Research Spotlight

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 Apr 3. [Epub ahead of print].

Full text of this article.

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.

Wesson, D. E., V. Mathur, N. Tangri, Y. Stasiv, D. Parsell, E. Li, G. Klaerner and D. A. Bushinsky (2019). “Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial.” Lancet 393(10179):1417-1427. Epub 2019 Mar 8.

Full text of this article.

BACKGROUND: Patients with advanced chronic kidney disease lose the capacity to fully excrete endogenous acid, resulting in chronic metabolic acidosis that increases the risk of disease progression and causes muscle catabolism and bone resorption. Veverimer, a non-absorbed, counterion-free, polymeric drug, selectively binds and removes hydrochloric acid from the gastrointestinal lumen, unlike current oral sodium bicarbonate therapy for metabolic acidosis that only neutralises accumulated acid. We assessed the efficacy and safety of veverimer as a treatment for metabolic acidosis in patients with chronic kidney disease. METHODS: We did a multicentre, parallel, randomised, double-blind, placebo-controlled study at 37 sites (hospitals and specialty clinics) in Bulgaria, Croatia, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA. Eligible participants were patients aged 18-85 years with non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate of 20-40 mL/min per 1.73 m(2)) and metabolic acidosis (serum bicarbonate concentration of 12-20 mmol/L). Patients were randomly assigned (4:3) to veverimer 6 g/day or placebo for 12 weeks while they consumed their typical diet. Both drugs were taken as oral suspensions in water with lunch. Randomisation was done by study site personnel with a computer-generated randomisation code with balanced permuted blocks (block size of seven) and stratified by baseline bicarbonate (18 mmol/L). Patients and investigators were masked to treatment allocation; however, because the appearance of placebo differed from veverimer, a non-masked site staff member who had no other role in the study dispensed, prepared, and supervised dosing of the study drugs. The composite primary efficacy endpoint was the difference (veverimer-placebo) in the proportion of patients achieving at week 12 either an increase of 4 mmol/L or more from baseline in serum bicarbonate concentration or serum bicarbonate in the normal range of 22-29 mmol/L, assessed in the modified intention-to-treat population (all patients with a baseline and at least one post-baseline serum bicarbonate value). Patients fasted for at least 4 h (consuming only water) before measurements of bicarbonate. Safety was assessed in all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, number NCT03317444. FINDINGS: Between Sept 26, 2017, and Feb 9, 2018, we randomly assigned 124 participants to veverimer and 93 to placebo. The composite primary endpoint was met by 71 (59%) of 120 patients in the veverimer group versus 20 (22%) of 89 patients in the placebo group (a difference of 37%, 95% CI 23-49; p<0.0001). The most common body system in which adverse events in the veverimer group occurred was gastrointestinal; of these, non-treatment limiting diarrhoea was the most common event (11 [9%] vs three [3%] in the veverimer and placebo groups, respectively). The most common treatment-related adverse events were gastrointestinal (diarrhoea, flatulence, nausea, and constipation) occurring in 16 (13%) patients with veverimer and five (5%) patients with placebo. Two deaths occurred during the study, both in the placebo group (unstable angina and pneumonia). INTERPRETATION: Veverimer effectively and safely corrected metabolic acidosis. Longer-term studies are warranted to assess the effects of veverimer on physical functioning and to assess other deleterious consequences of metabolic acidosis including progression of chronic kidney disease and bone health. FUNDING: Tricida.

Holmes, D. R., Jr. and M. J. Mack (2019). “Rational Dispersion for the Introduction of Transcatheter Mitral Valve Repair Into Clinical Practice: Lessons Learned From TAVR.” JAMA 321(11): 1043-1044.

Full text of this article.

The introduction of new medical devices to address unmet clinical needs into the patient care arena, with little or no previous physician experience with the therapy, is a complex process with several important considerations. The questions regarding implementation of transcatheter mitral valve therapy are generally the same as the questions that occurred with TAVR, but with some important nuances. What are the safety and effectiveness profiles, the risk/benefit ratio, and cost-effectiveness of the new therapy compared with other available therapies? In the case of the transcatheter mitral valve repair device for functional mitral regurgitation, additional questions include the following: which specific patient populations may derive the maximal intended benefit of the device (responders), what are the characteristics and qualifications of the centers that care for these patients, what is the optimal geographic dispersion to facilitate patient access, and what specific training and qualifications will the operators need? Surgical and cardiovascular professional societies will need to work closely with the FDA, the Centers for Medicare & Medicaid Services, and device manufacturers to address these issues and develop appropriate methods for rational dispersion to help improve the outcome of patients treated with this new technology. (Excerpt from text, p. 1044; no abstract available.)

Conrad, C. and J. W. Fleshman, Jr. (2019). “Minimally Invasive Oncologic Surgery, Part II.” Surg Oncol Clin N Am 28(2): xv-xvii.

Full text of this article.

Minimally invasive techniques for the management of intra-abdominal cancer have become an accepted option for almost all solid tumors. Some of these approaches have been vetted with prospective trials, some even randomized, but it is unusual to find a discussion that encompasses all in one publication. It was this reason that led to these two-part Surgical Oncology Clinics of North America issues that contain discussions of almost every solid intra-abdominal tumor. The experts who have participated are experienced with both open and minimally invasive approaches, and they understand the issues that arise when making recommendations for treatment of curable cancer with new techniques. Dr Conrad and I are indebted to them for their truly authoritative contributions. The discussion around limitations of a technique is almost more important than the assumed possibilities and the recovery outcomes beyond cancer cure. As the advanced techniques are applied in institutions beyond academic institutions where clinical trials are underway, the most important consideration becomes whether generalization of the technique is possible or even appropriate. As one reads this compilation of articles, it is hoped that a balanced message will be apparent, and that the thoughtful application of surgical judgment will be enhanced by the contents herein. Each year brings more applications for minimally invasive surgery regardless of the specific technique. The current level of application of minimally invasive techniques to cancer shows that we have the opportunity to expand their use for even the most basic and appropriate indications. Educators involved in the continued education of surgical trainees and practicing surgeons should be able to use the articles within this issue to engage trainees in a thoughtful approach to expand their use of minimally invasive surgery for resection of cancer. (Excerpt from commentary on a special issue of the journal, p. xvi.)

Fleshman, J., M. E. Branda, D. J. Sargent, A. M. Boller, V. V. George, M. A. Abbas, W. R. Peters, Jr., D. C. Maun, G. J. Chang, A. Herline, A. Fichera, M. G. Mutch, S. D. Wexner, M. H. Whiteford, J. Marks, E. Birnbaum, D. A. Margolin, D. W. Larson, P. W. Marcello, M. C. Posner, T. E. Read, J. R. T. Monson, S. M. Wren, P. W. T. Pisters and H. Nelson (2019). “Disease-free Survival and Local Recurrence for Laparoscopic Resection Compared With Open Resection of Stage II to III Rectal Cancer: Follow-up Results of the ACOSOG Z6051 Randomized Controlled Trial.” Ann Surg 269(4): 589-595.

Full text of this article.

OBJECTIVE: To determine the disease-free survival (DFS) and recurrence after the treatment of patients with rectal cancer with open (OPEN) or laparoscopic (LAP) resection. BACKGROUND: This randomized clinical trial (ACOSOG [Alliance] Z6051), performed between 2008 and 2013, compared LAP and OPEN resection of stage II/III rectal cancer, within 12 cm of the anal verge (T1-3, N0-2, M0) in patients who received neoadjuvant chemoradiotherapy. The rectum and mesorectum were resected using open instruments for rectal dissection (included hybrid hand-assisted laparoscopic) or with laparoscopic instruments under pneumoperitoneum. The 2-year DFS and recurrence were secondary endpoints of Z6051. METHODS: The DFS and recurrence were not powered, and are being assessed for superiority. Recurrence was determined at 3, 6, 9, 12, and every 6 months thereafter, using carcinoembryonic antigen, physical examination, computed tomography, and colonoscopy. In all, 486 patients were randomized to LAP (243) or OPEN (243), with 462 eligible for analysis (LAP = 240 and OPEN = 222). Median follow-up is 47.9 months. RESULTS: The 2-year DFS was LAP 79.5% (95% confidence interval [CI] 74.4-84.9) and OPEN 83.2% (95% CI 78.3-88.3). Local and regional recurrence was 4.6% LAP and 4.5% OPEN. Distant recurrence was 14.6% LAP and 16.7% OPEN.Disease-free survival was impacted by unsuccessful resection (hazard ratio [HR] 1.87, 95% CI 1.21-2.91): composite of incomplete specimen (HR 1.65, 95% CI 0.85-3.18); positive circumferential resection margins (HR 2.31, 95% CI 1.40-3.79); positive distal margin (HR 2.53, 95% CI 1.30-3.77). CONCLUSION: Laparoscopic assisted resection of rectal cancer was not found to be significantly different to OPEN resection of rectal cancer based on the outcomes of DFS and recurrence.