Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

BACKGROUND: Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. METHODS: PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 µg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. FINDINGS: Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). INTERPRETATION: Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. FUNDING: Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.

Tilt testing remains a valuable asset.

Head-up tilt test (TT) has been used for >50 years to study heart rate/blood pressure adaptation to positional changes, to model responses to haemorrhage, to assess orthostatic hypotension, and to evaluate haemodynamic and neuroendocrine responses in congestive heart failure, autonomic dysfunction, and hypertension. During these studies, some subjects experienced syncope due to vasovagal reflex. As a result, tilt testing was incorporated into clinical assessment of syncope when the origin was unknown. Subsequently, clinical experience supports the diagnostic value of TT. This is highlighted in evidence-based professional practice guidelines, which provide advice for TT methodology and interpretation, while concurrently identifying its limitations. Thus, TT remains a valuable clinical asset, one that has added importantly to the appreciation of pathophysiology of syncope/collapse and, thereby, has improved care of syncopal patients.

Incidence of cardiotoxicity and validation of the Heart Failure Association-International Cardio-Oncology Society risk stratification tool in patients treated with trastuzumab for HER2-positive early breast cancer.

PURPOSE: Trastuzumab improves survival in patients with HER2+ early breast cancer. However, cardiotoxicity remains a concern, particularly in the curative setting, and there are limited data on its incidence outside of clinical trials. We retrospectively evaluated the cardiotoxicity rates [left ventricular ejection fraction (LVEF) decline, congestive heart failure (CHF), cardiac death or trastuzumab discontinuation] and assessed the performance of a proposed model to predict cardiotoxicity in routine clinical practice. METHODS: Patients receiving curative trastuzumab between 2011 and 2018 were identified. Demographics, treatments, assessments and toxicities were recorded. Fisher's exact test, Chi-squared and logistic regression were used. RESULTS: 931 patients were included in the analysis. Median age was 54 years (range 24-83) and Charlson comorbidity index 0 (0-6), with 195 patients (20.9%) aged 65 or older. 228 (24.5%) were smokers. Anthracyclines were given in 608 (65.3%). Median number of trastuzumab doses was 18 (1-18). The HFA-ICOS cardiovascular risk was low in 401 patients (43.1%), medium in 454 (48.8%), high in 70 (7.5%) and very high in 6 (0.6%). Overall, 155 (16.6%) patients experienced cardiotoxicity: LVEF decline ≥ 10% in 141 (15.1%), falling below 50% in 55 (5.9%), CHF NYHA class II in 42 (4.5%) and class III-IV in 5 (0.5%) and discontinuation due to cardiac reasons in 35 (3.8%). No deaths were observed. Cardiotoxicity rates increased with HFA-ICOS score (14.0% low, 16.7% medium, 30.3% high/very high; p = 0.002). CONCLUSIONS: Cardiotoxicity was relatively common (16.6%), but symptomatic heart failure on trastuzumab was rare in our cohort. The HFA-ICOS score identifies patients at high risk of cardiotoxicity.

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.

Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.

BACKGROUND: Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown. METHODS: We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311. FINDINGS: Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5-67·2]; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% [95% CI 20·6-57·8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure. INTERPRETATION: Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely. FUNDING: British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust.

Platypnoea-orthodeoxia syndrome: beware of investigations undertaken supine.

Platypnoea-orthodeoxia syndrome (POS) is a rare disorder, manifesting as deoxygenation occurring when the patient is in the upright position. Four broad mechanisms for the condition have been described: intracardiac shunts, intrapulmonary shunts, hepatopulmonary syndrome and pulmonary ventilation-perfusion mismatch. Here, we present the first case of POS in a patient with a proven right to left intracardiac shunt occurring in the context of postural hypotension and normal right heart pressures. We highlight the need to carry out investigations in the upright position before discounting intracardiac shunting as a cause for the syndrome. Short-term improvement of the syndrome was obtained with medical management of the patient's orthostatic hypotension and as such suggests a conservative management strategy for similar patients, which may delay the need for invasive procedures to close the anatomical defect.

Association Between Midwall Late Gadolinium Enhancement and Sudden Cardiac Death in Patients With Dilated Cardiomyopathy and Mild and Moderate Left Ventricular Systolic Dysfunction.

BACKGROUND: Current guidelines only recommend the use of an implantable cardioverter defibrillator in patients with dilated cardiomyopathy for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF) <35%. However, registries of out-of-hospital cardiac arrests demonstrate that 70% to 80% of such patients have an LVEF >35%. Patients with an LVEF >35% also have low competing risks of death from nonsudden causes. Therefore, those at high risk of SCD may gain longevity from successful implantable cardioverter defibrillator therapy. We investigated whether late gadolinium enhancement (LGE) cardiovascular magnetic resonance identified patients with dilated cardiomyopathy without severe LV systolic dysfunction at high risk of SCD. METHODS: We prospectively investigated the association between midwall LGE and the prespecified primary composite outcome of SCD or aborted SCD among consecutive referrals with dilated cardiomyopathy and an LVEF ≥40% to our center between January 2000 and December 2011 who did not have a preexisting indication for implantable cardioverter defibrillator implantation. RESULTS: Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the prespecified end point, compared with 7 of 298 (2.3%) without (hazard ratio [HR], 9.2; 95% confidence interval [CI], 3.9-21.8; P<0.0001). Nine patients (8.9%) with LGE compared with 6 (2.0%) without (HR, 4.9; 95% CI, 1.8-13.5; P=0.002) died suddenly, whereas 10 patients (9.9%) with LGE compared with 1 patient (0.3%) without (HR, 34.8; 95% CI, 4.6-266.6; P<0.001) had aborted SCD. After adjustment, LGE predicted the composite end point (HR, 9.3; 95% CI, 3.9-22.3; P<0.0001), SCD (HR, 4.8; 95% CI, 1.7-13.8; P=0.003), and aborted SCD (HR, 35.9; 95% CI, 4.8-271.4; P<0.001). Estimated HRs for the primary end point for patients with an LGE extent of 0% to 2.5%, 2.5% to 5%, and >5% compared with those without LGE were 10.6 (95% CI, 3.9-29.4), 4.9 (95% CI, 1.3-18.9), and 11.8 (95% CI, 4.3-32.3), respectively. CONCLUSIONS: Midwall LGE identifies a group of patients with dilated cardiomyopathy and an LVEF ≥40% at increased risk of SCD and low risk of nonsudden death who may benefit from implantable cardioverter defibrillator implantation. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00930735.

The effect of head-up tilt upon markers of heart rate variability in patients with atrial fibrillation.

BACKGROUND: Heart rate variability (HRV) analysis is uncommonly undertaken in patients with atrial fibrillation (AF) due to an assumption that ventricular response is random. We sought to determine the effects of head-up tilt (HUT), a stimulus known to elicit an autonomic response, on HRV in patients with AF; we contrasted the findings with those of patients in sinus rhythm (SR). METHODS: Consecutive, clinically indicated tilt tests were examined for 207 patients: 176 in SR, 31 in AF. Patients in AF were compared to an age-matched SR cohort (n = 69). Five minute windows immediately before and after tilting were analyzed using time-domain, frequency-domain and nonlinear HRV parameters. Continuous, noninvasive assessment of blood pressure, heart rate and stroke volume were available in the majority of patients. RESULTS: There were significant differences at baseline in all HRV parameters between AF and age matched SR. HUT produced significant hemodynamic changes, regardless of cardiac rhythm. Coincident with these hemodynamic changes, patients in AF had a significant increase in median [quartile 1, 2] DFA-α2 (+0.14 [-0.03, 0.32], p < .005) and a decrease in sample entropy (-0.17 [-0.50, -0.01], p < .005). CONCLUSION: In the SR cohort, increasing age was associated with fewer HRV changes on tilting. Patients with AF had blunted HRV responses to tilting, mirroring those seen in an age matched SR group. It is feasible to measure HRV in patients with AF and the changes observed on HUT are comparable to those seen in patients in sinus rhythm.

Quality-of-life outcomes from the Prostate Adenocarcinoma: TransCutaneous Hormones (PATCH) trial evaluating luteinising hormone-releasing hormone agonists versus transdermal oestradiol for androgen suppression in advanced prostate cancer.

OBJECTIVES: To compare quality-of-life (QoL) outcomes at 6 months between men with advanced prostate cancer receiving either transdermal oestradiol (tE2) or luteinising hormone-releasing hormone agonists (LHRHa) for androgen-deprivation therapy (ADT). PATIENTS AND METHODS: Men with locally advanced or metastatic prostate cancer participating in an ongoing randomised, multicentre UK trial comparing tE2 versus LHRHa for ADT were enrolled into a QoL sub-study. tE2 was delivered via three or four transcutaneous patches containing oestradiol 100 µg/24 h. LHRHa was administered as per local practice. Patients completed questionnaires based on the European Organisation for Research and Treatment of Cancer quality of life questionnaire 30-item core (EORTC QLQ-C30) with prostate-specific module QLQ PR25. The primary outcome measure was global QoL score at 6 months, compared between randomised arms. RESULTS: In all, 727 men were enrolled between August 2007 and October 2015 (412 tE2, 315 LHRHa) with QoL questionnaires completed at both baseline and 6 months. Baseline clinical characteristics were similar between arms: median (interquartile range) age of 74 (68-79) years and PSA level of 44 (19-119) ng/mL, and 40% (294/727) had metastatic disease. At 6 months, patients on tE2 reported higher global QoL than those on LHRHa (mean difference +4.2, 95% confidence interval 1.2-7.1; P = 0.006), less fatigue, and improved physical function. Men in the tE2 arm were less likely to experience hot flushes (8% vs 46%), and report a lack of sexual interest (59% vs 74%) and sexual activity, but had higher rates of significant gynaecomastia (37% vs 5%). The higher incidence of hot flushes among LHRHa patients appear to account for both the reduced global QoL and increased fatigue in the LHRHa arm compared to the tE2 arm. CONCLUSION: Patients receiving tE2 for ADT had better 6-month self-reported QoL outcomes compared to those on LHRHa, but increased likelihood of gynaecomastia. The ongoing trial will evaluate clinical efficacy and longer term QoL. These findings are also potentially relevant for short-term neoadjuvant ADT.

Differing autonomic responses to dobutamine stress in the presence and absence of myocardial ischaemia.

KEY POINTS: Dobutamine stress echocardiography is a validated tool for the non-invasive evaluation of myocardial ischaemia and enables the recording of heart rate variability in non-resting conditions. In this study we determined whether individuals with transient myocardial ischaemia had different autonomic responses to the stress of dobutamine infusion compared to non-ischaemic (normal) responders. Non-ischaemic responders had a residual predominance of parasympathetic over sympathetic activity. However, under conditions of myocardial ischaemia, there was a directionally opposite cardiac autonomic response with a residual increase of sympathetic over parasympathetic modulation. The sympathetic response to dobutamine stress is augmented as the burden of myocardial ischaemia is increased. ABSTRACT: Cardiac autonomic dysfunction has prognostic significance in patients with coronary artery disease. This investigation aimed to assess changes in autonomic modulation induced by dobutamine stress in the presence and absence of myocardial ischaemia. In total, 314 individuals underwent dobutamine stress echocardiography to detect or exclude myocardial ischaemia. Simultaneous autonomic and haemodynamic data were obtained using a plethysmographic device. Total power spectral density and associated low-frequency (LF) and high-frequency (HF) power spectral components in absolute (ms(2) ) and normalised units (nu) were determined. Participants were categorised as non-ischaemic (NI) or ischaemic (IS) responders. There were no significant differences in LFnu or HFnu between groups at baseline. At peak stress, LFnu decreased from baseline in NI (43 ± 1.8 to 40 ± 1.8%), but increased from baseline in IS responders (39.5 ± 2 to 56 ± 2%, P < 0.05). In contrast, HFnu increased in NI patients (57 ± 1.8 to 60 ± 1.8%) but decreased in IS responders (60.5 ± 2 to 44 ± 2%, P < 0.05). Those with a high ischaemic burden [more than three ischaemic left ventricular (LV) segments] had a greater increase in LFnu (41 ± 4.8 to 65 ± 3.2% vs. 44.8 ± 3.8 to 57.7 ± 3.1%, P < 0.05) and greater decrease in HFnu (59 ± 4.8 to 35 ± 3.2% vs. 55.2 ± 3.8 to 42.3 ± 3.1%, P < 0.05) compared to patients with a low ischaemic burden (1-3 ischaemic LV segments) respectively, at peak stress. In the absence of myocardial ischaemia, dobutamine stress is associated with a residual predominance of parasympathetic over sympathetic activity. Under conditions of ischaemia, there is a directionally opposite autonomic response with a significant residual increase of sympathetic over parasympathetic modulation. This response is augmented as the burden of ischaemia is increased.

Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09).

BACKGROUND: Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen. METHODS: In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 µg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov, number NCT00303784. FINDINGS: 85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12-31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7-14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0-15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and -0·16 mmol/L (-2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and -0·23 mmol/L (-3·3%), respectively (p<0·0001). Other adverse events reported by 6 months included gynaecomastia (15 [19%] of 78 patients in the LHRHa group vs 104 [75%] of 138 in the oestrogen-patch group), hot flushes (44 [56%] vs 35 [25%]), and dermatological problems (10 [13%] vs 58 [42%]). INTERPRETATION: Parenteral oestrogen could be a potential alternative to LHRHa in management of prostate cancer if efficacy is confirmed. On the basis of our findings, enrolment in the PATCH trial has been extended, with a primary outcome of progression-free survival. FUNDING: Cancer Research UK, MRC Clinical Trials Unit.

Late cardiotoxicity related to HER2-targeted cancer therapy.

Long-term anti-HER2 therapy in metastatic HER2 + cancers is increasing, but data about the incidence and risk factors for developing late Cancer therapy-related cardiac dysfunction (CTRCD) are missing. We conducted a single-centre, retrospective analysis of a cohort of late anti-HER2 related cardiac dysfunction referred to our Cardio-Oncology service. We include seventeen patients with metastatic disease who developed CTRCD after at least five years of continuous anti-HER2 therapy. Events occurred after a median time of 6.5 years (IQR 5.3-9.0) on anti-HER2 therapy. The lowest (median) LVEF and GLS were 49% (IQR 45-55) and - 15.4% (IQR - 14.9 - -16.3) respectively. All our patients continued or restarted, after a brief interruption, their anti-HER2 therapy. Most (16/17) were started on heart failure medical therapy and normalized their left ventricular ejection fraction at a follow-up. Our study has demonstrated that CTRCD can occur after many years of stability on anti-HER2 therapy and reinforces the importance of continuing cardiovascular surveillance in this population.

Cancer therapy related cardiac dysfunction as a result of Panitumumab.

Panitumumab is a human immunoglobulin monoclonal antibody designed to target the epidermal growth factor receptor (EGFR) which is used in the treatment of metastatic colorectal cancer alone or in combination with chemotherapy. In this report, we present a case of new onset heart failure with reduced ejection fraction in a patient following panitumumab therapy. A 73-year-old gentleman with metastatic rectal adenocarcinoma presented to his local hospital with increased shortness of breath, two months after his first and only dose of panitumumab. A transthoracic echocardiogram demonstrated dilated left ventricle with global hypokinesis and an estimated left ventricular ejection fraction of 25%. Our patient underwent a comprehensive diagnostic assessment at his presentation, including ECG, transthoracic echocardiogram, cardiac magnetic resonance, computed tomography coronary angiography (CTCA), invasive coronary angiogram and 18F-FDG PET-CT. These investigations revealed no evidence of ischemic events or inflammatory processes that could account for the severe left ventricular dysfunction. To our knowledge, this is the first reported case of heart failure with reduced ejection fraction linked to panitumumab with subsequent deep phenotyping. The current guidelines do not recommend specific cardiovascular monitoring protocols for patients receiving anti-EGFR monoclonal antibodies. Until more data are available, it would be prudent to implement the same cardiovascular surveillance measures outlined for individuals receiving osimertinib, which is an EGFR tyrosine kinase inhibitor.

Echocardiography versus Cardiac MRI for Measurement of Left Ventricular Ejection Fraction in Individuals with Cancer and Suspected Cardiotoxicity.

Purpose To compare left ventricular ejection fraction (LVEF) measured with echocardiography and cardiac MRI in individuals with cancer and suspected cardiotoxicity and assess the potential effect on downstream clinical decision-making. Materials and Methods In this prospective, single-center observational cohort study, participants underwent same-day two-dimensional (2D) echocardiography and cardiac MRI between 2011 and 2021. Participants with suboptimal image quality were excluded. A subset of 74 participants also underwent three-dimensional (3D) echocardiography. The agreement of LVEF derived from each modality was assessed using Bland-Altman analysis and at relevant thresholds for cardiotoxicity. Results A total of 745 participants (mean age, 60 years ± 5 [SD]; 460 [61.7%] female participants) underwent same-day echocardiography and cardiac MRI. According to Bland-Altman analysis, the mean bias was -3.7% ± 7.6 (95% limits of agreement [LOA]: -18.5% to 11.1%) for 2D echocardiography versus cardiac MRI. In 74 participants who underwent cardiac MRI, 3D echocardiography, and 2D echocardiography, the mean LVEFs were 60.0% ± 10.4, 58.4% ± 9.4, and 57.2% ± 8.9, respectively (P < .001). At the 50% LVEF threshold for detection of cardiotoxicity, there was disagreement for 9.3% of participants with 2D echocardiography and cardiac MRI. Agreement was better with 3D echocardiography and cardiac MRI (mean bias, -1.6% ± 6.3 [95% LOA: -13.9% to 10.7%]) compared with 2D echocardiography and cardiac MRI (mean bias, -2.8% ± 6.3 [95% LOA: -15.2% to 9.6%]; P = .016). Conclusion Two-dimensional echocardiography had variations of ±15% for LVEF measurement compared with cardiac MRI in participants with cancer and led to misclassification of approximately 10% of participants for cardiotoxicity detection. Three-dimensional echocardiography had better agreement with cardiac MRI and should be used as first-line imaging. Keywords: Echocardiography, MR Functional Imaging, Cardiac Supplemental material is available for this article. © RSNA, 2024.

Cardiovascular events in CML patients treated with Nilotinib: validation of the HFA-ICOS baseline risk score.

BACKGROUND: The therapeutic landscape of chronic myeloid leukaemia (CML) has been transformed by tyrosine kinase inhibitors (TKI). Nilotinib, showed higher rates of major molecular response than imatinib, however associated with higher cardiovascular (CV) toxicity. We sought to describe the CV events associated with nilotinib in a real-world population and assess the predictive value of the HFA-ICOS risk score. METHODS: The HFA-ICOS baseline risk was calculated for patients with CML treated with nilotinib beween 2006 and 2021. The primary end point was the incidence of all CV events. The secondary end point was the incidence of ischaemic events. Survival analysis evaluated the risk (hazard ratio [HR]) of events stratified by baseline risk category, whilst on nilotinib therapy. RESULTS: Two hundred and twenty-nine eligible patients were included. The incidence of CV events was 20.9% (95% CI: 15.7-26.2%) following a median duration of treatment of 34.4 months. The secondary end point occurred in 12.7% (95% CI: 8.4-16.9%) of the population. Patients with higher HFA-ICOS baseline score had higher rates of CV events (low: 11.2%, medium: 28.2% [HR: 2.51, 95% CI: 1.17-5.66], high/very high: 32.4% [HR: 3.57, 95% CI: 1.77-7.20]) and ischaemic events (low: 5.20%, medium: 17.9% [HR: 2.19, 95% CI: 0.97-4.96], high/very high: 21.6% [HR: 3.9, 95% CI: 1.91-7.89]). In patients who did not have a CV event, the median total dose at last follow up or cessation of nilotinib therapy was lower when compared to the total daily median dose of nilotinib in patients who had a CV event (450 mg vs. 600 mg, p = 0.0074). CONCLUSIONS: The HFA-ICOS risk stratification tool is an efficient discriminator at low, medium and high/very high risk of developing cardiovascular events, with an overall positive trend towards increasing cardiotoxicity rates with rising risk catergories. This study provides evidence to support the use of this predictive tool in nilotinib treated patients.

Clinical Utility and Prognostic Value of Coronary Computed Tomography Angiography in Patients With Cancer.

There is growing interest in the role of coronary computed tomography angiography (CTA) in cardio-oncology. However, there is a paucity of real-world experience and outcome data for patients with cancer. This study sought to determine the clinical utility and prognostic value of coronary CTA in patients with cancer. In this prospective, single-center study, we recruited patients with cancer who underwent coronary CTA. Coronary artery disease (CAD) extent was classified as normal, nonobstructive (1% to 49% stenosis), and potentially obstructive (≥50% stenosis). Patients were followed up for a median of 9 months (interquartile range 3 to 30 months) for cancer-related deaths and major adverse cardiovascular events (MACEs) defined as nonfatal myocardial infarction, urgent unplanned revascularization, or cardiovascular death. The mean age of patients (n = 113) was 61 ± 12 years, and 68 were female (60%). The most common underlying cancers were breast (29%) and lymphoma (13%). A total of 25 patients had potentially obstructive CAD, most commonly of the left anterior descending artery. After coronary CTA, 88% statin-naive patients with potentially obstructive CAD were initiated on statin therapy. A total of 28/32 patients who were taking fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine) continued therapy, of whom none had MACEs. Overall, there were no episodes of MACEs in this cohort and 11% had cancer-related deaths. Coronary CTA has an important role in the clinical decision-making in patients with cancer to detect CAD, initiate primary preventative therapy, and guide coronary revascularization. No MACEs occurred. Using this coronary CTA-guided approach, preventative therapy was initiated, and most patients continued prognostically important cancer therapy.

Healthcare systems data in the context of clinical trials - A comparison of cardiovascular data from a clinical trial dataset with routinely collected data.

BACKGROUND: Routinely-collected healthcare systems data (HSD) are proposed to improve the efficiency of clinical trials. A comparison was undertaken between cardiovascular (CVS) data from a clinical trial database with two HSD resources. METHODS: Protocol-defined and clinically reviewed CVS events (heart failure (HF), acute coronary syndrome (ACS), thromboembolic stroke, venous and arterial thromboembolism) were identified within the trial data. Data (using pre-specified codes) was obtained from NHS Hospital Episode Statistics (HES) and National Institute for Cardiovascular Outcomes Research (NICOR) HF and myocardial ischaemia audits for trial participants recruited in England between 2010 and 2018 who had provided consent. The primary comparison was trial data versus HES inpatient (APC) main diagnosis (Box-1). Correlations are presented with descriptive statistics and Venn diagrams. Reasons for non-correlation were explored. RESULTS: From 1200 eligible participants, 71 protocol-defined clinically reviewed CVS events were recorded in the trial database. 45 resulted in a hospital admission and therefore could have been recorded by either HES APC/ NICOR. Of these, 27/45 (60%) were recorded by HES inpatient (Box-1) with an additional 30 potential events also identified. HF and ACS were potentially recorded in all 3 datasets; trial data recorded 18, HES APC 29 and NICOR 24 events respectively. 12/18 (67%) of the HF/ACS events in the trial dataset were recorded by NICOR. CONCLUSION: Concordance between datasets was lower than anticipated and the HSD used could not straightforwardly replace current trial practices, nor directly identify protocol-defined CVS events. Further work is required to improve the quality of HSD and consider event definitions when designing clinical trials incorporating HSD.

Cardiovascular health-related quality of life in cancer: a prospective study comparing the ESC HeartQoL and EORTC QLQ-C30 questionnaire.

AIMS: Health-related quality of life (HRQoL) is highly relevant in cancer and often assessed with the EORTC QLQ-C30. Cardiovascular HRQoL in cancer can be measured with the ESC HeartQoL questionnaire. We compared these instruments and examined their prognostic value. METHODS AND RESULTS: Summary scores for EORTC QLQ-C30 (0-100 points) and ESC HeartQoL (0-3 points) questionnaires were prospectively assessed in 290 patients with mostly advanced cancer (stage 3/4: 81%, 1-year mortality: 36%) and 50 healthy controls (similar age and sex). Additionally, physical function and activity assessments were performed. Both questionnaires demonstrated reduced HRQoL in patients with cancer versus controls (EORTC QLQ-C30: 67 ± 20 vs. 91 ± 11, p < 0.001; ESC HeartQoL: 1.8 ± 0.8 vs. 2.7 ± 0.4, p < 0.001). The instruments were strongly correlated with each other (summary scores [r = 0.76], physical [r = 0.81], and emotional subscales [r = 0.75, all p < 0.001]) and independently associated with all-cause mortality (best cut-offs: EORTC QLQ-C30 <82.69: hazard ratio [HR] 2.33, p = 0.004; ESC HeartQoL <1.50: HR 1.85, p = 0.004 - adjusted for sex, age, left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide [NT-proBNP], high-sensitivity troponin T, cancer stage/type), with no differences in the strength of the association by sex (p-interaction > 0.9). Combining both questionnaires identified three risk groups with highest mortality in patients below both cut-offs (vs. patients above both cut-offs: HR 3.60, p < 0.001). Patients with results below both cut-offs, showed higher NT-proBNP and reduced physical function and activity. CONCLUSIONS: The EORTC QLQ-C30 and ESC HeartQoL - assessing cancer and cardiovascular HRQoL - are both associated with increased mortality in cancer patients, with even greater stratification by combing both. Reduced HRQoL scores were associated with elevated cardiovascular biomarkers and decreased functional status.

Clinical and Prognostic Relevance of Cardiac Wasting in Patients With Advanced Cancer.

BACKGROUND: Body wasting in patients with cancer can affect the heart. OBJECTIVES: The frequency, extent, and clinical and prognostic importance of cardiac wasting in cancer patients is unknown. METHODS: This study prospectively enrolled 300 patients with mostly advanced, active cancer but without significant cardiovascular disease or infection. These patients were compared with 60 healthy control subjects and 60 patients with chronic heart failure (ejection fraction <40%) of similar age and sex distribution. RESULTS: Cancer patients presented with lower left ventricular (LV) mass than healthy control subjects or heart failure patients (assessed by transthoracic echocardiography: 177 ± 47 g vs 203 ± 64 g vs 300 ± 71 g, respectively; P < 0.001). LV mass was lowest in cancer patients with cachexia (153 ± 42 g; P < 0.001). Importantly, the presence of low LV mass was independent of previous cardiotoxic anticancer therapy. In 90 cancer patients with a second echocardiogram after 122 ± 71 days, LV mass had declined by 9.3% ± 1.4% (P < 0.001). In cancer patients with cardiac wasting during follow-up, stroke volume decreased (P < 0.001) and resting heart rate increased over time (P = 0.001). During follow-up of on average 16 months, 149 patients died (1-year all-cause mortality 43%; 95% CI: 37%-49%). LV mass and LV mass adjusted for height squared were independent prognostic markers (both P < 0.05). Adjustment of LV mass for body surface area masked the observed survival impact. LV mass below the prognostically relevant cutpoints in cancer was associated with reduced overall functional status and lower physical performance. CONCLUSIONS: Low LV mass is associated with poor functional status and increased all-cause mortality in cancer. These findings provide clinical evidence of cardiac wasting-associated cardiomyopathy in cancer.

Utility of overnight pulse oximetry and heart rate variability analysis to screen for sleep-disordered breathing in chronic heart failure.

BACKGROUND: Sleep-disordered breathing (SDB) is under diagnosed in chronic heart failure (CHF). Screening with simple monitors may increase detection of SDB in a cardiology setting. This study aimed to evaluate the accuracy of heart rate variability analysis and overnight pulse oximetry for diagnosis of SDB in patients with CHF. METHODS: 180 patients with CHF underwent simultaneous polysomnography, ambulatory electrocardiography and wrist-worn overnight pulse oximetry. SDB was defined as an apnoea-hypopnoea index ≥15/h. To identify SDB from the screening tests, the per cent very low frequency increment (%VLFI) component of heart rate variability was measured with a pre-specified cutoff ≥2.23%, and the 3% oxygen desaturation index was measured with a pre-specified cutoff >7.5 desaturations/h. RESULTS: 173 patients with CHF had adequate sleep study data; SDB occurred in 77 (45%) patients. Heart rate variability was measurable in 78 (45%) patients with area under the %VLFI receiver operating characteristic curve of 0.50. At the ≥2.23% cutoff, %VLFI sensitivity was 58% and specificity was 48%. The 3% oxygen desaturation index was measurable in 171 (99%) patients with area under the curve of 0.92. At the pre-specified cutoff of >7.5 desaturations/h, the 3% oxygen desaturation index had a sensitivity of 97%, specificity of 32%, negative likelihood ratio of 0.08 and positive likelihood ratio of 1.42. Diagnostic accuracy was increased using a cutoff of 12.5 desaturations/h, with sensitivity of 93% and specificity of 73%. CONCLUSIONS: The high sensitivity and low negative likelihood ratio of the 3% oxygen desaturation index indicates that pulse oximetry would be of use as a simple screening test to rule out SDB in patients with CHF in a cardiology setting. The %VLFI component of heart rate variability is not suitable for detection of SDB in CHF.