Symptomatic Left Ventricular Dysfunction Research Articles

How Did I Manage a Case of Pulseless Electrical Activity During Transcatheter Aortic Valve Implantation in a Patient with Severe Aortic Valve Stenosis with Left Ventricular Dysfunction?

Cardiac arrest during transcatheter aortic valve implantation (TAVI) is rare but is generally associated with dramatic consequences including mortality and severe neurological damage. Our patient is an 89-year-old male with symptomatic severe aortic valve stenosis and left ventricular dysfunction. He had a prolonged cardiac arrest in the form of pulseless electrical activity (PEA) during TAVI. After ruling out cardiac tamponade and bleeding, we decided to do the TAVI while doing cardiopulmonary resuscitation. The hemodynamics of the patient improved immediately after TAVI and we could avoid the use of a mechanical circulatory support. We have also discussed in detail the cause, diagnosis, and management of PEA during TAVI.

Unraveling the mystery of Takutsubo cardiomyopathy: a descendant of COVID-19 heart syndrome

Takutsubo, or stress cardiomyopathy (TCM) is one of the important cardiovascular disorders encountered during the COVID-19 pandemic. We performed a PubMed search of relevant articles and presented this review which included epidemiology, etiopathogenesis, diagnosis and treatment of this clinical disorder. Takutsubo is usually more common in women than men. COVID-19 infection or vaccination can incite severe emotional disorders such as anxiety and depression, which flames up impaired neural networks in the limbic system. This stirs up disorganized regulation of autonomic nervous system with predominance and excessive firing of sympathetic nervous system to the ventricular myocardium. Moreover, direct invasion and systemic effects of COVID-19 infection including hormonal influences, autoimmunity, cytokine storm and neighboring infections might also play a significant role in the manifestation of this disorder. It commonly presents signs and symptoms of left ventricular dysfunction. Although most cases are undergoing remission within a few weeks, complications such as LV outflow tract obstruction, thromboembolism and arrhythmias were also reported. Since clinical symptoms are non-specific, a high degree of clinical suspicion is warranted particularly with the co-existing COVID-19 infections. Clinicians often leaned upon battery of tests including ECG, echocardiography and CMR to rule out myocarditis and coronary artery disease. Supportive management including treatment of heart failure and any associated arrhythmias and thromboembolism. Recurrences are common, but the treatment of underlying psychiatric disorders, including relaxation techniques, is the key strategy to avoid future occurrences.

The Impact of Complete Revascularization in Symptomatic Severe Left Ventricular Dysfunction between Coronary Artery Bypass Graft and Percutaneous Coronary Intervention.

The study aimed to compare the clinical outcomes between the patients receiving coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) for the patients with symptomatic severe left ventricular (LV) dysfunction and coronary artery disease (CAD). Between February 2007 and February 2020, a total of 745 patients who received coronary artery angiography for reduced LV ejection fraction (LVEF) < 40% and symptomatic New York Heart Association (NYHA) functional class ≥ 3 were recruited. The patients (N = 236) who were diagnosed with dilated cardiomyopathy or valvular heart disease without coronary artery stenosis, those with prior history of CABG or valvular surgery (N = 59), those who presented ST-segment elevated myocardial infarction (STEMI), those with a CAD and SYNTAX score of ≦ 22 (N = 175), those who received emergent CABG for coronary perforation (N = 3), and those who had NYHA class ≦ 2 (N = 65) were excluded. Finally, 116 patients with reduced LVEF and those who had a SYNTAX score >22, who received CABG (N = 47) and PCI (N = 69), were recruited for this study. There was no significant difference in the incidence values of in-hospital course and those of in-hospital mortality, acute kidney injury, and postprocedural hemodialysis. There was no significant difference in the 1-yearfollow-up of recurrent MI, revascularization, or stroke between the groups. The 1-year heart failure (HF) hospitalization rate was significantly lower in the CABG group than in all patients of the PCI group (13.2% vs. 33.3%; p = 0.035); however, there was no significant difference in the same variable between the CABG group and the complete revascularization subgroup (13.2% vs. 28.2%; p = 0.160). The revascularization index (RI) was significantly higher in the CABG group than in all patients of the PCI group or complete revascularization subgroup (0.93 ± 0.12 vs. 0.71 ± 0.25; p < 0.001) and (0.93 ± 0.12 vs. 0.86 ± 0.13; p = 0.019). The 3-year HF hospitalization rate was significantly lower in the CABG group than in all patients of the PCI group (16.2% vs. 42.2%; p = 0.008); however, there was no difference in the same variable between the CABG group and the complete revascularization subgroup (16.2% vs. 35.1%; p = 0.109). In patients with symptomatic (NYHA class ≥ 3) severe LV dysfunction and CAD, CABG brought less HF admission when compared to patients in the PCI group, but this did not differ when compared to the complete revascularization subgroup. Therefore, an extensive revascularization, achieved by CABG or PCI, is associated with a lower HF hospitalization rate during the 3-yearfollow-up period in such populations.

Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): final analysis of a phase III, randomized, double-blind, placebo-controlled study

PurposePUFFIN (NCT02896855), a Chinese bridging study in patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer, assessed consistency of efficacy and safety of pertuzumab plus trastuzumab and docetaxel versus placebo, trastuzumab, and docetaxel, with CLEOPATRA (NCT00567190).MethodsEligible patients, n = 243, were randomized 1:1, stratified by visceral disease and hormone receptor status, to pertuzumab, trastuzumab, and docetaxel or placebo, trastuzumab, and docetaxel. Primary endpoint: investigator-assessed progression-free survival (PFS). Secondary endpoints: safety and overall survival (OS). After primary analysis, patients could cross over to the pertuzumab arm.ResultsUpdated median PFS: 16.5 months (pertuzumab arm) and 12.5 months (placebo arm), with a hazard ratio (HR) of 0.60 [95% confidence interval (CI) 0.45, 0.81; p = 0.0008]. Median OS was not reached in either arm; the OS HR was 0.68 (95% CI 0.45, 1.03; p = 0.0658). Safety was similar in both arms with no new safety signals: 73.8% (pertuzumab arm) and 69.2% (placebo arm) experienced grade ≥ 3 adverse events. No heart failure, symptomatic left ventricular systolic dysfunction, or left ventricular ejection fraction decline of < 40% were reported.ConclusionsThe PUFFIN final analysis showed, per the primary analysis, that overall efficacy of pertuzumab plus trastuzumab and docetaxel was consistent with CLEOPATRA. Safety remained consistent with the known pertuzumab profile. Overall, PUFFIN contributes to the totality of data with pertuzumab in previously untreated HER2-positive locally recurrent or metastatic breast cancer and supports the favorable benefit–risk profile of pertuzumab in Chinese patients.Trial registration: ClinicalTrials.gov, NCT02896855, registered 7 September 2016.

Clinical Outcomes With Transcatheter Edge-to-Edge Repair in Atrial Functional MR From the EXPAND Study

BackgroundAlthough transcatheter edge-to-edge repair (TEER) has been shown to improve clinical outcomes and improve quality of life in patients with symptomatic secondary mitral regurgitation (SMR) and left ventricular dysfunction, its effect in patients with atrial SMR (aSMR) has not been well described. ObjectivesThe aim of this study was to assess the safety, echocardiographic outcomes, and clinical effectiveness of TEER for aSMR. MethodsPatients with aSMR in the prospective, observational, multicenter EXPAND (A Contemporary, Prospective, Multi-Center Study Evaluating Real-World Experience of Performance and Safety for the Next Generation of MitraClip Devices) study were identified by an echocardiography core laboratory. Follow-up occurred at discharge, 30 days, and 1 year. Key endpoints included mitral regurgitation (MR) severity, functional class, heart failure hospitalizations, mortality, and 30-day major adverse events. ResultsAmong 1,041 patients enrolled in EXPAND, 835 patients had evaluable echocardiograms at baseline. Of these, 53 patients had aSMR and 360 had ventricular SMR (vSMR). In the aSMR cohort, TEER resulted in a significant reduction in MR through 1 year (MR grade ≤2 in 100.0%), significantly increased 1-year Kansas City Cardiomyopathy Questionnaire score (+26.6 ± 30.5 points; P < 0.0001), and improved functional class from baseline, similar to the effects among patients with vSMR (MR grade ≤2 in 99.5% at 1 year, 1-year increase in Kansas City Cardiomyopathy Questionnaire score 21.23 ± 24.92 points). Major adverse events at 30 days and leaflet adverse events at 1 year were infrequent in both groups. ConclusionsIn a prospective, real-world, global registry, TEER for aSMR was associated with significant MR reduction and improvement in quality of life and functional class, similar to patients with vSMR. This suggests that TEER may provide clinical benefit in patients with atrial fibrillation with SMR in the setting of heart failure with preserved ejection fraction. (The MitraClip® EXPAND Study of the Next Generation of MitraClip® Devices; NCT03502811)

SGLT-2 Inhibitors on Top of Current Pharmacological Treatments for Heart Failure: A Comparative Review on Outcomes and Cost Effectiveness.

Heart failure (HF) represents a major global health and economic burden with still unacceptably high morbidity and mortality rates. In recent decades, novel therapeutic opportunities with a significant impact on HF outcomes have been introduced in addition to angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and mineralocorticoid receptor antagonists. These include drugs such as ivabradine, sacubitril-valsartan, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. The availability of an extremely large pharmacological armamentarium to face this chronic global disease highlights the importance of assessing cost effectiveness to promote sustainable healthcare. In light of the recent approval of SGLT-2 inhibitors for the treatment of HF with reduced ejection fraction, including in individuals without type 2 diabetes mellitus, the aim of this review was to provide an updated comparative evaluation of the efficacy and cost effectiveness of different pharmacological treatments for the prevention (stage A) and treatment of asymptomatic (stage B) and symptomatic (stages C-D) left ventricular dysfunction.

Emerging Treatment Options for the Systemic Right Ventricle: A Single Centre Experience of Sacubitril/Valsartan in Transposition of Great Arteries

Over the last few decades, we are appreciating the need of tailored treatment options for adults with congenital heart disease. Patients with D-transposition of great arteries (D-TGA) with atrial switch operations or L-TGA often develop systemic right ventricular (sRV) dysfunction as a long-term complication. Sacubitril/valsartan has become guideline-based therapy for patients with symptomatic left ventricular systolic dysfunction, however it is unclear if these results can be extrapolated to patients with a sRV.

Transcatheter aortic valve implantation with a novel pre-packaged self-expandable dry-tissue transcatheter aortic valve: a case report.

BackgroundCurrent commercially available transcatheter aortic valves are stored separately in a glutaraldehyde solution and mounted onto the delivery system by a technical expert during the transcatheter aortic valve implantation (TAVI) procedure. A pre-mounted dry-tissue valve that is crimped on a ready-to-use delivery system could simplify the procedure. The Vienna self-expanding transcatheter valve (P&F, GmbH, Wessling, Germany) is a novel ready-to-use pre-mounted dry-tissue transcatheter aortic valve. There are no prior reports on the efficacy of this valve system.Case summaryHere, we report our experience of an implantation of a novel ready-to-use dry-tissue Vienna transcatheter aortic valve in a 72-year-old male with symptomatic severe aortic stenosis and severe left ventricular systolic dysfunction. He had presented with heart failure [N-terminal pro-brain natriuretic peptide (NT-proBNP) level at the admission of 10 600 pg/mL], New York Heart Association Class-3, and recurrent syncope. A 26 mm Vienna valve was successfully implanted via the transfemoral route under conscious sedation. There were no complications. The patient was discharged in a stable condition on the third post-procedure day. At 1-year follow-up, the valve is functioning well with no evidence of structural degeneration (mean gradient 9 mmHg, no valvular regurgitation). Currently, he is asymptomatic with normal left ventricular systolic function on echocardiography (NT-proBNP 57 pg/mL).DiscussionTo our knowledge, this is the first case of TAVI performed with the dry-tissue pre-mounted VIENNA valve. Our case highlights the feasibility and short-term efficacy of the VIENNA valve. Further safety and durability need to be addressed by a multicentre trial.

Efficacy of the eribulin, pertuzumab, and trastuzumab combination therapy for human epidermal growth factor receptor 2\u2013positive advanced or metastatic breast cancer: a multicenter, single arm, phase II study (JBCRG-M03 study)

SummaryPurpose To date, it is not clear which anticancer agent is useful in combination with trastuzumab and pertuzumab As the first and second selective regimens for advanced or metastatic breast cancer (AMBC), this multicenter, open-label, phase II trial (JBCRG-M03: UMIN000012232) presents a prespecified analysis of eribulin in combination with pertuzumab and trastuzumab. Methods We enrolled 50 patients with no or single prior chemotherapy for HER2-positive AMBC during November 2013–April 2016. All patients received adjuvant or first-line chemotherapy with trastuzumab and a taxane. The treatment comprised eribulin on days 1 and 8 of a 21-day cycle and trastuzumabplus pertuzumab once every 3 weeks, all administered intravenously. While the primary endpoint was the progression-free survival (PFS), secondary endpoints were the response rate and safety. Results Of 50 patients, 49 were eligible for safety analysis, and the full analysis set (FAS) included 46 patients. We treated 8 (16%) and 41 (84%) patients in first- and second-line settings, respectively. While 11 patients (23.9%) had advanced disease, 35 (76.1%) had metastatic disease. The median PFS was 9.2 months for all patients [95% confidence interval (CI): 7.0–11.4]. In the FAS, 44 patients had the measurable lesions and the complete response rate (CR) was 17.4%, and partial response rate (PR) was 43.5%. The grade 3/4 adverse events were neutropenia (5 patients, 10.2%), including febrile neutropenia (2 patients, 4.1%), hypertension (3 patients, 6.1%), and other (1 patient). The average of the left ventricular ejection fraction did not decline markedly. No symptomatic left ventricular systolic dysfunction was observed. Conclusions In patients with HER2-positive AMBC, eribulin, pertuzumab, and trastuzumab combination therapy exhibited substantial antitumor activity with an acceptable safety profile. Hence, we have started a randomized phase III study comparing eribulin and a taxane in combination with pertuzumab and trastuzumab for the treatment of HER2-positive AMBC. Trial registration ID: UMIN-CTR: UMIN000012232.

Mid-Term Follow-Up of the Revivent System as a Less-Invasive Ventricular Reconstruction Procedure - Preliminary Results from a Multicenter-Trial

Background Surgical ventricular reconstruction to remodel, reshape and reduce ventricular volume is an effective therapy in selected patients with ischemic heart failure (IHF). The BioVentrix Revivent System offers comparable efficacy to conventional surgical ventricular reconstruction aiming to exclude nonfunctioning myocardium, reshape ventricular size and reduce ventricular volume in selected patients with IHF, but is a less-invasive procedure on the beating heart. With this study we aimed to assess its functional effectiveness. Methods Patient were considered eligible for the procedure when they presented with symptomatic (at least NYHA II) left ventricular (LV) dilatation and dysfunction, caused by myocardial infarction (MI) that occurred at least 90 days prior to study enrollment, and with akinetic and/or dyskinetic scarred myocardium of at least 50% transmurality located in the antero-septal, anterolateral, and/or apical regions. The BioVentrix Revivent System consists of polyester-covered titanium anchor pairs that are drawn together to exclude scarred areas of the LV free wall. The anchors were implanted via sternotomy or, alternatively, through a combined mini-thoracotomy and transcatheter procedure. Results Eighty-nine patients were enrolled. At 2 years, a significant improvement in LVEF(30 ± 8% vs 34 ± 9%, p Conclusions Less invasive reconstruction with the BioVentrix Revivent system in patients with symptomatic IHF results in significant and sustained improvement of LV function, reduction in LV volumes with reduction of heart failure symptoms and improved quality of life at mid-term follow-up.

End-of-study analysis from the phase III, randomized, double-blind, placebo (Pla)-controlled CLEOPATRA study of first-line (1L) pertuzumab (P), trastuzumab (H), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC).

1020 Background: Progression-free and overall survival (PFS and OS) were significantly improved with 1L P + H + D v Pla + H + D in 808 pts with HER2-positive MBC in CLEOPATRA (NCT00567190). OS was increased by an unprecedented 15.7 mo (median 56.5 mo with P + H + D v 40.8 mo with Pla + H + D; HR 0.68; 95% CI 0.56, 0.84; p &lt; .001) with a median follow-up of 50 mo [Swain et al. NEJM 2015]). Here we report the end-of-study analysis with a median follow-up of 99 mo (max 120 mo). Methods: In this descriptive analysis, OS was compared between arms using the log-rank test, stratified by prior treatment status and geographic region. The Kaplan–Meier approach was used to estimate median OS, and a stratified Cox proportional hazards model was used to estimate the HR and 95% CIs. Subgroup analyses of OS were performed for stratification factors and other baseline characteristics. Results: Clinical cutoff was Nov 23, 2018. Since Jul 2012, 50 pts crossed from the Pla to the P arm. These pts are counted in the Pla arm for efficacy analyses and up to the first dose of P for safety analyses. The OS HR was 0.69 (95% CI 0.58, 0.82), favoring P + H + D. Median OS was 57.1 mo in the P arm (402 pts) and 40.8 mo in the Pla arm (406 pts; Δ 16.3 mo). The 8-year landmark OS rates were 37% and 23%, respectively. The OS benefit in predefined subgroups, including in pts previously treated with H in the (neo)adjuvant setting (88 pts, HR 0.86; 95% CI 0.51, 1.43), remained consistent with the overall result and previous reports. The overall safety profile of P + H + D was consistent with the known P safety profile. There was only one new serious adverse event suggestive of congestive heart failure (onset ~77 mo on treatment in the P arm, resolution in 34 days, pt continued on study medication) and one new symptomatic left ventricular systolic dysfunction (onset ~46 mo after crossing to the P arm, resolution in 34 days) since the previous analysis. Conclusions: The OS improvement with 1L P + H + D v Pla + H + D for pts with HER2-positive MBC was maintained after an additional 4 years of long-term follow-up, as were the safety and cardiac safety profiles. Clinical trial information: NCT00567190.

MID-TERM FOLLOW-UP OF THE REVIVENT SYSTEM AS A LESS-INVASIVE VENTRICULAR RECONSTRUCTION PROCEDURE: PRELIMINARY RESULTS FROM A MULTICENTER-TRIAL

Background Surgical ventricular reconstruction to remodel, reshape and reduce ventricular volume is an effective therapy in selected patients with ischemic heart failure (IHF). The BioVentrix Revivent System offers comparable efficacy to conventional surgical ventricular reconstruction aiming to exclude nonfunctioning myocardium, reshape ventricular size and reduce ventricular volume in selected patients with IHF, but is a less-invasive procedure on the beating heart. With this study we aimed to assess its functional effectiveness. Methods Patient were considered eligible for the procedure when they presented with symptomatic (at least NYHA II) left ventricular (LV) dilatation and dysfunction, caused by myocardial infarction (MI) that occurred at least 90 days prior to study enrollment, and with akinetic and/or dyskinetic scarred myocardium of at least 50% transmurality located in the antero-septal, anterolateral, and/or apical regions. The BioVentrix Revivent System consists of polyester-covered titanium anchor pairs that are drawn together to exclude scarred areas of the LV free wall. The anchors were implanted via sternotomy or, alternatively, through a combined mini-thoracotomy and transcatheter procedure. Results Eighty-nine patients were enrolled. At 2 years, a significant improvement in LVEF(30 ± 8% vs 34 ± 9%, p Conclusions Less invasive reconstruction with the BioVentrix Revivent system in patients with symptomatic IHF results in significant and sustained improvement of LV function, reduction in LV volumes with reduction of heart failure symptoms and improved quality of life at mid-term follow-up.

Prescribing patterns of evidence-based heart failure pharmacotherapy and outcomes in the ASIAN-HF registry: a cohort study.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), β blockers, and mineralocorticoid receptor antagonists (MRAs) are of proven benefit and are recommended by guidelines for management of patients with heart failure and reduced ejection fraction (HFrEF). We aimed to examine the first prospective multinational data from Asia on prescribing patterns of guideline-directed medical therapies and analyse its effect on outcomes. In the prospective multinational ASIAN-HF registry (with enrolment from 46 centres in 11 countries in Asia), we enrolled patients aged 18 years or older, with symptomatic heart failure (stage C, with at least one episode of decompensated heart failure in the past 6 months that resulted in admission to hospital or was treated in an outpatient clinic) and left ventricular systolic dysfunction (ejection fraction ≤40% on baseline echocardiography, consistent with 2016 European Society of Cardiology guidelines). We excluded patients with heart failure caused by severe valvular heart disease, life-threatening comorbidity with a life expectancy of less than 1 year, who were unable or unwilling to give consent, or who had concurrent participation in a clinical trial. Patients were followed up for 3 years for the outcomes of death and cause-specific admittance to hospital. Primary outcomes were uptake of guideline-directed medical therapies (as proportions) by therapeutic class, achieved doses as proportions of guideline-recommended doses, and their association with 1-year composite outcome of all-cause death or admittance to hospital because of heart failure. This study is registered with ClinicalTrials.gov, number NCT01633398. Between Oct 1, 2012, and Dec 31, 2015, we enrolled 5276 patients with HFrEF (mean age 59·6 years [SD 13·2], 77% men, body-mass index 24·9 kg/m2 [5·1], 33% New York Heart Association class III or IV). Follow-up data were available for 4544 (90%) of 5061 eligible patients taking medication for heart failure, with median follow-up of 417 days (IQR 214-735). ACE inhibitors or ARBs were prescribed to 3868 (77%) of 5005 patients, β blockers to 3975 (79%) of 5061, and MRAs to 2998 (58%) of 5205, with substantial regional variation. Guideline-recommended dose was achieved in only 17% of cases for ACE inhibitors or ARB, 13% for β blockers, and 29% for MRAs. Country (all three drug classes), increasing body-mass index (ACE inhibitors or ARBs and MRAs), and in-patient recruitment (ACE inhibitors or ARBs and β blockers) were associated with attainment of guideline-recommended dose (all p<0·05). When adjusted for indication bias, increasing drug doses, from low dose (1-<25% of guideline-recommended dose) upwards were associated with lower hazards of a 1-year composite outcome for ACE inhibitors or ARBs and β blockers compared with non-users. The lowest adjusted hazards were in the group that attained guideline-recommended doses above 50% (hazard ratio [HR] 0·54, 95% CI 0·50-0·58 for ACE inhibitors or ARBs [50-99·9%]; HR 0·47, 0·46-0·50 for β blockers, and HR 0·77, 0·72-0·81 for MRAs [≥100%]). Guideline-directed medical therapies at recommended doses are underutilised in patients with HFrEF. Improved uptake and uptitration of guideline-directed medical therapies are needed for better patient outcomes. National Medical Research Council (Singapore), A*STAR Biomedical Research Council ATTRaCT program, Boston Scientific Investigator Sponsored Research program, and Bayer.

Abstract P5-21-07: Phase II study of eribulin in combination with pertuzumab plus trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer

Abstract Background: Pertuzumab provided overall and progression-free survival (PFS) benefits in HER2-positive metastatic breast cancer patients (pts) in the CLEOPATRA (Clinical evaluation of docetaxel, pertuzumab and trastuzumab) study. However, few studies have described the efficacy of other drugs in combination with pertuzumab plus trastuzumab. Here, we present a pre-specified analysis of eribulin in combination with pertuzumab plus trastuzumab as first- and second-line therapy for advanced or metastatic breast cancer (AMBC) in a multicenter, open-label phase II study (UMIN000012232, JBCRG-M03). Methods: HER2-positive AMBC with no or single prior chemotherapy for AMBC were enrolled. All pts were administered trastuzumab and taxane as adjuvant or first-line chemotherapy. Treatment consisted of eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) plus pertuzumab (840 mg/body loading dose, then 420 mg/ body) once every 3 weeks, all administered intravenously. The primary endpoint was PFS, and secondary endpoints included overall response rate (ORR) and safety. PFS was determined using Kaplan–Meier analysis. Tumor response was assessed according to RECIST ver. 1.1. Results: Fifty pts were enrolled from November 2013 to April 2016. Forty-nine pts were eligible for safety analysis and the full analysis set (FAS) included 46 pts. The median age was 56 years (23–70), and 8 (16%) and 41 (84%) pts were treated in first- and second-line settings, respectively. Eleven pts (23.9%) were de-novo Stage 4, and 35 pts (76.1%) had progressed in metastatic disease after completion of local therapy. Median PFS was 9.3 months (M) (95% confidence interval [CI]: 6.4–12.3). Table 1 shows the efficacy data for each treatment line and includes ORR, complete response rate (CR), partial response rate (PR), stable disease rate (SD), progressive disease rate (PD), not evaluable rate (NE) and PFS in the FAS. The median relative dose intensities of eribulin, trastuzumab, and pertuzumab were 93.3% (77.0%–100%), 100% (96.0%–100%), and 100% (89.7%–100%), respectively, in the FAS. The grade 3/4 adverse events (AE) were neutropenia in 5 pts (10.2%), including 2 pts (4.1%) with febrile neutropenia; hypertension in 3 pts (6.1%), and other AEs in only one patient. The average of the ejection fraction did not decrease significantly. Symptomatic left ventricular systolic dysfunction was not observed. Conclusion: In pts with HER2-positive AMBC, first- and second-line therapy of eribulin in combination with pertuzumab plus trastuzumab demonstrated substantial antitumor activity with an acceptable safety profile. We are planning a phase III study comparing eribulin with taxanes in combination with pertuzumab plus trastuzumab for the treatment of HER2-positive AMBC. Efficacy data for each treatment lineTreatment LineTotal (n=46)First line (n=8)Second line (n=38)PFS (95% CI), months9.3 (6.4-12.3)20.8 (2.8-38.7)8.7 (7.2-10.2)ORR (%)28 (60.9)7 (87.5)21 (55.3)CR (%)8 (17.4)3 (37.5)5 (13.2)PR (%)20 (43.5)4 (50.0)16 (42.1)SD (%)11 (23.9)1 (12.5)10 (26.3)PD (%)5 (10.9)05 (13.2)NE (%)2 (4.3)02 (5.3) Citation Format: Kawaguchi H, Yamashita T, Masuda N, Kitada M, Narui K, Hattori M, Yoshinami T, Matsunami N, Yanagihara K, Kawasoe T, Nagashima T, Bando H, Yano H, Hasegawa Y, Nakamura R, Kashiwaba M, Morita S, Ohno S, Toi M. Phase II study of eribulin in combination with pertuzumab plus trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-07.

Eribulin in combination with pertuzumab plus trastuzumab for HER2-positive advanced or recurrent breast cancer (JBCRG-M03).

1025 Background: Pertuzumab (P) provided overall and progression-free survival (PFS) benefits in HER2-positive metastatic breast cancer (MBC) in the CLEOPATRA study as a first-line therapy. However, long-term administration of intravenous docetaxel at a dose of 75 mg/m2 every 3 weeks in MBC patients is difficult. Eribulin (E) is a well-tolerated cytotoxic agent. We report the efficacy and safety of E in combination with trastuzumab (T) plus P as first- and second-line therapy for metastatic or advanced BC in a multicenter, open-label phase II study (UMIN000012232). Methods: HER2-positive advanced or recurrent BC patients with no or a single prior therapy as advanced or recurrent chemotherapy were enrolled. All patients were administered T and taxane as adjuvant or first-line chemotherapy. Treatment consisted of E 1.4 mg/m2 on days 1 and 8 of a 21-day cycle and T (8 mg/kg loading dose &gt; 6 mg/kg) plus P (840 mg loading dose &gt; 420 mg) once every 3 weeks, all given intravenously. The primary end point was PFS. Results: From November 2013 to April 2016, 50 patients were enrolled. Forty-nine patients were eligible for safety analysis; full analysis set (FAS) includes 46 patients. The median patient age was 56 years (range 23–70), and 8 (16%) and 41 (84%) patients were treated in first- and second-line settings, respectively. Twenty-eight patients out of 49 patients (57%) continued the protocol therapy at the end of 8 cycles and median PFS was not yet reached. The response rate by RECIST ver.1.1 was 56.5% in FAS. The relative dose intensity of E, T, and P were 93.3% (range 77.0%–100%), 100% (range 96.0%–100%) and 100% (range 89.7%–100%), respectively in FAS. The grade 3/4 adverse effects (AE) were neutropenia in 5 patients (10.2%) including 2 patients (4.1%) with febrile neutropenia, hypertension in 3 patients (6.1%), and other AEs in only one patient. Average of the ejection fraction did not decrease significantly. Symptomatic left ventricular systolic dysfunction was not observed. Conclusions: E in combination with T plus P was well-tolerated and could be an alternative to docetaxel-based combination therapy for HER2-positive MBC. Clinical trial information: 000012232.

A phase III trial of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2+ breast cancer: The TRAIN-2 study (BOOG 2012-03).

507 Background: Neoadjuvant chemotherapy with dual HER2 blockade boosts pathologic complete response (pCR) rates in HER2+ breast cancer. The optimal chemotherapy backbone in this setting is unknown. We conducted a multicenter phase III trial to study whether anthracyclines would improve outcome compared to a carboplatin-taxane regimen (NCT01996267). Methods: We randomly assigned (1:1) patients with stage II-III HER2+ breast cancer to receive 9 cycles paclitaxel (80mg/m2 day 1 and 8) and carboplatin (AUC = 6mg/ml·min) (arm A) or 3 cycles 5-fluoruoracil (500mg/m2), epirubicin (90mg/m2), and cyclophosphamide (500mg/m2) followed by 6 cycles paclitaxel and carboplatin (arm B). Both arms received trastuzumab (6mg/kg, loading dose 8mg/kg) and pertuzumab (420mg, loading dose 840mg) concurrent with all chemotherapy cycles, and cycles were repeated every 3 weeks. The primary endpoint was pCR in breast and axilla (ypT0/is,ypN0). Results: 438 patients were included and 418 (arm A 206 vs arm B 212) were evaluable for the primary endpoint. The pCR rate did not differ between arms (arm A 68% [95% CI 61-74] vs arm B 67% [95% CI 60-73], p = 0.75). Hormone receptor (HR) negative tumors had significantly higher pCR rates (87% vs 54%, p &lt; 0.0001), but we found no evidence for treatment-by-HR interaction (p = 0.23). Common adverse events grade ≥3 were neutropenia (arm A 53% vs arm B 57%, p = 0.34), febrile neutropenia (arm A 2% vs arm B 11%, p = 0.0001), and diarrhea (arm A 17% vs arm B 12%, p = 0.14). Neuropathy grade ≥2 was common in both arms (arm A 31% vs arm B 29%, p = 0.83), while left ventricular ejection fraction (LVEF) decline grade ≥2 (defined as ≥10% decline from baseline or LVEF &lt; 50%) was more common in arm B (arm A 18% vs arm B 29%, p = 0.007). Symptomatic left ventricular systolic dysfunction was rare ( &lt; 1%) in both arms. Conclusions: Anthracyclines increase the incidence of febrile neutropenia and grade ≥2 LVEF decline, but do not improve pCR rate in the contemporary neoadjuvant treatment of HER2+ breast cancer with dual HER2 blockade. Therefore, we currently favor a carboplatin-taxane based regimen. Follow-up is required to confirm these results with regard to long-term outcome. Clinical trial information: NCT01996267.

Abstract P4-21-02: Pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: Efficacy analysis of a phase II cardiac safety study (TRYPHAENA)

Abstract Background: The multicenter, open-label Phase II TRYPHAENA study (NCT00976989) showed that neoadjuvant pertuzumab (P) + trastuzumab (H) + chemotherapy (anthracycline-containing or anthracycline-free) was generally well tolerated with low rates of symptomatic left ventricular systolic dysfunction (LVSD, the primary endpoint), in patients (pts) with HER2-positive, operable, locally advanced or inflammatory breast cancer. All three arms were highly clinically active: total pathologic complete response in the breast and axilla (tpCR; ypT0/is, ypN0) rates were 55–64%. We now report long-term disease-free survival (DFS), progression-free survival (PFS), overall survival (OS), and cardiac safety. Methods: Pts were randomized 1:1:1 to six 3-weekly neoadjuvant treatment cycles. Arm A: H + P (cycles 1–6) + fluorouracil, epirubicin, cyclophosphamide (FEC, cycles 1–3) + docetaxel (T) (cycles 4–6), Arm B: FEC (cycles 1–3) followed by T + H + P (cycles 4–6), Arm C: T + H + P + carboplatin (cycles 1–6). Adjuvant H was then given to complete 1 year of treatment. Doses: P 840mg loading and 420mg maintenance; H 8mg/kg loading and 6mg/kg maintenance; T 75mg/m2, up to 100mg/m2 if tolerated (Arms A and B); fluorouracil 500mg/m2; epirubicin 100mg/m2; cyclophosphamide 600mg/m2; carboplatin area under the plasma concentration–time curve 6. A preplanned descriptive analysis of DFS (time from surgery until disease progression or death), PFS (time from randomization until disease progression or death, equivalent to the common definition of event-free survival), and OS (time from randomization until death from any cause) was conducted 5 years after randomization of the last pt. Results: Median follow-up was balanced across arms (61.1 months in Arm A; 61.8 months in Arm B; 60.9 months in Arm C); 3-year Kaplan–Meier (KM) survival estimates and 95% CIs are shown in the table. Arm A n=73Arm B n=75Arm C n=773-year KM survival estimate, %DFS87 (79–95)88 (80–96)90 (82–97) PFS89 (81–96)89 (81–96)87 (80–95) OS94 (89–100)94 (89–100)93 (87–99) For all three arms combined, the hazard ratio for DFS in pts who achieved tpCR versus those who did not achieve tpCR was 0.27 (95% CI 0.11–0.64). During post-treatment follow-up, 2/72 (2.8%) pts in Arm A, 3/75 (4.0%) in Arm B, and 4/76 (5.3%) in Arm C had LVSD (any grade). Of the pts with LVSD, only 1 pt experienced an event indicative of symptomatic LVSD (assessed as NYHA class II and grade ≥3). Also during this period, 8 pts in Arm A (11.1%), 12 (16.0%) in Arm B, and 9 (11.8%) in Arm C experienced LVEF declines to &amp;lt;50% and ≥10% from baseline. Conclusions: The 3-year DFS and PFS rates were similar between treatment arms and were comparable to rates previously observed in the neoadjuvant NeoSphere study. Pts who achieved tpCR had improved DFS compared with those who did not achieve tpCR, supporting previous findings of an association between pCR and long-term outcomes (Cortazar et al, Lancet 2014). The combination of P, H, and standard anthracycline-containing or anthracycline-free chemotherapy regimens was generally well tolerated and no new safety signals were identified with 5 years follow-up. Citation Format: Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Waldron-Lynch M, Eng-Wong J, Kirk S, Cortés J. Pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: Efficacy analysis of a phase II cardiac safety study (TRYPHAENA) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-02.

Abstract P4-21-23: A retrospective evaluation of cardiovascular recovery and oncologic outcomes associated with interrupted and continuous adjuvant trastuzumab in the setting of mild left ventricular dysfunction

Abstract Background: Trastuzumab is a monoclonal antibody that targets the HER2 receptor. In the adjuvant setting, 12 months of trastuzumab therapy has been shown to significantly reduce the risk of cancer recurrence. However, treatment with trastuzumab may also be associated with a decline in left ventricular (LV) function that, in most cases, will recover after trastuzumab therapy is stopped. When severe or symptomatic left ventricular dysfunction (LVD) occurs, trastuzumab is generally held with the intention of restoring cardiac function. It is less clear how to manage trastuzumab to optimize both cancer therapy and cardiovascular care when mild, asymptomatic drops in LV function are observed. The intention of this study was to assess how trastuzumab was managed immediately after the development of mild LVD in a non-trial setting and evaluate these outcomes. Methods: Patients who received adjuvant trastuzumab therapy for breast cancer between September 2005 and September 2010 in British Columbia were identified. Heart function imaging data for these patients were subsequently reviewed to identify those who experienced either a drop in LV ejection fraction (LVEF) to 40-49% or a greater than 15% drop in LVEF relative to their pre-chemotherapy baseline to a final LVEF ≥50%. The charts of patients who met these inclusion criteria were then reviewed for demographic information, comorbidities, trastuzumab dosing regime, subsequent cardiac events, and breast cancer outcomes. Results: A total of 171 patients were included in this study. 121 (70.8%) patients had an immediate hold in their trastuzumab therapy while the remaining 50 (29.2%) continued with their next scheduled dose. The number of patients who experienced a cancer relapse event in the therapy interruption and continuation groups were 21 (17.4%) and 5 (10.0%), respectively (P = 0.25). Cardiovascular events in the therapy interruption group included a subsequent drop in LVEF to &amp;lt;40% in 11 (9.1%) patients, long-term congestive heart failure (CHF) in 2 (1.7%) patients, and 1 (0.9%) death related to CHF. Cardiovascular events in the therapy continuation group included a subsequent drop in LVEF to &amp;lt;40% in 3 (6.0%) patients and long-term CHF in 1 (2.0%) patient. 24 (19.8%) patients in the therapy interruption group had a final LV function measurement that had fallen more than 10% below their baseline value while 12 (24.0%) patients in the therapy continuation group met this criterion (P=0.54). The mean numbers of adjuvant trastuzumab doses administered in the therapy interruption and continuation groups were 11.3 and 14.3, respectively. Finally, mean follow up times for the therapy interruption and continuation groups were 5.6 and 5.8 years, respectively. Conclusions: Continuing trastuzumab immediately after the development of mild LVD did not appear to be associated with an increased risk of long-term cardiovascular events. However, holding trastuzumab immediately after the development of mild LVD appeared to be associated with a 7.4% absolute risk increase in breast cancer recurrence. While these results are not statistically significant, they are concerning and warrant further investigation. Citation Format: Gibson JD, Yao RJR, Davis MK, Simmons CE. A retrospective evaluation of cardiovascular recovery and oncologic outcomes associated with interrupted and continuous adjuvant trastuzumab in the setting of mild left ventricular dysfunction [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-23.

Trastuzumab in combination with weekly paclitaxel and carboplatin as neo-adjuvant treatment for HER2-positive breast cancer: The TRAIN-study

AimTo determine the efficacy and safety of an anthracycline-free neo-adjuvant regimen consisting of weekly paclitaxel, carboplatin and trastuzumab in HER2-positive breast cancer. Patients and methodsPatients with stage II or III HER2-positive breast cancer received weekly paclitaxel ([P], 70 mg/m2), trastuzumab ([T], 2 mg/kg, loading dose 4 mg/kg) and carboplatin ([C], AUC = 3 mg ml−1 min) for 24 weeks. In weeks 7, 8, 15, 16, 23 and 24, trastuzumab was administered without chemotherapy. The primary end-point was pathologic complete response in the surgical resection specimen, defined as the absence of invasive tumour cells in breast and axilla. ResultsOne hundred and eleven patients were included in the study, and 108 were evaluable for the primary end-point. The pathologic complete response rate was 43% (95% confidence interval [CI]: 33–52). Median follow-up was 52 months, and the 3-year event-free survival was 88% (95% CI: 82–94), and the 3-year overall survival was 92% (95% CI: 88–98). The most common grade 3–4 adverse events were neutropenia (67%) and thrombocytopenia (43%). Less than five percent of patients experienced febrile neutropenia. No symptomatic left ventricular systolic dysfunction was observed during neo-adjuvant treatment. ConclusionAn anthracycline-free neo-adjuvant regimen of weekly paclitaxel, trastuzumab and carboplatin is highly effective in HER2-positive breast cancer with manageable toxicity.

Transapical transcatheter aortic valve replacement for high risk elderly patients with predominant aortic incompetence

To introduce the application of the J-Valve™ system in elderly patients with predominant aortic incompetence without significant valve calcification, and to evaluate its feasibility. From April 2014 to July 2015, 33 cases of transapical implantation of J-Valve™ were performed in Department of Cardiac Surgery, Zhongshan Hospital, Fudan University. Sixteen of these patients were diagnosed as predominant aortic incompetence without significant valve calcification. There were 11 male and 5 female patients aged from 61 to 84 years, with a mean age of (76±6) years. All patients had symptoms of left ventricular dysfunction for at least 3 months. They were considered to be prohibitive for surgical valve replacement (logistic European system for cardiac operative risk evaluation: 22.2% to 44.4%, mean 27%±6% after evaluation by an interdisciplinary heart team. The J-Valve™ system was applied in transapical transcatheter aortic valve replacement for patients. The multi-slice CT was performed before discharge. Clinical evaluation including patients' history, symptoms and New York Heart Association classification and echocardiogram evaluation were performed before discharge, 1(st) month, 3(th) month and 12(th) month after the operation respectively. Implantations were successful in all patients. One patient died from moderate paravalvular leak which led to multi-organ failure during the hospital stay. The mean time of postoperative hospital stay of the other 15 patients was (6.1±1.3) days. The 15 patients were followed by 174 to 410 days, with a median time of 188 days. Only two patients had trivial prosthetic valve incompetence, the other 13 patients had no prosthetic valve incompetence; two patients had no paravavular leak and the other 13 patients had paravavular leak of no more than moderate grade. There were no major complication or mortality during the follow-up. The transapical implantation of the J-Valve™ system in high risk elderly patients with predominant aortic incompetence is feasible.The early postoperative outcome is satisfactory.