Cardiovascular disease (CVD) and neoplasms are the first and second leading causes of death, respectively, worldwide.1 However, the downward trend seen in CVD incidence and mortality in recent decades has not been observed in neoplasms, which have exhibited an increase in incidence and no relevant reductions in mortality in most cases.2 In Europe alone, in 2012 there were more than 3.5 million cases of de novo cancer and nearly 2 million deaths due to these diseases.3 National estimates forecast a rise of more than 30% in the incidence of cancer in Spain compared with past decades, mainly due to an aging population and changes in risk factors.4

In recent years, there is stronger interest in the incidence and mortality of CVD in patients treated for neoplasms, as up to 30% of deaths among cancer patients may have a cardiovascular cause.5 Furthermore, the progressive drop in mortality among patients with acute coronary syndrome (ACS) or stable chronic ischemic heart disease has also increased long-term survival in these patients, who are at greater risk of de novo tumors or recurrence of previous diseases, thus posing a major challenge for clinical care and affecting the prognosis of these patients.

Because cancer and atherosclerosis share risk factors, concomitant ischemic heart disease and neoplasms in the same person are not rare, and 4% to 10% of patients with ACS or chronic ischemic heart disease have a history of cancer.6,7 The RECALCAR (REcursos y CALidad en CARdiología [Resources and Quality in Cardiology] registry describes a prevalence of 2.77% for malignant tumors in patients hospitalized for ACS, associated with higher in-hospital mortality (odds ratio=2.26; 95% confidence interval [95%CI], 1.99-2.55).6 A prospective study of all patients hospitalized for ACS in a single Spanish center between 2009 and 2016 observed that neoplasms were present at admission in 3.4% (95%CI, 2.7-4.4) of these patients and that the most common sites were the colon, bladder, lung, and prostate.8 The median time between neoplasm diagnosis and ACS was 5.5 years, and most patients had undergone cancer-specific surgery (74.2%) or chemotherapy (46.8%). Only 41.9% of patients were considered disease-free when hospitalized for ACS, which had major implications for in-hospital treatment and long-term prognosis.

Age, sedentary lifestyle, smoking, and a fat- and carbohydrate-rich diet are established risk factors for CVD, but also for neoplasms.9 The latest data from REDECAN (Red Española de Registros de Cáncer [Spanish Network of Cancer Registries]) in Spain show that the most common cancers are prostate, colon, lung, and bladder neoplasms in men and breast, colon, uterus, and lung in women,10 consistent with large registries in Europe3 and the United States.2 Smoking is the risk factor most strongly associated with ischemic heart disease and neoplasms and, in fact, is considered the leading cause of avoidable mortality due to its impact on the first 2 causes of death worldwide.11 An analysis of the Spanish health survey of 2011 to 2012 and the vital statistics of the National Institute of Statistics showed that the total prevalence of smoking in Spain in 2012 was 23.6%, and it was estimated that 125 men and 40 women died each day due to causes attributable to tobacco use, accounting for over 60 000 deaths in 1 year.12 The main causes of smoking-related death were tracheal, bronchial, and lung cancer in men and heart disease in women. Smoking is also a major risk factor in the incidence of ACS, particularly in young people.12 Because mortality among young patients with ACS is very low, most patients survive for a considerably long period and are susceptible to cancers over time. In fact, recent data show that patients who were smokers or exsmokers at the time of ACS have a 3-fold risk of neoplasm after ACS.

Diabetes mellitus is one of the cardiovascular risk factors that most increases the risk of death due to ischemic heart disease. Extensive follow-up of more than 400 000 people with diabetes in Sweden, compared with more than 2 million controls, showed that patients with diabetes had higher mortality due to CVD, but also due to cancer.13 Furthermore, that study showed that metabolic control of diabetes, assessed by blood glucose and glycohemoglobin concentration, was clearly associated with cardiovascular and noncardiovascular mortality, and revealed that hyperglycemia played a key role in activating other pathophysiologic pathways. The stronger presence of cardiovascular risk factors also produced a linear increase in serum inflammation markers, such as C-reactive protein, shown to be an independent marker of the risk of ischemic heart disease incidence and mortality.14 Of these, diabetes mellitus by itself has the highest levels of C-reactive protein and is also the risk factor most strongly associated with ischemic heart disease.14 Although the etiology of cancer varies considerably, the underlying pathophysiology for almost neoplasms is a chronic inflammatory condition and a lack of resolution of proinflammatory stimuli that alter the immune system; this phenomenon is very similar to macrophage activation in the artery wall due to low-density-lipoprotein accumulation.15 Therefore, chronic activation of the immune system and the inflammatory state underlie the pathophysiology of both atherosclerosis and neoplasms, which would explain many of the CANTOS16 findings. That study showed that canakinumab, a monoclonal antibody that blocks the action of interleukin 1ß, found in the pathway where interleukin 6 and C-reactive protein act, reduced the incidence of major cardiovascular complications and cancer in persons with a history of acute myocardial infarction (AMI) and elevated C-reactive protein (> 2mg/L).16 The decrease in the incidence of the primary endpoint (AMI, stroke, or cardiovascular death) was related to the canakinumab dose received, which was also very closely associated with decreases in C-reactive protein and interleukin 6. A subsequent subanalysis showed that the incidence of lung cancer and cancer death was noticeably lower in patients who received canakinumab than in those who received placebo, and that this reduction was dose-dependent.17 Because canakinumab did not affect serum glucose or lipid concentration,18 nor did it have any direct impact on oncogenesis, it appears to be clearly proven that inflammation plays a critical role in both atherosclerosis and the appearance of neoplasms.

Apart from inflammation, which also seems be a possible target for common treatment, atherothrombotic disease and neoplasms share many pathophysiologic pathways (Figure 1). Cell proliferation and apoptosis are 2 of the key mechanisms of tissue homeostasis. A change in homeostatic balance often leads to neoplasms, while also being related to the development and destabilization of coronary atheromatous plaques.19 Another of the characteristic mechanisms of neoplasms is neoangiogenesis, which has also been linked to their capacity for local and remote invasion because cell proliferation requires oxygen and nutrients. Similarly, the formation of neovessels, known as vasa vasorum, inside the plaque creates one of the main entry points for lipoproteins, erythrocytes, and inflammatory cells in plaques. The role of these neovessels is 2-fold, as they can be a recovery mechanism when lipoprotein concentrations drop due to intensive lipid-lowering treatment; however, it has also been reported that a large part of these neovessels are highly dysfunctional, promote particle passage to the plaque, and produce destabilization.19 Another common major pathophysiologic mechanism between cancer and atherosclerosis consists of RNA microparticles, which are noncoding fragments of messenger RNA that regulate the posttranscriptional expression of genes. These microparticles are released as a cellular response to any aggression and have been clearly related to oxidative stress and inflammation; hence, it is not surprising that various molecules related to both atherosclerosis and various neoplasms have been identified.20

Figure 1.

Common risk factors for cancer and atherosclerosis. DNA, deoxyribonucleic acid; RNA, ribonucleic acid.

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Ongoing advances in the treatment of neoplastic processes have significantly increased the survival of cancer patients and, consequently, have affected the appearance of high rates of comorbidities and medical complications associated with or favored by cancer. This means that CVD is one of the main causes of morbidity and mortality in patients with malignant neoplasms (Figure 2). For instance, women with an early diagnosis of breast cancer are more likely to die from CVD than from the cancer itself.21

Figure 2.

Simplified diagram of the spectrum of cardiovascular conditions secondary to cancer and its treatments (radiotherapy and chemotherapy). AMI, acute myocardial infarction; DVT, deep vein thrombosis; PT, pulmonary thromboembolism.

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Compared with patients not diagnosed with cancer, adults who experience a neoplastic process have a significant increase in CVD risk. A recent study has shown that patients newly diagnosed with cancer had an almost 3-fold risk (hazard ratio [HR]=2.9; 95%CI, 2.8-3.1) for AMI compared with that of the control population,22 and that the increase in risk was proportional to cancer stage (significantly higher in patients with greater tumor burden or disease spread). That study specifically covered the period in which this excess cardiovascular risk is higher (limited to the first year after the cancer diagnosis), which may be particularly relevant when considering possible primary prevention strategies, such as antithrombotic therapy or statins, in these stages.

Although cancer can cause atherosclerosis through different mechanisms, the most common are sequelae of antitumor drugs and radiotherapy (RT). However, many patients with cancer and CVD have a common substrate—apart from RT and chemotherapy—that links the 2 conditions. For instance, patients with cancer are often found to have metabolic and vascular abnormalities, among them, abdominal obesity, altered glucose metabolism, lipoprotein abnormalities, and hypertension.23

Before discussing the increased cardiovascular risk associated with RT and chemotherapy, it is interesting to mention the cardiovascular risk of patients with hematologic neoplasms who have undergone hematopoietic cell transplantation, mainly due to graft-versus-host disease (endothelial lesion), increase in cardiovascular risk factors due to immunosuppressive treatment (accelerated atherosclerosis), and sedentary lifestyle (proatherosclerotic habits). A study by Chow et al.24 in more than 1000 patients who had received hematopoietic cell transplantation found that the risk of a coronary event was more than 3-fold that of the control group, consistent with previous studies reporting that up to 1 of every 5 patients who had received allogenic hematopoietic transplantation had been diagnosed with CVD within 20 years, an onset of ischemic heart disease about 10 to 15 years earlier than in the control population.

Chemotherapy and atherosclerotic disease

A number of chemotherapy drugs have been associated with an increased incidence of atherosclerotic CVD (Table 1), although the cumulative incidence of ischemic heart disease is usually fewer than 5 cases per 100 patients a year in those treated with chemotherapy.30 Most notably, the chemotherapy drugs with the highest atherosclerotic risk are the antimetabolites, antimicrotubule agents, and tyrosine kinase inhibitors. In addition, in the case of fluorouracil, the vasospasm rate is around 40% to 70% of patients, in the various series, and the event occurred within a few hours or days of treatment.31 This drug should not be administered over more than 3 hours or in combination with cisplatin. Tyrosine kinase inhibitors, particularly nilotinib, have been associated with accelerated arteriosclerosis, particularly of peripheral manifestation, reported in approximately 10% to 25% of patients,32 a risk not extrapolated to imatinib. A higher risk of arterial thrombosis has also been reported.

Table 1.

Chemotherapy agents associated with cardiovascular diseases

Drug	Angina	AMI	Tako-tsubo	Raynaud	Stroke	Peripheral artery disease
Antimetabolites
5-fluorouracil	X	X	X	X
Capecitabine	X	X	X	X
Gemcitabine	X	X		X
Paclitaxel	X	X
Alkylating agents
Cisplatin	X	X		X	X	X
Cyclophosphamide	X
Bleomycin	X	X		X	X
Vincristine	X	X		X
mTOR inhibitors
Everolimus	X
Temsirolimus	X
Proteasome inhibitors
Bortezomib		X			X
Carfilzomib		X
Combretastatin	X	X	X
Monoclonal antibodies
Bevacizumab	X	X	X		X
Ramucirumab	X	X			X
Rituximab	X	X	X
Aflibercept		X			X
Tyrosine kinase inhibitors
Sorafenib/pazopanib/axitinib	X	X			X
Sunitinib	X	X	X		X
Regorafenib	X	X
Cabozantinib/lenvatinib		X			X
Vandetanib					X
Nilotinib	X	X			X	X
Ponatinib	X	X			X	X
Interferon alpha	X	X		X	X	X

AMI, acute myocardial infarction; mTOR, mammalian target of rapamycin.

There are no firm recommendations on the need to perform regular screening tests for subclinical atherosclerosis in these patients, although several scientific societies have issued consensus documents4,31,33 (Figure 3). Patients who have received chest RT, chemotherapy with high-risk drugs, or hematopoietic cell transplants should be considered at high cardiovascular risk. These patients should be advised to maintain healthy lifestyle habits and strict risk factor control, but there are no guidelines on the prophylactic use of antiplatelet agents. For patients with angina, the recommendation is to optimize antianginal therapy and to monitor triggers, such as anemia. In the case of persistent symptoms, patients should undergo ischemia diagnostic tests, and possibly revascularization to allow therapy to be tolerated, assessing the risks and benefits. The protocols for ACS are similar to those for noncancer patients, with an individualized approach taken to revascularization and antithrombotic regimens. However, patients with cancer and a history of AMI are often treated without adhering to the current scientific recommendations, which sometimes leads to a worse prognosis in terms of mortality.34 According to Mayo Clinic35 data, up to 1 of every 10 patients with AMI had a history of cancer, and these patients have higher noncardiovascular mortality rates, with no differences in short- and long-term cardiac mortality rates when they are treated according to the recommendations of clinical practice guidelines. It is important to consider that patients with cancer and an ACS have an increased risk of hemorrhagic events,36 whether in-hospital or during follow-up, making it essential for these patients to achieve a careful balance between ischemic risk and hemorrhagic risk when optimizing antiplatelet medication.37

Figure 3.

Algorithm for assessment of atherosclerotic and thrombotic risks in patients with cancer. ABI, ankle-brachial index; AMI, acute myocardial infarction; CT, computed tomography; CVRF, cardiovascular risk factors; DLP, dyslipidemia; DM, diabetes mellitus; ECG, electrocardiogram; HTN, hypertension; MRA, magnetic resonance angiography; PT, pulmonary thromboembolism; RT, radiotherapy.

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The incidence of neoplasms in patients with ACS has been insufficiently studied in contemporary series, despite abundant evidence to support a common pathophysiology. A recent cohort study with ACS patients showed that the incidence of neoplasms was 3.1% (95%CI, 2.4-4.0) during a mean follow-up of 33 months, and the most common sites were colon, lung, bladder, and pancreas.8 The median time to the appearance of new neoplasms was 25.0 [interquartile range, 12.0-56.0] months, and the factors associated with the appearance of cancer were age (HR=1.03; 95%CI, 1.01-1.06; P=.01) and smoking or history of smoking (HR=2.68; 95%CI, 1.11-6.49; P=.03).8 That study reported that patients who developed any type of neoplasm during follow-up had the highest mortality during this follow-up period (64.2%), followed by patients with neoplasms already known at the time of ACS (40.0%); additionally, more than half the deaths were directly attributed to neoplasms. However, higher cardiovascular mortality was not seen in patients with incident neoplasms, but was observed in patients with neoplasms present in ACS, a finding attributed by the authors to less aggressive ACS treatment, such as reduced use of drug-eluting stents or complete revascularization. These data show that patients with ACS who have or develop neoplasms have a worse and clearly different prognosis, revealing the need for very specific follow-up and treatment for these patients.

Several prospective and multicenter studies have found that the long-term mortality of patients with ACS or chronic ischemic heart disease is higher for noncardiovascular causes than cardiovascular causes8,34; however, the impact of neoplasms has been specifically investigated in only a few series. For example, the SYNTAX18 study in patients with stable chronic ischemic heart disease found a noncardiovascular mortality rate of 4.3% in patients who underwent percutaneous coronary intervention and 5.3% in patients treated by surgery, whereas cancer mortality was 2.2% and 2.4%, respectively.18

The effect of antiplatelet drugs on tumor growth and its prognostic implications in cancer patients is not a new topic, but the issue has become more relevant in scientific research in recent years. Some authors defend a complex causal association attributed to the direct action of certain antithrombotic drugs in cancer processes, inhibiting tumor growth and metastatic dissemination. However, most scientists advocate an incidental association, mediated by confounding factors, based on the idea that “cancer follows bleeding”, which lends credibility to the idea of an indirect association between antithrombotic medication and cancer. The evidence on the association between cancer and various antiplatelet drugs is described below.

In industrialized nations, cancer and CVD are the main causes of death. Up to 1 of every 10 patients with ischemic heart disease has a history of cancer, whereas 1 of every 30 patients with ischemic heart disease develops a new cancer. Both conditions share various risk factors, and the inflammatory theory is a common pathophysiologic mechanism. Although cancer can cause atherosclerosis through several mechanisms, the most common are those associated with antitumor drugs and RT, which are associated with a rather important risk of CVD and have led to a cooperative effort between cardiologists and oncologists for follow-up of oncologic patients. Additionally, there is obviously a 2-way relationship between these conditions that affects patient prognosis, as CVD is a major cause of morbidity and mortality in patients with malignant tumors and cancer doubles the risk of mortality in patients with CVD.

None declared.