Publications
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Omland, Torbjørn; Heck, Siri Lagethon; Holte, Espen; Gynnild, Mari Nordbø; Gulati, Geeta & Wethal, Torgeir
(2026).
Response by Omland et al to Letter Regarding Article, “Sacubitril/Valsartan and Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: The PRADA II Randomized Clinical Trial”.
Circulation.
ISSN 0009-7322.
153(22).
doi:
10.1161/circulationaha.126.079810.
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Rakisheva, Amina; Farmakis, Dimitrios; Attanasio, Andrea; Genis, Antoni Bayes; Cohen‐Solal, Alain & Gulati, Geeta
[Show all 20 contributors for this article]
(2025).
Prevention of cancer therapy‐related cardiac dysfunction and heart failure in cancer patients and survivors. A Clinical Consensus Statement of the Heart Failure Association, the European Association of Preventive Cardiology of the ESC, and the ESC Council of Cardio‐Oncology.
European Journal of Heart Failure.
ISSN 1388-9842.
27(11),
p. 2099–2099.
doi:
10.1002/ejhf.3753.
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Abstract Despite advances in cancer treatments with significant improvement in patient outcomes, chemotherapy, targeted molecular therapies and radiotherapy may cause a range of cardiovascular complications, such as cancer therapy‐related cardiac dysfunction (CTRCD), which represents a broad spectrum of possible presentation and aetiological link with the broad scope of various cancer therapies, including chemotherapy, targeted agents, immunotherapies, and radiation therapy, aiming at reducing the associated morbidity and mortality. However, practical guidelines on the primary prevention of CTRCD in high‐risk patients, a key element in improving prognosis, are lacking in cancer patients and related evidence remains inconclusive. This Clinical Consensus Statement, authored by experts from the Heart Failure Association (HFA) and the European Association of Preventive Cardiology (EAPC) of the European Society of Cardiology (ESC), and the ESC Council of Cardio‐Oncology, aims to discuss the definition and epidemiology of CTRCD, the implicated factors for risk stratification, and the appropriate early diagnostic pathways, while focusing on lifestyle modifications, and pharmacological interventions to reduce the incidence of CTRCD. In addition, a holistic cardio‐oncology management approach is advised for prevention and long‐term management.
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Gynnild, Mari Nordbø; Vinje-Jakobsen, Victoria; Holtrop, Joris; Hageman, Steven H.J.; Holte, Espen & Gulati, Geeta
[Show all 14 contributors for this article]
(2025).
Prognostic Performance of a Modified HFA-ICOS Tool for Prediction of Cardiovascular Complications in Cancer Patients.
JACC: Advances.
4(12).
doi:
10.1016/j.jacadv.2025.102344.
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Background
The 2022 European Society of Cardiology Cardio-oncology Guidelines recommend the Heart Failure Association and International Cardio-Oncology Society risk stratification tool to predict cardiovascular disease (CVD) risk in cancer patients. Developed from expert consensus rather than mathematical derivation, its quantitative prognostic value in unselected cancer populations remains uncertain.
Objectives
The objective of the study was to assess the prognostic utility of a modified Heart Failure Association and International Cardio-Oncology Society tool, excluding biomarkers and imaging, in predicting CVD complications in cancer patients, thereby providing a quantitative correlate to an expert consensus-based method.
Methods
We included 2,290 cancer patients from the third follow-up of the Trøndelag Health study, diagnosed within 4 years of participation, and followed through 2023. Cancer therapy details were obtained from the Norwegian Cancer Registry. The primary outcome was a composite of myocardial infarction, heart failure hospitalization, stroke, or CVD mortality, identified via national registries.
Results
The mean age was 65.8 years; 48% were female. The most common cancers were gastrointestinal (23%), prostate (19%), and breast (12%). The median follow-up was 6.9 years. The modified tool classified 28% as low-, 35% moderate-, 34% high-, and 3% very high-risk. CVD incidence rose across categories: 7%, 21%, 29%, and 37% (P < 0.001). The C-statistic was 0.696 (95% CI: 0.674-0.718), and 0.746 (95% CI: 0.676-0.812) among anthracycline-treated patients. Within the low-to-moderate group, event rates ranged from 6% to 8% (0-1 points) to 24% to 27% (3-4 points).
Conclusions
The tool stratifies CVD risk in cancer patients and may guide tailored follow-up and cardioprotection. Heterogeneity within moderate-risk patients highlights the need for refinement to improve individualized assessment.
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Chadwick, Jessica; Berry, Colin; Carpenter, Meredith A.; Gulati, Geeta; Heck, Siri Lagethon & Hinterberg, Michael A.
[Show all 18 contributors for this article]
(2025).
Utilization of Proteomic Measures for Early Detection of Drug Benefits and Adverse Effects.
Journal of clinical pharmacology.
ISSN 0091-2700.
65(11),
p. 1460–1473.
doi:
10.1002/jcph.70077.
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Recognition of benefits and adverse effects of therapies in earlier clinical trial phases could improve the safety, efficiency, and cost of clinical trials. Using four clinical trials representing a diverse set of diseases and drug classes (EXSCEL: exenatide/GLP‐1 RA, SUGAR‐DM‐HF: empagliflozin/SGLT2i, PRADA: epirubicin/anthracycline, and AMPLE: abatacept/immunomodulator and adalimumab/TNF inhibitor), we hypothesized that previously validated proteomic measures for cardiometabolic outcomes could enable the detection of beneficial and adverse drug effects in fewer participants over a shorter follow‐up period. Changes in SomaSignal TM proteomic tests over time in response to treatment were assessed in the EXSCEL (baseline vs 1 year; once‐weekly exenatide (EQW) (n) = 1812 vs control (n) = 1787), SUGAR‐DM‐HF (baseline vs 12 weeks and 36 weeks; empagliflozin (n) = 45 vs control (n) = 52), AMPLE (baseline vs 85 days and 1 year; abatacept (n) = 210, adalimumab (n) = 222), and PRADA (baseline vs 7–10 days and 3 months, n = 120) trial. Improvement of cardiovascular risk and cardiometabolic traits with EQW was detectable within 1 year ( P = .002) in sample sizes significantly smaller than the original study. Cardio‐ and kidney‐protective ( P = .06, P = .037) effects of empagliflozin were detectable within 36 weeks in a small sample size (n ∼ 50). Abatacept and adalimumab treatment demonstrated significant improvements in cardiovascular risk ( P ≤ .001, P ≤ .001) and cardiorespiratory fitness ( P ≤ .001, P ≤ .001) within 85 days. In contrast, anthracycline treatment led to significant increases in heart failure mortality risk ( P ≤ 0.001) and cardiovascular risk ( P = .004) after the first cycle of chemotherapy treatment. These findings provide preliminary evidence that proteomics may provide a powerful tool for optimizing drug pipelines by predicting the effects of novel therapeutics in smaller, shorter trials.
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Omland, Torbjørn; Heck, Siri Lagethon; Holte, Espen; Mecinaj, Albulena; Gynnild, Mari Nordbø & Fagerland, Morten
[Show all 13 contributors for this article]
(2025).
Sacubitril/Valsartan and Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: The PRADA II Randomized Clinical Trial.
Circulation.
ISSN 0009-7322.
152(16),
p. 1136–1145.
doi:
10.1161/circulationaha.125.076616.
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Background: Anthracycline- and trastuzumab-associated cardiotoxicity may lead to cardiac dysfunction and dose reduction or halt in potentially life-saving adjuvant cancer therapy. Whether angiotensin receptor neprilysin inhibitors can prevent cancer therapy-related cardiac dysfunction and injury remains to be established. Methods: PRADA II was a randomized, parallel-group, placebo-controlled, double-blind multicenter trial conducted at 4 academic medical centers in Norway that evaluated the cardioprotective effect of sacubitril-valsartan vs. placebo administered concomitantly with anthracycline-containing breast cancer therapy and continued for 18 months. The target dose was 97/103 mg b.i.d. The primary outcome was change in left ventricular ejection fraction by cardiovascular magnetic resonance from prior to initiation of chemotherapy to 18 months after. Secondary outcomes included change in echocardiographic global longitudinal strain, circulating cardiac troponins, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Results: In total, 138 women (mean (±SD) age: 54.0 ± 9.4 years) were randomized. The overall decline in left ventricular ejection fraction from baseline to 18 months was 2.2 percentage points (95% confidence interval [CI], 1.1 to 3.3) in the placebo group and 1.1 percentage points (95% CI, -0.01 to 2.2) in the sacubitril-valsartan group. The between-group difference was 1.1 percentage points (95% CI, -0.4 to 2.7; P=0.16). Left ventricular global longitudinal strain was normal and remained stable in the sacubitril-valsartan group throughout the study (change from baseline to 18 months -0.32 [95% CI, -0.80 to 0.15]). In contrast, there was a progressive decline in the placebo group (change from baseline to 18 months 0.53 [95% CI, 0.05 to 1.00]). The between-group difference was -0.85 (95% CI, -1.52 to -0.18). The mean increases in NT-proBNP and cardiac troponin I concentrations from baseline to 18 months were greater in the placebo than in the sacubitril-valsartan group (log difference 0.303 (95% CI 0.0547 to 0.552) for NT-proBNP and 0.534 (95% CI 0.114 to 0.954) for cardiac troponin I). Conclusions: Anthracycline-based treatment for early breast cancer is associated with a reduction in left ventricular ejection fraction that was not significantly attenuated by sacubitril-valsartan.
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Tocchetti, Carlo Gabriele; Farmakis, Dimitrios; Koop, Yvonne; Andres, Maria Sol; Couch, Liam S. & Formisano, Luigi
[Show all 51 contributors for this article]
(2024).
Cardiovascular toxicities of immune therapies for cancer – a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology.
European Journal of Heart Failure.
ISSN 1388-9842.
26(10),
p. 2055–2076.
doi:
10.1002/ejhf.3340.
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Mecinaj, Albulena; Gulati, Geeta; Ree, Anne Hansen; Gravdehaug, Berit; Røsjø, Helge Rørvik & Steine, Kjetil
[Show all 10 contributors for this article]
(2024).
Impact of the ESC Cardio-Oncology Guidelines Biomarker Criteria on Incidence of Cancer Therapy–Related Cardiac Dysfunction.
JACC: CardioOncology.
6(1),
p. 83–95.
doi:
10.1016/j.jaccao.2023.10.008.
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Background The impact of recent consensus definitions of cancer therapy–related cardiac dysfunction (CTRCD) from the European Society of Cardiology cardio-oncology guidelines on the reported incidence of CTRCD has not yet been assessed. Objectives The aim of this study was to assess the: 1) cumulative incidence; 2) point prevalence during and after adjuvant therapy; and 3) prognostic value of CTRCD as defined by different asymptomatic CTRCD guideline criteria. Methods The cumulative incidence and point prevalence of CTRCD were retrospectively assessed in 118 patients participating in the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial. Asymptomatic CTRCD was assessed using alternative cardiac troponin (cTn) 99th percentile upper reference limits (URLs) to define cTnT and cTnI elevation. Results The cumulative incidence of moderate or severe CTRCD was low (1.7%), whereas the cumulative incidence of mild asymptomatic CTRCD was higher and differed markedly according to the biomarker criteria applied, ranging from 49.2% of patients when cTnT greater than the sex-specific 99th percentile URL was used to define cTn elevation to 9.3% when sex-neutral cTnI was used. The point prevalence of CTRCD was highest at the end of anthracycline therapy (47.8%) and was driven primarily by asymptomatic cTn elevation. CTRCD during adjuvant therapy was not prognostic for CTRCD at extended follow-up of 24 months (Q1-Q3: 21-29 months) after randomization. Conclusions Mild asymptomatic CTRCD during adjuvant breast cancer therapy was frequent and driven mainly by cTn elevation and was not prognostic of subsequent CTRCD. The incidence of mild, asymptomatic CTRCD differed markedly depending on the cTn assay and whether sex-neutral or sex-dependent URLs were applied. (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy [PRADA]; NCT01434134)
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Lee, G.A.; Aktaa, S.; Baker, E.; Gale, C.P.; Yaseen, Israa F. & Gulati, Geeta
[Show all 27 contributors for this article]
(2022).
European Society of Cardiology quality indicators for the prevention and management of cancer therapy-related cardiovascular toxicity in cancer treatment.
European Heart Journal - Quality of Care and Clinical Outcomes.
ISSN 2058-5225.
9(1),
p. 1–7.
doi:
10.1093/ehjqcco/qcac070.
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Abstract Aims To develop quality indicators (QIs) for the evaluation of the prevention and management of cancer therapy-related cardiovascular toxicity. Methods and results We followed the European Society of Cardiology (ESC) methodology for QI development which comprises (i) identifying the key domains of care for the prevention and management of cancer therapy-related cardiovascular toxicity in patients on cancer treatment, (ii) performing a systematic review of the literature to develop candidate QIs, and (iii) selecting of the final set of QIs using a modified Delphi process. Work was undertaken in parallel with the writing of the 2022 ESC Guidelines on Cardio-Oncology and in collaboration with the European Haematology Association, the European Society for Therapeutic Radiology and Oncology and the International Cardio-Oncology Society. In total, 5 main and 9 secondary QIs were selected across five domains of care: (i) Structural framework, (ii) Baseline cardiovascular risk assessment, (iii) Cancer therapy related cardiovascular toxicity, (iv) Predictors of outcomes, and (v) Monitoring of cardiovascular complications during cancer therapy. Conclusion We present the ESC Cardio-Oncology QIs with their development process and provide an overview of the scientific rationale for their selection. These indicators are aimed at quantifying and improving the adherence to guideline-recommended clinical practice and improving patient outcomes.
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Gevaert, Sofie; Halvorsen, Sigrun; Sinnaeve, Peter; Sambola, Antonia; Gulati, Geeta & Lancellotti, Patrizio
[Show all 14 contributors for this article]
(2022).
Evaluation and management of cancer patients presenting with acute cardiovascular disease: a Clinical Consensus Statement of the Acute CardioVascular Care Association (ACVC) and the ESC council of Cardio-Oncology-part 2: acute heart failure, acute myocardial diseases, acute venous thromboembolic diseases, and acute arrhythmias.
European Heart Journal: Acute Cardiovascular Care.
ISSN 2048-8726.
11(11),
p. 865–874.
doi:
10.1093/ehjacc/zuac107.
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Omland, Torbjørn; Heck, Siri Lagethon & Gulati, Geeta
(2022).
The Role of Cardioprotection in Cancer Therapy Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review.
JACC: CardioOncology.
4(1),
p. 19–37.
doi:
10.1016/j.jaccao.2022.01.101.
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Cardiotoxicity is a relatively frequent and potentially serious side effect of traditional and targeted cancer therapies. Both general measures and specific pharmacologic cardioprotective interventions as well as imaging- and biomarker-based surveillance strategies to identify patients at high risk have been tested in randomized controlled trials to prevent or attenuate cancer therapy–related cardiotoxic effects. Although meta-analyses including early trials suggest an overall beneficial effect, there is substantial heterogeneity in results. Recent randomized controlled trials of neurohormonal inhibitors in patients receiving anthracyclines and/or human epidermal growth factor receptor 2–targeted therapies have shown a lower rate of cancer therapy–related cardiac dysfunction than previously reported and a modest or no sustained effect of the interventions. Data on preventive cardioprotective strategies for novel cancer drugs are lacking. Larger, prospective multicenter randomized clinical trials testing traditional and novel interventions are required to more accurately define the benefit of different cardioprotective strategies and to refine risk prediction and identify patients who are likely to benefit.
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Heck, Siri Lagethon; Mecinaj, Albulena; Ree, Anne Hansen; Hoffmann, Pavel; Schulz-Menger, Jeanette & Fagerland, Morten
[Show all 12 contributors for this article]
(2021).
Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): Extended follow-up of a 2×2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol.
Circulation.
ISSN 0009-7322.
143(25),
p. 2431–2440.
doi:
10.1161/CIRCULATIONAHA.121.054698.
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Background: Adjuvant breast cancer therapy containing anthracyclines with or without anti–human epidermal growth factor receptor–2 antibodies and radiotherapy is associated with cancer treatment–related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the β-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury. Methods: In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations. Results: A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group (P=0.021) and attenuated decline in global longitudinal strain (P=0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed. Conclusions: Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01434134.
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Haakensen, Vilde Drageset; Thunold, Solfrid M. H. & Gulati, Geeta
(2021).
Case Report: Fatal myocarditis after combination of immune checkpoint inhibitor and platinum doublet chemotherapy [version 1; peer review: 1 not approved].
F1000.
10,
p. 1–9.
doi:
10.12688/F1000RESEARCH.27967.1.
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Mecinaj, Albulena; Gulati, Geeta; Heck, Siri Lagethon; Holte, Espen; Fagerland, Morten Wang & Larsen, Alf Inge
[Show all 10 contributors for this article]
(2021).
Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial.
Cardio-Oncology.
7.
doi:
10.1186/s40959-021-00115-w.
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Objective
To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction.
Methods
PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations.
Results
The study is ongoing. Results will be published when the study is completed.
Conclusion
PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy.
Trial registration
The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588). Registered 30 November 2018.
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Broberg, Agneta Månsson; Geisler, Jürgen; Tuohinen, Suvi; Skytta, Tanja; Hrafnkelsdóttir, Þórdís Jóna & Nielsen, Kirsten Melgaard
[Show all 11 contributors for this article]
(2020).
Prevention, detection, and management of heart failure in patients treated for breast cancer.
Current Heart Failure Reports.
ISSN 1546-9530.
17(6),
p. 397–408.
doi:
10.1007/s11897-020-00486-8.
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Abstract Purpose of Review Long-term survival has increased significantly in breast cancer patients, and cardiovascular side effects are surpassing cancer-related mortality. We summarize risk factors, prevention strategies, detection, and management of cardiotoxicity, with focus on left ventricular dysfunction and heart failure, during breast cancer treatment. Recent Findings Baseline treatment of cardiovascular risk factors is recommended. Anthracycline and trastuzumab treatment constitute a substantial risk of developing cardiotoxicity. There is growing evidence that this can be treated with beta blockers and angiotensin antagonists. Early detection of cardiotoxicity with cardiac imaging and circulating cardiovascular biomarkers is currently evaluated in clinical trials. Chest wall irradiation accelerates atherosclerotic processes and induces fibrosis. Immune checkpoint inhibitors require consideration for surveillance due to a small risk of severe myocarditis. Cyclin-dependent kinases4/6 inhibitors, cyclophosphamide, taxanes, tyrosine kinase inhibitors, and endocrine therapy have a lower-risk profile for cardiotoxicity. Summary Preventive and management strategies to counteract cancer treatment–related left ventricular dysfunction or heart failure in breast cancer patients should include a comprehensive cardiovascular risk assessment and individual clinical evaluation. This should include both patient and treatment-related factors. Further clinical trials especially on early detection, cardioprevention, and management are urgently needed.
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Gulati, Geeta; Heck, Siri Lagethon; Røsjø, Helge; Ree, Anne Hansen; HOFFMANN, PAVEL & Hagve, Tor-Arne
[Show all 11 contributors for this article]
(2017).
Neurohormonal blockade and circulating cardiovascular biomarkers during anthracycline therapy in breast cancer patients: Results from the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) study.
Journal of the American Heart Association (JAHA).
6(11).
doi:
10.1161/JAHA.117.006513.
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Background Anthracyclines are associated with cardiotoxic effects. Cardiovascular biomarkers may reflect myocardial injury, dysfunction, inflammation, and fibrosis and may precede and predict the development of left ventricular impairment. The aim of this study was to assess: (1) longitudinal change in circulating cardiovascular biomarkers, (2) the effect of metoprolol succinate and candesartan cilexetil on the biomarker response, and (3) the associations between on‐treatment changes in biomarker concentrations and subsequent left ventricular dysfunction in patients with early breast cancer receiving anthracyclines. Methods and Results This report encompasses 121 women included in the 2×2 factorial, placebo‐controlled, double‐blind PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial with metoprolol and candesartan given concomitantly with anticancer therapy containing the anthracycline, epirubicin (total cumulative dose, 240–400 mg/m2). Cardiovascular magnetic resonance, echocardiography images, and circulating levels of biomarkers were obtained before and after anthracycline treatment. Cardiac troponins I and T, B‐type natriuretic peptide, N‐terminal pro‐B‐type natriuretic peptide, C‐reactive protein, and galectin‐3 increased during anthracycline therapy (all P<0.05). The troponin response was attenuated by metoprolol (P<0.05), but not candesartan. There was no association between change in biomarker concentrations and change in cardiac function during anthracycline therapy. Conclusions Treatment with contemporary anthracycline doses for early breast cancer is associated with increase in circulating cardiovascular biomarkers. This increase is, however, not associated with early decline in ventricular function. Beta‐blockade may attenuate early myocardial injury, but whether this attenuation translates into reduced risk of developing ventricular dysfunction in the long term remains unclear. Clinical Trial Registration URL: http://www.clinicaltrial.gov. Unique identifier: NCT01434134.
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Heck, Siri Lagethon; Gulati, Geeta; HOFFMANN, PAVEL; Knobelsdorff-Brenkenhoff, Florian von; Storås, Tryggve & Ree, Anne Hansen
[Show all 12 contributors for this article]
(2017).
Effect of candesartan and metoprolol on myocardial tissue composition during anthracycline treatment: The PRADA trial.
European Heart Journal-Cardiovascular Imaging.
ISSN 2047-2404.
19(5),
p. 544–552.
doi:
10.1093/ehjci/jex159.
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Aims:
Anthracycline treatment may cause myocyte loss and expansion of the myocardial extracellular volume (ECV) fraction by oedema and fibrosis. We tested the hypotheses that adjuvant treatment for early breast cancer with the anthracycline epirubicin is dose dependently associated with increased ECV fraction and total ECV, as well as reduced total myocardial cellular volume, and that these changes could be prevented by concomitant angiotensin or beta-adrenergic blockade.
Methods and results:
PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA) was a 2 × 2 factorial, placebo-controlled, double-blinded trial of candesartan and metoprolol. Sixty-nine women had valid ECV measurements. ECV fraction, total ECV, and total cellular volume were measured by cardiovascular magnetic resonance before and at the completion of anthracycline therapy. ECV fraction increased from 27.5 ± 2.7% to 28.6 ± 2.9% (P = 0.002). A cumulative doxorubicin equivalent dose of 268 mg/m2 was associated with greater increase in ECV fraction than doses <268 mg/m2 (mean change 3.4% [95% confidence interval (CI) 1.2, 5.5] vs. 0.7% [95% CI 0.0, 1.5], P = 0.006), as well as greater increase in total ECV (1.9 mL [95% CI 0.4, 3.5] vs. 0.1 mL [95% CI -0.6, 0.8], P = 0.04). In patients receiving candesartan, total cellular volume decreased (-3.5 mL [95% CI - 4.7, -2.2], P < 0.001) while in patients not receiving candesartan, it remained unchanged (P = 0.45; between group difference P = 0.003).
Conclusions:
Anthracycline therapy is associated with dose-dependent increase in ECV fraction and total ECV. Concomitant treatment with candesartan reduces left ventricular total cellular volume.
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Gulati, Geeta; Heck, Siri Lagethon; Ree, Anne Hansen; HOFFMANN, PAVEL; Schulz-Menger, Jeanette & Fagerland, Morten
[Show all 15 contributors for this article]
(2016).
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.
European Heart Journal.
ISSN 0195-668X.
37(21),
p. 1671–1680.
doi:
10.1093/eurheartj/ehw022.
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Vinje-Jakobsen, Victoria; Gynnild, Mari Nordbø; Mecinaj, Albulena; Wisløff, Torbjørn; Holte, Espen & Wethal, Torgeir
[Show all 13 contributors for this article]
(2026).
The effect of sacubitril/valsartan on functional disability and skeletal muscle injury during breast cancer therapy: insights from the PRADA II trial.
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Background: Anthracycline therapy induces dose-dependent cardiotoxicity and systemic adverse effects, including functional disability. While sacubitril/valsartan attenuates early subclinical myocardial injury during breast cancer therapy, its impact on functional capacity and skeletal muscle injury remains unknown.
Purpose: To evaluate whether sacubitril/valsartan attenuates anthracycline-induced decline in functional capacity and skeletal muscle injury compared to placebo.
Methods: PRADA II was a randomised, double-blind, placebo-controlled multicentre trial including 138 women with early breast cancer receiving (neo)adjuvant anthracycline therapy±trastuzumab. Participants were randomised prior to anthracycline initiation to sacubitril/valsartan or placebo for 18 months. The predefined primary outcome of this substudy was change in maximal handgrip strength from baseline to 18 months. Secondary outcomes included changes in 6-minute walk distance and circulating creatine kinase (CK) and myoglobin concentrations. Assessments were performed at baseline, post-anthracycline (Visit 2), and at 18 months (Visit 3). Changes were analysed using generalised linear mixed models, and a two-sided alpha level of 0.05 was applied to the primary outcome of this predefined substudy.
Results: Maximal handgrip strength declined in both groups from baseline to Visit 2, with partial recovery at Visit 3 in the sacubitril/valsartan group and continued decline in the placebo group. No significant between-group difference was observed in handgrip strength (between-group change from baseline to Visit 3: -0.3 kg, 95% CI -1.5 to 0.8, p=0.57). However, a greater decline from baseline to Visit 2 was observed with sacubitril/valsartan than placebo, corresponding to a between-group difference of -1.8 kg, 95% CI -3.0 to -0.6. 6-minute walk distance increased from baseline to both follow-up timepoints in the sacubitril/valsartan group, and a transient reduction was observed in the placebo group from baseline to Visit 2. Between-group changes did not differ at Visit 2 (8.8 m, 95% CI -19.3 to 36.9) or Visit 3 (13.6 m, 95% CI -13.3 to 40.5). CK and myoglobin were numerically higher in the placebo group from baseline to Visit 3, however, the confidence intervals for between-group differences included the null value (CK geometric mean ratio 1.17, 95% CI 0.94 to 1.45; myoglobin 1.10, 95% CI 0.98 to 1.23). Temporal changes by randomisation group are shown in Figure 1.
Conclusions: Sacubitril/valsartan did not significantly attenuate anthracycline-related decline in functional capacity assessed by maximal handgrip strength and 6-minute walk distance or changes in biomarkers of skeletal muscle injury. These findings suggest a neutral effect of sacubitril/valsartan on functional capacity, without challenging its potential cardioprotective role during anthracycline therapy.
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Vinje-Jakobsen, Victoria; Orstad, Eivind Bjørkan; Gulati, Geeta; Nerdrum, Tone; Iqbal, Naveed & Schirmer, Henrik
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(2026).
Incidence and severity of cancer-therapy-related cardiac dysfunction during contemporary breast cancer therapy in a real-world cohort.
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Background: Cancer therapy-related cardiac dysfunction (CTRCD) is a well-known complication in breast cancer patients exposed to anthracyclines and Human Epidermal Growth Factor Receptor 2 (HER2) targeted therapy. However, the incidence of CTRCD in unselected contemporary breast cancer populations treated according to current standard-of-care regimens remains incompletely investigated.
Purpose: To determine the incidence of CTRCD in women receiving (neo-)adjuvant breast cancer therapy in a real-world setting.
Methods: In this prospective observational study, women scheduled for (neo-)adjuvant breast cancer therapy were included. Participants were categorized into three treatment regimen groups: 1) anthracycline therapy only, 2) HER2-targeted therapy only, and 3) sequential treatment with anthracycline therapy followed by HER2-targeted therapy. The primary endpoint was the incidence of CTRCD, defined according to the echocardiographic criteria included in the 2022 ESC Cardio-Oncology Guidelines (Figure 1), from baseline to 12 months after completion of scheduled therapy. Echocardiography was assessed at baseline, after completion of scheduled therapy, and 12 months thereafter. In addition, echocardiography was performed every 3 months during HER2-targeted therapy and when clinically indicated.
Results: In total, 515 women were included (median age: 53 years (IQR 45,64)). During follow-up, 123 (24%) developed CTRCD. Of these, 78% were classified as mild, 19% moderate, and 2% severe. The highest incidence of CTRCD was observed among participants receiving sequential anthracycline therapy (EC90 x 4) and HER2-targeted therapy (Table 1). This regimen also had the highest incidence of moderate and severe CTRCD (13%), compared with 4% in the anthracycline-only group and 1% in the HER2-only group. Overall, severe CTRCD was observed in 0.6% of all study participants. The cumulative incidence of the worst observed severity of CTRCD during follow-up, overall and by treatment regimen, is summarized in Table 1.
Conclusion: In this real-world breast cancer cohort, nearly one in four women developed CTRCD during follow-up; however, most cases were categorised as mild. Moderate and severe cardiac dysfunction were primarily observed in patients receiving sequential anthracycline and HER2-targeted therapy. Severe CTRCD was rare in the overall study population.
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Vinje-Jakobsen, Victoria; Orstad, Eivind Bjørkan; Gulati, Geeta; Caliskan, Gulser; Nerdrum, Tone & Iqbal, Naveed
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(2026).
Rationale, design and baseline characteristics of the cardio-oncology registry (CARE) study: a prospective, observational study of cardiotoxic effects during breast cancer therapy.
European Heart Journal, Supplement.
ISSN 1520-765X.
28(Supplement_8).
doi:
10.1093/eurheartjsupp/suag097.103.
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Background: Anthracycline and Human Epidermal Growth Factor Receptor 2 (HER2) targeted therapy may induce cancer therapy-related cardiac dysfunction (CTRCD). Current guidelines recommend risk stratification using the Heart Failure Association–International Cardio-Oncology Society (HFA-ICOS) risk assessment tool. However, data on the incidence of CTRCD in contemporary breast cancer populations treated according to current standard-of-care regimens remain limited. Moreover, the actual cardiovascular risk associated with the HFA-ICOS risk categories in breast cancer treatment remains uncertain. Real-world evaluation of whether this consensus-based stratification appropriately separates patients according to subsequent CTRCD risk has been highlighted as a key research priority. Purpose: Overall, the study aims to determine the incidence of CTRCD and to evaluate cardiovascular risk stratification using the HFA-ICOS tool and its association with subsequent CTRCD. Methods: CARE is a prospective observational study including women scheduled for (neo)adjuvant anthracycline therapy and/or HER2-targeted therapy. Echocardiography, using standard and novel echocardiographic parameters, and circulating cardiac biomarkers were assessed at baseline (visit 1), after completion of scheduled therapy (visit 2), and 12 months after completion of scheduled therapy (visit 3). Participants were categorized into three treatment regimen groups: 1) Anthracycline therapy only, 2) HER2-targeted therapy only, and 3) HER2-targeted therapy sequentially to anthracyclines (Figure 1). The primary outcome is incidence of CTRCD. Secondary outcomes include HFA-ICOS risk stratification in relation to subsequent CTRCD. Results: In total, 515 women (median age (Q1,Q3): 53 (45,64) years) were included. Overall, 335 (63%) participants received anthracycline therapy only, 100 (15%) received HER2-targeted therapy only, and 80 (19%) received anthracycline therapy followed by HER2-targeted therapy. Baseline cardiovascular risk factors included hypertension in 20%, current smoking in 13%, diabetes in 7%, and a history of heart disease in 7.6%, while 3.5% had received previous anti-cancer treatment (Table 1). Conclusion: The CARE study is a large prospective observational cardio-oncology study evaluating the incidence of CTRCD after contemporary breast cancer therapy regimens. With systematic echocardiographic and biomarker assessment, the study will provide important insights into the incidence of CTRCD, the performance of the HFA-ICOS risk stratification tool and follow-up strategies in routine cardio-oncology care.Table 1Baseline Characteristics CARE Figure 1Consort Diagram
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Gynnild, Mari Nordbø; Gulati, Geeta; Mecinaj, Albulena; Wethal, Torgeir; Holte, Espen & Vinje-Jakobsen, Victoria
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(2026).
Baseline and early changes in cardiac biomarkers as predictors of global longitudinal strain deterioration during breast cancer therapy: a PRADAII substudy.
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Background: Cardiac biomarkers are recommended for risk stratification before and during potentially cardiotoxic cancer therapy, but the prognostic value of baseline levels and early changes for subsequent left ventricular (LV) dysfunction remains unclear.
Objectives:
To evaluate whether baseline and early changes in high-sensitivity cardiac troponins (hs-cTnI, hs-cTnT) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) predict changes in global longitudinal strain (GLS) over 18 months.
Methods:
In the randomized PRADAII, 138 women treated with anthracyclines (±trastuzumab) received sacubitril/valsartan or placebo and underwent serial biomarker sampling and cardiac imaging at baseline, post-anthracycline, and 18 months. Longitudinal changes in GLS and left ventricular ejection fraction (LVEF) were analyzed using adjusted linear mixed models, including exploratory analyses of combined, persistent, and peak biomarker elevations.
Results:
Mean age was 54.0±9.4 years. At baseline, no patients had hs-cTnI values above the sex-specific 99th percentile, 6 (4%) had hs-cTnT >99th percentile, and 16 (12%) had NT-proBNP >125 ng/L. Mean baseline GLS was −19.5±2.1% and CMR- and echocardiography-derived LVEF was 60.3±4.8% and 58.3±6.2%, respectively. GLS declined modestly over follow-up, with less deterioration in the sacubitril/valsartan group than in the placebo group (ΔΔ −1.26, 95% CI −2.19 to −0.33).
Both hs-cTnI and hs-cTnT increased markedly after anthracycline therapy, with 16.7% and 71.7% exceeding the sex-specific 99th percentile at peak, whereas NT-proBNP showed modest changes with wide inter-individual variability. Transient and persistent troponin elevation occurred in 60.1% and 11.6%, respectively; corresponding NT-proBNP elevations in 5.1% and 7.3%, and combined troponin and NT-proBNP elevation in 9.4%.
Baseline biomarker levels were not associated with GLS deterioration, and no biomarker–treatment interactions were observed (all p for interaction >0.27). Early post-anthracycline changes in hs-cTnI, hs-cTnT, or NT-proBNP were not predictive of subsequent GLS decline, nor were peak or persistent elevations (Table 1, Figure 1). No significant associations were observed between baseline or early biomarker levels and changes in LVEF assessed by echocardiography or CMR.
Conclusions:
In our breast cancer cohort with preserved baseline LV function, baseline levels and early changes in hs-cTnI, hs-cTnT, and NT-proBNP were not associated with subsequent deterioration in GLS over 18 months. Larger studies including higher-risk patients and clinical endpoints are needed to clarify the role of cardiac biomarkers in individualized cardiotoxicity risk stratification.
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Gynnild, Mari Nordbø; Gulati, Geeta; Mecinaj, Albulena; Wethal, Torgeir; Holte, Espen & Vinje-Jakobsen, Victoria
[Show all 11 contributors for this article]
(2026).
Baseline and early changes in cardiac biomarkers as predictors of global longitudinal strain deterioration during breast cancer therapy: a PRADAII substudy.
European Heart Journal, Supplement.
ISSN 1520-765X.
28(Supplement_8).
doi:
10.1093/eurheartjsupp/suag097.089.
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Abstract Background Cardiac biomarkers are recommended for risk stratification before and during potentially cardiotoxic cancer therapy, but the prognostic value of baseline levels and early changes for subsequent left ventricular (LV) dysfunction remains unclear. Objectives To evaluate wheter baseline and early changes in high-sensitivity cardiac troponins (hs-cTnI, hs-cTnT) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) predict changes in global longitudinal strain (GLS) over 18 months. Methods In the randomized PRADAII, 138 women treated with anthracyclines (±trastuzumab) received sacubitril/valsartan or placebo and underwent serial biomarker sampling and cardiac imaging at baseline, post-anthracycline, and 18 months. Longitudinal changes in GLS and left ventricular ejection fraction (LVEF) were analyzed using adjusted linear mixed models, including exploratory analyses of combined, persistent, and peak biomarker elevations. Results Mean age was 54.0±9.4 years. At baseline, no patients had hs-cTnI values above the sex-specific 99th percentile, 6 (4%) had hs-cTnT >99th percentile, and 16 (12%) had NT-proBNP >125 ng/L. Mean baseline GLS was −19.5±2.1% and CMR- and echocardiography-derived LVEF was 60.3±4.8% and 58.3±6.2%, respectively. GLS declined modestly over follow-up, with less deterioration in the sacubitril/valsartan group than in the placebo group (ΔΔ −1.26, 95% CI −2.19 to −0.33). Both hs-cTnI and hs-cTnT increased markedly after anthracycline therapy, with 16.7% and 71.7% exceeding the sex-specific 99th percentile at peak, whereas NT-proBNP showed modest changes with wide inter-individual variability. Transient and persistent troponin elevation occurred in 60.1% and 11.6%, respectively; corresponding NT-proBNP elevations in 5.1% and 7.3%, and combined troponin and NT-proBNP elevation in 9.4%. Baseline biomarker levels were not associated with GLS deterioration, and no biomarker–treatment interactions were observed (all p for interaction >0.27). Early post-anthracycline changes in hs-cTnI, hs-cTnT, or NT-proBNP were not predictive of subsequent GLS decline, nor were peak or persistent elevations (Table 1, Figure 1). No significant associations were observed between baseline or early biomarker levels and changes in LVEF assessed by echocardiography or CMR. Conclusions In our breast cancer cohort with preserved baseline LV function, baseline levels and early changes in hs-cTnI, hs-cTnT, and NT-proBNP were not associated with subsequent deterioration in GLS over 18 months. Larger studies including higher-risk patients and clinical endpoints are needed to clarify the role of cardiac biomarkers in individualized cardiotoxicity risk stratification.
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Gulati, Geeta; Tjessem, Kristin Holm; Horndalsveen, Henrik; Halvorsen, Sigrun & Haakensen, Vilde Drageset
(2022).
Sjekkpunkthemmerindusert myokardi.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
142(18).
doi:
10.4045/tidsskr.21.0817.
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Immunologiske sjekkpunkthemmere har vært revolusjonerende innen kreftbehandlingen. En sjelden, men alvorlig bivirkning er utviklingen av hjertemuskelbetennelse (myokarditt). Forekomsten av denne typen myokarditt er økende etter hvert som flere kreftpasienter mottar behandling med sjekkpunkthemmere. Kunnskap om sjekkpunkthemmerindusert myokarditt er viktig for å kunne stille diagnosen og igangsette behandling tidlig. I denne artikkelen gir vi en klinisk oversikt over dette.
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Heck, Siri Lagethon; Gulati, Geeta; HOFFMANN, PAVEL; Knobelsdorff-Brenkenhoff, Florian von; Storås, Tryggve & Ree, Anne Hansen
[Show all 11 contributors for this article]
(2016).
Effects of Candesartan and Metoprolol on Myocardial Mass, Edema, and Fibrosis During Anthracycline Treatment in Early Breast Cancer: APRADA-CMR substudy.
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Gulati, Geeta; Heck, Siri Lagethon; HOFFMANN, PAVEL; Ree, Anne Hansen; Schulz-Menger, Jeanette & Knobelsdorff-Brenkenhoff, Florian von
[Show all 12 contributors for this article]
(2016).
Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Primary Results of a Randomized, 2 x 2 Factorial, Placebo-Controlled, Double-Blind Clinical Trial.
Circulation.
ISSN 0009-7322.
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Heck, Siri Lagethon; Gulati, Geeta; Knobelsdorff-Brenkenhoff, Florian von; Storås, Trygve H; Schulz-Menger, Jeanette & HOFFMANN, PAVEL
[Show all 7 contributors for this article]
(2016).
Validation of myocardial extracellular volume equation by serial cardiac magnetic resonance imaging measurements in patients with varying hematocrit.
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Gulati, Geeta; Heck, Siri Lagethon; Geisler, Jürgen; Fagerland, Morten; HOFFMANN, PAVEL & Gravdehaug, Berit
[Show all 10 contributors for this article]
(2016).
Effect of candesartan and metoprolol on subclinical myocardial injury during anthracycline therapy: data from the prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA) study.
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Mar. 20, 2025 1:49 PM
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