Research Spotlight

Mack, M. J. and M. B. Leon (2019). “Transcatheter Aortic-Valve Replacement in Low-Risk Patients. Reply.” New England Journal of Medicine 381(7): 684-685.

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Kaul’s major concern is that there were fewer primary end-point events in the Placement of Aortic Transcatheter Valves (PARTNER) 3 trial than in earlier trials. He states that the inclusion of rehospitalization in the composite primary end point led it to become the main driver for the superiority of TAVR and also introduced a bias against surgery owing to the number of concomitant procedures performed in the surgical group. In PARTNER 3, the primary end point was specifically chosen to account for the lower event rate expected in low-risk patients and was powered on the basis of anticipated event rates from previous PARTNER trials. The sample size assumed a composite end-point event rate of 16.6% in the surgery group and 14.6% in the TAVR group. In fact, the primary event rates were 15.1% and 8.5%, respectively, and all components of the composite end point directionally favored TAVR. Rehospitalization was included because we believe it is a meaningful adverse outcome in low-risk patients, and it has been used as the sole primary end point in other recent trials. The higher rate of concomitant procedures in surgery (26.4% vs. 7.9%), mentioned both by Kaul and by Perella and Anwar, is a reflection of real-world surgical practice. The heart team at each site concluded before randomization that either approach, surgery or TAVR, would yield the best possible outcome. Since those patients who had a concomitant procedure did not have a higher rate of primary end-point events, there was no bias against surgery. Data available at the 10-year follow-up should give further insight into the risks and benefits of each approach, especially among patients who underwent concomitant coronary revascularization. Baldetti et al. noted a higher incidence of new-onset LBBB among patients who underwent TAVR, which suggests the possibility of the unfavorable prognostic effect of mechanical dyssynchrony. We agree and have recently published an analysis of patients in the earlier, higher-risk trials that shows worse left ventricular systolic function and more adverse clinical outcomes in patients with new LBBB. Precisely for these reasons, all patients will be followed with clinical, echocardiographic, and electrocardiographic assessment annually for 10 years. Finally, Savas et al. express concern that the higher rate of mild paravalvular leak with TAVR may lead to increased late mortality, citing data from a PARTNER trial involving high-risk patients. Although we share their concern, subsequent analyses of intermediate-risk patients have not shown an increase in mortality with mild paravalvular regurgitation.4 Nonetheless, all patients will be carefully followed for 10 years to address this concern. (Authors’ response to several commentaries on their previously published studies: Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients. N Engl J Med 2019;380:1695-1705 and Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609-1620.)

Dheda, K., T. Gumbo, G. Maartens, K. E. Dooley, M. Murray, J. Furin, E. A. Nardell and R. M. Warren (2019). “The Lancet Respiratory Medicine Commission: 2019 update: epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant and incurable tuberculosis.” Lancet Respir Med 7(9): 820-826.

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The Lancet Respiratory Medicine Commission on drug-resistant tuberculosis was published in 2017, which comprehensively reviewed and provided recommendations on various aspects of the disease. Several key new developments regarding drug-resistant tuberculosis are outlined in this Commission Update. The WHO guidelines on treating drug-resistant tuberculosis were updated in 2019 with a reclassification of second line anti-tuberculosis drugs. An injection-free MDR tuberculosis treatment regimen is now recommended. Over the past 3 years, advances in treatment include the recognition of the safety and mortality benefit of bedaquiline, the finding that the 9-11 month injectable-based ‘Bangladesh’ regimen was non-inferior to longer regimens, and promising interim results of a novel 6 month 3-drug regimen (bedaquiline, pretomanid, and linezolid). Studies of explanted lungs from patients with drug-resistant tuberculosis have shown substantial drug-specific gradients across pulmonary cavities, suggesting that alternative dosing and drug delivery strategies are needed to reduce functional monotherapy at the site of disease. Several controversies are discussed including the optimal route of drug administration, optimal number of drugs constituting a regimen, selection of individual drugs for a regimen, duration of the regimen, and minimal desirable standards of antibiotic stewardship. Newer rapid nucleic acid amplification test platforms, including point-of-care systems that facilitate active case-finding, are discussed. The rapid diagnosis of resistance to other drugs, (notably fluoroquinolones), and detection of resistance by targeted or whole genome sequencing will probably change the diagnostic landscape in the near future.

Wall, A., G. H. Lee, J. Maldonado and D. Magnus (2019). “Medical Contraindications to Transplant Listing in the USA: A Survey of Adult and Pediatric Heart, Kidney, Liver, and Lung Programs.” World Journal of Surgery 43(9): 2300-2308.

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INTRODUCTION: Listing practices for solid organ transplantation are variable across programs in the USA. To better characterize this variability, we performed a survey of psychosocial listing criteria for pediatric and adult heart, lung, liver, and kidney programs in the USA. In this manuscript, we report our results regarding listing practices with respect to obesity, advanced age, and HIV seropositivity. METHODS: We performed an online, forced-choice survey of adult and pediatric heart, kidney, liver, and lung transplant programs in the USA. RESULTS: Of 650 programs contacted, 343 submitted complete responses (response rate = 52.8%). Most programs have absolute contraindications to listing for BMI > 45 (adult: 67.5%; pediatric: 88.0%) and age > 80 (adult: 55.4%; pediatric: not relevant). Only 29.5% of adult programs and 25.7% of pediatric programs consider HIV seropositivity an absolute contraindication to listing. We found that there is variation in absolute contraindications to listing in adult programs among organ types for BMI > 45 (heart 89.8%, lung 92.3%, liver 49.1%, kidney 71.9%), age > 80 (heart 83.7%, lung 76.9%, liver 68.4%, kidney 29.2%), and HIV seropositivity (heart 30.6%, lung 59.0%, kidney 16.9%, liver 28.1%). CONCLUSIONS: We argue that variability in listing enhances access to transplantation for potential recipients who have the ability to pursue workup at different centers by allowing different programs to have different risk thresholds. Programs should remain independent in listing practices, but because these practices differ, we recommend transparency in listing policies and informing patients of reasons for listing denial and alternative opportunities to seek listing at another program.

Culp, B. L., J. W. Roden-Foreman, E. V. Thomas, E. E. McShan, M. M. Bennett, K. R. Martin, M. B. Powers, M. L. Foreman, L. B. Petrey and A. M. Warren (2019). “Better with age? A comparison of geriatric and non-geriatric trauma patients’ psychological outcomes 6 months post-injury.” Cognitive Behaviour Therapy 48(5): 406-418.

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This is the first study to compare both physical and psychological outcomes in geriatric and non-geriatric patients (n = 268) at baseline and 6 months post-trauma. Demographic, clinical, and psychological data, including screens for alcohol use, depressive symptoms, and post-traumatic stress symptoms (PTSS) were collected from 67 geriatric patients (70.7 +/- 8.0 years) and 201 non-geriatric patients (40.2 +/- 12.8 years) admitted to a Level I trauma center for >/= 24 h. Geriatric patients were significantly less likely to screen positive for alcohol use at baseline, and depression, PTSS, and alcohol use at follow-up. When not controlling for discharge to rehabilitation or nursing facility, geriatric patients had significantly lower odds of alcohol use at follow-up. There was no significant difference in injury severity, resilience, or pre-trauma psychological status between the two groups. Results indicate that geriatric trauma patients fare better than their younger counterparts at 6 months post-trauma on measures of alcohol use, depression, and PTSS. Screenings and interventions for both age groups could improve psychological health post-trauma, but younger patients may require additional attention.

Jones, V. E., K. J. McIntyre, D. Paul, S. T. Wilks, S. M. Ondreyco, S. Sedlacek, A. Melnyk, S. P. Oommen, Y. Wang, S. R. Peck and J. A. O’Shaughnessy (2019). “Evaluation of Miracle Mouthwash plus Hydrocortisone Versus Prednisolone Mouth Rinses as Prophylaxis for Everolimus-Associated Stomatitis: A Randomized Phase II Study.” Oncologist 24(9): 1153-1158.

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BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid-based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus. MATERIALS AND METHODS: This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor-positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA], 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1-2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks. RESULTS: A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% (n = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse-related toxicity. CONCLUSION: Prophylactic use of steroid-containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse. IMPLICATIONS FOR PRACTICE: This prospective phase-II study showed that two steroid-containing mouthrinses substantially reduced incidences of all-grade and grade >/=2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose-delays and/or dose-reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost-effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor.