Cardio-oncology in Austria: cardiotoxicity and surveillance of anti-cancer therapies : Position paper of the Heart Failure Working Group of the Austrian Society of Cardiology.

Survival in cancer is continuously improving due to evolving oncological treatment. Therefore, cardiovascular short-term and long-term side effects gain crucial importance for overall outcome. Cardiotoxicity not only presents as heart failure, but also as treatment-resistant hypertension, acute coronary ischemia with plaque rupture or vasospasm, thromboembolism, arrhythmia, pulmonary hypertension, diastolic dysfunction, acute myocarditis and others. Recent recommendations have proposed baseline cardiac risk assessment and surveillance strategies. Major challenges are the availability of monitoring and imaging resources, including echocardiography with speckle tracking longitudinal strain (GLS), serum biomarkers such as natriuretic peptides (NT-proBNP) and highly sensitive cardiac troponins. This Austrian consensus encompasses cardiotoxicity occurrence in frequent antiproliferative cancer drugs, radiotherapy, immune checkpoint inhibitors and cardiac follow-up considerations in cancer survivors in the context of the Austrian healthcare setting. It is important to optimize cardiovascular risk factors and pre-existing cardiac diseases without delaying oncological treatment. If left ventricular ejection fraction (LVEF) deteriorates during cancer treatment (from >10% to <50%), or myocardial strain decreases (>15% change in GLS), early initiation of cardioprotective therapies (angiotensin-converting enzyme inhibitors, angiotensin or beta receptor blockers) is recommended, and LVEF should be reassessed before discontinuation. Lower LVEF cut-offs were recently shown to be feasible in breast cancer patients to enable optimal anticancer treatment. Interdisciplinary cardio-oncology cooperation is pivotal for optimal management of cancer patients.

The use of semi-compliant versus non-compliant balloon systems for predilatation during the implantation of self-expandable transcatheter aortic valves: Data from the VIenna CardioThOracic Aortic Valve RegistrY (VICTORY).

BACKGROUND: This study aimed to evaluate the differences in outcome arising from the use of semi-compliant (SCB) versus non-compliant balloon (NCB) systems for predilatation during self-expanding transcatheter aortic valve replacement (TAVR). METHODS: 251 TAVR procedures with the implantation of self-expanding valves after predilatation were analyzed. SCB systems were used in 166 and NCB systems in 85 patients. The primary endpoint was defined as device success, a composite endpoint comprising the absence of procedural mortality, correct valve positioning, adequate valve performance and the absence of more than a mild paravalvular leak. The secondary endpoints were chosen in accordance with the valve academic research consortium (VARC-2) endpoint definitions. RESULTS: No significant differences were observed with regard to procedural device success between the SCB- and NCB cohort (SCB: 142 [85.5%%] vs. NCB: 77 [90.6%]; P = .257). There was a notable difference between the rates of conversion to open surgery and the postdilatation rate, both of which were higher for the NCB group (SCB: 1 [0.6%] vs. NCB: 4 [5.1%]; P = .042; SCB: 30 [18.1%] vs. NCB: 34 [40%]; P < .001). In a multivariate logistic regression analysis, the use of semi-compliant balloon systems for predilatation was associated with a lower risk for postdilatation (OR: 0.296; 95% CI: 0.149-0.588) and conversion to open surgery (OR: 0.205; 95% CI: 0.085-0.493; P = .001) but not for device success. CONCLUSION: While the balloon compliance did not affect the procedural mortality, device success or the rate of paravalvular leakage, the use of semi-compliant balloons for predilatation during TAVR should be investigated in larger randomized trials in the light of the lower rates of postdilatation and conversion to open surgery compared to their non-compliant counterparts.

Burden of medical co-morbidities and benefit from surgical revascularization in patients with ischaemic cardiomyopathy.

AIMS: The landmark STICH trial found that surgical revascularization compared to medical therapy alone improved survival in patients with heart failure (HF) of ischaemic aetiology and an ejection fraction (EF) ≤ 35%. However, the interaction between the burden of medical co-morbidities and the benefit from surgical revascularization has not been previously described in patients with ischaemic cardiomyopathy. METHODS AND RESULTS: The STICH trial (ClinicalTrials.gov Identifier: NCT00023595) enrolled patients ≥ 18 years of age with coronary artery disease amenable to coronary artery bypass grafting (CABG) and an EF ≤ 35%. Eligible participants were randomly assigned 1:1 to receive medical therapy (MED) (n = 602) or MED/CABG (n = 610). A modified Charlson co-morbidity index (CCI) based on the availability of data and study definitions was calculated by summing the weighted points for all co-morbid conditions. Patients were divided into mild/moderate (CCI 1-4) and severe (CCI ≥ 5) co-morbidity. Cox proportional hazards models were used to evaluate the association between CCI and outcomes and the interaction between severity of co-morbidity and treatment effect. The study population included 349 patients (29%) with a mild/moderate CCI score and 863 patients (71%) with a severe CCI score. Patients with a severe CCI score had greater functional limitations based on 6-min walk test and impairments in health-related quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire. A total of 161 patients (Kaplan-Meier rate = 50%) with a mild/moderate CCI score and 579 patients (Kaplan-Meier rate = 69%) with a severe CCI score died over a median follow-up of 9.8 years. After adjusting for baseline confounders, patients with a severe CCI score were at higher risk for all-cause mortality (hazard ratio 1.44, 95% confidence interval 1.19-1.74; P < 0.001). There was no interaction between CCI score and treatment effect on survival (P = 0.756). CONCLUSIONS: More than 70% of patients had a severe burden of medical co-morbidities at baseline, which was independently associated with increased risk of death. There was not a differential benefit of surgical revascularization with respect to survival based on severity of co-morbidity.

Quality of medical therapy in heart failure patients undergoing elective revascularisation: A protective effect of disease modifying therapy at discharge.

The STICH(-ES) trial showed that coronary artery bypass grafting was superior to medical therapy alone in treating ischemic heart failure. However, dosages of disease modifying drugs were not reported. We included 128 (84% male, mean age 66 ± 11 years) consecutive patients with ischemic heart failure and an ejection fraction ≤35% undergoing isolated elective coronary artery bypass grafting. We defined optimal medical therapy (OMT) as prescription of ≥50% dosages of guideline recommended medications (i.e. beta-blocker (BB) and renin angiotensin system (RAS) antagonist) plus prescription of a mineralocorticoid receptor antagonist (MRA). The mean logistic EuroSCORE was 12.3 ± 13.8%. The five year survival was 74%. At discharge, 111 patients (87%) were on a BB and 106 (83%) were on a RAS antagonist. Forty-nine patients (38%) received an MRA. Only 8 patients (6%) received OMT. A Cox regression analysis revealed EuroSCORE (p < 0.001) and the use of MRA (p = 0.003) and BB (p = 0.037) at discharge as significant predictors of 5 year survival. Prescription rates of heart failure medication are comparable to those reported in the STICH trial, but rates of OMT are very low at admission and discharge. Prescription of BB and MRA was associated with improved survival, highlighting the need for disease management programs and rigorous discharge management.

Contemporary use of P2Y12-inhibitors in patients with acute coronary syndrome undergoing percutaneous coronary intervention in Austria: A prospective, multi-centre registry.

BACKGROUND: To this day, there is no data concerning guideline adherence on P2Y12-inhibitors in Austria. Prasugrel and ticagrelor have been shown to be superior to clopidogrel in the treatment of acute coronary syndromes (ACS). However, recent data from European registries showed a reluctant prescription policy with rates of clopidogrel at discharge ranging from 35 to 55%. METHODS: In this prospective, multi-centre registry we assessed prescription rates of P2Y12-inhibitors in patients with ACS in four Austrian PCI centres. Parameters associated with the use of clopidogrel have been evaluated in multivariate logistic regression. RESULTS: Between January and June 2015, 808 patients with ACS undergoing PCI were considered for further analysis. 416 (51.5%) presented with STEMI and 392 (48.5%) with NSTE-ACS. Mean age was 65.7 ± 12.4 and 240 (30.9%) were female. Twenty-eight (3.5%) died during the hospital stay. At discharge, 212 (27.2% of all patients) received clopidogrel, 260 (32.2%) prasugrel and 297 (36.8%) ticagrelor, while 11 (1.4%) did not receive any P2Y12-inhibitor. Of those patients, who were discharged with clopidogrel, 117 (55.2%) had no absolute contraindication against a more potent P2Y12-inhibitor. Diagnosis of NSTE-ACS (p<0.001), COPD (p = 0.049), and age (p<0.001) next to factors contributing to absolute contraindication were positively associated with the use of clopidogrel. CONCLUSIONS: Despite a high level of care, a considerable number of patients were not treated with the more potent P2Y12-inhibitors. Parameters associated with a presumably higher risk of bleeding and side-effects against the more effective P2Y12 inhibitors were the most prominent factors for the prescription of clopidogrel.

GDF-15 Is Associated with Cancer Incidence in Patients with Type 2 Diabetes.

BACKGROUND: Diabetes has been linked epidemiologically to increased cancer incidence and mortality. Growth differentiation factor 15 (GDF-15) is increased in patients with diabetes and has recently been linked to the occurrence of cancer. We investigated whether circulating GDF-15 concentrations can predict the incidence of malignant diseases in a diabetic patient cohort already facing increased risk for cancer. METHODS: We prospectively enrolled a total of 919 patients with type 2 diabetes and no history of malignant disease, who were clinically followed up for 60 months. GDF-15, N-terminal pro-B-type natriuretic peptide and troponin T were measured at baseline; an additional 4 cardiovascular biomarkers were determined for a subpopulation (n = 259). Study end point was defined as the first diagnosis of any type of cancer during the follow-up period. RESULTS: During a median follow-up of 60 months, 66 patients (7.2%) were diagnosed with cancer. Baseline circulating GDF-15 concentrations were higher in patients that developed cancer over the follow-up period when compared to cancer-free patients. Increased GDF-15 concentrations were significantly associated with cancer incidence [crude hazard ratio (HR) per 1-IQR (interquartile range) increase 2.13, 95% CI 1.53-2.97, P < 0.001]. This effect persisted after multivariate adjustment with an adjusted HR of 1.86 (95% CI 1.22-2.84; P = 0.004). Among the 4 additionally tested cardiovascular markers in the subpopulation, only troponin T and C-terminal proendothelin-1 showed a significant association with future cancer incidence with unadjusted HRs of 1.71 (95% CI 1.28-2.28, P < 0.001) and 1.68 (95% CI 1.02-2.76, P = 0.042), respectively. CONCLUSIONS: Increased circulating concentrations of GDF-15 are associated with increased cancer incidence in patients with type 2 diabetes.

Ten-Year Outcomes After Coronary Artery Bypass Grafting According to Age in Patients With Heart Failure and Left Ventricular Systolic Dysfunction: An Analysis of the Extended Follow-Up of the STICH Trial (Surgical Treatment for Ischemic Heart Failure).

BACKGROUND: Advancing age is associated with a greater prevalence of coronary artery disease in heart failure with reduced ejection fraction and with a higher risk of complications after coronary artery bypass grafting (CABG). Whether the efficacy of CABG compared with medical therapy (MED) in patients with heart failure caused by ischemic cardiomyopathy is the same in patients of different ages is unknown. METHODS: A total of 1212 patients (median follow-up, 9.8 years) with ejection fraction ≤35% and coronary disease amenable to CABG were randomized to CABG or MED in the STICH trial (Surgical Treatment for Ischemic Heart Failure). RESULTS: Mean age at trial entry was 60 years; 12% were women; 36% were nonwhite; and the baseline ejection fraction was 28%. For the present analyses, patients were categorized by age quartiles: quartile 1, ≤54 years; quartile, 2 >54 and ≤60 years; quartile 3, >60 and ≤67 years; and quartile 4, >67 years. Older versus younger patients had more comorbidities. All-cause mortality was higher in older compared with younger patients assigned to MED (79% versus 60% for quartiles 4 and 1, respectively; log-rank P=0.005) and CABG (68% versus 48% for quartiles 4 and 1, respectively; log-rank P<0.001). In contrast, cardiovascular mortality was not statistically significantly different across the spectrum of age in the MED group (53% versus 49% for quartiles 4 and 1, respectively; log-rank P=0.388) or CABG group (39% versus 35% for quartiles 4 and 1, respectively; log-rank P=0.103). Cardiovascular deaths accounted for a greater proportion of deaths in the youngest versus oldest quartile (79% versus 62%). The effect of CABG versus MED on all-cause mortality tended to diminish with increasing age (Pinteraction=0.062), whereas the benefit of CABG on cardiovascular mortality was consistent over all ages (Pinteraction=0.307). There was a greater reduction in all-cause mortality or cardiovascular hospitalization with CABG versus MED in younger compared with older patients (Pinteraction=0.004). In the CABG group, cardiopulmonary bypass time or days in intensive care did not differ for older versus younger patients. CONCLUSIONS: CABG added to MED has a more substantial benefit on all-cause mortality and the combination of all-cause mortality and cardiovascular hospitalization in younger compared with older patients. CABG added to MED has a consistent beneficial effect on cardiovascular mortality regardless of age. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00023595.

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality.

OBJECTIVE: Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer. METHODS: We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP. CONCLUSIONS: Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Clinical characteristics and outcomes of patients with and without diabetes in the Surgical Treatment for Ischemic Heart Failure (STICH) trial.

AIMS: Hypothesis 1 of the Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with an LVEF of ≤35% and CAD amenable to coronary artery bypass grafting (CABG). Patients were randomized to CABG and optimal medical therapy (MED) or MED alone. The objective was to assess whether or not patients with diabetes mellitus (DM) enrolled in the STICH trial would have greater benefit from CABG than patients without DM. METHODS AND RESULTS: The characteristics and clinical outcomes of patients with and without DM randomized to CABG and MED or MED alone were compared. DM was present in 40%. At baseline, patients with DM had more triple vessel CAD, higher LVEF, and smaller left ventricular volumes. In patients with DM, the primary outcome of all-cause mortality occurred in 39% of patients in the MED group and 39% in the CABG group [hazard ratio (HR) with CABG 0.96, 95% confidence interval (CI) 0.73-1.26]. In patients without DM, the primary outcome occurred in 41% of patients in the MED group and 32% in the CABG group (HR with CABG 0.80, 95% CI 0.63-1.02). While numerically it would appear that the treatment effect of CABG is blunted in patients with DM, there was no significant interaction between DM and treatment group on formal statistical testing. CONCLUSIONS: Patients with DM enrolled in the STICH trial had more triple vessel disease, smaller hearts, and higher LVEF than those without DM. CABG did not exert greater benefit in patients with DM.

NT-proBNP as a means of triage for the risk of hospitalisation in primary care.

BACKGROUND: In primary care, identification of patients who are at risk of major adverse events is of great importance. At the same time identifying individuals who are at very low risk and do not need further diagnostic workup and therapy is also important and may help to correctly allocate scarce healthcare resources. AIM: This study evaluated amino-terminal pro B-natriuretic peptide (NT-proBNP) as a risk marker in primary care patients with hypertension, diabetes, clinically suspected heart failure (HF), history of coronary artery disease or myocardial infarction. METHODS AND RESULTS: A prospective observational study was conducted in 1203 primary care patients. The primary endpoint, time to all-cause hospitalisation, was reached in 282 (24%) individuals within 12 months. Of all variables analysed, only NT-proBNP (HR 1.001 [1.000-1.001], p < 0.001) and age (HR 1.018 [1.007-1.028], p = 0.001) were of independent predictive value in a stepwise Cox regression analysis regarding all-cause hospitalisation. Neither systolic dysfunction nor signs and symptoms of HF added independent information to predict outcome. The negative predictive value (NPV) increased depending on the specificity of the endpoint (NPV was 86% for all-cause, 98% for cardiac and 100% for HF-related hospitalisation for 125 pg/ml). Positive predictive value and NPV were superior for NT-proBNP compared to clinical signs and symptoms of HF at every cut-point between 100 and 500 pg/ml. CONCLUSION: NT-proBNP levels predicted clinical events in primary care patients at risk. NPVs were excellent in this high risk population, proving NT-proBNP measurement a safe diagnostic tool.

Quality of life and economic outcomes with surgical ventricular reconstruction in ischemic heart failure: results from the Surgical Treatment for Ischemic Heart Failure trial.

BACKGROUND: Surgical ventricular reconstruction (SVR) is used in conjunction with coronary artery bypass graft surgery (CABG) to improve left ventricular function and clinical outcomes in selected patients with ischemic heart failure. The impact of SVR on quality of life (QOL) and medical costs is unknown. METHODS: We compared CABG plus SVR with CABG alone in 1,000 patients with ischemic heart failure, an anterior wall scar, and a left ventricular ejection fraction or=92% complete. Cost data were collected on 196 (98%) of 200 patients enrolled in the United States. RESULTS: Heart-failure-related QOL outcomes did not differ between the 2 treatment strategies out to 3 years (median Kansas City Cardiomyopathy Questionnaire scores for CABG alone and CABG plus SVR, respectively: baseline 53 versus 54, P = .53; 3 years 85 versus 84, P = .89). There were no treatment-related differences in other QOL measures. In the US patients, total index hospitalization costs averaged over $14,500 higher for CABG plus SVR (P = .004) due primarily to 4.2 extra postoperative, high-intensity care days in the hospital. CONCLUSIONS: Addition of SVR to CABG in patients with ischemic heart failure did not improve QOL but significantly increased health care costs.

High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an enigmatic disorder lacking signs, symptoms and classical risk factors for venous thromboembolism. The objective of the prospective case controlled study, carried out at the Pulmonary Hypertension Unit, University Hospital Vienna, Austria, was to investigate whether plasma FVIII is elevated in CTEPH patients. The study examined 122 consecutive patients diagnosed with CTEPH. Plasma FVIII was measured and compared with plasma FVIII of healthy controls (n = 82) and of patients with nonthromboembolic pulmonary arterial hypertension (PAH, n = 88). Results show that CTEPH patients had higher FVIII levels than controls (233 +/- 83IU/dl versus 123 +/- 40IU/dl, p < 0.0001) and PAH patients (158 +/- 61IU/dl, p < 0.0001). Plasma FVIII one year after surgery (212 +/- 94IU/dl) was statistically unchanged compared with preoperative values (FVIII: 226 +/- 88IU/dl, n = 25). FVIII > 230IU/dl was more prevalent in CTEPH patients (41%) than in controls (5%, p < 0.0001) and PAH patients (22%, p = 0.022). We can conclude that elevated plasma FVIII is the first prothrombotic factor identified in a large proportion of CTEPH patients.