The current guidelines provide specific recommendations on CTRCD due to AC, HER2-targeted therapies, chimeric antigen receptor T cell, tumor-infiltrating lymphocytes, HF during hematopoietic stem cell transplantation, immune checkpoint inhibitor myocarditis, and cancer-related tako-tsubo syndrome.

The management of AC CTRCD depends on whether patients have symptomatic HF or not and on the severity of ventricular dysfunction. Generally, patients with severe symptomatic cardiotoxicity will discontinue AC permanently; patients with moderate symptomatic cardiotoxicity and those with asymptomatic cardiotoxicity with LVEF<50% will temporarily discontinue AC and the MDT should discuss whether to rechallenge or not based on a risk-benefit assessment. In patients with mild symptomatic cardiotoxicity, it will also be the MDT who will decide whether to maintain or interrupt treatment with AC. The cardio-oncology guidelines aim to address those situations that differ in cancer patients, and medical treatment of ventricular dysfunction and symptomatic HF must follow ESC HF guidelines.6,7 In addition, 3 cardioprotective strategies are proposed for patients with CTRCD who restart AC, over HF treatment, and after LVEF recovery: dose reduction, liposomal AC, and dexrazoxane.

Mild asymptomatic CTRCD is a frequent clinical situation in cardio-oncology, defined as new global longitudinal strain decline>15% and/or an increase in cardiac biomarkers (either troponin or NP) with normal LVEF and without signs or symptoms of HF. Although the clinical evidence in this scenario is based on small studies and the results are heterogeneous, the guidelines recommend the initiation of angiotensin-converting enzyme inhibitors or beta-blockers in these patients to avoid progression of cardiotoxicity (IIa class B for those with troponin elevation or global longitudinal strain impairment; IIb class C for those with NP elevation).

Similar recommendations are given for CTRCD involving HER2-targeted therapies, but due to its less severe toxicity and its frequently reversible effect, the threshold for discontinuation is higher. This is an important message, because the fear of CTRCD leads to unnecessary interruption of anti-HER2 with potential oncologic benefit even though moderate cardiotoxicity can be tolerated.8 We believe that to apply all these recommendations, the work of cardio-oncology units should be integrated with that of HF units.

Immune checkpoint inhibitor-related myocarditis is clearly addressed. The 3 pillars of management are the following: a) to stop immune checkpoint inhibitors when suspected; b) to confirm diagnosis quickly: raised troponin, electrocardiogram, cardiac imaging (with a leading role of CMR), exclusion of other causes of myocardial injury such as acute coronary syndrome (ACS) or viral myocarditis; and c) to start high-dose boluses of methylprednisolone in all suspected patients, especially in fulminant cases where emergent differential diagnosis (including endomyocardial biopsy, IIaB) cannot be delayed. Despite the lack of an evidence-based recommendation, it is worth having a clear guide on how to manage corticoid weaning, when to use a second-line immunosuppressor and when to rechallenge (always through MDT) in this rare complication.

Readers are made aware of other specific HF complications in patients with cytokine releasing syndrome in chimeric antigen receptor T cell and tumor-infiltrating lymphocyte therapies, and in those receiving hematopoietic stem cell transplants, in whom cardiovascular toxicities include arrhythmias, pericardial effusion and tamponade, or HF from mild congestion to cardiogenic shock. Finally, tako-tsubo syndrome management in patients with cancer is approached and essential messages are given to confirm diagnosis, excluding ACS and myocarditis (again with an important role of CMR). The document stresses the avoidance of QT-prolonging drugs during the acute phase and the risk of restarting a cancer drug suspected of being the culprit drug after tako-tsubo syndrome should be preceded by MDT discussion.

Patients with cancer are at an increased risk of coronary artery disease because of shared risk factors but also because of the prothrombotic state and the toxicity of many cancer therapies. Patients admitted because of an ACS have higher mortality and bleeding rates. Diagnosis of ACS should be the same as in patients without cancer. Percutaneous revascularization is safe and leads to better outcomes and is therefore recommended when life expectancy is ≥ 6 months (IB). Antithrombotic therapy should probably be less aggressive in most cancers due to the increased bleeding risk. The duration of dual antiplatelet therapy should be individualized, and short duration of clopidogrel strategy after PCI for ACS could be an option for patients with cancer and very high bleeding risk (IIa C).

Cancer therapies should be temporally interrupted when cancer therapy is suspected as a contributing cause. A rechallenge with fluoropyrimidines after a vasospasm is controversial but could be attempted, especially after prophylactic therapy with long-term nitrates and calcium channel blockers. Therapies not associated with ischemia can be restarted once the patient is stabilized. Patients with new stable angina during treatment should undergo careful clinical evaluation, aggressive risk factor modification, and initiate anti-ischemic drugs.

Valvular heart disease increases the risk of cardiac toxicity. New or worsening valvular heart disease in patients with cancer may be related to coexisting conditions. Cardiac surgery is challenging because of comorbidities, frailty, or mediastinal fibrosis due to prior radiotherapy, and therefore percutaneous valve interventions may be an option to limit delays in starting cancer treatments. Patients with cancer suspected of new or worsening valvular heart disease should be screened for endocarditis and managed according to guideline recommendations but prioritizing the cancer-related prognosis.

All types of cancer carry an increased risk of AF and are associated with a 2-fold higher risk of systemic thromboembolism/stroke and a 6-fold increase in the risk of heart failure. The management of AF in patients with cancer should initially follow the ‘ABC pathway’ of the 2020 ESC guidelines but could differ in these patients due to the clinical particularities and concomitant treatment. The Spanish cardio-oncology group has previously published a consensus document on this topic to guide management in our setting.9

Initiation of anticoagulation in new-onset cases of AF should be based on CHA2DS2-VASC and HAS-BLED scores and is recommended in adult patients with CHA2DS2-VASc score ≥ 2 in men or ≥ 3 in women and must also be considered when the score is ≥ 1 in men and ≥ 2 in women. However, factors that may modify the embolic or hemorrhagic risk of patients with cancer must be considered. Direct oral anticoagulants (DOAC) should be preferred over vitamin-K antagonists in nonvalvular AF. To evaluate these risks in more detail and address complex clinical scenarios, in 2020 the Spanish Society of Cardiology (SEC) Cardio-Oncology group created anticoagulation algorithms that facilitate assessment10 and the Spanish Thrombosis Group created an application to simplify the indication of anticoagulant treatment.11

The guidelines offer comprehensive recommendations on hypertension management in patients with cancer including a clear threshold for systolic blood pressure (BP) ≥ 180 mmHg or diastolic BP ≥ 110 mmHg when cancer medication should be deferred or stopped until BP control is adequate. Uncontrolled hypertension is acknowledged as a driver of cardiac toxicity and HF during treatment with anthracyclines, ibrutinib, or vascular endothelial growth factor inhibitors. The new algorithm emphasizes the use of angiotensin-converting enzyme inhibitors or ARB as the first option alone or in combination with dihydropyridine calcium channel blockers. This algorithm is highly useful in both cardiology and oncology/hematology practice. The new recommendation on using different thresholds for BP depending on cancer prognosis is based on expert opinion.

A new algorithm is presented which balances thromboembolic and bleeding risks to support difficult decisions in daily clinical practice.

For VTE secondary prevention, the first step (as in AF) is to assess thromboembolic risk, bleeding risk, treatment interactions, and patient preferences. When there is no contraindication to starting anticoagulation, the cardio-oncology guidelines recommend the use of LMWH or DOAC (both IA indications). LMWH will be the first option in unoperated gastrointestinal (GI) or genitourinary cancer, GI comorbidities or toxicity, severe renal dysfunction (creatinine clearance ≤ 15mL/min), DOAC major drug-drug interactions or platelet count<50 000/μL. In the remaining scenarios, LMWH or DOAC are recommended with the same class of recommendation, and patient-preference should be considered.

Use of half-dosage LMWH is assigned a class IIb indication if the platelet count is between 25 000 and 50 000/μL. In patients with a very high bleeding risk assessed by the presence of recent or active major bleeding, new or evolving intracranial lesions, or a platelet count of less than 25 000/μL, anticoagulation should be withheld even in the presence of VTE.

For primary prevention of VTE, the use of prophylactic LMWH is recommended in hospitalized patients (IB indication). In outpatients at high risk of VTE, LMWH, apixaban, or rivaroxaban may be used in the absence of contraindications (IIb B).

Despite the published evidence on the use of DOACs in patients with cancer and the fact that it is a more efficient and better tolerated treatment than LMWH, the lack of reimbursement in the Spanish health system is the main limitation to the use of these drugs in VTE or cancer-related thrombosis.

While there is little novelty on peripheral artery disease, there are new recommendations on how to monitor dasatinib-related pulmonary hypertension and when to stop the treatment (level of evidence C). Novelties on pericardial disease include recommendations on the treatment of immune checkpoint inhibitor-related pericarditis and the management of recurrent pericardial effusions with a pericardial surgical window or intrapericardial infusion of sclerosing agents.

The cardio-oncology guidelines recommend cardiovascular assessment after cancer treatment. At the end of cancer therapy, cardiovascular risk assessment is circumscribed at 12 months after the last potentially cardiotoxic treatment. As a novelty, the document provides a risk classification and the corresponding clinical approach. The main objective of follow-up is to rule out CTRCD by using biomarkers and TTE and the frequency of follow-up will vary depending on the estimated risk. In our clinical setting, this follow-up can be eased using the SEC-Primaria program associated with an e-consult system that limits face-to-face hospital visits to the performance of TTE. 12,13

Since patients with low cardiorespiratory fitness have a poor prognosis, it is crucial to promote physical activity. CPET is recommended to assess the level of cardiorespiratory fitness in each patient and physical exercise is advised to all patients in cardiac rehabilitation programs. In our environment, it may be difficult to have a CPET for everyone, but selected patients may be offered a specific rehabilitation program. When CPET is not available, a simpler approach such as 30-second sit-to-stand and 6-minute walk tests can be used as an alternative to estimate functional capacity.14

Last, the withdrawal of HF drugs at the end of anticancer treatment in patients who had asymptomatic mild or moderate cardiotoxicity and who have fully recovered (normalized LVEF and biomarkers) is assigned a IIa C recommendation. This could be controversial in patients who had a significant drop in LVEF. It is true that this recommendation is limited to selected low-risk patients, but it is not clear whether the response of these patients may be similar or not to that of patients with HF and recovered LVEF, in which the ESC Heart Failure guidelines recommend withholding HF treatment due to the risk of cardiomyopathy recurrence.6,15 If HF treatment is withdrawn, the cardio-oncology guidelines highlight the importance of subsequent monitoring with biomarkers and TTE.

The guidelines provide a specific risk classification for those patients who had an onco-hematological process during their youth or adulthood. The follow-up of these patients revolves around ruling out CTRCD in the first group and covers premature atherosclerosis in the second group. In both groups, the guidelines recommend complex image screening, which we could try to implement at least in high-risk patients.

It is important to emphasize the control of CVRF, which can be achieved with the SEC-Primaria program.5,12,13 Of note, the current long-term survivors referred to in this section do not have tomorrow's pharmacological treatments or radiological equipment, and consequently the recommendations in future guidelines could well change.

The document contains a nice figure showing the most frequent locations of primary and secondary cardiac tumors, reminding readers at a glance what to rule out in the different cardiac chambers.

There is a specific section dedicated to pregnancy, covering a highly complex area. Even if there are no relevant specific studies in high-risk cancer survivors, prepregnancy counseling and management during pregnancy and around delivery by a multidisciplinary pregnancy heart team is given a class I recommendation.

Rare diseases such as carcinoid or cardiac AL-amyloidosis are also discussed in this section. TTE is recommended for the detection of NP levels and/or clinical signs of carcinoid heart disease, and for surveillance every 3 or 6 months depending on the severity of cardiac involvement and clinical status. Cardiac amyloidosis has even more impact in clinical practice due to recent therapeutic progress. TTE and CMR, NP and troponin are recommended for the diagnosis of amyloid light-chain cardiac amyloidosis in patients with plasma cell dyscrasia (class IC). Endomyocardial biopsy is assigned a IIa class recommendation.

The section ends with a highly practical recommendation on the management of patients with a cardiac implantable electronic device located in the radiotherapy treatment beam and of those located outside the radiotherapy treatment volume.

This is probably the only section that the authors of the current document find deficient. Although there are some sections that address lifestyle habits, physical exercise, diet, etc, and that the “specification of roles of different health care professionals, including nurses and pharmacists” is considered a gap in evidence, we would have liked an explicit section on nursing in cardio-oncology. The guidelines highlight the importance of the MDT and communication with patients, encouraging their involvement and participation in their management, and this task should be led by nurses. Unhealthy lifestyles and poor therapeutic adherence encourage CVRF, CVD, and cardiotoxicity. Integrated general and specific self-care support programs in different oncological processes have shown a marked improvement in the perceived quality of life and level of self-care of affected individuals, improving their degree of autonomy and overall outcomes. Structured counseling should be provided to encourage healthy behaviors and the identification and strict CVRF control (healthy diet, smoking cessation, regular exercise, and weight control) before, during and after treatment, the appropriate use of available resources, and clinical follow-up to rule out symptoms and signs suggestive of cardiotoxicity.16

In the SEC cardiovascular risk assessment consensus document,5 nurses play a fundamental role in cardiotoxicity prevention, with cost-effective strategies such as the identification, control, and monitoring of CVRFs before, during and after treatment, early detection of warning signs and/or symptoms, and promotion of a healthy lifestyle.

Quality improves when it is monitored; however, best practices should be based on those actions that provide the greatest benefit, and the scant clinical evidence in cardio-oncology makes it difficult to strictly establish quality indicators in this field at present.

The guidelines recognized the importance of developing tools for measuring quality, and another task force is preparing a dedicated document that will be published soon. Many parameters may be used to define quality in different domains and all should be at least visible; however, considering the existing level of evidence, it would be better to at least highlight a few truly relevant and amenable parameters for easy audits and benchmarking.

We would expect the inclusion of simple data, such as a) a cardio-oncology unit/team officially structured, organized, and recognized at each hospital/site; b) the number of cases with at least 1 visit (at baseline) among the total number of patients with a new cancer diagnosis who will be prescribed potentially cardiotoxic therapies; and c) the number of patients with HF or another major cardiovascular event/year with and without a recorded previous visit by the MDT.

Linked to quality, the national and international cardiology societies may provide guidance and audits at a local level. The SEC is currently developing a program to help the organization and certification of cardio-oncology units.