Embed Size (px)
Citation preview
Cancer diagnosis in patients with heart failure: epidemiology, clinical implications and gaps in
knowledge.
Pietro Ameri1*, Marco Canepa1*, Markus S Anker2, Yury Belenkov3, Jutta Bergler-Klein4, Alain Cohen-
Solal5, Dimitrios Farmakis6, Teresa Lopez Fernandez7, Mitja Lainscak8, Radek Pudil9, Frank
Ruschitska10, Petar Seferovic11, Gerasimos Filippatos6, Andrew Coats12, Thomas Suter13, Stephan Von
Haehling14, Fortunato Ciardiello15, Rudolf A.de Boer16, Alexander R. Lyon17** and Carlo G
Tocchetti18** for the Heart Failure Association Cardio-Oncology Study Group of ESC
* These authors contributed equally to the article
1 Department of Internal Medicine, University of Genova & Cardiology Unit, IRCCS Policlinic
Hospital San Martino, Genova, Italy
2 Charité Campus Benjamin Franklin, Department of Cardiology, Berlin, Germany
3 Cardiology Research Institute, Moscow, Russia
4 Dept. of Cardiology, Medical University of Vienna, Vienna, Austria
5 Department of Cardiology, Lariboisière Hospital, Paris, France; U942 INSERM, BIOCANVAS
(Biomarqueurs Cardiovasculaires), Paris, France; Department of Cardiology, University of Paris VII
Denis Diderot, Paris, France
6 Cardio-Oncology Clinic, Heart Failure Unit, Department of Cardiology, Athens University Hospital
“Attikon”, National and Kapodistrian University of Athens, Athens, Greece
7 Cardio-Oncology Unit, Cardiac Imaging Unit; Department of Cardiology, La Paz University
Hospital, IdiPAz, Madrid, Spain
8 Department of Cardiology, Department of Research and Education, General Hospital Celje, Celje,
Slovenia, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
9 1st Department of Internal Medicine - Cardioangiology, University Hospital Hradec Kralove, Czech
Republic
10 University Heart Center, University Hospital Zurich, Zurich, Switzerland
11 Belgrade University Medical Center, Belgrade, Serbia
12 Monash University, Australia and University of Warwick, UK
13 Department of Cardiology, Cardio-Oncology, Bern University Hospital, Bern, Switzerland
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
12
14 Klinik für Kardiologie und Pneumologie, Herzzentrum Göttingen, Universitätsmedizin Göttingen,
Georg-August-Universität, Göttingen, Deutschland; Deutsches Zentrum für Herz- und
Kreislaufforschung, Standort Göttingen, Göttingen
15 Luigi Vanvitelli University of Campania, Naples, Italy
16 University of Groningen, University Medical Center Groningen, Department of Cardiology,
Hanzeplein 1, 9713 GZ, Groningen, the Netherlands
17 Royal Brompton Hospital and Imperial College London, UK
18 Department of Translational Medical Sciences, Federico II University, Naples, Italy
** Correspondence to:
Alexander Lyon MA BM BCh PhD FRCP FHFA
Senior Lecturer and Honorary Consultant Cardiologist
Royal Brompton Hospital
London, UK
SW3 6NP
Office +44 (0) 207 352 8121 ext 2396
Fax +44 (0) 207 351 8776
OR
Carlo Gabriele Tocchetti, MD, PhD, FHFA
Associate Professor of Medicine
Dipartimento di Scienze Mediche Traslazionali
Universita’ degli Studi di Napoli Federico II
Via Pansini 5, Edificio 2
80131, Napoli, ITALY
Phone +39-081-746-4512
Fax +39-081-746-2246
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
Abstract
Cancer and heart failure (HF) are common medical conditions with a steadily rising prevalence in
industrialized countries, particularly in the elderly, and they both potentially carry a poor prognosis. A
new diagnosis of malignancy in subjects with pre-existing HF is not infrequent, and challenges HF
specialists as well as oncologists with complex questions relating to both HF and cancer management.
An increased incidence of cancer in patients with established HF has also been suggested. This review
paper summarizes the epidemiology and the prognostic implications of cancer occurrence in HF, the
impact of pre-existing HF on cancer treatment decisions and the impact of cancer on HF therapeutic
options, while providing some practical suggestions regarding patient care and highlighting gaps in
knowledge.
Keywords: heart failure, cancer, therapy, prognosis, comorbidity.
3
1
2
3
4
5
6
7
8
9
10
11
12
12
Introduction
The population of industrialized countries is progressively ageing, and older age predisposes to
alterations in cardiac structure and function that may culminate with heart failure (HF), especially HF
with preserved left ventricular ejection fraction (LVEF) 1, 2. Furthermore, major advances in treatment
have led to a dramatic reduction in short-term mortality following acute myocardial infarction and
other acute cardiovascular events, but have not influenced to the same extent the subsequent adverse
myocardial remodeling that often leads to HF with reduced LVEF (HFrEF)3. As a result, HF is a
syndrome with steadily growing prevalence and largely affecting elderly individuals 4. Accordingly, in
2014 the HF Association (HFA) of the European Society of Cardiology (ESC) published a White
Paper, already endorsed by 49 national HF working groups, stressing the burden of HF with a clear call
to action to promote prevention, improve disease awareness, ensure equity of care, support patients and
their caregivers, and foster research 1.
The incidence of most cancers also increases with age 5. According to the last American Cancer Society
estimates, the probability of developing invasive cancer at any site is 1 in 19 and 1 in 29 for females
and males, respectively, from birth to 49 years of age. It increases to 1 in 17 and 1 in 15 during the
sixth decade of life, becomes 1 in 10 and 1 in 7 in the seventh decade, and reaches1 in 4 and 1 in 3 after
70 years of age 6.
Cardiovascular and malignant disease is responsible for most deaths worldwide, with about 40% of all
deaths attributable to each. In last decades, some shifts were observed and in several countries,
cardiovascular disease is not leading cause of death anymore, particularly in men [6]. Nonetheless, the
cumulative burden remains excessively high and further comprehensive actions, accounting both
diseases rather than focusing on one are needed [7,8]. Therapeutic advances have converted HF and
several cancer types into chronic diseases and in these patients prognostic considerations need to be
reevaluated along new guidelines.
Within this epidemiological framework, diagnosis of cancer is not infrequent in patients with HF, and it
has recently been reported that malignancies are actually detected more often in subjects with HF than
in the general population 7-9. and poses a number of issues:
Does the diagnosis of cancer affect the prognosis of HF and vice versa?
How can oncological therapies be given safely to patients with HF who develop cancer?
4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
12
Do options regarding HF therapies change after a diagnosis of cancer, particularly in patients with
advanced HF?
While knowledge regarding HF secondary to the cardiotoxicity of anti-cancer drugs is important 8
Surprisingly, however, the problem of malignancies in patients with pre-existing HF has been far less
discussed than the one of HF secondary to the cardiotoxicity of anti-neoplastic treatments. In fact,
cancer is often not considered among the comorbidities that may be associated with and impinge on HF
management and outcomes 10 in part due to the fact that subjects with cancer are usually excluded from
HF randomized controlled trials.
While knowledge of the cardiotoxicity of oncological therapies is important 11, the Cardio-Oncology
Study Group of the ESC HFA calls for efforts to better characterize the burden of incident cancer in
pre-existing HF and to promote comprehensive actions, accounting both diseases rather than focusing
on one. These initiatives should include well-designed studies specifically addressing the occurrence of
malignancies in HF, which have been limited in number so far, with the goal of having solid data in
support of the recommendations for management of cancer in HF, rather than expert opinions based on
clinical experience as it is at present. This paper was endorsed by the Cardio-Oncology Study Group of
the ESC HFA and was initially conceived in a meeting held during the 2016 HFA Congress of the ESC
in Florence, Italy. The following issues were identified as especially relevant and are discussed below:
1. Which is the incidence of cancer among patients already having HF?
2. Does incident cancer affect the prognosis of HF and vice versa?
3. How can oncological therapies be given safely to patients with HF who develop cancer?
4. Do options regarding HF therapies change after a diagnosis of cancer, particularly in patients
with advanced HF?
Incidence of cancer in heart failure: facts and theoriesIncidence and outcomes for HF patients
diagnosed with cancer
The incidence of cancer in established HF has been estimated to be in the range of 18.9-33.7 per 1,000
person-years by retrospective analyses 7-9. These studies have consistently reported a higher risk of
malignancy in subjects with HF than in non-HF controls, despite differences in the cohorts evaluated,
the definition of cancer, and the statistical methods applied. This finding may be due to a surveillance
bias, since active follow-up of HF patients with regular visits may result in detection of tumors at an
early, asymptomatic stage, which is missed in the general population 7-9. Silent malignancies may be 5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
discovered by exams routinely performed for HF management (e.g. red blood cell count revealing
anemia due to primary or secondary neoplastic infiltration of the bone marrow, or chest X-ray showing
a pulmonary nodule). It is also possible that HF therapies render clinically overt tumors that would be
otherwise asymptomatic: this may be for instance the case with prostate carcinoma being revealed by
difficult voiding in response to diuretics, or intestinal neoplasms that start to bleed due to chronic
antithrombotic treatment. Strikingly, these scenarios are well known by clinical practice, but have not
actually been put in evidence by the scientific literature. Moreover, silent tumors may start to bleed due
to antithrombotic therapies that HF patients often take chronically. On the other hand, symptoms due to
a tumor may overlap with those of HF and be attributed to heart disease. This may even delay cancer
diagnosis, as symptoms might be thought of as due to advancing disease rather than new cancer 12, 13.
The association between HF and cancer may otherwise be the consequence of shared risk factors:
besides ageing, many habits and conditions predispose to both HF and cancer, e.g. cigarette smoking,
inactivity and obesity (Table 1) 14, 15. It has also been hypothesized that HF itself may promote
carcinogenesis through mechanisms yet to be characterized. For instance, the tumorigenic role of HF-
related low-grade inflammation has been suggested 7, 9, and hyperactivity of the sympathetic nervous
system and the renin-angiotensin system elevated sympathetic tone and natriuretic peptide levels may
also drive malignancy 16, 17.
Meta-analyses of randomized controlled trials and population studies have revealed a positive
correlation between treatment with medications that may be used for HF, especially angiotensin-
receptor blockers and digoxin 18, 19, and risk of cancer; however, these results have been refuted by other
investigators 20, 21. A major problem in interpretation of these data is the competing risk issue: if HF
patients receive life-saving therapies, development of malignancies has more “opportunity” and
patients may paradoxically be diagnosed with cancer more frequently 22. Nevertheless, there are also
theories that specific HF drugs may exert antitumor effects. In metastatic renal cell carcinoma, a better
progression-free survival was observed for patients taking angiotensin converting enzyme (ACE)-
inhibitors (often for pre-existing or cancer therapy-induced arterial hypertension) compared to other
anti-hypertensive drugs, and experimental work indicates that ACE-inhibitors may potentiate the
efficacy of vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors against renal
carcinoma cells 23. Several cancer cells express β-adrenergic receptors on the surface membranes and
their proliferation is increased after catecholamine exposure 24, making them potentially treatable with
beta-blockers. Moreover, β-adrenergic receptors may interact with other membrane receptors with
oncogenic activity, such as human epidermal growth factor receptor (HER)-2 25. A number of trials of 6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
beta-blockers to modify cancer outcomes are currently underway, with an analysis of cancer registry
data pointing to the fact that β2-, but not β1-adrenergic receptor blockade, may reduce breast cancer-
specific mortality 26. Statins have also been accused of increasing cancer incidence, but this hypothesis
has been recently rejected 27.
Outcomes for heart failure patients diagnosed with cancer
The prognosis of HF is dismal. A recent analysis of a database of 1.75 million people from primary
care practices in Scotland, of which more than 50,000 had HF, showed that 5-year survival of patients
with HF was lower than the one of patients with common malignancies, namely of the prostate and
bladder for men and of the breast for women 28. Outcomes may be even worse when cancer is
superimposed on pre-existing HF, with Regardless of whether HF and cancer are mechanistically
linked, epidemiological data indicate indicating that HF patients who are diagnosed with cancer have
higher all-cause mortality than both subjects with HF but no malignancy 7 and cancer patients without
HF 9. This partly reflects the increased risk of death that HF and cancer carry independently from each
other. Cancer also increases risk of recurrent HF admissions, irrespective of time after discharge [27].
The growing epidemiological evidence supports, but it is also likely the result of the negative impact
that each condition has on management of the other one (Figure 1). Indeed, cancer had been found to
increase the risk of HF readmission after a first HF hospitalization, similar to other comorbidities such
chronic kidney disease or diabetes mellitus 29.
Challenges in cancer therapy for patients with pre-existing heart failureHow can oncological
therapies be given safely to patients with heart failure who develop cancer?
Limitations in the tolerability of anti-neoplastic treatments
HF is characterized by a reduced cardiovascular reserve, which may be further impaired by cancer,
possibly by aggravating systemic inflammatory activation and endothelial dysfunction. It was recently
reported that subjects with colorectal cancer, but no overt cardiovascular disease, display subtle
alterations in cardiac and autonomic nervous system function, contributing to a decrease in exercise
capacity 30. Furthermore, common complications of malignancies, like electrolyte and water loss or
hormonal imbalance, may impinge on cardiovascular homeostasis 31. Even increased heart rate has been
found to be associated with poor survival in patients with advanced malignancies 32. As a result, the
ability of patients with HF to withstand oncological surgery, medical therapy or radiotherapy is often
limited, and this may be critical when a tumor requires aggressive management. In a recent Medicare-7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
based analysis of almost 100,000 cases of non-small cell lung cancer, the risk of death was increased
by concomitant HF at baseline for any combination of surgery, chemotherapy or radiotherapy 33.
Remarkably, HF was present in 14-22% of subjects at the time of lung cancer diagnosis, confirming
that occurrence of cancer in individuals with pre-existing HF is not rare. The symptoms of heart failure,
e.g. dyspnea, may remain unnoticed and therefore unreported in cancer patients, causing a possible
delay in indicated diagnostic and therapeutic procedures [32].
Concerns with potentially cardiotoxic drugs
Many oncological therapies are cardiotoxic and the balance between their anti-tumor activity and
cardiac side effects should be carefully assessed by a specialist before administering them to patients
with known HF 34.
For some drugs, such as anthracyclines, 5-fluorouracil and capecitabine, the HER-2 targeting antibody
trastuzumab, and vascular endothelial growth factor (VEGF)-directed tyrosine kinase inhibitors, the
potential of cardiac damage is particularly high 35. These drugs can cause (or aggravate) LV systolic or
diastolic dysfunction and may precipitate myocardial ischemia and arrhythmias exacerbate some
specific features of HF by a variety of mechanism (Table 21) 36, 37. HF is characterized by a chronic
state of inflammation and increased oxidative stress, with lower nitric oxide bioavailability, and
impaired energetics 35. Anthracyclines potently trigger a DNA damage response bringing to
mitochondrial derangement and oxidative stress 36. 5-fluorouracil and anti-VEGF TKIs drugs may
worsen post-ischemic remodeling by causing further myocardial ischemia, worsening the pathological
substrate for HF 37. Anti-HER-2 drugs impair the compensatory neuregulin/HER-2 signaling in the
failing myocardium 38. Hence, their use of trastuzumab, pertuzumab, T-DM1 and anti-VEGF TKIs in
patients with pre-existing HF must be extremely cautious, justified by the benefit to cancer outcomes
and the absence of alternative oncological treatments, and with appropriate informed consent and close
surveillance with clinical assessment, cardiac imaging and biomarkers. This is even more so
considering that there is paucity of data about these medications in HF.
Some Other oncological therapies may increase the risk of vascular events that could have a secondary
impact on HF. These include gonadotrophin-releasing hormone (GnRH) agonists and antiandrogens,
used to treat locally advanced and metastatic prostate cancer, VEGF TKIs tyrosine kinase inhibitors for
various solid tumors and BCR-ABL TKIs tyrosine kinase inhibitors for chronic myeloid leukemia.
Growing evidence shows that GnRH agonists increase the risk of ischemic heart disease and HF
hospitalization, potentially due to increased vascular inflammation, increases in LDL cholesterol and
development of insulin resistance 38, 39, which are predicted to . These effects disrupt pre-exiting 8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
vascular disease, and accelerate development of de novo vascular disease. Cardiologists, oncologists
and urologists should be aware of these side effects of androgen deprivation therapy, which is often
viewed as a safe treatment as compared with chemotherapy, since many endocrine and metabolic
changes secondary to low androgen levels occur slowly and the development and presentation of
cardiovascular toxicity is over a longer timeframe.
Ttraditional HF treatments, such as angiotensin and β-adrenergic receptor blockade, have been
proposed as a strategy to preserve LVEF in subjects without HF receiving anthracyclines and/or
trastuzumab 41, but so far results of randomized clinical trials have been discordant 40, 41. In HF, beta-
blockers and medications targeting the renin-angiotensin-aldosterone system (i.e. ACE-inhibitors,
mineralocorticoid receptor antagonists and, secondly, angiotensin receptor blockers and angiotensin
receptor/neprilysin inhibitors) are the mainstay of medical treatment and should be prescribed
irrespective of chemotherapy. Nonetheless, specific molecules within each of these pharmacological
classes might be particularly protective against the toxicity of antineoplastic therapies: one example is
carvedilol, which may be more effective than selective β1-adrenergic receptor blockers in
counteracting cardiomyocyte oxidative stress induced by anticancer drugs according to in vitro studies 42. However, there are no clinical data confirming this experimental evidence.
Preparing patients with heart failure for anti-tumor therapies
Once a cancer treatment protocol suitable for a patient with HF is identified, baseline review by a HF
specialist or Cardio-Oncology service is essential to take general cardioprotective measures and
improve HF management prior to starting antineoplastic therapy (Figure 2Table 3).
The first goal is to eliminate or reduce residual major cardiovascular risk factors, such as smoking,
dyslipidemia, arterial hypertension and diabetes, through evidence-based and guideline-approved
lifestyle and pharmacological approaches.
Some comorbidities including chronic obstructive pulmonary disease and diabetes are common among
the HF population, but can be effectively treated if recognized 29, 43, 44. Depression should not be
neglected not only because it may impair quality of life and may lead to non-adherence to HF therapy 45, but also because it may result in the loss of motivations to cope with cancer diagnosis and treatment.
The Beck Depression Inventory and Cardiac Depression Scale have been formally validated as reliable
tools for the evaluation of depressive mood in patients with HF 46.
Understanding the risks of the cancer therapies scheduled for the HF patient with new diagnosis of
cancer is of paramount importance, since every medication has its own panel of cardiovascular side
effects (LV dysfunction, hypertension and vascular toxicities, thrombosis, ischemia, QT prolongation 9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
and arrhythmias), and prompt correction of conditions which may exacerbate such toxicities, e.g.
electrolyte disturbances, is fundamental 34.
In the context of optimizing HF management, re-evaluation of the status and underlying cause of HF is
advisable before proceeding to oncological therapies. A detailed baseline assessment with clinical
review, ECG, cardiac biomarkers and cardiac imaging can help in defining the further treatment. In HF
due to coronary heart disease, provocative testing may be required to exclude any residual myocardial
ischemia in symptomatic patients; stress echocardiography is generally preferred in order to avoid
radiation but in selected cases e.g. poor echo windows, myocardial scintigraphy is appropriate 34. If
valvular heart disease is the etiology of HF, the degree of valvular stenosis or regurgitation should be
reassessed: if it is severe, multidisciplinary discussion with the heart team is advocated in order to
determine whether correction of the valve disease should be attempted before the patient receives
anticancer treatments. Stress echocardiography may help in risk stratification of asymptomatic, but
severe valvular dysfunction 47. The possibility of implanting a pacemaker for biventricular
pacingcardiac resynchronization therapy (CRT) should be discussed in the case of HFrEF with
untreated left bundle branch block, even if minimally symptomatic 48. In this regard, it is interesting to
note that in a contemporary HF cohort in Sweden cancer in the last three years was not associated with
omission of CRT, suggesting that cardiologists are not discouraged by a history of malignancy when
considering CRT 49.
Nonetheless, all tThese decisions are frequently mostly based on opinion as there is a lack of evidence
from randomized controlled trials and registries to guide decision making.
Ideally, oncological treatments should be started when clinical HF status is stable and optimally
managed. However, aAchievement of this goaloptimal HF management may require months for
initiation and potentiation of HF medication and device interventions, with possible delays in cancer
surgery or systemic anti-neoplastic treatment. The time required to maximize medical therapy,
including up-titration of ACE-inhibitors and beta-blockers in HFrEF patients, and the choice of
pursuing advanced device therapies requires an informed discussion between HF specialists or cardio-
oncologists and oncologist to compare the choices – starting cancer treatment whilst HF is sub-
optimally treated versus deferring cancer treatment. More rapid up-titration strategies can be
considered with cautious implementation and regular review by the HF team if cancer treatments
cannot be delayed for prognostic reasons. Again, however, there is no evidence supporting physicians
facing these issues, and more research is required to fill these gaps in knowledge.
Following patients with heart failure during cancer therapy10
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
Regular cardiovascular monitoring of subjects with HF receiving oncological treatments is strongly
advised, in order to detect early signs of decompensation or cardiotoxicity and institute additional
measures or discuss temporary or permanent interruption of cancer therapy if necessary (Table 3Figure
2). More frequent monitoring compared to the standard ‘guideline’ strategy may be necessary, using
cardiac imaging and biomarkers like natriuretic peptides 50. Special attention should be given to specific
cardiovascular side effects of oncologic therapies, e.g. hypertension or ischemia in tyrosine kinase
inhibitor recipients 51.
Many systemic anti-neoplastic drugs, both cardiotoxic and non-cardiotoxic, are frequently prescribed
with large amounts of concomitant intravenous fluid to minimize nephrotoxicity. Care must be given in
patients with pre-existing HF who are prone to fluid retention, and where possible the total volume
administered should be reduced, the infusion time prolonged, and diuretics added to enhance diuresis
and reduce the risk of congestion 34.
Clinical surveillance should also include interrogation of cardiac implantable electronic devices (CIED)
before and after radiotherapy, because of the possibility of dysfunction or damage by scattered
radiation 52. Direct CIED irradiation and high-energy (>10 MV) or neutron-producing beams should be
avoided, and the estimated cumulative dose to CIED should be limited. ECG monitoring should be
available during radiotherapy sessions for pacemaker-dependent patients 52. Cardiac imaging should
follow irradiation to the chest, e.g. in lymphoma or breast cancer, in long-term intervals 53.
Awareness of the possible problems when administering anti-cancer treatments to HF patients should
not lead to therapeutic inertia with omission of potentially life-saving cancer drugs. The detrimental
impact of this approach was demonstrated in over 5,000 patients with locally advanced colorectal
cancer, in which subjects with concomitant HF were 50% less likely to receive adjuvant chemotherapy
than those without HF. However, once started, chemotherapy was completed with a similar frequency
and conferred a comparable improvement in survival in the two subgroups, suggesting that it was
underutilized in the presence of HF 54.
Challenges in heart failure treatment after a diagnosis of cancerDo options regarding HF
therapies change after a diagnosis of cancer, particularly in patients with advanced HF?
If HF may hinder cancer management, it is also becoming increasingly evident that a diagnosis of
cancer may hamper treatment of HF, especially HFrEF (Figure 1).
Risk of down-titrating or abandoning heart failure-specific drugs
11
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
12
First, it may not be possible to maintain the optimal medical therapy for HFrEF. This includes high
doses of a beta-blocker with either an ACE-inhibitor, an angiotensin receptor blocker or an angiotensin
receptor/neprilysin inhibitor, and a mineralocorticoid receptor antagonist 1. Diuretics are also frequently
required, and ivabradine may be added if the HF patient is in sinus rhythm with an elevated resting
heart rate. Experience suggests that this complex treatment is often simplified, with dose reduction or
even drug interruption, when performance and health status deteriorate due to malignancy or when
anti-tumor drugs are administered. There are several explanations for this behavior, such as
hypotension, electrolyte depletion and acutely worsening renal function caused by vomiting and/or
diarrhea, which are common in patients with advancing cancer or receiving chemotherapy. Eventually,
cessation of drugs inhibiting the renin-angiotensin-aldosterone axis is often required. Nonetheless,
longitudinal studies specifically investigating this scenario are lacking. The safety of spironolactone in
hormone-sensitive malignancies has not been clearly established, and it is best avoided in women with
estrogen receptor- and/or progesterone receptor-positive breast cancers; we believe that in these
patients eplerenone is a suitable alternative 55.
The conundrum of anticoagulation
Atrial fibrillation is a common complication of HF 56 as well as of cardiotoxic chemotherapy, and
should be considered when symptoms and signs of decompensation develop. Direct oral anticoagulants
are now recommended for the prevention of arterial thromboembolism associated with atrial
fibrillation, given their more favorable risk-benefit profile compared with the one of warfarin 57. This
holds true for patients with HF, in whom direct anticoagulants have been confirmed to have equal or
superior efficacy, but safer than warfarin 58. HF patients with cancer also face a substantial risk of deep
vein thrombosis, pulmonary embolism and central venous catheter-associated thrombosis, collectively
defined as venous thromboembolism. In this context, the long-term safety and efficacy of direct oral
anticoagulants are not known and are currently being tested in several ongoing randomized controlled
trials 31. Until the results of these studies are available, low molecular weight heparin remains the drug
of choice for prophylaxis or treatment of cancer-related venous thromboembolism 59. Thus,
cardiologists and oncologists face the conundrum of which anticoagulation strategy is preferable for
patients with pre-existing HF and atrial fibrillation who develop cancer and are at risk of neoplastic
venous thromboembolism. In addition, there is concern about the consequences of possible drug
interactions between direct anticoagulants and anticancer therapies, since patients taking the latter ones
have not been included in either clinical trials or observational registries 31, 59.
Utilization of devices and advanced therapies12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
In the setting of HF, cancer may represent a contraindication to eligibility for device therapy (Figure 2).
Implantable cardioverter defibrillator (ICD) implantation may be withheld if life expectancy is
predicted to be shorter than 1 year 1. Nevertheless, decisions regarding eligibility for ICD should be
kept under review as patients with substantial responses to modern targeted anti-tumor therapies may
have prolonged progression-free survival and may merit ICDs if the competing risk of sudden cardiac
death is high. This possibility is hardly predictable at present, and fuels the ongoing debate on which
patients are most likely to benefit from ICD in primary prevention. A recent analysis of a Danish
nationwide registry indicates that there has been a trend over the last years to use ICD for primary
prevention in patients with more comorbidities, who however are more likely to die without any
appropriate ICD therapy 60.
Active cancer with a life expectancy <2 years is also an absolute contraindication for mechanical
circulatory support with a LV assist device (LVAD) as both bridge to heart transplantation and
destination therapy 61. Conversely, according to the latest guidelines of the International Society for
Heart and Lung Transplantation, LVAD-destination therapy may be considered for subjects with a
history of recently treated or active malignancy and life expectancy ≥2 years 61. It must be noted that
the level of evidence supporting this statement is low (class C). In fact, a history of cancer was
associated with death or persistent HF symptoms and poor quality of life in patients from the
INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) registry who
received a LVAD for destination therapy or bridge to transplantation, but with low likelihood of being
actually transplanted 62. Discussion with the oncologist is key, as prognosis may be surprisingly good
for some patients with treatment-responsive cancers even if metastatic at presentation.
Post-transplant immunosuppression also poses a risk of malignancy recurrence, which is related to the
duration of cancer-free survival before organ transplantation 63. Therefore, past cancer does not
necessarily preclude access to cardiac transplantation, possibly bridged by mechanical support 61, 64. By
contrast, current malignancy, other than localized non-melanoma skin cancer, is an absolute exclusion
from cardiac transplantation 64. Cases have been described of patients who were implanted with a
LVAD in spite of being diagnosed with cancer during the preimplantation screening, underwent tumor
resection after hemodynamic improvement due to the mechanical support, and finally were
transplanted 65, 66. This scenario is rare, but highlights the challenge for the timing of cardiac and
oncological therapies when cancer is discovered in a patient with pre-existing advanced HFrEF.
Conclusions and gaps in knowledge13
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
Cancer diagnosis is not an uncommon event in patients with HF and carries important implications in
terms of prognosis and both cardiac and anti-tumor treatment. A close collaboration between
cardiologists and oncologists is fundamental to improve the management of these patients, with both
specialists understanding the benefits of therapy for HF and cancer, and the risks of withholding or
suboptimally treating either or both diseases 34. The prognostic impact of each condition should always
be well defined and considered in decision making. A multidisciplinary approach is encouraged and
should include other healthcare professionals, including cardiac rehabilitation, psychology and
palliative care where necessary.
The scientific evidence upon which clinical decisions can be based is very limited, but epidemiology is
showing that occurrence of cancer in HF is an increasingly common problem with an ageing population
and in the current era of cancer and post-myocardial infarction survivorship. The SAFE-HEaRT trial
has been recently designed to test whether anti-HER2 drugs may be safely administered in patients
with mildly reduced cardiac function in the setting of ongoing cardiac treatment 67. Further well-
designed studies are required to clarify the thresholds at which cancer treatment should not be
administered in patients with pre-existing HF, and the optimal cardioprotective and surveillance
strategies for patients in whom these two serious conditions coexist.
Funding
CGT is supported by the grant “Ricerca di Ateneo Federico II 2017”.
Conflict of interest
CGT received speaking fees from Alere.
14
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
References
1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey
JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B,
Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force
M, Document R. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart
failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the
European Society of Cardiology (ESC). Developed with the special contribution of the Heart
Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18(8):891-975.
2. Christ M, Stork S, Dorr M, Heppner HJ, Muller C, Wachter R, Riemer U, Trend HFGP. Heart
failure epidemiology 2000-2013: insights from the German Federal Health Monitoring System.
Eur J Heart Fail 2016;18(8):1009-1018.
3. Cleland JG, Torabi A, Khan NK. Epidemiology and management of heart failure and left
ventricular systolic dysfunction in the aftermath of a myocardial infarction. Heart 2005;91 Suppl
2:ii7-13; discussion ii31, ii43-18.
4. Guha K, McDonagh T. Heart failure epidemiology: European perspective. Curr Cardiol Rev
2013;9(2):123-127.
5. Serrano M. Unraveling the links between cancer and aging. Carcinogenesis 2016;37(2):107.
6. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66(1):7-30.
7. Hasin T, Gerber Y, McNallan SM, Weston SA, Kushwaha SS, Nelson TJ, Cerhan JR, Roger VL.
Patients with heart failure have an increased risk of incident cancer. J Am Coll Cardiol
2013;62(10):881-886.
8. Hasin T, Gerber Y, Weston SA, Jiang R, Killian JM, Manemann SM, Cerhan JR, Roger VL. Heart
Failure After Myocardial Infarction Is Associated With Increased Risk of Cancer. J Am Coll
Cardiol 2016;68(3):265-271.
9. Banke A, Schou M, Videbaek L, Moller JE, Torp-Pedersen C, Gustafsson F, Dahl JS, Kober L,
Hildebrandt PR, Gislason GH. Incidence of cancer in patients with chronic heart failure: a long-
term follow-up study. Eur J Heart Fail 2016;18(3):260-266.
10. Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, Kjeldsen K, Jankowska EA,
Atar D, Butler J, Fiuzat M, Zannad F, Pitt B, O'Connor CM. Noncardiac comorbidities in heart
failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014;64(21):2281-2293.
15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
12
11. Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM. Cardiotoxicity of
anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer
Inst 2010;102(1):14-25.
12. Walsh D, Donnelly S, Rybicki L. The symptoms of advanced cancer: relationship to age, gender,
and performance status in 1,000 patients. Support Care Cancer 2000;8(3):175-179.
13. O'Leary N, Murphy NF, O'Loughlin C, Tiernan E, McDonald K. A comparative study of the
palliative care needs of heart failure and cancer patients. Eur J Heart Fail 2009;11(4):406-412.
14. Thavendiranathan P, Nolan MT. An emerging epidemic: cancer and heart failure. Clin Sci (Lond)
2017;131(2):113-121.
15. Farmakis D, Stafylas P, Giamouzis G, Maniadakis N, Parissis J. The medical and socioeconomic
burden of heart failure: A comparative delineation with cancer. Int J Cardiol 2016;203:279-281.
16. Le CP, Nowell CJ, Kim-Fuchs C, Botteri E, Hiller JG, Ismail H, Pimentel MA, Chai MG, Karnezis
T, Rotmensz N, Renne G, Gandini S, Pouton CW, Ferrari D, Moller A, Stacker SA, Sloan EK.
Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat
Commun 2016;7:10634.
17. Egami K, Murohara T, Shimada T, Sasaki K, Shintani S, Sugaya T, Ishii M, Akagi T, Ikeda H,
Matsuishi T, Imaizumi T. Role of host angiotensin II type 1 receptor in tumor angiogenesis and
growth. J Clin Invest 2003;112(1):67-75.
18. Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC. Angiotensin-receptor blockade and risk
of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 2010;11(7):627-636.
19. Biggar RJ, Andersen EW, Kroman N, Wohlfahrt J, Melbye M. Breast cancer in women using
digoxin: tumor characteristics and relapse risk. Breast Cancer Res 2013;15(1):R13.
20. Bangalore S, Kumar S, Kjeldsen SE, Makani H, Grossman E, Wetterslev J, Gupta AK, Sever PS,
Gluud C, Messerli FH. Antihypertensive drugs and risk of cancer: network meta-analyses and trial
sequential analyses of 324,168 participants from randomised trials. Lancet Oncol 2011;12(1):65-
82.
21. Couraud S, Dell'Aniello S, Bouganim N, Azoulay L. Cardiac glycosides and the risk of breast
cancer in women with chronic heart failure and supraventricular arrhythmia. Breast Cancer Res
Treat 2014;146(3):619-626.
22. Wuerzner G, Burnier M, Waeber B. Critical review of cancer risk associated with angiotensin
receptor blocker therapy. Vasc Health Risk Manag 2011;7:741-747.
16
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
12
23. McKay RR, Rodriguez GE, Lin X, Kaymakcalan MD, Hamnvik OP, Sabbisetti VS, Bhatt RS,
Simantov R, Choueiri TK. Angiotensin system inhibitors and survival outcomes in patients with
metastatic renal cell carcinoma. Clin Cancer Res 2015;21(11):2471-2479.
24. Coelho M, Soares-Silva C, Brandao D, Marino F, Cosentino M, Ribeiro L. beta-Adrenergic
modulation of cancer cell proliferation: available evidence and clinical perspectives. J Cancer Res
Clin Oncol 2017;143(2):275-291.
25. Sysa-Shah P, Tocchetti CG, Gupta M, Rainer PP, Shen X, Kang BH, Belmonte F, Li J, Xu Y, Guo
X, Bedja D, Gao WD, Paolocci N, Rath R, Sawyer DB, Naga Prasad SV, Gabrielson K.
Bidirectional cross-regulation between ErbB2 and beta-adrenergic signalling pathways. Cardiovasc
Res 2016;109(3):358-373.
26. Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer
mortality: a population- based study. J Clin Oncol 2011;29(19):2635-2644.
27. Mei Z, Liang M, Li L, Zhang Y, Wang Q, Yang W. Effects of statins on cancer mortality and
progression: A systematic review and meta-analysis of 95 cohorts including 1,111,407 individuals.
Int J Cancer 2017;140(5):1068-1081.
28. Mamas MA, Sperrin M, Watson MC, Coutts A, Wilde K, Burton C, Kadam UT, Kwok CS, Clark
AB, Murchie P, Buchan I, Hannaford PC, Myint PK. Do patients have worse outcomes in heart
failure than in cancer? A primary care-based cohort study with 10-year follow-up in Scotland. Eur
J Heart Fail 2017;19(9):1095-1104.
29. Omersa D, Farkas J, Erzen I, Lainscak M. National trends in heart failure hospitalization rates in
Slovenia 2004-2012. Eur J Heart Fail 2016;18(11):1321-1328.
30. Cramer L, Hildebrandt B, Kung T, Wichmann K, Springer J, Doehner W, Sandek A, Valentova M,
Stojakovic T, Scharnagl H, Riess H, Anker SD, von Haehling S. Cardiovascular function and
predictors of exercise capacity in patients with colorectal cancer. J Am Coll Cardiol
2014;64(13):1310-1319.
31. Farmakis D, Parissis J, Filippatos G. Insights into onco-cardiology: atrial fibrillation in cancer. J
Am Coll Cardiol 2014;63(10):945-953.
32. Anker MS, Ebner N, Hildebrandt B, Springer J, Sinn M, Riess H, Anker SD, Landmesser U,
Haverkamp W, von Haehling S. Resting heart rate is an independent predictor of death in patients
with colorectal, pancreatic, and non-small cell lung cancer: results of a prospective cardiovascular
long-term study. Eur J Heart Fail 2016;18(12):1524-1534.
17
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
12
33. Kravchenko J, Berry M, Arbeev K, Kim Lyerly H, Yashin A, Akushevich I. Cardiovascular
comorbidities and survival of lung cancer patients: Medicare data based analysis. Lung Cancer
2015;88(1):85-93.
34. Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, Habib
G, Lenihan DJ, Lip GY, Lyon AR, Lopez Fernandez T, Mohty D, Piepoli MF, Tamargo J,
Torbicki A, Suter TM, Authors/Task Force M, Guidelines ESCCfP. 2016 ESC Position Paper on
cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee
for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the
European Society of Cardiology (ESC). Eur J Heart Fail. 2017 Jan;19(1):9-42. doi:
10.1002/ejhf.654.
35. Bloom MW, Hamo CE, Cardinale D, Ky B, Nohria A, Baer L, Skopicki H, Lenihan DJ,
Gheorghiade M, Lyon AR, Butler J. Cancer Therapy-Related Cardiac Dysfunction and Heart
Failure: Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging. Circ Heart Fail
2016;9(1):e002661.
36. Mercurio V, Pirozzi F, Lazzarini E, Marone G, Rizzo P, Agnetti G, Tocchetti CG, Ghigo A, Ameri
P. Models of Heart Failure Based on the Cardiotoxicity of Anticancer Drugs. J Card Fail
2016;22(6):449-458.
37. Di Lisi D, Madonna R, Zito C, Bronte E, Badalamenti G, Parrella P, Monte I, Tocchetti CG, Russo
A, Novo G. Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond. Int J
Cardiol 2017;227:11-17.
38. Bosco C, Bosnyak Z, Malmberg A, Adolfsson J, Keating NL, Van Hemelrijck M. Quantifying
observational evidence for risk of fatal and nonfatal cardiovascular disease following androgen
deprivation therapy for prostate cancer: a meta-analysis. Eur Urol 2015;68(3):386-396.
39. Martin-Merino E, Johansson S, Morris T, Garcia Rodriguez LA. Androgen deprivation therapy and
the risk of coronary heart disease and heart failure in patients with prostate cancer: a nested case-
control study in UK primary care. Drug Saf 2011;34(11):1061-1077.
40. Boekhout AH, Gietema JA, Milojkovic Kerklaan B, van Werkhoven ED, Altena R, Honkoop A,
Los M, Smit WM, Nieboer P, Smorenburg CH, Mandigers CM, van der Wouw AJ, Kessels L, van
der Velden AW, Ottevanger PB, Smilde T, de Boer J, van Veldhuisen DJ, Kema IP, de Vries EG,
Schellens JH. Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-
Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial.
JAMA Oncol 2016;2(8):1030-1037.18
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
41. Gulati G, Heck SL, Ree AH, Hoffmann P, Schulz-Menger J, Fagerland MW, Gravdehaug B, von
Knobelsdorff-Brenkenhoff F, Bratland A, Storas TH, Hagve TA, Rosjo H, Steine K, Geisler J,
Omland T. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2
x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and
metoprolol. Eur Heart J 2016;37(21):1671-1680.
42. Spallarossa P, Garibaldi S, Altieri P, Fabbi P, Manca V, Nasti S, Rossettin P, Ghigliotti G,
Ballestrero A, Patrone F, Barsotti A, Brunelli C. Carvedilol prevents doxorubicin-induced free
radical release and apoptosis in cardiomyocytes in vitro. J Mol Cell Cardiol 2004;37(4):837-846.
43. Canepa M, Temporelli PL, Rossi A, Rossi A, Gonzini L, Nicolosi GL, Staszewsky L, Marchioli R,
Maggioni AP, Tavazzi L, Investigators G-H. Prevalence and Prognostic Impact of Chronic
Obstructive Pulmonary Disease in Patients with Chronic Heart Failure: Data from the GISSI-HF
Trial. Cardiology 2017;136(2):128-137.
44. Canepa M, Straburzynska-Migaj E, Drozdz J, Fernandez-Vivancos C, Pinilla JMG, Nyolczas N,
Temporelli PL, Mebazaa A, Lainscak M, Laroche C, Maggioni AP, Piepoli MF, Coats AJS, Ferrari
R, Tavazzi L, Investigators E-HHFL-TR. Characteristics, treatments and 1-year prognosis of
hospitalized and ambulatory heart failure patients with chronic obstructive pulmonary disease in
the European Society of Cardiology Heart Failure Long-Term Registry. Eur J Heart Fail 2017.
45. Ghosh RK, Ball S, Prasad V, Gupta A. Depression in heart failure: Intricate relationship,
pathophysiology and most updated evidence of interventions from recent clinical studies. Int J
Cardiol 2016;224:170-177.
46. Freedland KE, Carney RM, Rich MW, Steinmeyer BC, Rubin EH. Cognitive Behavior Therapy for
Depression and Self-Care in Heart Failure Patients: A Randomized Clinical Trial. JAMA Intern
Med 2015;175(11):1773-1782.
47. Lancellotti P, Pellikka PA, Budts W, Chaudhry FA, Donal E, Dulgheru R, Edvardsen T, Garbi M,
Ha JW, Kane GC, Kreeger J, Mertens L, Pibarot P, Picano E, Ryan T, Tsutsui JM, Varga A. The
clinical use of stress echocardiography in non-ischaemic heart disease: recommendations from the
European Association of Cardiovascular Imaging and the American Society of Echocardiography.
Eur Heart J Cardiovasc Imaging 2016;17(11):1191-1229.
48. Suter TM, Ewer MS. Cancer drugs and the heart: importance and management. Eur Heart J
2013;34(15):1102-1111.
49. Lund LH, Braunschweig F, Benson L, Stahlberg M, Dahlstrom U, Linde C. Association between
demographic, organizational, clinical, and socio-economic characteristics and underutilization of 19
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
cardiac resynchronization therapy: results from the Swedish Heart Failure Registry. Eur J Heart
Fail 2017;19(10):1270-1279.
50. Lenihan DJ, Stevens PL, Massey M, Plana JC, Araujo DM, Fanale MA, Fayad LE, Fisch MJ, Yeh
ET. The Utility of Point-of-Care Biomarkers to Detect Cardiotoxicity During Anthracycline
Chemotherapy: A Feasibility Study. J Card Fail 2016;22(6):433-438.
51. Schmidinger M, Bergler-Klein J. Therapy management of cardiovascular adverse events in the
context of targeted therapy for metastatic renal cell carcinoma. Int J Urol 2012;19(9):796-804.
52. Viganego F, Singh R, Fradley MG. Arrhythmias and Other Electrophysiology Issues in Cancer
Patients Receiving Chemotherapy or Radiation. Curr Cardiol Rep 2016;18(6):52.
53. Lancellotti P, Nkomo VT, Badano LP, Bergler-Klein J, Bogaert J, Davin L, Cosyns B, Coucke P,
Dulgheru R, Edvardsen T, Gaemperli O, Galderisi M, Griffin B, Heidenreich PA, Nieman K, Plana
JC, Port SC, Scherrer-Crosbie M, Schwartz RG, Sebag IA, Voigt JU, Wann S, Yang PC, European
Society of Cardiology Working Groups on Nuclear C, Cardiac Computed T, Cardiovascular
Magnetic R, American Society of Nuclear C, Society for Cardiovascular Magnetic R, Society of
Cardiovascular Computed T. Expert consensus for multi-modality imaging evaluation of
cardiovascular complications of radiotherapy in adults: a report from the European Association of
Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J Cardiovasc
Imaging 2013;14(8):721-740.
54. Gross CP, McAvay GJ, Guo Z, Tinetti ME. The impact of chronic illnesses on the use and
effectiveness of adjuvant chemotherapy for colon cancer. Cancer 2007;109(12):2410-2419.
55. Lother A, Bergemann S, Kowalski J, Huck M, Gilsbach R, Bode C, Hein L. Inhibition of the
cardiac myocyte mineralocorticoid receptor ameliorates doxorubicin-induced cardiotoxicity.
Cardiovasc Res 2017.
56. Santhanakrishnan R, Wang N, Larson MG, Magnani JW, McManus DD, Lubitz SA, Ellinor PT,
Cheng S, Vasan RS, Lee DS, Wang TJ, Levy D, Benjamin EJ, Ho JE. Atrial Fibrillation Begets
Heart Failure and Vice Versa: Temporal Associations and Differences in Preserved Versus
Reduced Ejection Fraction. Circulation 2016;133(5):484-492.
57. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC,
Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van
Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca
A, De Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B,
Guenoun M, Hohnloser SH, Kolh P, Lip GY, Manolis A, McMurray J, Ponikowski P, Rosenhek R, 20
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3212
Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, Van Gelder IC, Voors
AA, Windecker S, Zamorano JL, Zeppenfeld K. 2016 ESC Guidelines for the management of
atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37(38):2893-2962.
58. Savarese G, Giugliano RP, Rosano GM, McMurray J, Magnani G, Filippatos G, Dellegrottaglie S,
Lund LH, Trimarco B, Perrone-Filardi P. Efficacy and Safety of Novel Oral Anticoagulants in
Patients With Atrial Fibrillation and Heart Failure: A Meta-Analysis. JACC Heart Fail
2016;4(11):870-880.
59. Farge D, Bounameaux H, Brenner B, Cajfinger F, Debourdeau P, Khorana AA, Pabinger I,
Solymoss S, Douketis J, Kakkar A. International clinical practice guidelines including guidance for
direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients
with cancer. Lancet Oncol 2016;17(10):e452-e466.
60. Ruwald AC, Vinther M, Gislason GH, Johansen JB, Nielsen JC, Petersen HH, Riahi S, Jons C. The
impact of co-morbidity burden on appropriate implantable cardioverter defibrillator therapy and
all-cause mortality: insight from Danish nationwide clinical registers. Eur J Heart Fail
2017;19(3):377-386.
61. Feldman D, Pamboukian SV, Teuteberg JJ, Birks E, Lietz K, Moore SA, Morgan JA, Arabia F,
Bauman ME, Buchholz HW, Deng M, Dickstein ML, El-Banayosy A, Elliot T, Goldstein DJ,
Grady KL, Jones K, Hryniewicz K, John R, Kaan A, Kusne S, Loebe M, Massicotte MP, Moazami
N, Mohacsi P, Mooney M, Nelson T, Pagani F, Perry W, Potapov EV, Eduardo Rame J, Russell
SD, Sorensen EN, Sun B, Strueber M, Mangi AA, Petty MG, Rogers J, International Society for H,
Lung T. The 2013 International Society for Heart and Lung Transplantation Guidelines for
mechanical circulatory support: executive summary. J Heart Lung Transplant 2013;32(2):157-187.
62. Arnold SV, Jones PG, Allen LA, Cohen DJ, Fendler TJ, Holtz JE, Aggarwal S, Spertus JA.
Frequency of Poor Outcome (Death or Poor Quality of Life) After Left Ventricular Assist Device
for Destination Therapy: Results From the INTERMACS Registry. Circ Heart Fail 2016;9(8).
63. Sigurdardottir V, Bjortuft O, Eiskjaer H, Ekmehag B, Gude E, Gustafsson F, Hagerman I, Halme
M, Lommi J, Mared L, Riise GC, Simonsen S. Long-term follow-up of lung and heart transplant
recipients with pre-transplant malignancies. J Heart Lung Transplant 2012;31(12):1276-1280.
64. Banner NR, Bonser RS, Clark AL, Clark S, Cowburn PJ, Gardner RS, Kalra PR, McDonagh T,
Rogers CA, Swan L, Parameshwar J, Thomas HL, Williams SG. UK guidelines for referral and
assessment of adults for heart transplantation. Heart 2011;97(18):1520-1527.
21
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
12
65. Smail H, Pfister C, Baste JM, Nafeh-Bizet C, Gay A, Barbay V, Bessou JP, Peillon C, Litzler PY.
A difficult decision: what should we do when malignant tumours are diagnosed in patients
supported by left ventricular assist devices? Eur J Cardiothorac Surg 2015;48(3):e30-36.
66. Gkouziouta A, Farmakis D, Manginas A, Sfyrakis P, Saroglou G, Adamopoulos S, Iliodromitis
EK. Double organ transplantation in cardiac amyloidosis. J Cardiovasc Med (Hagerstown)
2016;17(2):126-129.
67. Lynce F, Barac A, Tan MT, Asch FM, Smith KL, Dang C, Isaacs C, Swain SM. SAFE-HEaRt:
Rationale and Design of a Pilot Study Investigating Cardiac Safety of HER2 Targeted Therapy in
Patients with HER2-Positive Breast Cancer and Reduced Left Ventricular Function. Oncologist
2017;22(5):518-525.
22
1
2
3
4
5
6
7
8
9
10
11
12
12
Anti-cancer drug class
Main mechanism(s) of cardiotoxicity
Main clinical presentation
Frequency (% of treated patients)
Anthracyclines (doxorubicin, epirubicin)
DNA damage, mitochon-drial dysfunction and oxidative stress of cardiomyocytes
LVSD / HFrEF (dose-dep., irreversible, often delayed-onset)
With current doses 3-5%; with liposomal anthracyclines 2%
Alkylating agents (cyclophosphamide, ifosfamide)
Myocarditis; epicardial coronary artery spasm LVSD / HFrEF
Up to 28% (cyclophospha-mide > ifosfamide)
Fluoropyrimidines (5-fluorouracil, capecitabine)
Epicardial coronary artery spasm and/or coronary microvascular dysfunction
Acute myocardial ischemia Up to 18%
Anti-HER2 agents (trastuzumab, lapa-tinib, pertuzumab)
Inhibition of HER2 pro-homeostatic activities in the heart
LVSD / HFrEF(dose-indep., reversible with discontinuation)
Up to 28% if with anthra-cycline (trastuzumab >> lapatinib and pertuzumab)
Multiple TKI (sunitinib, sorafenib)
Inhibition of VEGF and other pro-homeostatic tyrosine kinase receptors
HypertensionArterial thrombosisLVSD / HFrEF
Up to 47% (sun) - 43% (sora) Up to 1.7% (sun) - 1.4% (sora)Up to 19% (sun) - 8% (sora)
VEGF-directed TKI (bevacizumab)
Systemic endothelial and coronary microvascular dysfunction; ↓ angiogenesis
HypertensionArterial thrombosisHFrEF
Up to 35%Up to 3.8%Up to 4%
Platinum agents(cisplatin)
Endothelial dysfunction and disruption; platelet activation
Thromboembolism Up to 2%
Table 1. Mechanisms and main clinical manifestation of the cardiotoxicity of anti-cancer drugs
with known and clinically relevant potential for cardiac adverse effects.
The highest frequency reported in the literature are presented in the Table. For more detailed
information about the incidence of anti-cancer therapy cardiotoxicity, see ref. 34 .
LVSD: left ventricular systolic dysfunction; HFrEF: heart failure with reduced ejection fraction; TKI:
tyrosine kinase inhibitors; VEGF: vascular endothelial growth factor.
23
1
2
3
4
5
6
7
12
Figure legends
Figure 1. Cancer and heart failure carry an independent risk of mortality, but also potentially hinder the
treatment of one another, with the result being a further increase in mortality.
Diagnosis of cancer worsens the prognosis of a patient with pre-existing heart failure, and each
condition carries an independent risk of mortality and potentially hinders treatment of the other one.
ICD: implantable cardioverter defibrillator; LVAD: left ventricular assist device; CIED: cardiac
implantable electronic device; RT: radiotherapy.
Figure 2. While management of HF and various types of cancer relies on detailed evidence-based
guidelines, much less data are available to inform the decisions of physicians caring a patient with HF
who is also diagnosed with a malignancy. Key issues that should be taken into account are presented in
the Figure.
CV: cardiovascular; IHD: ischemic heart disease; VHD: valvular heart disease; CRT: cardiac
resynchronization therapy; CIED: cardiac implantable electronic device; RT: radiation therapy; ICD:
implantable cardioverter defibrillator; LVAD: left ventricular assist device.* Treatment of ischemic heart disease and valvular heart disease must also meet the criteria of current
guidelines.# Presence of a potentially treatable cardiac electrical dyssynchrony is requisite for considering cardiac
resynchronization therapy.§ Drugs that were shown to modify heart failure hospitalizations and mortality in randomized controlled
trials: beta-blockers, angiotensin-converting enzyme-inhibitors, angiotensin receptor blockers,
sacubitril/valsartan, mineralocorticoid receptor antagonists, and ivabradine.
24
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
12
