Atherosclerotic development is a dynamic process which begins early in life, with injury to the endothelium through a variety of interactions and then progresses over time until the vessel lumen is compromised and clinical symptoms are produced. It begins with inactivation of endothelial vasodilation by impairing the production of nitric oxide, the major vasodilator. Endothelial dysfunction is associated with most traditional risk factors: hypercholesterolemia, diabetes, hypertension, cigarette smoking, and especially oxidized low-density lipoprotein (LDL) . The oxidized LDL cholesterol enters the media cell and is taken up by macrophages, forming foam cells. These cells ultimately die leading to the development of a necrotic core in the media. This leads to intimal thickening, fibroatheroma formation with a lesion consisting of a necrotic core with a thin-cap fibroatheroma. This thin-cap fibroatheroma has been called “the vulnerable plaque” as it has a tendency to rupture, leading to acute thrombosis of the vessel [14, 15]. Acute thrombosis can also occur as a result of erosion of the endothelium at the plaque which produces a thrombogenic stress [16]. The rupture of this plaque or the plaque erosion leads to the clinical state of acute coronary syndrome (ACS) which may present as an acute closure of an epicardial artery and subsequent development of ST-segment elevation acute myocardial infarction (STEMI) (type I myocardial infarction) [17] leading to a transmural myocardial infarction [18]. If the resulting thrombus is subtotally occlusive, the ACS can present as a smaller infarction (non-transmural) without elevation of the ST segments: the non-STEMI (NSTEMI) or NSTEMI-ACS [17]. In both events, necrosis of myocardial cells leads to release of cardio-specific proteins and enzymes which constitute cardiac biomarkers such as troponin and CK-MB. Unstable angina is the third manifestation of ACS, and it is also caused by a partial occlusion of the lumen of an epicardial artery, but without myocardial cell death and subsequent elevation in cardiac markers. It has been convincingly opined that as biomarkers become more sensitive, the distinction between NSTEMI-ACS and unstable angina will be lost [19], so in this chapter we will describe ACS as either STEMI or NSTEMI-ACS. ACS is an unstable condition and, if untreated, frequently progresses to a complete occlusion with a transmural infarction.

Chronic stable coronary disease follows different pathway. The plaques can progress into more complicated lesions with fibrosis and calcification, without rupture. There can be hemorrhage into the lipid core which does not expose the necrotic center to the circulating blood, so the lumen may be compromised little by little. ACS does not develop but exercise tolerance or the ability to respond to increased demand is compromised [20]. In situations of extreme demand, such as would occur with surgery, sepsis, hypotension, severe anemia, severe hypertension, and pulmonary embolism with right heart decompensation [17], troponin may be released which defines a NSTEMI type II infarction, a supply/demand imbalance [17]. There can be significant atherosclerosis and lipid accumulation without compromise of the lumen as a result of positive remodeling of the artery where the plaque essentially expands the outer wall of the artery so the lumen may be maintained. This can allow a larger plaque burden to be carried without symptoms [21]. However, these lesions with large plaque burdens may ultimately lead to an ACS infarction at a later date. A goal of therapy, in these cases, is to lower the circulating lipid levels, to permit some stabilization of the plaque interrupting this path to disaster.

A number of chemotherapeutic agents have been associated with ischemic events and myocardial infarction [22, 23]. In addition to 5-FU and capecitabine which cause endothelial injury and vasospasm, a wide variety of other agents have been associated with endothelial injury and vasospasm leading to angina, acute coronary syndrome, and myocardial infarction. Paclitaxel and docetaxel-antimicrotubule agents have been associated with these complications [24]. Cisplatin is associated with endothelial damage, platelet activation, and platelet aggregation [25, 26] and has been reported to provoke coronary spasm causing ischemia [27]. When cisplatin is given with bleomycin or vinblastine , endothelial damage can be severe [28]. The vascular endothelial growth factor signaling pathway inhibitors , sunitinib and sorafenib , are associated with marked increase in cardiovascular events [29]. Tyrosine kinase inhibitors including pazopanib , nilotinib , and ponatinib are also associated with progression of coronary disease. Bevacizumab is associated with an increased risk of ischemic heart disease and events [30]. Other drugs which act using hormonal therapy such as aromatase inhibitors , antiandrogens , and others used to treat prostate cancer are associated with myocardial infarctions and angina [31].

Thus, many of the drugs used to treat cancer are known by one mechanism or another to cause or exacerbate cardiac ischemia or even infarction. It has also been shown that a person can harbor a large atherosclerotic burden without overt symptoms. The stresses of cancer treatment, surgery, drug-induced vasospasm, thrombosis, platelet activation, and endothelial damage can “activate” the coronary disease to cause acute coronary syndrome. Alternatively the demands on the heart during non-cardiac surgery or the development of sepsis may stress the coronary reserve and bring coronary disease to the foreground. The similar demographics of cancer and coronary disease suggests that certainly middle-aged and senior patients could harbor an atherosclerotic burden that could set the stage for an acute coronary syndrome. The likelihood of actively developing the coronary complications of chemotherapy is greater in the presence of coronary disease and the injury can be greater. This makes the case to evaluate the patient’s risk for coronary disease prior to or simultaneous with treating the cancer so that coronary risk reduction can be performed prophylactically . The major modifiable risk factors are abnormal lipids, hypertension, cigarette smoking, and diabetes (Table 8.1) [32].

Standard risk factors such as diabetes, hypertension, hypercholesterolemia, smoking, and obesity need to be addressed in all cases. Smoking cessation, control of diabetes, and control of hypertension all reduce inflammatory stresses on the endothelium and atherosclerotic progression can be controlled in many cases using available risk modification therapy [32–34].

While hypertension and diabetes need to be controlled, the most effective therapy both for primary and secondary prevention of coronary events is with hydroxymethylglutaryl-CoA reductase inhibitors (statins). Statins have been shown to improve survival in patients with high cholesterol and those who have proven coronary disease [35]. The mechanism of this protection is not clear, since improved survival has been shown by 6 months after the start of the treatment, well before any change in lesion size has occurred [35, 36]. The reduction in clinical events was far greater than what one would expect from the limited lesion regression. This suggests that the statins may cause regression of the lipid-rich lesions which are prone to rupture and or that statins impact atherosclerosis through mechanisms not related to anatomic changes [37, 38].

This concept has been carried further in the most recent guidelines for the use of statins in coronary disease [34] where statin use is indicated over a broad range of LDL values in persons with documented coronary disease and those at high risk of developing it.

The risk for coronary disease has been quantified in several models [39]. A model estimating 10-year and lifetime risk for atherosclerotic cardiovascular disease and calculators are available at http://​my.​americanheart.​org/​cvriskcalculator​ and http://​www.​cardiosource.​org/​scienceand-quality/​practice-guidelines-and-quality-standards/​2013-prevention-guideline-tools.​aspx. Coronary calcifications, a marker of coronary disease, may also be seen on staging CT scans in cancer patients (Fig. 8.2).

Because of the results of statin therapy even in patients with cholesterol levels formerly thought to be “normal,” the recent guidelines for the use of statin therapy are based more on anticipated risk than on actual levels of LDL cholesterol [34]. The abandonment of targets of LDL has not been without controversy, but identifying populations at risk where statin therapy has been effective may permit protection to persons at risk for developing manifest coronary disease. In addition to the usual risk factors for the development of coronary disease, as established by population studies, the Framingham risk factors, smoking, diabetes, family history with manifest coronary disease in a first-degree relative at age 55 or below, and hypertension, treatment with statins has been recommended for four cohorts of patients [34]:

Assessment before embarking on a course of potentially stressful oncologic therapy is analogous to assessing the coronary risk in a person undergoing non-cardiac surgery. That person, much like the cancer patient, will be undergoing similar stresses, anemia, hypotension, and the potential for sepsis, but the cancer patient also has the potential addition of thrombocytopenia as a result of therapy as well as a potential prothrombotic state [40]. Because of the need for prolonged double antiplatelet therapy (DAPT) after coronary stenting, or the need for hemostasis with coronary artery surgery in the cancer patient, interventions and treatment options may be limited if there is the development of ACS during cancer treatment. Thus an aggressive approach to minimizing coronary risk factors is rational [41]. The mainstay of this “prophylactic” approach, in addition to smoking cessation and control of blood pressure, is aggressive treatment of hyperlipidemia with a statin.

The statins differ in their metabolic pathways. Simvastatin and atorvastatin both are metabolized by the P450 CPY3A4 pathway [42, 43], so that interactions with other drugs, especially drugs used in cancer therapy, some antibiotics and antifungals, are a potential concern in cancer patients (Table 8.2). On the other hand, pravastatin, rosuvastatin, and pitavastatin are excreted largely unchanged and do not interact with the metabolism of other drugs. For that reason many cardio-oncologists prefer to use rosuvastatin or pravastatin as their statin of first choice to avoid interactions. At this time, however, that does pose some real-world problems. Pravastatin is not as effective in lowering the LDL cholesterol as the other statins, while rosuvastatin [34] is perhaps the most efficient in reducing cholesterol.

Cardiac troponin (cTN) plays a central role in assessing myocardial injury and, especially, the management of coronary artery disease [48]. The cardiac troponin complex has been used for over 15 years as the definitive marker of myocardial necrosis. The troponin complex, consisting of three subunits is located on the actin (thin) filament of striated muscle. Troponin C, the subunit that actually binds calcium is the same in striated and cardiac muscle, but the subunits troponin I which modulates the binding of actin and myosin and troponin T which binds the troponin complex to tropomyosin to complete the actin myosin linkage, have different isoforms in cardiac and skeletal muscle and so are better markers isolating cardiac injury/infarction [49].

Troponin is released when there is myocardial injury or infarction. A number of clinical situations can lead to cardiac injury reflected in low-level elevations in cTN in the absence of coronary disease. These have been enumerated [17, 50] and reflect supply/demand imbalance or underlying myocardial disease. For the patient with cancer, the common scenarios leading to elevated troponin, which may not reflect coronary disease, include atrial tachyarrhythmia, sepsis or septic shock, severe anemia, severe respiratory failure, severe hypertension, coronary spasm, stress cardiomyopathy (takotsubo), or significant pulmonary embolism , among others [17]. Of course, underlying chronic coronary disease, which may not cause symptoms, may lower the threshold for myocardial injury in such situations. Before assuming the limited troponin elevation is due to demand, however, severe underlying coronary disease must be considered. A history of angina, electrocardiographic evidence of infarction, or segmental hypokinesia on an echocardiogram would be clues to a serious underlying coronary stenosis, which may require further evaluation, before dismissing it as the result of increased demand.

Before addressing the specific problems posed by the patients with cancer, it is useful to discuss management of patients with coronary disease in general.

Chronic stable angina in most cases can be handled by reducing demand with beta-blockers; reducing progression of atheroma with aggressive statin administration, control of blood pressure, and excellent management of diabetes; improving cardiac metabolism with ranolazine [51–53]; enhancing coronary vasodilation with nitrates and calcium channel blockers; and reducing thrombogenicity and platelet inhibition with smoking cessation and aspirin in most cases [32, 54–57]. The decision to perform revascularization in patients with chronic stable coronary disease has been a major area of research almost from the development of revascularization procedures [58]. Several studies have shown that in stable patients, in the absence of certain anatomic lesions, such as left main obstruction or large areas of jeopardized myocardium, if symptoms can be controlled medically, there is no survival advantage to revascularization [55, 58–64]. If the symptoms cannot be controlled medically, then revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) is beneficial. The BARI-2D [56] and COURAGE trials compared intervention to medical therapy [65] in patients with stable coronary artery disease. Only 40 % of patients randomized to medical therapy in each trial ultimately required revascularization, primarily to control symptoms which could not be controlled with medical therapy alone [61]. This has been confirmed in other studies [32].

In contrast, acute coronary syndrome requires immediate action [66]. For the acutely occluded artery presenting as a myocardial infarction with ST-segment elevation (STEMI) on the electrocardiogram, success in salvaging myocardium is measured in minutes from the time of occlusion (severe symptoms) until some flow is restored. PCI is the treatment of choice if technically feasible, since surgery in these situations will take longer to institute and results are not necessarily better. In situations with severe multivessel disease, the infarct artery is opened, and then treatment of the other lesions is individualized, with acute multivessel interventions or a staged PCI. If PCI is not technically feasible, then CABG at a later date can complete the revascularization.

In patients presenting with an acute infarction without ST-segment elevation NSTEMI-ACS or “unstable angina,” the situation is quite unpredictable, usually a lesion has been unroofed, and a thrombus is forming at the site, which is not yet totally occlusive but certainly has a high likelihood of progressing in a short time [67, 68]. This situation also requires prompt evaluation and treatment. The presence of elevated troponin or ECG changes with symptoms or continuing or recurrent pain identifies patients at high risk [69]. Delay beyond 24 h in high-risk patients is associated with increased 30-day mortality (Table 8.3) [71]. Almost all patients who have suitable anatomy and acceptable procedural risk are revascularized [50]. Medical therapy is usually not adequate to control the situation in the long term, but anticoagulation and platelet inhibition can usually cool the process down. The decision as to type of definitive therapy can only be made after the coronary anatomy is visualized and is made on an individual basis. An experienced interventionalist can stent most complex anatomies, left main, ostial or proximal LAD, or ostial circumflex lesions or bifurcation lesions, but certain situations are best treated, ideally, with coronary artery bypass graft surgery (CABG) . In a substudy by Holvang of the FRISC study of dalteparin in patients with NSTEMI-ACS [49], patients with more ST depression were more likely to undergo bypass surgery because of a higher prevalence of two- and three-vessel disease or left main disease. The choice of therapy requires consideration of the type of cancer, the expected effect of cancer therapy especially on platelets, and the need for cancer surgery in the near future so that in this situation, active consultation with the oncologist is essential.

Percutaneous coronary intervention (PCI) has been evolving since its introduction by Andreas Gruentzig in 1977 [72, 73]. The initial problems of consistency, stability in the acute setting, and restenosis have been minimized if not solved, and many devices are available to conquer difficult problems such as plaque burden in grafts (filters), thrombotic burden in acute infarction, and heavily calcified lesions (rotational [ 74 ] or orbital athrectomy) [75]. The introduction of coronary stents in 1985 by Sigwart et al. [76] revolutionized PCI [77], essentially eliminating the need for standby cardiac surgery. Although stents presented many serious problems, most notably thrombosis of the stent and restenosis of the lesion, these problems have been reduced so that the incidence of these complications is low. The problem of immediate and late stent thrombosis has been minimized by emphasis on perfect stent positioning and sizing, out to the medial elastic lamina of the vessel and avoiding stent edge dissections aided by routine use of intravascular ultrasound [78, 79]. In cancer patients where there is a possibility of premature termination of DAPT because of a need for additional cancer surgery or severe thrombocytopenia, perfect stent positioning using ultrasound is essential [41]. The recognition of the role of the platelet in thrombosis and the development of effective antiplatelet agents has minimized the occurrence of stent thrombosis [80–82]. Drug-eluting stents (DESs) using an anti-inflammatory agent bonded to the stent were introduced to reduce the occurrence of restenosis, but these early versions of the drug-eluting stents were susceptible to late thrombosis [83] from hypersensitivity to the polymer [84] or delayed healing or endothelialization [83, 84]. Current stents have been redesigned to limit that problem and have reduced [83] the thrombogenicity, but concern remains [85–87]. A recent study by Valgimigli (ZEUS) [88] and reviewed by Kandzari [89] compared the performance of Endeavor zotarolimus-eluting stent (ZES) , designed to improve the rate of endothelialization, with that of bare-metal stents (BMS) in patients thought to be at risk for noncompliance with double antiplatelet therapy (DAPT) -aspirin plus a thienopyridine. In this study, by 30 days 43.6 % of patients had discontinued DAPT (aspirin + a thienopyridine ) and by 60 days 62.5 % had done so. The rates of death, myocardial infarction, and stent thrombosis were all lower than the BMS, and the rate of 1-year target vessel revascularization was lower (10.7 % vs 5.9 %) with the ZES.

The original recommendation for duration of DAPT had been to continue the DAPT for 1 year, but the question as to the (minimal) optimal duration with DAPT remains open [90]. Several studies have been reported, and others are in progress to determine if a 6-month DAPT treatment plan would be adequate [91, 92]. Gilard et al. evaluated patients who obtained a Xience V everolimus-eluting stent and who demonstrated responsiveness to aspirin and found non-inferiority in a study, comparing 6 and 12 months of DAPT [93]. On the other hand, Yeh et al. in a review found a lower risk of stent thrombosis and infarction (although a doubling of the risk of bleeding) in patients remaining on DAPT for 30 months [92]. There are no studies comparing optimal duration of DAPT in patients with cancer, so recommendations need to be extrapolated from the available data in patients without cancer, a process that is not necessarily justified [94].

Prasugrel and ticagrelor have since been approved for preventing stent thrombosis. Studies have shown improved results over clopidogrel for stent thrombosis but at a higher risk of bleeding, especially intracranial hemorrhage [95–97]. Patients with cancer were not studied, and there is no experience with these drugs in patients who are thrombocytopenic—for obvious reasons.

Non-cardiac surgery after an artery is stented carries a high risk of stent thrombosis, especially until the stent is incorporated into the vessel wall. This was first reported following surgery within 2 weeks of stenting with BMS with four deaths in patients operated within 1 day of the stenting [98]. The evaluation of the risks following DES placement was based on the first-generation DES which is known to have a higher risk of stent thrombosis than the subsequent generations of stents. Surgery has traditionally been delayed 1 year for elective procedures with semi-elective procedures put off for 6 months [32]. The risk of major adverse cardiac events (MACE) in the experience of the Erasmus Medical Center was reported, and a very high risk of complications was found with both DES and BMS within 30 days, with the complication rate dropping off with delays up to a year [99]. The rate of MACE during non-cardiac surgery for the intervals of <30 days, 30 days to 3 months, and >3 months was 50 %, 14 %, and 4 % in patients getting BMS and for patients getting DES was 35 %, 13 %, 15 %, 6 %, and 9 % for patients undergoing non-cardiac surgery <30 days, 30 days to 3 months, 3–6 months, 6–12 months, and > 12 months, respectively (Table 8.4). This is consistent with other reports [100–108].

Recent guidelines for performing non-cardiac surgery in patients after PCI show a conservative recommendation delaying all elective surgery for 1 year after a drug-eluting stent and 4–12 weeks after a BMS stent [106, 109, 110]. The European guideline permits surgery after a new-generation DES after 6 months [106], but the US guideline recommends delaying elective surgery 1 year for all DESs [111]. The ACC/AHA guidelines do permit surgery after 6 months if the risks of waiting outweigh the risk of the surgery. The recent data on the everolimus-eluting stents, the Endeavor or the Xience V, have not yet been incorporated into these guidelines, but the data are only on spontaneous MACE, not on the MACE following non-cardiac surgery. The prothrombotic state of both surgery and cancer [40] could be expected to increase the occurrence of MACE in the perioperative period.

A careful analysis of the relative advantages of coronary bypass surgery and PCI has been presented in the European Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease [32, 54] and the American counterpart [54]. The decision as to whether PCI with a drug-eluting stent is the superior treatment when compared with CABG even in patients without cancer is somewhat limited by the paucity of randomized clinical trials [112]. However, it seems reasonable to conclude from SYNTAX which quantified the complexity of the coronary anatomy that outcomes of patients undergoing PCI or CABG in those with relatively uncomplicated and lesser degrees of CAD are comparable, whereas in those with complex and diffuse CAD, CABG appears to be preferable [54]. Most studies have shown that patients with diabetes with three-vessel disease do better in the long run with CABG than with PCI [113]. The long-term results are in part dependent on the complexity of the lesion as well as other factors such as impaired renal function which will be taxed if repeated procedures are required, which is often the case with PCI (Table 8.5).

The circumstance of a cancer patient diagnosed with CAD during active cancer therapy carries a different risk/benefit ratio, and the algorithms that guide ACS management may not apply in the setting of ongoing cancer management. Decision-making needs to consider multiple priorities, both related to the acuity/severity of the cardiac condition, as well as the stage, treatment plan, and goals of care for the cancer. This requires active communication between the oncologist and the cardiologist, The severity and acuity of the coronary disease, the severity and stage of the cancer, the renal function which may be damaged with repeated PCI procedures, the anticipated long-term toxicity of the cancer therapy, the likelihood of developing severe thrombocytopenia on treatment, and the need for cancer surgery within 6 months of the cardiac event all need to be considered by both the oncologist and cardiologist to optimize the overall treatment of the patient. In a patient actively receiving cancer therapy, the primary indication for urgent revascularization is acute coronary syndrome (ACS) , where the risks of inaction are high. Additionally, revascularization could be considered in a patient with chronic stable coronary disease where complex cancer surgery is urgently needed and it is felt that the patient would be unable to tolerate the procedure unless some revascularization was done in advance (usually limited to severe left main disease or very proximal anterior descending involving the left main) (Fig. 8.3).

PCI poses several specific problems to the cancer patient but has several important positive aspects. The advantage for PCI is that the procedure is well tolerated and recovery is fast. Frailty and the physical stress of recovery as well as delaying chemotherapy (if thrombocytopenia is not an issue) are not a concern.

However:

In hematological malignancies , after bone marrow transplant, or as a side effect of gemcitabine , carboplatin , TDM-1 (ado-trastuzumab emtansine), nucleoside inhibitors and others or multi-agent chemotherapy, thrombocytopenia can be severe. The need for DAPT after the stent is placed is a great concern in these patients, although actual data are sparse, but surprisingly encouraging [41, 117]. The development of newer DESs that may not require a year of DAPT [88] has the potential to reduce the risk of this therapy in the future. The limited experience reported suggests that DES may be used, and perhaps ZES, but a prospective study or registry is needed to state this with confidence.

Coronary artery bypass surgery is the alternative method of revascularization. If the therapy for the cancer is expected to lead to severe thrombocytopenia or if non-cardiac surgery is planned in the near future, CABG may be considered as alternative since it poses less of a problem than placing a DES with the need for DAPT, regardless of severe thrombocytopenia. If the patient will require major surgery to remove a cancer, it may be possible to perform both the CABG and the cancer surgery at the same “sitting” or as a two-stage procedure to minimize the delay in the cancer surgery [118, 119]. Frailty adds to CABG risk and may be present in cancer patients [120–123].

The cardiologist needs to understand goals of cancer therapy. A sizeable proportion of patients with cancer are treated with curative intent with primary surgery and preoperative or postoperative chemotherapy (generally for fixed duration of 3–6 months). It is important for these patients to receive timely cancer therapy, so interventions for CAD should be chosen to minimize delay or interference with cancer therapy. Definitive treatments like CABG may be delayed till after completion of cancer therapy. Other patients with cancer (typically metastatic cancer or stage IV disease) are seldom cured with anticancer therapy. The patient’s non-cardiac prognosis must be a part of the decision-making for selecting the appropriate cardiac intervention, and “the objectives for such patients may be limited to symptom relief and improved quality of life, obtained with the minimum of early hazard and with the shortest duration of functional recovery” [124].

Patients with chronic stable angina usually can be managed in the short run without revascularization. Consider these outcomes of PCI:

Since the major indication for most patients is a relief of symptoms, there is no imperative to “protect” the patient from cardiac events by performing revascularization. Thus in patients with chronic stable angina or underlying silent ischemia, aggressive medical therapy with the aim of avoiding PCI or surgery during ongoing chemotherapy should be considered until the cancer is stable.

The situation with ACS is quite different. STEMI is a true emergency. The prognosis of a patient with an occluded infarct-related artery is orders of magnitude worse than the prognosis of a patient whose artery is opened promptly and myocardium is protected or salvaged. Myocardium is infarcting and the only way to prevent that or to minimize it is to open the infarct-related artery as promptly as possible. In the case of the active cancer or chemotherapy, this means to develop a technique that permits operating in the setting of possible neutropenia and/or thrombocytopenia.

PCI requires placing a catheter in an artery to access the central circulation, passing the catheter to the ostia of the two coronary arteries, and usually inserting a stent in the “culprit” artery to prevent immediate vessel closure and long-term restenosis. Anticoagulation of the patient with a thrombin inhibitor, usually heparin, is routinely performed to avoid thrombosis in the radial or coronary artery during the procedure.

There are essentially two techniques for access: the femoral artery approach and the radial artery approach . The brachial artery was the original access site, entered with a cut down and suturing the vessel after completion of the procedure, but the simplicity and speed of the percutaneous technique aided by the development of smaller equipment has essentially made the brachial cutdown approach obsolete. Percutaneous brachial access , especially in a thrombocytopenic patient, includes a high risk of brachial hemorrhage with the potential for a compartment syndrome entrapping the median nerve. In thrombocytopenic patients where femoral or radial access is not feasible, brachial artery access utilizing direct entry with direct suture after the procedure remains an option.

With either the femoral or radial approach, care must be taken to avoid uncontrollable bleeding. Although the radial approach takes advantage of the very superficial artery, which simplifies hemostasis after the procedure, there are certain pitfalls that can negate that advantage. The radial approach is a bit more technically challenging so it should not be attempted in thrombocytopenic persons by inexperienced operators. Anatomical variations can lead to failure in 3–7 % of procedures [125], and technical difficulties, mostly with the guide wire, have led to severe bleeding in the arm leading to a compartment syndrome and mediastinal hemorrhage when the right internal thoracic (mammary) artery was entered instead of the ascending aorta and perforated with the wire [126]. Occasionally severe spasm can develop, especially when the radial recurrent artery is inadvertently entered, but hemostasis after the procedure is simpler and more definite using wristband pressure devices.

The femoral approach suffers from the potential to enter the external iliac artery in the retroperitoneum if the entry is too proximal, with the result that hemostasis after the procedure (when the patient is on heparin and antiplatelet agents ) is not possible, and thrombosis must be depended upon for hemostasis after the procedure [127]. Entry into the common femoral artery can be assured by entering the artery over the lower half of the femoral head. This approach can be made safer using a “micropuncture set” to establish the safety of the entry prior to enlarging the entry or ultrasound guidance [41, 128]. Closure devices have been devised to plug the hole or suture it, but these devices not infrequently fail, or if arterial entry is in a branch, the closure device cannot be used so that a femoral approach under the best of circumstances carries a risk of uncontrolled bleeding after the procedure [41]. In an obese individual, this becomes more of an issue since pressure on the entry site is not assured and considerable bleeding can be hidden in the obese thigh. In addition, in an immunocompromised thrombocytopenic person, there is concern that the collagen plug of the puncture site can get infected.

Sarkiss et al. showed the importance of aspirin treatment even in patients who were thrombocytopenic [129]. In a group of 27 patients with ACS and with cancer and platelets <100,000 (mean of 32,000), after 7 days, only 6 % were alive if they had not been given aspirin, and 90 % were living at 7 days if they were. There is also experience using double platelet therapy (DAPT) usually with clopidogrel in patients with thrombocytopenia, with good outcomes [41].

Paradoxically, the safest management strategy is to perform a catheterization and then intervene on the culprit artery if possible. Iliescu describes his experience in the first 50 of his over 200 patients with cancer and thrombocytopenia [117, 130]. The results were excellent and several patients were treated with DAPT for many months with platelet counts less than 25,000. Patients whose thrombocytopenia was due to sepsis, active bleeding, or disseminated intravascular coagulopathy (DIC) were not candidates for the invasive strategy. Most of the patients were thrombocytopenic as a result of their cancer or its treatment. Patients with myeloid dysplastic syndromes (MDS) or leukemias , bone marrow transplant patients, or patients undergoing chemotherapy, most commonly with taxanes or gemcitabine, constituted the majority of patients, and 94 % of patients he intervened on had ACS. All patients were studied using the radial approach. Glycoprotein (GP) IIb/IIIa platelet receptor inhibitors were not used. There are other considerations in these patients which are yet to be tested. What is the role of the newer-generation drug-eluting stents vs the bare-metal stents? The first-generation DES was known to be thrombogenic, and the vascular endothelium covering was delayed often for 1 year or more. Newer stents have been devised to solve that problem with more rapid elution of the drug to avoid delays in endothelialization, metal scaffolds causing less inflammation, and more flexible to distort the artery less. This has raised the question with at least the Endeavor stent that this stent, which was not as efficient in preventing restenosis as other DESs, might be able to compete favorably with a bare-metal stent in terms of thrombogenicity with a limited period of DAPT [88, 89].

The process of stenting itself needs to be optimal. Early in the experience with stents, when there was great concern about thrombosis with the first bare-metal stents, Colombo et al. [79] showed that with careful stent placement using ultrasound to insure optimal interaction with the vessel wall and overstenting edge dissections, they were able to do almost as well with aspirin alone as using DAPT to prevent stent thrombosis. That principle still applies, and it may be critical in this setting, since it may be necessary to prematurely reduce the antiplatelet therapy if the thrombocytopenia becomes extreme [41]. Strut malposition remained important in late stent thrombosis with the first-generation stents [131]. Other questions remain, especially with complex stenting, bifurcation lesions, etc. In the study by Nakazawa et al., stent placement “off label” (bifurcation complex lesions) was associated with poor coverage of the stent by the endothelium [114]. A number of techniques have been devised to simplify the approach to bifurcation lesions, and it is unproven but logical to use the simplest approach possible, minimizing stenting both branches if possible, using a technique of stenting the side branch only if the stenosis remained severe (provisional stenting using the “jailed” wire technique) [132].

Coronary insufficiency can also be treated with coronary artery bypass surgery. Coronary bypass often improves the completeness of the revascularization. Studies comparing PCI and bypass often show that while the survival may be similar in most cases, the percutaneous route ends up with more repeat procedures [133]. However, there may be an increased risk of strokes, and the morbidity is greater with CABG. Importantly for cancer patients, recovery is a problem for a frail person who is dealing with an aggressive cancer. On the other hand, if there is a concern about needing major surgery soon after revascularization, coronary bypass may be safer [134], since even after 6 months there still is concern for stent thrombosis even with continuation of the DAPT [108, 135]. This risk of stent thrombosis needs to be balanced against the morbidity of the CABG surgery. Hawn et al. in a large VA study found a rate of 11.6 % MACE for people operated within 6 weeks of a stent, falling to 6.4 % for operations up to 6 months, 4.2 % if operated within 6–12 months, and 3.5 % after 12 months whether or not DAPT was maintained [136].

A common role for the cardiologist is “clearing” a patient for major non-cardiac cancer surgery. Recent guidelines from the European Society of Cardiology and the European Society of Anesthesiology [106, 109] have emphasized evaluation in three domains: functional evaluation of the patient, characterization of the patient’s risk for coronary disease, and the risk of the surgery itself.

The risk of the surgery itself has been characterized as low, intermediate, and high (Table 8.6). Patients are evaluated by functional capacity and are at low risk if they are able to walk 100 m at 3–6 km/h or climb two flights of stairs, the number of cardiac risk factors based on the Revised Cardiac Risk Index (history of ischemic heart disease, history of congestive heart failure, history of cerebrovascular disease, preoperative treatment with insulin, and preoperative serum creatinine >2.0 mg/dL), and the risk of the surgery [137]. The preoperative risk of perioperative cardiac arrest or infarction can also be calculated using an interactive risk calculator based on the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database (http://​www.​surgicalriskcalc​ulator.​com/​miorcardiacarres​t). The five predictors of perioperative myocardial infarction or cardiac arrest using the NSQIP database were type of surgery, dependent functional status, abnormal creatinine, American Society of Anesthesiologists’ class, and increasing age.

Preoperative ECG is recommended only for patients with more than one clinical risk factors and if over age 65. Stress testing can be considered in patients with excellent or good functional status undergoing high-risk surgery if they have risk factors for coronary disease; otherwise it is discouraged. There is a stronger recommendation for stress testing with imaging in patients with poor functional capacity with three or more risk factors undergoing high-risk surgery.

Preoperative coronary revascularization is rarely indicated since there is no convincing evidence that preoperative revascularization is beneficial in the stable patient [138]. Studies have not shown reduction of complications after presurgical revascularization with the non-cardiac surgery, but there may be some long-term benefit. This decision must be individualized bringing together the risk of the surgery and the likelihood of severe coronary disease [111].

There are three classes of medication which deserve special mention: