Research Spotlight

Makkar, R. R., S. H. Yoon, M. B. Leon, T. Chakravarty, M. Rinaldi, P. B. Shah, E. R. Skipper, V. H. Thourani, V. Babaliaros, W. Cheng, A. Trento, S. Vemulapalli, S. R. Kapadia, S. Kodali, M. J. Mack, G. H. L. Tang and T. Kaneko (2019). “Association Between Transcatheter Aortic Valve Replacement for Bicuspid vs Tricuspid Aortic Stenosis and Mortality or Stroke.” JAMA 321(22): 2193-2202.

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Importance: Transcatheter aortic valve replacement (TAVR) indications are expanding, leading to an increasing number of patients with bicuspid aortic stenosis undergoing TAVR. Pivotal randomized trials conducted to obtain US Food and Drug Administration approval excluded bicuspid anatomy. Objective: To compare the outcomes of TAVR with a balloon-expandable valve for bicuspid vs tricuspid aortic stenosis. Design, Setting, and Participants: Registry-based prospective cohort study of patients undergoing TAVR at 552 US centers. Participants were enrolled in the Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapies Registry from June 2015 to November 2018. Exposures: TAVR for bicuspid vs tricuspid aortic stenosis. Main Outcomes and Measures: Primary outcomes were 30-day and 1-year mortality and stroke. Secondary outcomes included procedural complications, valve hemodynamics, and quality of life assessment. Results: Of 81822 consecutive patients with aortic stenosis (2726 bicuspid; 79096 tricuspid), 2691 propensity-score matched pairs of bicuspid and tricuspid aortic stenosis were analyzed (median age, 74 years [interquartile range {IQR}, 66-81 years]; 39.1%, women; mean [SD] STS-predicted risk of mortality, 4.9% [4.0%] and 5.1% [4.2%], respectively). All-cause mortality was not significantly different between patients with bicuspid and tricuspid aortic stenosis at 30 days (2.6% vs 2.5%; hazard ratio [HR], 1.04, [95% CI, 0.74-1.47]) and 1 year (10.5% vs 12.0%; HR, 0.90 [95% CI, 0.73-1.10]). The 30-day stroke rate was significantly higher for bicuspid vs tricuspid aortic stenosis (2.5% vs 1.6%; HR, 1.57 [95% CI, 1.06-2.33]). The risk of procedural complications requiring open heart surgery was significantly higher in the bicuspid vs tricuspid cohort (0.9% vs 0.4%, respectively; absolute risk difference [RD], 0.5% [95% CI, 0%-0.9%]). There were no significant differences in valve hemodynamics. There were no significant differences in moderate or severe paravalvular leak at 30 days (2.0% vs 2.4%; absolute RD, 0.3% [95% CI, -1.3% to 0.7%]) and 1 year (3.2% vs 2.5%; absolute RD, 0.7% [95% CI, -1.3% to 2.7%]). At 1 year there was no significant difference in improvement in quality of life between the groups (difference in improvement in the Kansas City Cardiomyopathy Questionnaire overall summary score, -2.4 [95% CI, -5.1 to 0.3]; P = .08). Conclusions and Relevance: In this preliminary, registry-based study of propensity-matched patients who had undergone transcatheter aortic valve replacement for aortic stenosis, patients with bicuspid vs tricuspid aortic stenosis had no significant difference in 30-day or 1-year mortality but had increased 30-day risk for stroke. Because of the potential for selection bias and the absence of a control group treated surgically for bicuspid stenosis, randomized trials are needed to adequately assess the efficacy and safety of transcatheter aortic valve replacement for bicuspid aortic stenosis.

Vemulapalli, S., J. D. Carroll, M. J. Mack, Z. Li, D. Dai, A. S. Kosinski, D. J. Kumbhani, C. E. Ruiz, V. H. Thourani, G. Hanzel, T. G. Gleason, H. C. Herrmann, R. G. Brindis and J. E. Bavaria (2019). “Procedural Volume and Outcomes for Transcatheter Aortic-Valve Replacement.” N Engl J Med 380(26): 2541-2550.

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BACKGROUND: During the introduction of transcatheter aortic-valve replacement (TAVR) in the United States, requirements regarding procedural volume were mandated by the Centers for Medicare and Medicaid Services as a condition of reimbursement. A better understanding of the relationship between hospital volume of TAVR procedures and patient outcomes could inform policy decisions. METHODS: We analyzed data from the Transcatheter Valve Therapy Registry regarding procedural volumes and outcomes from 2015 through 2017. The primary analyses examined the association between hospital procedural volume as a continuous variable and risk-adjusted mortality at 30 days after transfemoral TAVR. Secondary analysis included risk-adjusted mortality according to quartile of hospital procedural volume. A sensitivity analysis was performed after exclusion of the first 12 months of transfemoral TAVR procedures at each hospital. RESULTS: Of 113,662 TAVR procedures performed at 555 hospitals by 2960 operators, 96,256 (84.7%) involved a transfemoral approach. There was a significant inverse association between annualized volume of transfemoral TAVR procedures and mortality. Adjusted 30-day mortality was higher and more variable at hospitals in the lowest-volume quartile (3.19%; 95% confidence interval [CI], 2.78 to 3.67) than at hospitals in the highest-volume quartile (2.66%; 95% CI, 2.48 to 2.85) (odds ratio, 1.21; P = 0.02). The difference in adjusted mortality between a mean annualized volume of 27 procedures in the lowest-volume quartile and 143 procedures in the highest-volume quartile was a relative reduction of 19.45% (95% CI, 8.63 to 30.26). After the exclusion of the first 12 months of TAVR procedures at each hospital, 30-day mortality remained higher in the lowest-volume quartile than in the highest-volume quartile (3.10% vs. 2.61%; odds ratio, 1.19; 95% CI, 1.01 to 1.40). CONCLUSIONS: An inverse volume-mortality association was observed for transfemoral TAVR procedures from 2015 through 2017. Mortality at 30 days was higher and more variable at hospitals with a low procedural volume than at hospitals with a high procedural volume. (Funded by the American College of Cardiology Foundation National Cardiovascular Data Registry and the Society of Thoracic Surgeons.).

Wesson, D. E., V. Mathur, N. Tangri, Y. Stasiv, D. Parsell, E. Li, G. Klaerner and D. A. Bushinsky (2019). “Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension.” Lancet Jun 24. [Epub ahead of print].

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BACKGROUND: Metabolic acidosis, a complication of chronic kidney disease, causes protein catabolism and bone demineralisation and is associated with adverse kidney outcomes and mortality. Veverimer, a non-absorbed, counterion-free, polymeric drug candidate selectively binds and removes hydrochloric acid from the gastrointestinal lumen. METHODS: We did a multicentre, randomised, blinded, placebo-controlled, 40-week extension of a 12-week parent study at 29 sites (hospitals and specialty clinics) in seven countries (Bulgaria, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA). Eligible patients were those with chronic kidney disease (estimated glomerular filtration rate 20-40 mL/min per 1.73 m(2)) and metabolic acidosis (serum bicarbonate 12-20 mmol/L), who had completed the 12-week parent study, for which they were randomly assigned (4:3) to veverimer (6 g/day) or placebo as oral suspensions in water with food. Participants in the extension continued with the same treatment assignment as in the parent study. The primary endpoint was safety; the four secondary endpoints assessed the long-term effects of veverimer on serum bicarbonate concentration and physical functioning. The safety analysis set was defined as all patients who received any amount of study drug. This trial is registered at ClinicalTrials.gov, number NCT03390842, and has now completed. FINDINGS: Participants entered the study between Dec 20, 2017, and May 4, 2018. Of the 217 patients randomly assigned to treatment in the parent study (124 to veverimer and 93 to placebo), 196 patients (114 veverimer and 82 placebo) continued on their blinded randomised treatment assignment into this 40-week extension study. Compared with placebo, fewer patients on veverimer discontinued treatment prematurely (3% vs 10%, respectively), and no patients on veverimer discontinued because of an adverse event. Serious adverse events occurred in 2% of veverimer-treated patients and in 5% of placebo patients (two of whom died). Renal system adverse events were reported in 8% and 15% in the veverimer and placebo groups, respectively. More patients on veverimer than placebo had an increase in bicarbonate (>/=4 mmol/L or normalisation) at week 52 (63% vs 38%, p=0.0015) and higher bicarbonate concentrations were observed with veverimer than placebo at all timepoints starting at week 1 (p<0.001). Veverimer resulted in improved patient-reported physical functioning (Kidney Disease and Quality of Life-Physical Function Domain) versus placebo with a mean placebo-subtracted change at end of treatment of 12.1 points (SE 3.3; p<0.0001). Time to do the repeat chair stand test improved by 4.3 s (1.2) on veverimer versus 1.4 s (1.2) on placebo (p<0.0001). INTERPRETATION: In patients with chronic kidney disease and metabolic acidosis, veverimer safely and effectively corrected metabolic acidosis and improved subjective and objective measures of physical function. FUNDING: Tricida.

Wesson, D. E., C. R. Lucey and L. A. Cooper (2019). “Building Trust in Health Systems to Eliminate Health Disparities.” JAMA Jun 7. [Epub ahead of print].

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Health systems are critical, but not sufficient, to successfully eliminating health disparities within the populations they serve. Health system leaders should adopt evidence-based strategies to build the trusting relationships needed to address this complex social problem that robs people of their health and lives. Such strategies include: 1. Seek, develop, and continuously nurture trust-based relationships with community institutions around improving health outcomes. 2. Establish institutional commitments with appropriate operational strategies, resources, and accountability systems to address health disparities in the community. This includes a willingness to discuss fundamental changes in operations (e.g., focus on health in addition to health care delivery). 3. Adopt co-production models that engage and empower community institutions to work as co-equals in the identification and design of interventions and dissemination of results. 4. Establish, monitor, and share progress on metrics that measure progress toward agreed on areas of focus. 5. Establish supporting systems for, and measure compliance with, an institutional commitment that all interactions with the community undertaken by the institution’s health professionals, administrators, faculty, and learners are conducted in alignment with respectful practices for community engagement. Eventual transition to systems that reward good health outcomes will require health systems to proactively partner with patient populations and communities to eliminate health disparities as a shared value, using strategies that incentivize healthy outcomes for the whole population while also addressing the unique needs of disadvantaged populations. Eliminating health and health care disparities is a necessary step on the journey to VBC and health equity, where “everyone has a fair and just opportunity to be as healthy as possible.” (Excerpt from text, p. E2; no abstract available.)

Schwartzberg, L., K. McIntyre, S. Wilks, S. Puhalla, J. O’Shaughnessy, E. Berrak, Y. He and L. Vahdat (2019). “Health-related quality of life in patients receiving first-line eribulin mesylate with or without trastuzumab for locally recurrent or metastatic breast cancer.” BMC Cancer 19(1): 578.

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BACKGROUND: Eribulin mesylate is a nontaxane microtubule dynamics inhibitor approved for second-line (European Union) or third-line (United States) treatment of metastatic breast cancer. Two phase 2 single trials, evaluating first-line eribulin as monotherapy (Study 206; NCT01268150) or in combination with trastuzumab (Study 208; NCT01269346) in locally recurrent or metastatic breast cancer, demonstrated objective response rates of 28.6 and 71.2%, respectively. Median progression-free survival was 6.8 and 11.6 months, respectively. Tolerability profiles were similar to those from previous studies. This secondary analysis was conducted to assess health-related quality of life (HRQoL) in both phase 2 trials. METHODS: Patients received eribulin mesylate 1.4 mg/m(2) intravenously on days 1 and 8 of each 21-day cycle. Patients in Study 208 also received intravenous trastuzumab on day 1 of each cycle (8 mg/kg in cycle 1, then 6 mg/kg). HRQoL was assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life (QLQ-C30) assessment tool and the Quality-of-Life Questionnaire for Breast Cancer (QLQ-BR23) at baseline and cycles 2, 4, and 6. Results for clinically meaningful changes were based on previously published minimum important differences. RESULTS: Of the 108 patients (56 in Study 206 and 52 in Study 208) treated, 57 and 87%, respectively, completed 6 cycles. Completion rates for both questionnaires were 94 and 98%, respectively, at cycle 6. Most patients had stable/improved HRQoL scores with some exceptions; for example, more patients experienced a worsening in cognitive functioning and systemic therapy side effects than experienced improvement. Mean QLQ-C30 symptom scores correlated with corresponding adverse event rates for nausea/vomiting, dyspnea, appetite loss, constipation, and diarrhea in Study 206 and for fatigue, nausea/vomiting, pain, dyspnea, insomnia, constipation, and diarrhea in Study 208. CONCLUSIONS: First-line eribulin +/- trastuzumab therapy did not lead to deterioration of overall HRQoL in most patients, with more than 60% of patients having stable/improved global health status/quality-of-life scores. Eribulin has been demonstrated to be comparable with other chemotherapy agents with an acceptable safety profile. Therefore, further evaluation is warranted to determine whether eribulin +/- trastuzumab therapy may be a potential option for first-line treatment in some patients with metastatic breast cancer who were recently treated in the neoadjuvant setting. TRIAL REGISTRATION: NCT01268150 (December 29, 2010), NCT01269346 (January 4, 2011).