Research Spotlight

Shahian, D. M., T. G. Gleason, R. J. Shemin, J. D. Carroll and M. J. Mack (2018). “TAVR 2.0: Collaborating to Measure, Assure, and Advance Quality.” Ann Thorac Surg Aug 1. [Epub ahead of print].

Full text of this article.

The 2018 TAVR Multisociety Expert Consensus Systems of Care Document is a substantial enhancement of the previous 2012 document, reflecting our continually improving understanding of the requirements for safe and effective use of this technology. Mandatory participation in the TVT registry, direct measures of quality, volume thresholds to assure adequate experience and sample sizes for quality measures, and consistent involvement of MDT’s are critical to the ongoing evolution of transcatheter aortic valve therapy; they are also a paradigm for similar new initiatives in the future. Finally, the Multisociety Writing Committee strongly supports continuation of the TAVR NCD to assure that gains made during the successful initial introduction of this technology are maintained. (Excerpt from unpaginated advanced text; no abstract available.)

Packer, M. and D. W. Kitzman (2018). “Obesity-Related Heart Failure With a Preserved Ejection Fraction: The Mechanistic Rationale for Combining Inhibitors of Aldosterone, Neprilysin, and Sodium-Glucose Cotransporter-2.” JACC Heart Fail 6(8): 633-639.

Full text of this article.

Obesity-related heart failure with a preserved ejection fraction (HFpEF) is an important phenotype prevalent in the community, especially in people with metabolic disorders (e.g., dyslipidemia, diabetes). These individuals exhibit a marked expansion of plasma volume, but ventricular distensibility is limited, most likely as a result of cardiac microvascular rarefaction acting in concert with myocardial and pericardial fibrosis. Consequently, the increase in plasma volume causes a disproportionate increase in cardiac filling pressures, leading to heart failure, even though systolic ejection is not impaired. The features of this syndrome appear to be related (in part) to the overproduction of adipocyte-derived cell-signaling molecules, including aldosterone and neprilysin. The resulting sodium retention and plasma volume expansion is exacerbated by their mutual actions to promote cardiac and systemic inflammation and fibrosis. Inhibitors of aldosterone, neprilysin, and the sodium-glucose transporter-2 (SGLT2) can ameliorate the plasma volume expansion and pro-inflammatory and profibrotic pathways, potentially opposing the action of diverse adipocytokines. All 3 classes of drugs can reduce the quantity of visceral adipose tissue and ameliorate its abnormal biological properties. This mechanistic framework is supported by the results of large-scale randomized trials with mineralocorticoid receptor antagonists and SGLT2 inhibitors and is being further tested in an ongoing large-scale trial of neprilysin inhibition. The promise of using mineralocorticoid receptor antagonists, neprilysin inhibitors, and SGLT2 inhibitors (alone or in combination) in the management of obesity-related HFpEF suggests that physicians might finally have a phenotype of HFpEF that they can understand and treat.

Savona, M. R., K. Kolibaba, P. Conkling, E. C. Kingsley, C. Becerra, J. C. Morris, R. M. Rifkin, E. Laille, A. Kellerman, S. M. Ukrainskyj, Q. Dong and B. S. Skikne (2018). “Extended dosing with CC-486 (oral azacitidine) in patients with myeloid malignancies.” Am J Hematol Jul 17. [Epub ahead of print].

Full text of this article.

CC-486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC-486 dosing included patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n=18, CMML n=4, and AML n=9) entered a clinical phase in which they received CC-486 300 mg once-daily for 21 days of repeated 28-day cycles. Median age was 71 years (range: 53-93); 42% of patients were aged >/=75 years. Five patients with AML (63%) had prior MDS. Median number of CC-486 treatment cycles was 4 (range: 1-32). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3-4 TEAEs were neutropenia (n=13, 42%) and anemia (n=9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC-486 dose was interrupted or reduced due to gastrointestinal (n=5, 16%) or hematologic (n=6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. RBC transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on-study. No baseline gene mutation was predictive of response/nonresponse. CC-486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics.

Packer, M. (2018). “Obesity-Associated Heart Failure as a Theoretical Target for Treatment With Mineralocorticoid Receptor Antagonists.” JAMA Cardiol Jul 25. [Epub ahead of print].

Full text of this article.

Importance: Despite their clinical benefits, mineralocorticoid receptor antagonists are greatly underprescribed by most practitioners who treat patients with chronic heart failure. A novel approach to encouraging the use of these drugs is to enhance awareness about the intimate link between aldosterone and obesity. Observations: There is a strong association between abdominal obesity and circulating levels of aldosterone, and markers of abdominal obesity identify patients most likely to benefit from mineralocorticoid receptor antagonism. In a trial of patients with heart failure and a reduced ejection fraction, patients with an increased waist circumference exhibited an approximately 50% reduction in the risk of a primary end point. The magnitude of benefit was more than twice as great in patients with abdominal obesity than in those with a normal waist circumference, and patients with abdominal obesity tolerated treatment better than nonobese patients. Similarly, in a trial of patients with heart failure and a preserved ejection fraction, those who were most likely to have abdominal obesity (identified by their level of natriuretic peptides) were most likely to demonstrate a benefit of treatment with spironolactone, exhibiting an approximately 80% reduction in the risk of a primary end point (based on a small number of events). Conclusions and Relevance: Although these analyses are post hoc, their concordance and strong biological foundation suggests that abdominal obesity may identify patients who respond most favorably to mineralocorticoid receptor antagonism. Given the easy availability of its measurement, targeting patients with an increased waist circumference could enhance the adoption of these important drugs for the treatment of chronic heart failure in clinical practice.

O’Shaughnessy, J., A. DeMichele, C. X. Ma, P. Richards, D. A. Yardley, G. S. Wright, K. Kalinsky, R. Steis, S. Diab, G. Kennealey, R. Geschwindt, W. Jiang and H. S. Rugo (2018). “A randomized, double-blind, phase 2 study of ruxolitinib or placebo in combination with capecitabine in patients with advanced HER2-negative breast cancer and elevated C-reactive protein, a marker of systemic inflammation.” Breast Cancer Res Treat 170(3): 547-557.

Full text of this article.

PURPOSE: The Janus-associated kinase (JAK)/signal transducer and activator of transcription pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. This randomized phase 2 trial evaluated the efficacy and safety of the addition of ruxolitinib, a JAK1/JAK2 inhibitor, to capecitabine in patients with HER2-negative advanced breast cancer and high systemic inflammation (modified Glasgow Prognostic Score [mGPS] >/= 1). METHODS: Patients with 2 or fewer prior chemotherapy regimens for advanced or metastatic disease or hormone receptor-positive patients with disease progression on prior hormonal therapies were randomized 1:1 to 21-day cycles of ruxolitinib (n = 76) or placebo (n = 73) plus capecitabine. The primary endpoint was overall survival (OS). RESULTS: Baseline characteristics were well balanced between groups. For ruxolitinib plus capecitabine versus placebo plus capecitabine, median OS was 11.2 months versus 10.9 months (log-rank test P = 0.762); median progression-free survival (PFS) was 4.5 months versus 2.5 months (log-rank test P = 0.151); and overall response rate (ORR) was 28.9% versus 13.7% (Cochran-Mantel-Haenszel test P = 0.024), respectively. A more favorable change in health-related quality of life (HRQoL) was observed with ruxolitinib plus capecitabine versus placebo plus capecitabine. Both regimens were generally tolerable. A higher incidence of grade 3/4 anemia (25.4% vs 5.6%) and a lower incidence of grade 3/4 palmar-plantar erythrodysesthesia (1.4% vs 12.7%) occurred with ruxolitinib plus capecitabine versus placebo plus capecitabine. CONCLUSIONS: The addition of ruxolitinib to capecitabine for patients with advanced breast cancer and high systemic inflammation was generally tolerable; ORR was numerically greater, a more favorable change in HRQoL was observed, but neither OS nor PFS was improved compared with placebo plus capecitabine.