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Heart, Lung and Circulation

First European Society of Cardiology Cardio-Oncology Guidelines: A Big Leap Forward for an Emerging Specialty

      Keywords

      The recent release of the European Society of Cardiology’s Cardio-Oncology guidelines represents a substantial and significant body of scholarly work [
      • Lyon A.R.
      • Lopez-Fernandez T.
      • Couch L.S.
      • Asteggiano R.
      • Aznar M.C.
      • Bergler-Klein J.
      • et al.
      2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS).
      ]. These are the first cardio-oncology guidelines to be published by a large multi-national cardiovascular professional society (in collaboration with the European Haematology Association and European Society for Therapeutic Radiology and Oncology) and also the first guidelines to be produced through joint partnership between cardiology and oncology multinational associations. Developed over 2 years by an accomplished and diverse team, the comprehensive guidelines consist of 133 pages and contain 50 tables, 48 figures and 837 references with 271 new recommendations. Cardio-toxicity monitoring protocols for 18 classes of anti-cancer treatments are discussed in detail and many aspects of cardiovascular pathology, from valvular diseases to arrhythmia to cardiomyopathic conditions, are considered. This breadth of information confirms what several thought leaders in cardiology have previously advocated [
      • Bhatt D.L.
      Birth and maturation of cardio-oncology.
      ]: cardio-oncology has expanded beyond being a facet of general cardiology and is now unquestionably an independent subspecialty that merits recognition and its own accredited training programs with oversight and formalised governance by appropriate professional associations.
      Underlying the treatment recommendations are several over-arching themes. Firstly, these guidelines implicitly support a re-pivot from “algorithmic” care to personalised cardiovascular care. Accompanying the impressive advances in cardiovascular medicine over the past several decades has been a growing understanding that diseases originally considered a single entity (e.g. heart failure) are actually a constellation of disorders influenced by the patient’s individual risk-factor profile. This insight has resulted in iterative guidelines progressively recommending ever more individualised management and a more personalised approach to patient care [
      • Califf R.M.
      Future of personalized cardiovascular medicine: JACC state-of-the-art review.
      ]. Cardio-oncology requires careful consideration of differences in patients’ cardiovascular risk factors, cancer type and treatment, cancer prognosis and type of cardiotoxicity leading to unique treatment considerations for each patient. Effective cardiovascular risk stratification at baseline confers several benefits, including improved communication, being able to commence any preventative treatments in a timely manner and creating an individualised surveillance strategy for cardiovascular health and any adverse cardiovascular outcomes [
      • Gilchrist S.C.
      • Barac A.
      • Ades P.A.
      • Alfano C.M.
      • Franklin B.A.
      • Jones L.W.
      • et al.
      Cardio-oncology rehabilitation to manage cardiovascular outcomes in cancer patients and survivors: a scientific statement from the American Heart Association.
      ]. In some aspects, this personalised approach may make cardio-oncology care more challenging and time-consuming, but it will likely improve patient outcomes and result in more efficient use of medical resources.
      The second over-arching theme of the new guidelines is the strengthened focus on optimising medical therapy for cardiovascular disease and risk factors. Of the 161 recommendations in the guidelines, only two mention invasive treatments such as percutaneous coronary intervention or pacemaker insertion. This focus correctly recognises that the greatest benefits can often be seen with readily and widely available cardiovascular medications prescribed at appropriately early points of patient contact. Interventional therapies should of course be used in the appropriate patient with cancer, recognising that increased bleeding, clotting risk and drug–drug interactions in some patients make interventional strategies more challenging. These medical measures can make the patient’s cancer journey more comfortable and can increase the likelihood of completing optimal doses of oncology treatment safely, within the desired timeframe [
      • Jeyaprakash P.
      • Sangha S.
      • Ellenberger K.
      • Sivapathan S.
      • Pathan F.
      • Negishi K.
      Cardiotoxic Effect of modern anthracycline dosing on left ventricular ejection fraction: a systematic review and meta-analysis of placebo arms from randomized controlled trials.
      ]. The document also sets out recommendations for adjusting neoadjuvant chemotherapy to reduce cardiovascular risk (Section 5). These are likely the first cardio-oncology guidance documents to include recommendations regarding oncological treatments and reinforces the pivotal role that oncologists will have in implementing cardio-oncology care. These guidelines correctly reposition the timing of cardio-oncologist input to the beginning of the patient’s cancer journey, on the premise that preventing cardiovascular disease will improve patient outcomes to a greater degree than treating established and frequently advanced disease [
      • Shapiro M.D.
      • Maron D.J.
      • Morris P.B.
      • Kosiborod M.
      • Sandesara P.B.
      • Virani S.S.
      • et al.
      Preventive cardiology as a subspecialty of cardiovascular medicine: JACC Council perspectives.
      ].
      The final over-arching theme is that cardio-oncology remains a developing field in need of further research efforts. Of the 271 recommendations enclosed in the tables, only seven have level of evidence A (i.e. supported by multiple randomised controlled trials [RCT] or a meta-analysis). In total, 57 recommendations have level of evidence B (derived from single RCT or multiple nonrandomised studies) and the majority of recommendations, 207 or 76% of all recommendations, are level of evidence C based on expert opinion. This gap in scientific evidence should be addressed through increased strategic priority-driven research, with an emphasis on cross-specialty collaboration [
      • Ky B.
      My Hope for cardio-oncology.
      ,
      • Lenihan D.J.
      • Fradley M.G.
      • Dent S.
      • Brezden-Masley C.
      • Carver J.
      • Filho R.K.
      • et al.
      Proceedings From the Global Cardio-Oncology Summit: the top 10 priorities to actualize for cardiooncology.
      ]. Priority should be given to research that improves the evidence base for class II recommendations (i.e. conflicting evidence or divergence of opinion for a treatment) which have greater equipoise as further research could change clinical practice in either direction. Health economics studies demonstrating cost-effectiveness of cardio-oncology services in other countries have been published but similar health economics studies in Australia are lacking [
      • de Mello Sampayo F.
      • Fiuza M.
      • Pinto F.
      • Fontes J.
      Cost-effectiveness of cardio-oncology clinical assessment for prevention of chemotherapy-induced cardiotoxicity.
      ]. The success of these research efforts would depend on close collaboration between oncologists and cardiologists and it is pivotal that efforts for generating inter-specialty research partnerships should be encouraged. Efforts in Australia and New Zealand to support institutional development of clinical cardio-oncology programs should be accompanied by an equal effort to boost scientific research in this area.
      What barriers remain between publication of these guidelines and seeing improved patient care and outcomes? Given that the guidelines contain 133 pages of densely-packed information, it is perhaps unrealistic to expect all members of the patient’s health care team, including oncologists, haematologists, cardiologists, primary care doctors and allied health, to be familiar with all of the contents within. Several strategies for disseminating the contained information are worth discussing. Firstly specific sections may be more relevant to some specialties than others; for example oncologists may be more interested in baseline assessment of cardiovascular risk and sections regarding care for patients with established cardiovascular disease or cardiotoxicity may be more relevant for cardiologists given their greater access to cardiac imaging and intervention services. A reasonable strategy that might improve uptake could be to effectively unpack and distribute guideline sections between specialties. Patients should be central and involved in their cardio-oncology care and given clear information regarding healthy lifestyle measures, as outlined in section 10 of guidelines. Secondly, innovative efforts at dissemination of new research findings should be encouraged to improve awareness. Physicians with greater cardio-oncology experience could be “impact-multipliers” for the guidelines by being accessible remote advice providers for their colleagues in regional and remote areas in particular. Thirdly, brief summaries of main points in the guidelines should be provided for time-pressured readers (see Table 1).
      Table 110 Take Home Messages From ESC 2022 Cardio-Oncology Guidelines.
      Message 1Effective cardio-oncology services require integration and broad knowledge of cardiology, oncology and haematology specialists. This can best be actualised by inter-specialty collaboration, communication, and training.
      Message 2
      • All cancer patients scheduled for treatment with potentially cardiotoxic anti-cancer therapy should have baseline comprehensive cardiovascular risk assessment.
      • HFA-ICOS risk assessment tool is recommended (class IIa) but online calculators are not yet available.
      Message 3
      • For patients deemed to be at high or very-high risk of cardiotoxicity, ongoing monitoring by cardiologists/cardio-oncologists with combined imaging and biomarkers approach is recommended.
      • Echocardiography is recommended first-line test, preferably with 3D-LVEF and GLS.
      • Cardiac MRI is recommended for second-line when echocardiography is unavailable or impractical
      • MUGA screening is advised only if echocardiography and cardiac MRI are unavailable.
      Message 4
      • New definition of cancer-treatment-related-cardiac-dysfunction (CTRCD) is provided.
      • Divided into symptomatic or asymptomatic
      • Further divided into mild, moderate, severe or very severe
      • Asymptomatic mild CTRCD defined as LVEF >50% with GLS relative decrement of >15% or biomarker rise
      • Asymptomatic moderate CTRCD defined as >10% absolute LVEF decrement to 40–49%, or <10% absolute decrement to 40-49% with GLS decrement or biomarker rise.
      • Asymptomatic severe CTRCD defined as LVEF drop to <40%.
      Message 5
      • Importance of avoiding interruptions or delays in anti-cancer treatment is emphasised.
      • For example, a patient with trastuzumab-related moderate CTRCD and LVEF in 40–49% range may safely continue trastuzumab without interruption if cardio-protective strategies are utilised.
      Message 6Primary prevention of CTRCD involves careful baseline risk assessment, optimisation of lifestyle and attention to cardiovascular risk factors. In certain instances cardioprotective therapies (e.g. dexrazoxane) could be considered.

      Secondary prevention typically requires a more comprehensive workup (e.g. biomarkers, ECG, cardiac imaging), more aggressive risk factor modification and, in selected high-risk cases, prophylactic use of ACE inhibitors, beta blockers and statins.
      Message 7
      • Diagnostic criteria for immune-checkpoint inhibitor myocarditis is provided:
      • Major criteria include CMR findings meeting modified Lake Louise criteria for myocarditis.
      • Minor criteria include physical symptoms, ventricular arrhythmias, LV dysfunction, other autoimmune phenomena and minor CMR findings
      Message 8
      • Long-term cardiovascular monitoring is recommended for high-risk and very-high-risk cancer survivors
      • Suggested categories for high-risk include cumulative doxorubicin or equivalent dose of >250 mg/m2, radiotherapy dose >15 Gy MDT or high-risk allogeneic stem-cell-transplant.
      • Suggested monitoring includes echocardiography at 1 year, 3 years, 5 years and every 5 years thereafter.
      Message 9
      • The five Class I recommendations (i.e. physicians should do) include:
      • Use of low molecular weight heparin (LMWH) for prophylaxis of venous thromboembolism (VTE) in patients with multiple myeloma and VTE risk factors.
      • QTc monitoring at baseline, 14 days, and 28 days in patients receiving ribociclib.
      • Treatment of VTE with apixaban, edoxaban, or rivaroxaban in patients with VTE and cancer.
      • Treatment of VTE with LMWH in patients with cancer and a platelet count >50,000.
      • Cardiac magnetic resonance imaging for the evaluation of patients with suspected AL cardiac amyloidosis
      Message 10The five class III recommendations (i.e. recommendations that physicians avoid these treatments) include:
      • Avoid QT-prolonging drugs in patients with cancer and Takotsubo cardiomyopathy.
      • Avoid aspirin in patients with cancer and thrombocytopaenia if platelets <10,000.
      • Avoid clopidogrel in cancer patients with platelets <30,000; avoid prasugrel and ticagrelor if platelets <50,000.
      • Aspirin or LMWH are not recommended for primary prevention of stroke or systemic thromboembolism in patients with cancer and atrial fibrillation.
      • Diltiazem and verapamil are not recommended for the treatment of hypertension in patients with cancer due to drug-drug interactions.
      Abbreviations: HFA-ICOS, Heart Failure Association-International Cardio-Oncology Society; 3D, three dimensional; LVEF, left ventricular ejection fraction; GLS, global longitudinal strain; CTRCD, cancer treatment-related cardiac dysfunction; ECG, electrocardiogram; ACE, angiotensin converting enzyme; CMR, cardiac magnetic resonance; MDT, multidisciplinary team care; LMWH, low molecular weight heparin; VTE, venous thromboembolism; AL, amyloid light chain.
      A key element that is missing from the guidelines is specific advice on what a cardio-oncology service should look like, the minimum standards required, and steps that should be taken to actualise such a service. Perhaps this is unavoidable for a society that covers 44 countries but it may be worthwhile to consider what such services could look like in Australia and New Zealand, where health services are more uniform. It is likely to become increasingly difficult for ever more diverse and specialised cardio-oncology care to be comprehensively managed by general cardiology clinics. This is especially true as development of new oncological therapies occurs at a remarkable pace. Creation of cardio-oncology mentoring and support services at quaternary centres to assist general cardiologists at primary, secondary and tertiary hospitals as a “hub-and-spoke” model could help disseminate clinical experience and practice points without generating overly onerous training requirements. Development of cardiology subspecialties is typically a slow process—it is notable that Andreas Grüntzig performed his first coronary angioplasty in 1977 but a subspecialty board certification for interventional cardiology in US was only established nearly 3 decades later in 2006 [
      • Bass T.A.
      Certification and competency in interventional cardiology: the changing landscape.
      ]. Creation of minimal standards for cardio-oncology independent practice would be an ideal first-step. These standards may need to be flexible depending on the clinical context, local hospital resources and location and could range from a mentoring program for motivated cardiologists in regional areas to formal certification through national or international programs. The development of cardio-oncology nurse specialist programs should also be encouraged as should shared care pathways with primary care physicians.
      An important requirement for the cardio-oncology subspecialty is the need for close interdisciplinary collaboration with cancer specialists, allied health, and primary care physicians. Currently, many medical specialties work in silos where specialists rarely interact with other subspecialists and attend different teaching programs, departmental meetings and even different social events. Cardiologists can certainly learn a great deal from oncologists and haematologists and their allied staff [
      • Zannad F.
      • Cotter G.
      • Alonso Garcia A.
      • George S.
      • Davison B.
      • Figtree G.
      • et al.
      What can heart failure trialists learn from oncology trialists?.
      ]. Although these European Society of Cardiology (ESC) guidelines state that “collaboration between healthcare providers is needed to address future needs”, a picture of what such collaboration would look like is missing. We suggest that collaborative partnerships, based on mutual intercollegial respect and support, with active dismantling of access barriers for improved and rapid communication are needed. An excellent initial step could be creation of multi-disciplinary cardio-oncology meetings and shared responsibility for training programs.
      Some limitations of the guidelines in terms of their application, including in Australasia, require further discussion. Direct implementation of such complex guidelines will be challenging and would require outreach and teaching by Australasian cardio-oncologists. Much of the text focusses on cardiovascular monitoring and imaging with relatively less information provided for changing oncology practice. There is limited information regarding specific treatment options and the guidelines refer to complementary ESC guidelines (e.g. valvular or preventative guidelines) several times when discussing treatment options. This increases the complexity for the use of the guidelines and might make it difficult for physicians to use guidelines for quickly answering ‘in-clinic’ questions. Several tools are recommended for risk assessment that may not be available in Australia. For example, the guidelines recommend use of the Heart Failure Association-International Cardio-Oncology Society (HFA-ICOS) score but no online calculator exists, and implementation would be challenging in Australia and New Zealand. It is also unclear which specialties (e.g. oncology, cardiology, primary care) would be expected to take on this responsibility. Readily available information on drug–drug interactions in cardio-oncology is scarce and inclusion of a user-friendly flow-diagram detailing a standardised approach to drug–drug interactions might have been helpful.
      In summary, these ESC guidelines provide the much needed and helpful guidance for physician and allied health staff caring for cancer patients and will go a long way to standardise care across institutions. They add value beyond existing guidelines by bringing together an enormous amount of scientific information into a single accessible document that provides support for best medical practice. Previously no single professional society cardio-oncology document has encompassed all of the treatments and conditions discussed in these guidelines. However, the length, complexity and wide scope of the guidelines may make it challenging for general cardiologists to implement, and cardiology leaders may wish to consider devoting resources to generating focussed and more concise local cardio-oncology practice guidance documents with these guidelines serving as a foundational support. This document serves as a strong step forward given that the complexity of the cardio-oncology field is only likely to increase in future, as iterative later guidelines incorporate even more scientific progress and evidence. Further research efforts in cardio-oncology by professionals from multiple specialties and at all levels of experience should be actively encouraged, as the generation of cardio-oncology services will in the long run benefit patients [
      • Ky B.
      How to Become a Cardio-Oncology Investigator.
      ]. It may take a village to birth a new subspecialty but it will take global collective action by passionate health care providers to make it an accessible reality.

      Funding

      AL Sverdlov is supported by the National Heart Foundation of Australia Future Leader Fellowship (Award ID 106025), DTM Ngo is supported by the National Heart Foundation of Australia Future Leader Fellowship (Award ID 104814).

      Declarations

      Professor Alex Lyon was lead author and co-chair on the ESC 2022 Cardio-Oncology guidelines.

      Conflicts of Interest/Competing Interest

      No conflicts of interest to report.

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