McCann, Gerry P

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P < .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P < .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P < .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P < .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

Aims Guidelines for suspected cardiac chest pain have used historical risk stratification tools, advocating invasive coronary angiography (ICA) first-line in those at highest risk. We aimed to determine whether different strategies to manage suspected stable angina affected medium-term cardiovascular event rates and patient-reported quality of life (QoL) measures. Methods CE-MARC 2, a three-arm parallel group trial, randomised patients with suspected stable cardiac chest pain and a Duke Clinical pretest likelihood of coronary artery disease between 10% and 90%. Patients were randomised to either first-line cardiovascular magnetic resonance (CMR), single-photon emission computed tomography (SPECT) or the UK National Institute for Health and Care Excellence (NICE) CG95 (2010) guidelines-directed care. For the three arms, 1-year and 3-year first major adverse cardiovascular event (MACE) rates and QoL assessed by the Seattle Angina Questionnaire, Short Form 12 (V.12) Questionnaire and EuroQol-5 Dimension Questionnaire were recorded. Results 1202 patients were randomised to CMR (n=481), SPECT (n=481) and NICE (n=240). Forty-two patients (18 CMR, 18 SPECT, 6 NICE) experienced one or more MACEs. The percentage rates (95% CIs) of MACE in the CMR, SPECT and NICE groups at 3 years were 3.7% (2.4%, 5.8%), 3.7% (2.4%, 5.8%) and 2.1% (0.9%, 4.8%), respectively. QoL scores did not significantly differ across domains. Conclusion Despite a fourfold increase in referrals for ICA, the NICE CG95 (2010) guidelines risk-stratified care strategy did not significantly reduce 3-year MACE or improve QoL, as compared with functional imaging with CMR or SPECT. Trial registration number ClinicalTrials.gov Registry (NCT01664858).

Objective To assess the cost-effectiveness of management strategies for patients presenting with chest pain and suspected coronary heart disease (CHD): (1) cardiovascular magnetic resonance (CMR); (2) myocardial perfusion scintigraphy (MPS); and (3) UK National Institute for Health and Care Excellence (NICE) guideline-guided care. Methods Using UK data for 1202 patients from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 trial, we conducted an economic evaluation to assess the cost-effectiveness of CMR, MPS and NICE guidelines. Health outcomes were expressed as quality-adjusted life-years (QALYs), and costs reflected UK pound sterling in 2016–2017. Cost-effectiveness results were presented as incremental cost-effectiveness ratios and incremental net health benefits overall and for low, medium and high pretest likelihood of CHD subgroups. Results CMR had the highest estimated QALY gain overall (2.21 (95% credible interval 2.15, 2.26) compared with 2.07 (1.92, 2.20) for NICE and 2.11 (2.01, 2.22) for MPS) and incurred comparable costs (overall £1625 (£1431, £1824) compared with £1753 (£1473, £2032) for NICE and £1768 (£1572, £1989) for MPS). Overall, CMR was the cost-effective strategy, being the dominant strategy (more effective, less costly) with incremental net health benefits per patient of 0.146 QALYs (−0.18, 0.406) compared with NICE guidelines at a cost-effectiveness threshold of £15 000 per QALY (93% probability of cost-effectiveness). Results were similar in the pretest likelihood subgroups. Conclusions CMR-guided care is cost-effective overall and across all pretest likelihood subgroups, compared with MPS and NICE guidelines.

Abstract Background: PARP inhibitor (PARPi) monotherapy has previously demonstrated clinical activity only in patients with a germline BRCA mutation (BRCAmut), while single-agent anti-programmed cell death protein 1 (PD-1) therapy has achieved response rates of only 5–20% in advanced triple negative breast cancer (TNBC). In preclinical studies, PARP inhibition enhanced anti-tumor immunity, increased infiltration of proliferating CD8+ T cells, and synergized with anti-PD-1 agents in BRCA wildtype (wt) tumors. TOPACIO is a fully enrolled, phase I/II trial of niraparib + pembrolizumab (pembro) in advanced TNBC. This combination achieved 28% objective response rate (ORR) and 50% disease control rate (DCR) in evaluable patients. Although activity was highest in patients with BRCAmut (ORR=60%; DCR=80%), durable clinical benefit was also observed in patients without BRCA mutations. In this study, we conducted exploratory biomarker analyses to evaluate their potential correlation with durable clinical benefit (any complete response [CR] or partial response [PR] regardless of duration or stable disease [SD] for ≥16 weeks) beyond BRCA mutations. Method: ORR was assessed by RECIST v1.1. Duration of disease control (DDC) was defined as time from first dose of study treatment to radiologic disease progression or death. Tumor mutational status of homologous recombination repair (HRR) and other DNA damage repair (DDR) pathway genes was determined using an NGS panel. Immunoprofiling was conducted using NanoString IO360 panel complimented with 30 DNA repair spike-ins. Tumor immune micro-environment was characterized using multiplex immuno-fluorescence (CycIF). PD-L1 status was determined using the Agilent/DAKO 22C3 IHC clinical trial assay. Results: Of 46 evaluable patients, 20 achieved durable clinical benefit (any CR/PR or SD≥16 weeks) with niraparib + pembro combination, of which 8 were tumor BRCA wild type (wt), and 1 was BRCA unknown. Of the 9 BRCAwt/unknown patients, 5 had deleterious mutations in HRR/DDR pathway genes, whereas the remaining 4 had no mutations (HRR/DDR wt). Mutations that were associated with response include CHEK1 (CR; DDC=10.3 mos), ATR (CR; DDC=6.4 mos), PALB2 (PR; DDC=3.5 mos), BLM (SD; DDC=8.1 mos), and NBN/RAD51C (SD; DDC=3.7 mos). Of 4 patients that had no identified mutations (HRR/DDR wt), 1 patient had CR; DDC=10.3 mos, and the remaining 3 patients had SD with DDC ranging from ∼4-8 mos. Of note, all 4 HRR/DDR wt patients were also PD-L1-negative. Table:Durable clinical benefit in BRCAwt/unknown patientsHRR/DRR MutationsPD-L1 StatusBest ResponseDDC (Months)CHEK1+CR10.3†ATR+CR6.4PALB2*UnknownPR3.5BLM-SD8.1NBN/RAD51C+SD3.7None-CR10.3†None-SD8.2None-SD4.2None-SD3.9*BRCA status unknown; †Treatment is ongoing. Conclusion: Patients with mutations beyond BRCA achieved durable clinical benefit with niraparib + pembro treatment; five of these patients had DDC >6 mos. Mutations in genes that are associated with the HRR/DDR pathway appear to confer sensitivity to niraparib + anti-PD1. Additional translational analyses, including immunoprofiling and CycIF, will be presented. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, Wahner Hendrickson A, Forero A, Anders C, Wulf G, Dillon P, Lynce F, Zarwan C, Erban J, Färkkilä A, Zhou Y, Buerstatte N, Graham JR, Arora S, Dezube B, Telli ML. Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-02.