Research Spotlight

Seferovic, J. P., B. Claggett, S. B. Seidelmann, E. W. Seely, M. Packer, M. R. Zile, J. L. Rouleau, K. Swedberg, M. Lefkowitz, V. C. Shi, A. S. Desai, J. J. McMurray and S. D. Solomon (2017). “Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial.” Lancet Diabetes Endocrinol: 2017 Mar [Epub ahead of print].

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BACKGROUND: Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF. METHODS: In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA1c >/=6.5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA1c, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Time to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups. FINDINGS: There were no significant differences in HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1c concentrations decreased by 0.16% (SD 1.40) in the enalapril group and 0.26% (SD 1.25) in the sacubitril/valsartan group (between-group reduction 0.13%, 95% CI 0.05-0.22, p=0.0023). HbA1c concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0.14%, 95% CI 0.06-0.23, p=0.0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0.71, 95% CI 0.56-0.90, p=0.0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0.77, 0.58-1.02, p=0.073) in the sacubitril/valsartan group. INTERPRETATION: Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF.

Fendler, T. J., M. E. Nassif, K. F. Kennedy, S. M. Joseph, S. C. Silvestry, G. A. Ewald, S. J. LaRue, J. M. Vader, J. A. Spertus and S. V. Arnold (2017). “Global outcome in patients with left ventricular assist devices.” Am J Cardiol 119(7): 1069-1073.

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Left ventricular assist devices (LVADs) improve survival and quality of life (QOL) for most, but not all, patients with advanced heart failure. We described a broader definition of poor outcomes after LVAD, using a novel composite of death, QOL, and other major adverse events. We evaluated the frequency of poor global outcome at 1 year after LVAD among 164 patients (86% Interagency Registry for Mechanically Assisted Circulatory Support profile 1 to 2; shock or declining despite inotropes) at a high-volume center. Poor global outcome (comprising death, poor QOL [Kansas City Cardiomyopathy Questionnaire <45], recurrent heart failure [>/=2 heart failure readmissions], or severe stroke) occurred in 58 patients (35%): 37 died, 17 had poor QOL, 3 had recurrent heart failure, and 1 had a severe stroke. Patients with poor global outcomes were more likely designated for destination therapy (46% vs 24%, p = 0.01), spent more days hospitalized per month alive (median [interquartile range] 18.6 [5.0 to 31.0] vs 3.7 [1.8 to 8.3], p <0.001), and had higher intracranial (12% vs 2%, p = 0.031) and gastrointestinal (44% vs 28%, p = 0.056) hemorrhage rates over the year after implant. Although LVADs often improve survival and QOL, approximately 1/3 of high-acuity patients experienced a poor global outcome over the year after LVAD. In conclusion, composite outcomes may better capture events that matter to patients with LVADs and thus support informed decisions about pursuing LVAD therapy.

Carey, S. A., K. Bass, G. Saracino, C. A. East, J. Felius, P. A. Grayburn, R. C. Vallabhan and S. A. Hall (2017). “Probability of accurate heart failure diagnosis and the implications for hospital readmissions.” Am J Cardiol 119(7): 1041-1046.

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Heart failure (HF) is a complex syndrome with inherent diagnostic challenges. We studied the scope of possibly inaccurately documented HF in a large health care system among patients assigned a primary diagnosis of HF at discharge. Through a retrospective record review and a classification schema developed from published guidelines, we assessed the probability of the documented HF diagnosis being accurate and determined factors associated with HF-related and non-HF-related hospital readmissions. An arbitration committee of 3 experts reviewed a subset of records to corroborate the results. We assigned a low probability of accurate diagnosis to 133 (19%) of the 712 patients. A subset of patients were also reviewed by an expert panel, which concluded that 13% to 35% of patients probably did not have HF (inter-rater agreement, kappa = 0.35). Low-probability HF was predictive of being readmitted more frequently for non-HF causes (p = 0.018), as well as documented arrhythmias (p = 0.023), and age >60 years (p = 0.006). Documented sleep apnea (p = 0.035), percutaneous coronary intervention (p = 0.006), non-white race (p = 0.047), and B-type natriuretic peptide >400 pg/ml (p = 0.007) were determined to be predictive of HF readmissions in this cohort. In conclusion, approximately 1 in 5 patients documented to have HF were found to have a low probability of actually having it. Moreover, the determination of low-probability HF was twice as likely to result in readmission for non-HF causes and, thus, should be considered a determinant for all-cause readmissions in this population.

Bardia, A., I. A. Mayer, J. R. Diamond, R. L. Moroose, S. J. Isakoff, A. N. Starodub, N. C. Shah, J. O’Shaughnessy, K. Kalinsky, M. Guarino, V. Abramson, D. Juric, S. M. Tolaney, J. Berlin, W. A. Messersmith, A. J. Ocean, W. A. Wegener, P. Maliakal, R. M. Sharkey, S. V. Govindan, D. M. Goldenberg and L. T. Vahdat (2017). “Efficacy and safety of anti-trop-2 antibody drug conjugate sacituzumab govitecan (immu-132) in heavily pretreated patients with metastatic triple-negative breast cancer.” J Clin Oncol: 2017 Mar [Epub ahead of print].

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Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease >/= 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade >/= 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.

Zoghbi, W. A., D. Adams, R. O. Bonow, M. Enriquez-Sarano, E. Foster, P. A. Grayburn, R. T. Hahn, Y. Han, J. Hung, R. M. Lang, S. H. Little, D. J. Shah, S. Shernan, P. Thavendiranathan, J. D. Thomas and N. J. Weissman (2017). “Recommendations for Noninvasive Evaluation of Native Valvular Regurgitation: A Report from the American Society of Echocardiography Developed in Collaboration with the Society for Cardiovascular Magnetic Resonance.” J Am Soc Echocardiogr: 2017 Mar [Epub ahead of print].

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This update on the evaluation of valvular regurgitation is a comprehensive review of the noninvasive assessment of valvular regurgitation with echocardiography and CMR in the adult. It provides recommendations for the assessment of the etiology and severity of valvular regurgitation based on the literature and a consensus of a panel of experts. This guideline is accompanied by a number of tutorials and illustrative case studies on evaluation of valvular regurgitation, posted on the following website (www. asecho.org/vrcases), which will build gradually over time. Issues regarding medical management and timing of surgical interventions are beyond the scope of this document and have been recently updated.