The year in cardiovascular medicine 2023: the top 10 papers in cardio-oncology (2024)

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Guidelines and consensus documents

Over the past year, there have been many outstanding contributions to the field of cardio-oncology, and the scope and depth of them are exemplified herein (Graphical Abstract). The first to mention is the update by the International Late Effects of Childhood Cancer Guideline Harmonization Group on tailored cardiomyopathy surveillance recommendations for healthcare providers and childhood and young adult (CAYA, defined as < 25 years at diagnosis) cancer patients, who are at least 2 years from the completion of cancer therapy, which included anthracyclines and/or radiation therapy (RT) with heart exposure.¹ The first guideline was published in 2015, but since then, new studies have been published redefining dose thresholds, cardiomyopathy risk over time, and importantly, the cost-effectiveness of different surveillance strategies, including cardiac biomarkers, cardiac magnetic resonance imaging (MRI), and echocardiography (3D preferred). Echocardiography remains as the primary surveillance strategy, to be considered every 5 years in those at moderate risk (defined as a cumulative anthracycline dose of 100–249 mg/m² or chest-directed radiation dose of 15–29 Gy) and to be recommended every 2 years in those at high risk (defined as a cumulative anthracycline dose of ≥250 mg/m² or chest-directed radiation dose of ≥30 Gy). Of note, serial surveillance is no longer recommended in low-risk CAYA survivors. Overall, these recommendations are in agreement with the 2022 European Society of Cardiology Guidelines on Cardio-Oncology.²

Chemotherapy (and cardioprotection)

Regarding prevention of cardiomyopathy, dexrazoxane is one of the advocated strategies, but data are lacking for a benefit beyond 5 years after treatment. This gap was addressed by a study, combining four Children's Oncology Group protocols (P9404, P9425, P9426, and P9754) and one Dana Faber Cancer Institute protocol (95-01), which were published between 2009 and 2016 and yielded 195 CAYA patients (age range 0–30 years), undergoing treatment with doxorubicin at doses ranging from 100 to 600 mg/m² with or without upfront random assignment to dexrazoxane for acute lymphoblastic leukaemia (n = 101), lymphoma (n = 84), or osteosarcoma (n = 10).³ On average, 18.1 ± 2.7 years after cancer diagnosis, fractional shortening (FS) was mildly but significantly higher, and conversely, myocardial global longitudinal strain and N-terminal pro-brain natriuretic peptide were mildly but significantly lower in those who received dexrazoxane. Absolute values of left ventricular ejection fraction (EF) were not significantly different, but the percentage of those with a FS <30% or EF <50% was reduced by dexrazoxane by two-thirds. The benefit was more prominent (80% risk reduction) and, in fact, confined to those who received a cumulative doxorubicin dose of 250 mg/m² or more. Collectively, these data support current recommendations that dexrazoxane may be used for cardio-protection in this high-risk group of CAYA patients.²

The merit of statin therapy for the prevention of anthracycline cardiotoxicity was tested in the STOP-CA trial.⁴ Between January 2017 and September 2021, this study randomized 300 adult lymphoma patients (73% non-Hodgkin lymphoma) across 9 sites in North America 1:1 to atorvastatin, 40 mg/day orally, or placebo, starting prior to the first scheduled anthracycline infusion and continued for 12 months thereafter. The primary endpoint of the rate of absolute decline in left ventricular EF of ≥10% from prior to chemotherapy to a final value of <55% over the 12-month study was reached in 9 and 22% in those randomized to atorvastatin and placebo, respectively (P = .002, 2.9-fold higher risk in those randomized to placebo). The number needed to treat to avoid one primary endpoint event was 7.7. The difference in the absolute change in EF from baseline to 12 months between the two groups was 1.3% (P = .03). There were no differences in clinical cardiovascular events and adverse events between the groups. While STOP-CA is supportive of statins for cardio-protection in adult cancer patients at high risk for anthracycline cardiotoxicity, not all trials on this topic have reached the same conclusion, and a class IIa recommendation remains.²

Exercise therapy

Exercise therapy has been advocated as a strategy to improve cardio-respiratory fitness, and the question of the most appropriate timing of doing so was addressed in a study on 158 women initiating adjuvant therapy for breast cancer at Memorial Sloan Kettering and Duke University Medical Center between December 2012 and March 2020.⁵ Neither concurrent [administered for the length of chemotherapy (≈14–20 weeks)] nor sequential [initiated within 14 days of final chemotherapy cycle (≈14–20 weeks)] led to a significant benefit. On the contrary, continuous exercise [administered during chemotherapy (≈14–20 weeks) and continued after the final chemotherapy cycle for an additional ≈14–20 weeks, i.e. ≈28–40 weeks in total] did improve cardiorespiratory fitness (peak oxygen consumption). These data are in agreement with the notion that the benefits of exercise are seen at a level that is (i) beyond the current recommendation for physical activity and (ii) starting as early and for as long as possible after cancer diagnosis/therapy initiation.

Radiation therapy

Considerable reductions in radiation dose exposures have been made over the past decades. The question whether radiation dose exposure to cardiac substructures still predicts the risk of major ischaemic events was addressed in a retrospective cohort study of 2158 Taiwanese women with breast cancer who underwent post-operative chest RT between 2005 and 2017.⁶ At a median follow-up of 7.9 years, 89 patients (4.1%) developed major ischaemic events, especially those with left-sided disease. Age, chronic kidney disease, and hyperlipidaemia were significant risk factors as was mean heart dose (MHD) with an excess risk of major ischaemic events of 6.2% per Gray (Gy) exposure. The model containing the relative volume of the left ventricle receiving 25 Gy (LV V25) with a cut-point of 4% presented the best goodness of fit and discrimination performance in left-sided breast cancer.⁶ This study henceforth provides supportive data to guide radiation dose exposure limits to the heart and major ischaemic event risk reduction efforts.

Immunotherapies

The best treatment strategy for patients with severe immune checkpoint inhibitor (ICI) myocarditis remains to be defined, and a prospective, single-centre cohort study from Pitié-Salpêtrière, Paris, France, reported important observations.⁷ The first 10 of the 40 consecutive patients with definite ICI myocarditis admitted to the cardio-oncology unit between 5 October 2018 and 18 August 2021 (Phase 1) were treated per expert consensus guidelines, i.e. starting with high-dose corticosteroid boluses followed by second-line agents if steroid resistant. The next 20–40 consecutive patients (Phase 2) were treated in a ‘mechanism-based approach’. This included the prompt use of high-dose abatacept with real-time CD86 receptor occupancy (RO) monitoring, ruxolitinib, lower doses of corticosteroids, and screening and early management of concomitant respiratory muscle failure. Survival improved from only 40% during Phase 1 to 97% during Phase 2. These are exciting data, and two ongoing trials are investigating the optimal dose (AbataCept for the Treatment of Immune-cHeckpoint Inhibitors Induced mYocarditiS, ACHLYS, NCT05195645) and efficacy and safety (Abatacept in Immune Checkpoint Inhibitor Myocarditis, ATRIUM, NCT05335928) of abatacept in ICI myocarditis, which will shape future practice recommendations for the management of patients with this condition.

A second study from Pitié-Salpêtrière, Paris, France, and the International ICI-Myocarditis Registry, using multiple lines of additional resources, found that patients with thymic epithelial tumours (TETs) had a 10–30-fold higher frequency of ICI myotoxicity than patients with other cancers.⁸ The onset of ICI myocarditis was earlier in TET patients and more commonly with additional presentation of myositis and myasthenia gravis-like syndrome and higher rate of serious adverse events including respiratory muscle failure, life-threatening ventricular arrhythmia, and death. Higher grade of tissue presence on computed tomography imaging of the thymus (Grade 3 and higher) and ICI combination therapy were profound predictors of ICI myocarditis not only on therapy but even before ICI therapy (odds ratio 25). Last but not least, positive anti-acetylcholine receptor auto-antibody status (AchR+) as a biological surrogate of thymic-associated autoimmunity signalled a more than five-fold higher risk of ICI myocarditis and two-fold higher risk of severe heart and respiratory muscle failure. Thus, this study provides several ICI myocarditis risk factors to check for combination ICI therapy, high radio-pathological thymus grade, and AchR autoantibodies. Importantly, even the latter (or history of myasthenia gravis) are often already defined before the initiation of ICI therapy.

Severe cardiovascular events (SCEs), including heart failure, cardiogenic shock, or myocardial infarction, have also been reported with chimeric antigen receptor T cell therapy (CAR-T), but best biomarker predictors and correlation with outcomes have remained undefined. Of 202 patients enrolled in a multicentre registry, 33 (16.3%) patients experienced SCE after anti-CD19 CAR-T therapy, and 108 (53.5%) patients died during a median follow-up of 297 days.⁹ Higher peak interleukin-6 and ferritin levels after CAR-T infusion identified those at risk of death and SCE; C-reactive protein and cardiac troponin were additional predictors for SCE (but not mortality). Importantly, SCE after CAR-T was an independent risk factor for overall mortality and non-relapse mortality (2.8- and 3.5-fold higher risk). This study thus raises awareness to better predict and manage cardiovascular events after CAR-T for improved survival outcomes. Future studies in this and other areas of cardio-oncology are very much needed, including basic and translational research efforts, as well as those outlined in a Global Cardio-Oncology Summit 2023 companion article.¹⁰

Arterial and venous thromboembolism

Thromboembolism and bleeding are challenging entities in cancer patients, prompting efforts of minimizing anticoagulation therapies, if possible, e.g. in presumed lower risk scenarios, as investigated in the optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer study trial.¹¹ This open-label study enrolled 601 patients with active cancer and newly diagnosed isolated distal deep vein thrombosis (DVT) across 60 institutions in Japan and randomized them 1:1 to either 3 or 12 months of edoxaban (60 mg once daily, unless creatinine clearance 30–50 mL/min, body weight ≤60 kg, or concomitant treatment with potent P-glycoprotein inhibitors, in which case the dose was 30 mg once daily). The primary endpoint was the composite of venous thromboembolism (VTE)–related death or symptomatic recurrent VTE at 12 months, which was reached in 1.0% of the patients in the 12-month edoxaban group and in 7.2% of the patients in the 3-month edoxaban group (87% risk reduction). Event curves started to separate right at the 3-month mark and were solely driven by symptomatic recurrent VTE (no VTE-related deaths). Major bleeding events were not significantly different between the groups and occurred in 9.5% of the patients in the 12-month edoxaban group and in 7.2% of the patients in the 3-month edoxaban group. The prespecified subgroups did not affect the estimates on the primary endpoint. These results are particularly noteworthy considering that only ∼60% of the patients in the 12-month edoxaban group were still taking the drug at 12 months (continuous drop out). Even more so then, these data argue for the recommendation that patients with active cancer and a distal DVT should continue with anticoagulation for a minimum of 12 months and likely as long as the malignancy is active.

Whether newly diagnosed cancer adds to the risk of arterial thromboembolism (ATE) in patients with atrial fibrillation/flutter (AF) remains an open question, especially in those with low-to-intermediate CHA₂DS₂-VASc scores, where evidence supporting anticoagulation is less robust. A population-based retrospective study pursued an answer to this question in AF patients with CHA₂DS₂-VASc scores of 0–2 seen at Clalit Health Services between 1 January 2002 and 31 December 2020.¹² Importantly, patients with a concomitant cancer diagnosis had a 2.7 times higher hazard of ATE (stroke, transient ischaemic attack, or systemic ATE) over 1 year (12-month cumulative incidence of ATE 2.13% vs. .8%). Of further note, the risk of ATE was highest (six-fold higher risk) in men with a CHA₂DS₂-VASc score of 1 and women with a CHA₂DS₂-VASc score of 2 (even higher than in men with a CHA₂DS₂-VASC score of 2 in whom anticoagulation is recommended). Collectively, these results support the use of anticoagulation in AF patients with newly diagnosed cancer who have a conventional indication for anticoagulation in the absence of a prohibitive bleeding risk.

Declarations

Disclosure of Interest

J.H. has received speaker, advisory board, or consultancy fees from Pfizer, Astellas Pharma, and AstraZeneca. T.L.-F. has received speaker, advisory board, or consultancy fees from AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Janssen-Cilag Ltd, Myocardial Solutions, Pfizer, and Philips. A.R.L. has received speaker, advisory board, or consultancy fees and/or research grants from Janssen-Cilag Ltd, Astellas Pharma, Pfizer, Novartis, Servier, AstraZeneca, Bristol Myers Squibb, GSK, Amgen, Takeda, Roche, Clinigen Group, Eli Lily, Eisai Ltd, Ferring Pharmaceuticals, Boehringer Ingelheim, Akcea Therapeutics, Myocardial Solutions, iOWNA Health, and Heartfelt Technologies Ltd.

References

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