Coronary Artery Stenting in Patients with Ischemic Heart Disease and Oncopathology

The dissertation is devoted to the analysis of immediate and mid-term results of endovascular myocardial revascularization in patients with ischemic heart disease and concomitant oncopathology. The work addresses questions of efficacy and safety of percutaneous coronary intervention performed as the first stage prior to surgical treatment of a malignant neoplasm, as well as the results of PCI in patients with oncopathology in remission. Particular attention is paid to the assessment of quality of life of patients in the mid-term period after endovascular treatment.

The research falls within specialty 14.00.06 — cardiology and was carried out at the A. N. Bakulev National Scientific and Practical Center for Cardiovascular Surgery. The work is aimed at optimizing the management strategy for patients with combined cardiac and oncological pathology and at clarifying the criteria for the use of coronary artery stenting in this category of patients.

INTRODUCTION

Relevance of the Problem

Ischemic heart disease and oncological diseases occupy leading positions among the causes of mortality worldwide. Given the prevalence of both nosologies, the combination of ischemic heart disease (IHD) and oncopathology is not uncommon [26,106,123,157].

In the majority of cases, the presence of concomitant IHD in patients with malignant neoplasms serves as an aggravating factor that complicates and/or limits the treatment of oncopathology [101]. In patients with oncopathology, ischemic heart disease may increase the rate of postoperative complications, in-hospital mortality, and also reduce long-term survival after radical surgery for a malignant neoplasm.

Myocardial revascularization performed as the first stage in patients with hemodynamically significant stenoses of the coronary arteries (CA) is the principal treatment method that prevents the development of cardiovascular complications during and after treatment for oncopathology.

At present, the foreign literature contains many studies that have evaluated the results of simultaneous surgery in this category of patients — aortocoronary bypass grafting (CABG) combined with surgical treatment of oncopathology [84,93,99,109,141,153]. A two-stage approach is also used as an alternative to simultaneous intervention [36,108,113,161].

In view of the dissemination of methods of endovascular myocardial revascularization, considerable interest attaches to the evaluation of staged surgical treatment of patients who underwent coronary artery stenting before the initiation of treatment for oncopathology.

However, at present only a few studies have assessed the efficacy of primary percutaneous coronary intervention (PCI) in patients with oncopathology, and the data obtained are rather contradictory [29,161]. A number of studies have evaluated only the short-term results of two-stage treatment performed in patients with IHD and oncopathology [3,29,161]. It should be taken into account that, so far, no sufficiently large-scale studies have been conducted in this field in order to define clear criteria that would guide the recommendation of angioplasty with stenting as the first stage in patients with IHD and oncopathology. Nevertheless, a number of studies have demonstrated the high efficacy of primary myocardial revascularization in this category of patients [8,150].

An analysis of immediate and long-term results of both single-stage and two-stage treatment of patients with IHD and oncopathology has been reported by Davydov M. I. and co-authors. In that observation, in the staged-treatment group, ten patients underwent endovascular myocardial revascularization as the first stage, with drug-eluting stents used in half of the cases, and ten patients underwent aortocoronary bypass grafting. In the simultaneous-treatment group, 13 patients underwent aortocoronary bypass grafting together with lung surgery. In the staged-treatment group, in-hospital mortality was significantly lower (4.3%) compared with the simultaneous-treatment group (15.4%). Lower mortality in the staged-treatment group was also observed at long-term follow-up — 22.7% versus 27.3% in the simultaneous-intervention group [8]. Nevertheless, the choice between a simultaneous and a staged surgical strategy in this category of patients remains debatable.

According to data by Uyokoshi L. et al., primary PCI in 16 patients (all of whom received bare-metal stents) followed by lung resection for malignant neoplasm showed good immediate and long-term results. At a mean follow-up of 30 days, none of the patients exhibited signs of myocardial ischemia, and 5 (31%) patients died due to metastatic disease. Five-year survival amounted to 53% [150].

In coronary artery stenting, a choice must be made between drug-eluting stents and bare-metal stents. The question of the possibility of safely discontinuing antiplatelet agents before performing the second stage — surgical treatment of oncopathology — is also ambiguous, which in each particular case often requires an individual approach taking into account the risk of stent thrombosis and bleeding.

The use of chemotherapeutic agents (cytostatics) may lengthen the time of stent endothelialization, which in some cases necessitates prolonging the duration of dual antiplatelet therapy in patients with previously implanted stents [81,101]. In turn, many chemotherapeutic agents, such as thalidomide, possess heightened thrombogenicity, which may also necessitate modification of the antiplatelet regimen. The use of chemotherapeutic agents capable of inducing thrombocytopenia may also create difficulties in the administration of antiplatelet drugs [101]. In the opinion of some authors, given the complexities of antiplatelet therapy in patients with oncopathology, the use of drug-eluting stents should be avoided, with preference given to bare-metal stents [81,101].

At present, a number of studies have traced the relationship between the high risk of cardiovascular complications in patients who have previously undergone treatment for oncopathology and are in remission from that disease.

The high incidence of cardiac complications in this category of patients is associated primarily with the cardiotoxic effects of radiation therapy [61,70], as well as with the adverse effects of many chemotherapeutic agents [18,37,53,55,114,159]. The efficacy and safety of PCI in this category of patients are also ambiguous. Data from a number of studies emphasize both the safety and efficacy of PCI [67,87] and the increase in cardiovascular complications when this method of myocardial revascularization is used in patients with oncopathology in remission [38,129,132].

In this connection, the present work is of great interest and is of important practical significance for evaluating the efficacy of endovascular revascularization in this category of patients. The results obtained will make it possible to provide more precise recommendations on the use of percutaneous coronary intervention in patients with IHD and oncopathology.

Aim of the Study

Analysis of the immediate and mid-term results of endovascular treatment of IHD in patients with oncopathology.

Objectives of the Study

1. To study the results of two-stage treatment of patients with IHD and oncopathology, in which endovascular myocardial revascularization is performed as the first stage and treatment of oncopathology as the second stage.

2. To analyze the results of PCI in patients with oncopathology in remission.

3. To assess the quality of life of patients in mid-term follow-up after PCI.

Scientific Novelty of the Study

The presented dissertation is one of the first studies in the Russian literature devoted to an analysis of the immediate and mid-term results of percutaneous coronary intervention in patients with concomitant oncopathology.

Practical Significance of the Study

1. The results obtained confirm the high efficacy of endovascular myocardial revascularization in this category of patients and make it possible to use this technique widely in clinical practice.

2. Recommendations have been developed aimed at optimizing the treatment strategy in patients with IHD and concomitant oncopathology.

Statements Defended

Percutaneous coronary intervention is an effective and safe method of myocardial revascularization in patients with concomitant oncopathology. PCI performed as the first stage reduces the risk of cardiac complications during surgical intervention for oncopathology and also reduces the risk of cardiovascular complications in the early postoperative period. Good results of PCI in patients with oncopathology have been demonstrated by us also at mid-term follow-up (freedom from angina, good exercise tolerance in the majority of patients). The safety of PCI in patients with IHD and oncopathology in remission has also been shown.

CHAPTER 1

LITERATURE REVIEW

Ischemic heart disease and oncological diseases occupy leading positions among the causes of mortality worldwide. The principal cause of mortality from diseases of the circulatory system remains ischemic heart disease. According to data from the demographic electronic journal (Demoscope Weekly), ischemic heart disease is the cause of death of more than half of those who die from diseases of the circulatory system (in the Russian Federation, 53.1% in 2012, or 29.2% of the total number of deaths). The second place among causes of death is occupied by neoplasms (mainly malignant). Thus, in 2012, malignant neoplasms were the cause of death in 15% of those who died. In recent years, the proportion of those dying from neoplasms has been growing, which is fully consistent with the trend of population aging [11].

The real prevalence of the combination of these diseases remains unknown to date; however, a number of authors have noted that in patients with oncological disease there is a high probability of the presence of ischemic heart disease [14,26,106,157,158]. According to data by Reicher-Reiss H., the combined manifestation of IHD and malignant neoplasms in the male population amounts to approximately 6.9% [123], while according to data by Mishra P. K., the combination of cardiovascular pathology and oncopathology reaches 25.4% [100]. According to data by Annie On Chan, the prevalence of rectal cancer in patients with ischemic heart disease was significantly greater compared with the general population and with patients without IHD. At the same time, smoking and metabolic syndrome were independent risk factors for the combined manifestation of late-stage rectal cancer and ischemic heart disease [26].

Observations exist proving that patients with oncopathology have an elevated risk of developing ischemic heart disease. For example, it has been shown that in patients with newly diagnosed malignant disease the rate of hospitalizations with newly diagnosed IHD is higher, especially within the first 6 months [162]. These data were obtained in patients with malignant tumors of the lung, small intestine, kidney, liver, and leukemia, as well as in patients with oncopathology and the presence of metastases.

Oncological diseases, especially at an advanced stage, are frequently associated with heightened platelet activity, which constitutes an unfavorable factor for the development of thrombotic complications [30,144]. Hypercoagulation is also characteristic of patients with oncopathology [22,40].

It is known that anemia belongs to the "minor" signs of the presence of an oncological disease. According to data by Mercadante S., anemia is detected in more than 30% of oncological patients, and its proportion rises with disease progression and with therapy of the underlying disease (radiation and chemotherapy) [98]. Paraneoplastic anemia may also contribute to the worsening of myocardial ischemia when the patient has ischemic heart disease [89].

These observations confirm the hypothesis of a high likelihood of aggravation of the atherosclerotic process in patients with oncopathology in the presence of existing IHD.

The heightened interest in patients with ischemic heart disease and oncopathology is due not only to the social significance and prevalence of these diseases, but also to the possible pathogenetic connection between them. The pathogenetic mechanisms of the interrelation between these two pathological processes remain unstudied to the end; however, at present there exist a number of observations aimed at investigating this question. Thus, there is a supposition about the existence of a connecting pathogenetic link — apoptosis — as well as changes in the rheological properties of blood underlying the pathogenetic chain [5]. Hansen E. S. suggested that the basis of the pathogenetic link uniting malignant neoplasms and atherosclerosis is constituted by somatic mutations arising under the influence of certain environmental factors, such as, for example, ionizing radiation [63].

Inflammation is also an important link in the pathogenesis and progression of atherosclerosis [88] and of the oncological process [32].

The existence of common risk factors also points to the presence of a connecting pathogenetic link. Thus, according to data by some authors, a connection is traced between obesity and the risk of development of both cardiovascular and oncological diseases [20,48].

The development and progression of ischemic heart disease may be promoted not only by the oncological disease itself, but also by its therapy (including chemotherapy and radiation therapy). According to data from the majority of authors, the rate of post-radiation arteriopathy amounts to approximately 5% of the number of persons who received radiation therapy; however, in individual patient groups it may be higher. Thus, according to data by Oshi I. T., radiation therapy at a dose of 40 Gy induces ischemic heart disease in 5–10% of cases [50].

Asymptomatic course of IHD is also characteristic of radiation injury. Marks L. B. in his study noted that impaired myocardial perfusion in asymptomatic patients was detected in 27% of cases at 6 months after radiation therapy for breast cancer. At the same time, a gradual increase in the number of patients with impaired myocardial perfusion to 42% by two years was noted [94].

It is known that radiological procedures themselves may also contribute to the development of oncological diseases. According to data by C. Goda, the risk of developing oncological diseases, predominantly lung cancer, rises after percutaneous coronary intervention for chronic total occlusions of the coronary arteries, especially in young patients (45–49 years) [51].

The high cardiotoxicity of certain chemotherapeutic agents, especially at high doses, has been demonstrated in a number of studies; here, a scenario is possible of the development both of heart failure/left ventricular dysfunction [18,55,59,121,139] and of myocardial ischemia [16,37,47,49,64], as well as of thromboembolic complications due to venous thromboses [33,97,115]. In turn, there exists a supposition that the use in cardiological practice of such agents as diuretics may increase the risk of developing oncological diseases — data have been obtained on the influence of diuretics on the development of renal carcinoma in women [57].

However, only very recently have data been obtained on the high probability of myocardial damage in patients with oncopathology even before the start of specific treatment of the malignant neoplasm. Thus, according to data by Pavo N. et al., a clear correlation was traced between elevated blood levels of markers of myocardial damage (including NT-proBNP and troponin T) and the presence of a malignant neoplasm. At the same time, it was also noted that the elevation of markers of myocardial damage increases overall mortality in these patients [116].

The history of the development of cardiac surgery in patients with IHD and oncopathology dates from the second half of the twentieth century. The first data on a simultaneous successful operation of aortocoronary bypass grafting and lung resection for adenocarcinoma were published by Dalton M. in 1978 [34]. By the present time, the foreign literature contains many studies with an evaluation of the results of simultaneous surgery in this category of patients [84,93,99,109,141,153].

The question of performing operations with cardiopulmonary bypass (CPB) in this category of patients remains unresolved to the end. On the one hand, CPB may suppress immune function and lead to systemic seeding of malignant cells. On the other hand, cardiopulmonary bypass may influence the activity of neutrophils and platelets and lead to activation of the complement system, which may exert a prophylactic effect in patients with neoplasms [155]. Thus, the results of aortocoronary bypass grafting using cardiopulmonary bypass in patients undergoing simultaneous lung resection for malignant neoplasm at one year and five years were comparable with the results of aortocoronary bypass grafting with cardiopulmonary bypass in patients with benign tumors [122]. Similar survival rates were also obtained when comparing the results of CABG with CPB in patients with oncological disease in remission and in patients without oncopathology [24,82].

Of interest is the study by Yamamoto S. et al., in which blood serum samples of patients who underwent aortocoronary bypass grafting using cardiopulmonary bypass (11 patients) and without its use (11 patients) were added to a culture of cancer cells in vitro. Blood serum taken immediately after CABG without the use of CPB exerted a significantly greater inhibitory effect on cancer cells than the serum of the control group (after operation with cardiopulmonary bypass). At the same time, all serum samples taken immediately after the operation exerted a lesser inhibitory effect on the cellular proliferation of malignant cells than the serum samples taken before the surgical intervention [156].

However, in a number of studies in which the results of aortocoronary bypass grafting with cardiopulmonary bypass were evaluated in comparison with off-pump revascularization in patients with oncopathology, no significant differences were obtained in the efficacy of the two techniques [68,128,138,151].

At present, in this category of patients the choice still rests with the minimally invasive strategy — off-pump aortocoronary bypass grafting — which defines this technique as the leading one. The majority of results obtained with simultaneous surgical treatment of IHD and oncopathology are represented predominantly by this technique [46,72,120,126].

Good results of off-pump surgery with simultaneous lung surgery for oncopathology have also been demonstrated in patients with an unstable course of ischemic heart disease [39].

A two-stage approach, in which aortocoronary bypass grafting is performed as the first stage and treatment of oncopathology as the second stage, is also used as an alternative to simultaneous intervention [36,108,113,161]. In the study by Voets A. J., a comparison was made of single- and two-stage approaches in the treatment of patients with stage 1–2 malignant lung disease, and comparable results were obtained; however, in both groups the number of patients was small — 24 and 10 persons, respectively [149]. According to data by Miller D. L., aortocoronary bypass grafting performed as the first stage, followed by lung resection in patients with oncopathology, has advantages over single-stage treatment. Long-term survival was significantly higher in the two-stage treatment group; however, this applied only to patients with early stages of oncopathology, while in the remaining cases the results did not differ statistically [99].

Experience with combined interventions in this category of patients also exists in the Russian Federation; in particular, by the joint efforts of the Institute of Clinical Oncology of the N. N. Blokhin Russian Cancer Research Center together with other clinics (including the Russian Cardiology Research and Production Complex; the N. V. Sklifosovsky Research Institute of Emergency Medicine; and the A. N. Bakulev Scientific Center for Cardiovascular Surgery), approximately 100 simultaneous and staged interventions were performed [7,8,9,10]. In the study by Andrushchuk V. V. and co-authors, an evaluation was also made of the quality of life in 21 patients both at early and at long-term periods after combined intervention — aortocoronary bypass grafting with simultaneous intervention for oncopathology. Improvement in quality of life was noted in patients within a period of up to three years after surgery [2]. Experience with both simultaneous and staged interventions, in which myocardial revascularization was performed by the method of aortocoronary bypass grafting, is also reported by other Russian authors [3,4].

Separate attention is warranted by the results of surgical treatment of IHD in patients with oncopathology in remission.

The study by Carrasco V. et al. included patients both with an active tumor process (group "A") and with oncopathology in remission (group "B"), as well as patients without concomitant oncopathology (group "C"). All groups were selected from 2146 patients who had undergone operations under conditions of cardiopulmonary bypass. No significant differences were obtained in in-hospital mortality between groups "B" and "C", and no reliable difference was obtained in the rate of postoperative complications between these groups. However, a significant difference was revealed in the causes of mortality from oncopathology and from cardiovascular complications between groups "A" and "C": 77.7% of deaths from oncopathology and 8.3% from cardiac complications in group "A", whereas in group "C" these figures amounted to 2.2 and 71.4%, respectively. At the same time, no reliable difference was noted in the causes of mortality between group "B" (patients with oncopathology in remission) and the control group — group "C" [24]. However, the study by Mishra P. et al., in which the outcomes of cardiac surgery for IHD or valvular pathology were evaluated, showed significantly higher mortality both at early and at long-term periods in patients with oncopathology in remission compared with the group of patients without oncopathology. At the same time, mortality from oncopathology increased significantly, especially in the period up to two years after surgical treatment [102].

Despite the widespread introduction of cardiac-surgical and interventional care into the treatment of ischemic heart disease, the questions of the tactics of surgical treatment in patients with IHD and oncopathology, of determining the optimal management strategy for these patients — sequential or simultaneous — and of the method of myocardial revascularization remain debatable.

Situations are still not uncommon in which patients with three-vessel disease of the coronary arteries (with stenoses of more than 75%) are denied surgical treatment of oncopathology. On the other hand, the presence of an oncological disease is frequently a contraindication to operations with cardiopulmonary bypass because of the risk of generalization of the oncological process.

In the American Guidelines on Myocardial Revascularization (2007), in patients with non-cardiac pathology, myocardial revascularization is absolutely indicated in three-vessel disease of the coronary arteries, significant stenoses of the left coronary artery, two-vessel disease with significant stenosis of the proximal third of the anterior descending artery and reduced left ventricular ejection fraction or stress-induced ischemia according to non-invasive tests, as well as at high risk of developing unstable angina [43].

It should be noted that in performing endovascular myocardial revascularization with the use of stents without antiproliferative coating, subsequent surgical treatment of non-cardiac pathology must be performed no earlier than 4 weeks (optimally 3 months) after myocardial revascularization, and in the case of implantation of drug-eluting stents — no earlier than one year for first-generation stents and no earlier than six months for second- and third-generation stents [79]. However, according to the latest data, the minimum duration of dual antiplatelet therapy in patients who received drug-eluting stents may be shorter. In a recently conducted randomized study, outcomes were evaluated in patients with stable angina who were implanted with drug-eluting stents (zotarolimus) followed by a three-month course of dual antiplatelet therapy, compared with patients who received antiplatelet therapy for one year after PCI. No significant differences were obtained in the number of adverse outcomes (including stent thrombosis) between these two groups of patients within one year after percutaneous coronary intervention [41]. In another large study, no connection was found between the type of implanted stent (drug-eluting and bare-metal) and adverse cardiovascular events after the second stage — surgical treatment of concomitant non-cardiac pathology [65]. However, in that study, adverse cardiac events were associated with the need to perform emergency surgery requiring premature discontinuation of antiplatelet therapy, as well as with progression of IHD.

In the European Guidelines (2009, 2014), primary prophylactic revascularization is possible in asymptomatic patients with proven IHD and in patients with stable angina and a high risk of cardiac complications before surgical intervention for concomitant disease (class of recommendation IIb, level of evidence B). However, these guidelines also emphasize that myocardial revascularization, including aortocoronary bypass grafting and angioplasty with stenting, must be performed in accordance with current guidelines on the treatment of stable angina (class of recommendation I, level of evidence B) [79,118].