mortality, was higher in group 1 (11.6%) patients than in group 2 (4.7%; p = 0.1). Freedom from cardiovascular events at the end of the 4-year follow-up was 69.6 ± 4.7% in group 1 and 86.6 ± 3.6% in group 2 with an absolute risk reduction of 16.7% corresponding to a relative risk reduction of 59.4% (95% CI 1.4–6.8; p = 0.04). Event freedom at 8 years was 53.5 ± 6.3% in group 1 and 77.5 ± 4.8% in group 2 with an absolute risk reduction of 19.8% corresponding to a relative risk reduction of 53.6% (95% CI 1.4–5.7; p = 0.002). The authors concluded that coronary angiography followed by coronary artery revascularization reduces the risk of cardiovascular events in these patients.

The consensus published by the American College of Cardiology, American Heart Association, Society of Cardiovascular Angiography and Intervention, and Society of Interventional Radiologists in 2018 confirmed that patients with intermittent claudication associated with the lesions in the aortoiliac, femoral, and patellar segments and tibial arteries and failure of conservative therapy should be considered for endovascular treatment [37]. This consensus also emphasizes the importance of diagnosing lesions in other arterial beds, including coronary arteries, to reduce high morbidity and mortality in patients with chronic lower limb ischemia. Endovascular and surgical lower extremity revascularization plays a crucial role in reducing mortality. Thus, the mortality rate reaches 20% within 6 months and 50% within 5 years in patients who remain without proper treatment [37].

4. Incidence of coronary artery lesions in patients with critical lower limb ischemia

The main cause of death in patients with peripheral arterial disease is coronary artery disease [14, 38, 39]. Critical lower limb ischemia is an aggressive form of systemic atherosclerosis and is the most common cause of amputation [36, 40, 41]. Due to the prevalence of atherosclerosis, diabetes mellitus, and smoking, patients with critical lower limb ischemia have a high risk of cardiovascular events, including death.

The worldwide prevalence of peripheral arterial disease, according to various authors, ranges from 3 to 10% in the general population and is increasing with aging, nutritional errors, and high incidence of diabetes mellitus [42, 43, 44]. Peripheral arterial disease is often associated with atherosclerotic diseases such as CAD or ICA lesions. A high prevalence of CAD in patients with peripheral arterial disease has been reported [45, 46].

The high-risk group of patients with peripheral arterial disease is the group of patients with critical lower limb ischemia, commonly present with ischemic rest pain in the foot or ankle and/or the presence of trophic ulcers or non-healing wounds. The prevalence of critical lower limb ischemia is estimated at 500 to 1000 cases per million people annually. Given the aging population, the global increase in metabolic syndrome, the burden of diabetes mellitus and tobacco smoking, the prevalence of both peripheral arterial disease and critical lower limb ischemia is projected to increase [46, 47].

Critical lower limb ischemia is associated with significant disability and mortality. Since its diagnosis in patients without limb revascularization, amputation is required in 20–40% of patients within 6 months and less than 80% of patients survive [19, 39, 48]. A large German registry reported that critical lower limb ischemia was associated with the 4-year amputation rate of 35–67% and the related mortality rate of 52–64% [49].

The large REACH registry included 68,236 patients with various arterial bed lesions. All the study population was divided into four groups: those who had risk factors but no verified arterial lesions (n = 11,587), those who had lesions of one arterial bed (n = 42,716), two arterial beds (n = 9542), and three arterial beds (n = 1132). The study was aimed at assessing the incidence of cardiovascular events in patients with atherosclerosis within the 12-month follow-up. Patients with isolated lower limb arterial lesions had fewer cardiovascular complications and deaths than patients with polyvascular disease, including those with concomitant CAD [50, 51, 52, 53].

In 2019, Alekyan B.G. et al. analyzed the data of 398 patients with peripheral artery disease admitted to the hospital for elective revascularization surgery within the 20-month period. According to the study protocol, all patients underwent selective coronary angiography to visualize the coronary bed. The treatment strategy of each patient was individually discussed with the Heart Team to select the optimal revascularization strategy. The authors concluded that 320 (80.4%) of 398 patients had at least one coronary artery stenosis over 50%. Of them, 177 (55.3%) patients underwent direct myocardial revascularization (93%—PCI and 7%—CABG). Patients with combined lesions of coronary and lower limb arteries and absolute contraindications to cardiac stress testing should undergo coronary artery imaging (MSCT, coronary angiography) to choose the optimal treatment strategy [16]. These findings are consistent with the previous study performed by Pokrovsky A.V. and Dogujeva R.M. in 2012. All patients underwent open surgery without prior coronary angiography and myocardial revascularization. The mean follow-up was 62.04 ± 1.23 months. The long-term results of treatment were evaluated in patients after reconstructive surgery for Leriche syndrome combined with diabetes mellitus. In 63.5% of patients, the main cause of death was MI in the long-term period. The authors concluded that coronary imaging is required before elective lower extremity revascularization. Prevention of cardiovascular events ensures the reduction of cardiovascular complications in patients with Leriche syndrome [16].

Chen C. et al. included 879 patients with chronic and critical lower limb ischemia who underwent lower extremity revascularization. All the patients were enrolled into two groups: patients with 2B chronic lower limb ischemia (n = 382 (43.4%)) and patients with critical lower limb ischemia (n = 497 (56.5%)). Two subgroups were allocated within each group: isolated chronic lower limb ischemia (n = 177 (46.3%)) and chronic lower limb ischemia and CAD (n = 205 (53.6%)) versus isolated critical lower limb ischemia (n = 246 (49.4%)) and critical lower limb ischemia and CAD (n = 251 (50.0%)). Major adverse cardiovascular and cerebrovascular events (MACCE) and all-cause mortality during 5 years of follow-up were evaluated. Patients with critical lower limb ischemia and CAD were more likely to receive medication therapy (aspirin, DAATs, beta blockers, and statins). In addition, they were older, more likely to have hypertension, heart failure, diabetes mellitus, and renal failure compared with the group with isolated critical lower limb ischemia. The subanalysis of the critical lower limb ischemia + CAD group reported that these patients had the worst rates of both, MACCE, and all-cause mortality after 5 years, compared to patients with isolated critical lower limb ischemia. Patients with critical lower limb ischemia and CAD demonstrated a fourfold increased incidence of MACCE as well as all-cause mortality after 5 years compared to patients with chronic lower limb ischemia and CAD.

The association between CAD and adverse long-term clinical outcomes was stronger in patients with isolated critical lower limb ischemia. MACCE and mortality rates increased by 52 and 64% in patients with critical lower limb ischemia and CAD, compared to patients with isolated critical lower limb ischemia [52, 53].

Nishijima A. et al. retrospectively studied the prevalence of CAD in 129 patients with critical lower limb ischemia who underwent lower limb amputation. Patients were divided into two groups: group 1 had major amputation above the ankle (n = 36) and group 2 had minor amputation below the ankle or necrotomy (n = 93). Selective coronary angiography was performed in 93.7% of patients with critical lower limb ischemia. Coronary artery lesions were detected in 69% of patients. A more detailed analysis revealed that 82% of patients who underwent major amputations had coronary artery lesions, whereas in the group with minor amputations the prevalence rate reached 63%. Thus, the authors proved that patients who underwent major amputations had a significantly higher prevalence of CAD compared to those patients who underwent minor amputations. In addition, the data of patients without critical lower limb ischemia (566 patients with grade 2B chronic lower limb ischemia) were reviewed. They underwent endovascular lower extremity revascularization. According to coronary angiography, only 40% (227 out of 566) of them had CAD [54].

The study of Soga Y. et al. evaluated the survival rate of 995 patients with critical lower limb ischemia within 2 years after endovascular lower extremity revascularization. The 2-year mortality rate was 41.4% (n = 412). The causes of death included cardiac events (n = 121, 29%), vascular events (n = 41, 10%), sudden death (n = 32, 8%), noncardiovascular events (n = 191, 46%), and unexplained causes (n = 27, 7%). Notably, 47% (194 of 412) of all deaths were due to cardiovascular causes. Heart failure was the most common cause of death in the cardiac mortality group (37.1%). Acute myocardial infarction (22.3%) and ventricular fibrillation (9.9%) ranked second and third, respectively. Thus, treatment of heart failure and prevention of ischemic complications are important for patients with critical lower limb ischemia. Sepsis, pneumonia, and cancer were the most frequent causes of noncardiovascular deaths. About 34% (n = 142) died due to infectious diseases [55].

The presence of CAD may be underestimated in patients with critical lower limb ischemia since they often suffer from diabetic neuropathy and/or physical inactivity due to rest pain or trophic ulcers. Therefore, these patients do not complain of typical heart pain. Helzer N.R. et al. evaluated coronary angiograms before vascular surgery in 300 patients with critical lower limb ischemia and showed that only 8% of patients had mild coronary artery stenoses [56].

Current evidence state that myocardial ischemia should be assessed in patients with critical lower limb ischemia [16, 33, 54]. However, there is no consensus on the screening method for determining myocardial ischemia in this group of patients. Patients with critical lower limb ischemia may not report cardiac complaints (angina and dyspnea) due to their physical inactivity. In addition, the prevalence of diabetes mellitus in patients with critical lower limb ischemia ranges from 75 to 83%, and therefore, clinical signs of angina may sometimes be underestimated, given the development of pain-free myocardial ischemia in patients [57, 58]. According to the 2019 ESC guidelines for the diagnosis and treatment of chronic coronary syndromes, when CAD cannot be excluded by clinical assessment of disease symptoms, noninvasive diagnostic tests should be considered to confirm the diagnosis and assess the risk of fatal events in the future. Noninvasive methods of myocardial ischemia imaging (scintigraphy, PET/CT) or coronary bed imaging using MSCT coronary angiography should be applied [59].

The role of coronary revascularization in patients with peripheral artery disease requiring vascular revascularization was assessed in the CARP study on 510 patients. Group 1 patients underwent coronary artery revascularization before lower extremity revascularization (n = 258). Group 2 patients were not referred to coronary artery revascularization (n = 252).

Coronary angiography was performed only in patients with a positive stress test. Patients with controversial results were not referred to coronary angiography. Preoperative coronary revascularization was not proven to be beneficial according to the results of the study. There were no significant differences in the incidence of myocardial infarction, mortality, or the length of the in-hospital stay when assessing the immediate results. There were 7 (3.1%) deaths in the myocardial revascularization group versus 8 (3.4%) deaths in the group without revascularization (p = 0.87). A total of 19 (8.4%) patients in the myocardial revascularization group had acute myocardial infarction (AMI) versus 20 (8.4%) without myocardial revascularization (p = 0.99). CHF leading to fatal outcomes was registered in one (0.4%) patient in the myocardial revascularization group versus two (0.8%) patients without myocardial revascularization (p = 0.59). In the long-term follow-up period, patients with and without myocardial revascularization had similar mortality rates after 2.6 years (22 vs. 23%). Among the patients who did not undergo preoperative coronary artery revascularization, 21 (8%) underwent coronary artery revascularization after lower extremity revascularization [33].

The CARP study was criticized by several researchers, who pointed out its significant limitations. Thus, Landesberg G. and Kertai M believe that complete myocardial revascularization in this group of patients could prevent postoperative AMI cases and could improve long-term survival rates [60].

Coronary angiography and myocardial revascularization in the CARP study were performed only in patients with confirmed myocardial ischemia using cardiac stress testing. Thus, the patients who had no complaints of cardiac pain did not undergo revascularization. Alekyan B.G. et al. showed that 66.4% of patients with chronic lower limb ischemia and critical lower limb ischemia with concomitant CAD are asymptomatic despite the presence of at least one coronary artery lesion of over 50% [16]. It means that a large proportion of patients in the CARP study could have severe coronary artery lesions. A total of 4% of patients who did not undergo myocardial revascularization were subjected to myocardial revascularization due to ACS in the in-hospital period. Moreover, 8% of patients who did not undergo myocardial revascularization before elective vascular surgery were referred to it due to the clinical symptoms in the long-term period [33].

In addition to the above-mentioned limitations of the CARP study, it is worth considering that 16 years have passed since the results of the study were presented. During this time, new endovascular technologies appeared, including new generation of stents, myocardial fractional flow reserve, various intracoronary imaging methods (intravascular ultrasound and optical coherence tomography), etc. These novel technologies may question the relevance and reliability of the presented findings.

Raghunathan A. et al. performed the subanalysis of the CARP study, which included 143 patients with critical lower limb ischemia. All these patients had concomitant CAD. Then, they were randomized into two groups: group 1 patients underwent myocardial revascularization before elective lower extremity revascularization (n = 61, of them 28 patients underwent CABG and 33 patients—PCI) and group 2 patients who did not undergo myocardial revascularization (n = 82). The immediate and long-term results were assessed using the incidence of MACCE. The 30-day overall mortality in patients with critical lower limb ischemia and CAD was 3.5% (n = 5). Three (4.9%) patients died in 1^st group, and in 2^nd group died 2 (2.4%) (p = 0.42). The incidence of MI in the in-hospital period was 8.4% (4.6% in group 1 vs. 11.5% in group 2; p = 0.19). The 2.7-year overall survival was 79% and the incidence of AMI was 16.1%. The authors concluded that AMI was the main cause of death in these patients. Coronary angiography and subsequent myocardial revascularization in this group of patients could have prevented possible acute myocardial infarction [35].

Several authors note that the incidence of diabetes mellitus (70.4%), chronic renal failure (27.8%), and smoking (70 to 90%) is higher in patients with critical lower limb ischemia compared to patients with chronic lower limb ischemia. These risk factors significantly increase the risk of developing adverse cardiovascular events, including mortality, acute cerebrovascular events, and acute myocardial infarction [57, 61, 62, 63].

At 1 year, 25% of patients with critical lower limb ischemia without coronary artery imaging will be dead and 30% will have undergone amputation. Only 45% will remain alive with both limbs. At 5 years, over 60% of patients with critical limb ischemia will be dead mainly from myocardial infarction or stroke [46, 61, 64, 65].

Taking into account that patients with critical lower limb ischemia have a high risk of cardiovascular complications, routine coronary angiography, and subsequent myocardial revascularization, if indicated, seems to be reasonable and rationale.

5. Multidisciplinary approach in the treatment of patients with peripheral arterial disease

The treatment of CAD in patients with coexisting peripheral arterial disease referred to endovascular or surgical lower extremity revascularization remains challenging. The accurate diagnosis of atherosclerotic lesions in all arterial beds and the optimal strategy of treatment are critical for these patients. Therefore, a multidisciplinary team should involve different healthcare specialists.

The multidisciplinary approach emerged in oncology in the 1960s and demonstrated its effectiveness in improving the treatment outcomes of cancer patients [66, 67]. Concerning myocardial revascularization this approach has been offered after several large randomized trials with the SYNTAX study to be the first one. The multidisciplinary approach has received a class 1C recommendation in the ESC guidelines on myocardial revascularization since 2010 [48]. But in case of combined coronary and peripheral artery lesions, this approach has not been widely used so far. The multidisciplinary approach in the treatment of patients with aortic and peripheral artery disease who should undergo preoperative CAD assessment was first mentioned in the ESC guidelines on non-cardiac surgery [68]. Preoperative myocardial revascularization should be performed in patients with proven myocardial ischemia and CAD risk factors, including angina, a positive history of postinfarction cardiosclerosis, heart failure, prior STEMI or TIA, renal dysfunction, and the presence of diabetes mellitus. If patients have at least two risk factors, it is recommended to perform preoperative stress testing or coronary imaging (Class II a). Recent ESC guidelines on peripheral artery diseases [69] have already indicated the need for using the multidisciplinary team for joint decision-making on the treatment of these patients.

Coexisting CAD should be confirmed in patients with peripheral artery disease. But it remains challenging in those patients who have absolute contraindications for cardiac stress testing (Leriche syndrome, prior stroke, and intermittent claudication). The second important issue is the necessity to choose the optimal strategy and staging of coronary and peripheral arterial bed revascularization.

6. Methods

A total of 693 patients with aortic and peripheral artery diseases admitted to the A.V. Vishnevsky National Medical Research Center of Surgery for elective revascularization were enrolled in the period from May 1, 2017 to December 31, 2018 (over 20 months).

The study protocol was approved by the Local Ethics Committee. The multidisciplinary team referred all patients to selective coronary angiography to identify the severity of coronary artery lesions and determine the optimal strategy for coronary and peripheral artery revascularization.

The exclusion criteria were as follows: acute coronary syndrome, acute peripheral artery thrombosis, renal failure, previously performed selective coronary angiography, or cardiac stress testing.

A significant coronary lesion on angiography was defined as a luminal narrowing with a diameter stenosis of more than 50%, and hemodynamically significant was defined as a luminal narrowing with a diameter stenosis of more than 75% or a lesion of less than 75%, but with proven myocardial ischemia.

The primary endpoints were AMI, STEMI, and death. The secondary endpoints included access site complications, bleeding, infections, and stroke.

A total of 693 patients with aortic and peripheral artery disease were recruited to the study. Of them, 171 (32.5%) were women and 522 (75.3%) were men. The age of the patients ranged from 29 to 93 years with the mean age of 67.2 ± 8.8 years. 32.5% (n = 223) of patients were over 71 years of age.

Only 203 (29.3%) patients had cardiac complaints, whereas 490 (70.7%) were asymptomatic. The majority of patients had isolated ICA lesion (n = 196, 28.3%). A total of 93 (13.4%) patients had combined ICA and lower extremity artery lesions, 70 (10.1%) patients were present with combined iliac and superficial femoral artery lesions, and 60 (8.6%) patients were with femoral artery lesions.

7. Results

Selective coronary angiography revealed that 554 (79.9%) patients out of 693 had at least one coronary artery lesion of more than 50%. Importantly, 368 (66.4%) of these patients were clinically asymptomatic and had no cardiac complaints (Table 1). About 80.5% of patients with isolated ICA lesion (n = 251) and 81.6% of patients with isolated lower extremity artery lesion (n = 327) had over 50% stenosis of at least one coronary artery (Table 2).

Heart complaints	Presence of coronary artery lesions				Total	%
	< 50%		> 50%
	n	%	n	%
Symptomatic	17	12.2	186	33.6	203	29.3
Asymptomatic	122	87.8	368	66.4	490	70.7
Total	139	100	554	100	693	100

Table 1.

Distribution of patients with peripheral arterial disease according to the CAD symptoms and signs.

Nature of peripheral arterial lesions	Presence of coronary artery lesions; > 50%		Total
	n	%
Isolated lesion of the lower extremity arteries	267	81.6	327
Isolated ICA lesion	202	80.5	251
Internal carotid arteries and lower extremities	44	73.3	60
Aortic aneurysms	22	68.8	32
Brachiocephalic arteries and lower extremities	9	81.1	11
Visceral and renal arteries	6	85.7	7
Brachiocephalic arteries	4	80.0	5
Total	554	79.9	693

Table 2.

Incidence of coronary artery stenoses of more than 50% in patients with peripheral artery disease.

Single-vessel, double-vessel, and triple-vessel coronary artery disease of more than 50% were found in 174 (31.4%), 140 (25.3%), and 135 (24.4%) patients, respectively. The left main coronary artery disease was found in 88 (15.9%) patients.

A comparative analysis of the CAD incidence showed that 314 (77.0%) patients with a single arterial bed lesion had stenoses of more than 50%. The incidence of CAD increased with the number of affected peripheral arterial beds. Atherosclerotic lesions of at least two arterial beds were associated with the stenoses of more than 50% ranging from 83.2 to 89.3%. The incidence of CAD increases with the number of affected arterial beds.

After coronary angiography, all patients were discussed by the multidisciplinary Heart Team to choose the optimal treatment strategy and staging for both myocardial and lower extremity revascularizations.

A total of 238 (43.0%) patients with at least one coronary artery stenosis of more than 50% did not undergo myocardial revascularization. Seventeen (3.0%) patients were referred to additional examination to verify myocardial ischemia. 221 (40.0%) patients had no indications for revascularization. A total of 316 (57.0%) patients underwent myocardial revascularization according to the decision of the multidisciplinary team. Twenty-one (6.7%) patients underwent CABG and 295 (50.3%)—PCI. Thus, a total of 45.6% (n = 316) of patients underwent myocardial revascularization by the multidisciplinary team decision. About 57.0% of patients with at least one coronary artery stenosis of more than 50% underwent myocardial revascularization.

A total of 295 patients underwent staged PCIs. Eighty-one (27.5%) and 79 (26.8%) patients underwent the LAD and RCA stenting, respectively. Thirty-nine (13.2%) patients underwent the LAD + RCA stenting, and 17 (5.7%) patients underwent LMCA stenting. All patients were implanted with the latest generation of the antiproliferative drug-eluting stents (the mean of 1.7 stents per patient).

A total of 207 (29.9%) of 693 patients were not referred to vascular surgery according to the multidisciplinary team decision. Eighteen (8.7%) patients were referred to additional examinations, and 40 (19.3%) patients were prescribed optimal medication therapy. Eighty-three (40.1%) did not return to the hospital for surgery, and 66 patients were discharged for the final stage of intervention.

Surgical and endovascular surgeries for aortic and peripheral artery disease were performed in 486 (70.1%) patients. Myocardial revascularization was performed in 226 (46.5%) patients in addition to vascular surgery, while no myocardial revascularization was performed in 260 (53.5%). Of 226 patients, 214 (94.7%) underwent PCI and 12 (5.3%) underwent CABG. A total of 486 patients underwent 509 vascular surgeries: 341 (67.0%) underwent surgical lower extremity revascularization, 165 (32.4%)—endovascular lower extremity revascularization, and 3 (0.6%)—hybrid revascularization.

As for the strategy for CAD treatment in patients with aortic and peripheral artery disease, myocardial revascularization was performed in 50% of patients who underwent CEA (47.3%—PCI, 2.7%—CABG) and in 51.3% of patients (50%—PCI, 1.3%—CABG) who underwent open surgery in the aorto-femoral segment, and in 66.7% of patients (66.7%—PCI) who underwent ICA stenting.

A total of 923 (564 endovascular and 359 surgical) interventions were performed in 580 patients. Three (0.51%) patients died in the in-hospital period. Hemorrhagic stroke provoked by the hypertensive crisis after successful PCI was the cause of one (0.17%) death. Two other patients (0.34%) died because of hemorrhagic and ischemic strokes after CEA. Two (0.56%) patients had stroke: one patient after ICA grafting and one patient after CEA. There were no cases of acute myocardial infarction in the in-hospital period in both groups. Among the secondary endpoints, hematomas in the postoperative wound area after open interventions occurred in 2 (0.56%) cases, vascular conduit infections in 2 (0.56%), and hemopericardium after PCI in 1 case that did not require pericardiocentesis.

8. Conclusion

Our results demonstrated that 79.9% (n = 558) of patients with atherosclerotic lesions of the aorta and peripheral arteries had at least one coronary artery stenosis of more than 50% according to selective coronary angiography. The relationship between the number of the affected coronary arteries with stenoses of over 50.0% and the number of affected arterial beds has been found. The more arterial beds are affected, the more coronary arteries are affected. The prevalence of CAD reaches almost 90%, when four or more peripheral arterial beds are affected. About 66.4% of patients with aortic and peripheral arterial disease and coexisting coronary artery stenosis of more than 50% were asymptomatic.

Importantly, 316 (45.6%) out of 693 patients with aortic and peripheral artery diseases had hemodynamically significant coronary artery stenoses, requiring direct myocardial revascularization (295—PCI and 21—CABG). Combined significant aortic lesions, peripheral artery disease, critical lesions of the carotid arteries, as well as other comorbidities were the main reasons for the refusal of CABG in some patients with severe CAD and the Syntax Score over 23.

Out of 398 staged PCIs, 295 patients had only one (0.34%) fatal outcome associated with hemorrhagic stroke caused by uncontrolled arterial hypertension. Taking into account the low incidence of in-hospital complications following PCI, we may consider that PCI is the method of choice for treating this group of patients.

We agree with the current guidelines suggesting first to collect patients’ medical history and complaints to define possible coronary artery stenosis. If a patient is likely to have CAD, noninvasive stress testing is recommended with the subsequent referral to intracoronary imaging (CT or invasive coronary angiography). However, we face some challenges in the real clinical practice that we should keep in mind. A large proportion of patients have absolute contraindications for cardiac stress testing (symptomatic ICA lesion, stroke, and chronic and critical lower limb ischemia) and socio-economic limitations (lack of availability of stress testing and myocardial scintigraphy in most hospitals, and the out-of-pocket expenses for patients to undergo additional testing). In addition, the results of noninvasive stress testing do not necessarily correspond to angiographic findings. Patel et al. have previously shown important relationships between the clinical profile of patients, findings after noninvasive stress testing, and the absence of coronary artery stenoses according to selective coronary angiography on 661,063 patients from 1128 hospitals in the USA. The patients were divided into two groups according to the presence or absence of significant coronary artery atherosclerotic lesions. As a result, 37.6% of patients who did not undergo stress testing before coronary angiography had CAD. About 33.7% patients with controversial stress testing results had CAD. About 30% of patients with negative stress testing results had coronary obstructions [70].

When noninvasive testing to confirm CAD is unavailable, we should use other options to detect it. The results of our study have shown a high prevalence (79.9%) of coronary atherosclerosis in patients with aortic and peripheral artery diseases, as well as the resultant high rate of myocardial revascularization (45.7%).

Out of 923 endovascular and surgical interventions performed on 580 patients in the in-hospital period, three (0.51%) patients died, and two (0.34%) patients experienced AMI. This indicates the high efficiency and safety of the multidisciplinary approach in the treatment of CAD patients with aortic and peripheral artery diseases. None of the patients had ACS in the in-hospital period, confirming the accurate preoperative assessment of coronary artery disease and the optimal decision on PCI and CABG.

We have previously published in-hospital outcomes of endovascular treatment of patients with combined coronary and ICA lesions, showing high efficacy and safety of the complex treatment and complete revascularization of both carotid and coronary arterial beds with complete absence of both fatal outcomes and acute myocardial infarction and stroke among these patients [16]. According to the secondary endpoints, the following complications were registered in four (12.9%) patients: One (3.2%) patient had radial artery thrombosis after PCI, two (6.5%) were diagnosed with pulsatile hematoma of the access site (common right femoral artery) after ICA stenting. All these complications were treated conservatively.

The treatment strategy for patients with polyvascular disease should include both, accurate assessment of all arterial beds prior to the intervention and treatment of all, even clinically unapparent, significant lesions of the remaining segments.

Conflict of interest

The authors declare no conflict of interest.