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ment. We believe that the most likely explanation John W. Eikelboom, M.D. for our trial results is that dabigatran is less ef- McMaster University fective than warfarin in suppressing coagulation Hamilton, ON, Canada activation resulting from exposure of the blood Martina Brueckmann, M.D. to the artificial surface of a mechanical valve. Boehringer Ingelheim Gasparovic and colleagues are concerned Ingelheim am Rhein, Germany about a lack of concomitant antiplatelet therapy Frans Van de Werf, M.D., Ph.D. in our trial. The 2012 Guidelines on the ManKU Leuven agement of Valvular Heart Disease published by Leuven, Belgium the European Society of Cardiology and the Euro- [email protected] pean Association for Cardio-Thoracic Surgery Since publication of their article, the authors report no fursuggest that antiplatelet therapy should not be ther potential conflict of interest. routinely prescribed for all patients who have a 1. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the mechanical valve but instead should be reserved management of valvular heart disease (version 2012): the Joint 1 for specific indications. Approximately one Task Force on the Management of Valvular Heart Disease of the third of the patients in our trial received con- European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur J Cardiothorac comitant antiplatelet therapy, and there is no Surg 2012;42:S1-S44. evidence that this concomitant therapy explains the results of the trial. DOI: 10.1056/NEJMc1315004

High-Flow Nasal Cannulae in Very Preterm Infants after Extubation No potential conflict of interest relevant to this letter was re-

To the Editor: Manley et al (Oct. 10 issue)1 re- ported. port that the use of high-flow nasal cannulae in 1. Manley BJ, Owen LS, Doyle LW, et al. High-flow nasal canvery preterm infants was noninferior to the use nulae in very preterm infants after extubation. N Engl J Med of nasal continuous positive airway pressure 2013;369:1425-33. (CPAP). The pressures that are delivered to the 2. Spence KL, Murphy D, Kilian C, McGonigle R, Kilani RA. High-flow nasal cannula as a device to provide continuous posiairways with these approaches determine the pri- tive airway pressure in infants. J Perinatol 2007;27:772-5. mary and secondary outcomes of the study. Air- 3. Wilkinson DJ, Andersen CC, Smith K, Holberton J. Pharynway pressures that are delivered by high-flow geal pressure with high-flow nasal cannulae in premature infants. J Perinatol 2008;28:42-7. nasal cannulae and CPAP are difficult to com- 4. Sreenan C, Lemke RP, Hudson-Mason A, Osiovich H. Highpare and might vary considerably according to flow nasal cannulae in the management of apnea of prematurity: the infant’s weight, cannula size, and flow rate.2‑6 a comparison with conventional nasal continuous positive airway pressure. Pediatrics 2001;107:1081-3. The authors do not provide means and standard 5. Saslow JG, Aghai ZH, Nakhla TA, et al. Work of breathing deviations of the CPAP pressures and flow rates using high-flow nasal cannula in preterm infants. J Perinatol that are unadjusted and adjusted for weight and 2006;26:476-80. 6. De Paoli AG, Lau R, Davis PG, Morley CJ. Pharyngeal presdiameter of the nasal cannulae and CPAP tubes. sure in preterm infants receiving nasal continuous positive airway Providing this information might reflect the pressure. Arch Dis Child Fetal Neonatal Ed 2005;90:F79-F81. wide variability in airway pressures delivered to DOI: 10.1056/NEJMc1314238 the two groups. A description of variability could help interpret the results of this study and the conclusions that were drawn. To the Editor: Manley et al. conclude that the use of high-flow nasal cannulae is noninferior to Samridh Nagar, M.D. Nepean Hospital CPAP, but this critically depends on the margin Sydney, NSW, Australia of noninferiority chosen (20%), which should be [email protected] clinically justified.1 The rationale for this arbiRalph Nanan, Dr.Med.Habil. trary margin is that “many clinicians strongly Anthony Liu, M.P.H. prefer” high-flow nasal cannulae for the “perUniversity of Sydney Sydney, NSW, Australia ceived benefits over CPAP,” yet the justification 384

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for the margin was not provided. If we translate the results into a “number needed to treat” (NNT),2 a 20% difference yields an NNT of five. For every five infants treated with high-flow ­nasal cannulae instead of CPAP, one will pay the price of failure (e.g., acidosis, apneas, and reintubation) for the benefit of easier administration and less nasal trauma, which is superficial in most cases.3 Is the price right? Analogously, are we willing to withhold antenatal glucocorticoid prophylaxis in newborns with a gestational age of more than 29 weeks because the difference is less than 20% and the NNT to avoid one case of the respiratory distress syndrome is more than five?4 The margin that was chosen by the authors may be unconvincing to many clinicians, and their conclusions of noninferiority questionable. Luigi Gagliardi, M.D. Ospedale Versilia Viareggio, Italy [email protected]

already very generous equivalence limit. The article offers no justification for accepting such a large noninferiority margin, although a more clinically acceptable margin would require a substantially larger trial. We believe that this trial offers no evidence in favor of the use of highflow nasal cannulae and that larger trials that are powered to eliminate meaningful differences in outcomes are required. Stephen A. Roberts, Ph.D. University of Manchester Manchester, United Kingdom

Simon Mitchell, M.D. Central Manchester University Hospitals NHS Foundation Trust Manchester, United Kingdom

Suresh Victor, Ph.D. University of Manchester Manchester, United Kingdom [email protected] No potential conflict of interest relevant to this letter was reported. DOI: 10.1056/NEJMc1314238

Franca Rusconi, M.D. Anna Meyer Children’s University Hospital Florence, Italy No potential conflict of interest relevant to this letter was reported. 1. Le Henanff A, Giraudeau B, Baron G, Ravaud P. Quality of

reporting of noninferiority and equivalence randomized trials. JAMA 2006;295:1147-51. 2. Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 1988;318:1728-33. 3. Fischer C, Bertelle V, Hohlfeld J, Forcada-Guex M, Stadelmann-Diaw C, Tolsa J-F. Nasal trauma due to continuous positive airway pressure in neonates. Arch Dis Child Fetal Neonatal Ed 2010;95:F447-F451. 4. Sinclair JC. Evidence-based therapy in neonatology: distilling the evidence and applying it in practice. Acta Paediatr 2004; 93:1146-52. DOI: 10.1056/NEJMc1314238

To the Editor: In the study by Manley et al., the authors express a degree of caution, but we are concerned that this study will be interpreted as supporting the use of high-flow nasal cannulae. The statement of equivalence assumes that a 20% increase in extubation failure is clinically acceptable, nearly doubling the rate from 25% to 45%. The estimate from the trial is that the use of high-flow nasal cannulae is inferior to CPAP, with an absolute increase of 8.4% and a relative increase of 33.6% in the extubation failure rate, and the authors acknowledge that the upper limit of the 95% confidence interval was close to the

To the Editor: In the study by Manley et al., the flow of high-flow nasal cannulae ranged from 2 to 7 liters on the basis of the size of the prongs and physician’s discretion, and for each given flow level, the delivered positive pressure is unpredictable.1 Thus, we do not know what level of flow delivered by high-flow nasal cannulae has similar effectiveness to the 5 to 8 cm of water that CPAP delivered in the control group. This uncertainty about flow limits the clinical application of these results. Moreover, it is of some concern that the set pressure limit of 45 cm of water for the high-flow nasal cannulae circuit seems to be too high to be sufficiently safe. Carlo Dani, M.D. Careggi University Hospital of Florence Florence, Italy [email protected] No potential conflict of interest relevant to this letter was reported. 1. Dani C, Pratesi S, Migliori C, Bertini G. High flow nasal

cannula therapy as respiratory support in the preterm infant. Pediatr Pulmonol 2009;44:629-34.

DOI: 10.1056/NEJMc1314238

The authors reply: Our trial was a pragmatic clinical study that compared the use of high-flow nasal cannulae with the standard support, nasal CPAP. We agree with Nagar et al. and Dani that

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there is considerable variability in the pressure delivered by the two methods. During CPAP, clinicians set the pressure. However, leakage at the nares and mouth means that the delivered pressure is lower than that set and varies considerably over time and among infants.1,2 During the use of high-flow nasal cannulae, the gas flow is set, but variable pressure may be generated.3 Other factors (e.g., nasopharyngeal washout) may contribute to the effects of high-flow nasal cannulae.3 We chose flow rates that are typical in current practice4 and followed manufacturers’ guidelines. We did not measure the actual pressures generated by either nasal CPAP or highflow nasal cannulae. In response to Dani’s concern regarding the safety pressure limit of the Fisher & Paykel high-flow nasal cannulae: the internal circuit pressure is limited to less than 45 cm of water, but the pressure that is delivered to the infant is typically one tenth that level.5 Other high-flow nasal cannulae systems do not have similar safety features. We performed a noninferiority trial because clinicians were already opting to use high-flow nasal cannulae, given the perceived advantages of this method: ease of use, reduced nasal trauma, and improved infant tolerance.4 With this in mind, we chose a generous noninferiority margin (20% above the treatment failure rate for nasal CPAP). In response to the concerns of Gagliardi and Rusconi and Roberts et al.: since our primary outcome was treatment failure, rather than a more severe outcome, such as bronchopulmonary dysplasia or reintubation (when a lower noninferiority margin would be appropriate), infants who were treated with high-flow nasal cannulae were exposed to minimal additional risk. We found no previous reports of noninferiority trials in the neonatal literature and thus had no precedents on which to base our

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choice. Ultimately, almost half the infants in whom the use of high-flow nasal cannulae failed were rescued from reintubation by subsequent nasal CPAP. The great majority of infants in the nasal-cannulae group had no respiratory acidosis or deterioration requiring urgent intubation (95% of the nasal-cannulae group vs. 96% of the CPAP group), providing further reassurance that the use of high-flow nasal cannulae did not expose infants to clinically significant harm. We agree with Roberts et al. that our study does not suggest the superiority of high-flow nasal cannulae over nasal CPAP. However, it does suggest that the use of high-flow nasal cannulae is a viable alternative that does not harm infants and may offer novel advantages. Ultimately, each clinician will appraise the results and make a decision about the use of this method as respiratory support for preterm infants after extubation. Brett J. Manley, M.B., B.S. Louise S. Owen, M.D. Peter G. Davis, M.D. Royal Women’s Hospital Parkville, VIC, Australia [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. De Paoli AG, Morley CJ, Davis PG, Lau R, Hingeley E. In vitro

comparison of nasal continuous positive airway pressure devices for neonates. Arch Dis Child Fetal Neonatal Ed 2002;87:F42-F45. 2. De Paoli AG, Lau R, Davis PG, Morley CJ. Pharyngeal pressure in preterm infants receiving nasal continuous positive airway pressure. Arch Dis Child Fetal Neonatal Ed 2005;90:F79-F81. 3. Dysart K, Miller TL, Wolfson MR, Shaffer TH. Research in high flow therapy: mechanisms of action. Respir Med 2009;103: 1400-5. 4. Hough JL, Shearman AD, Jardine LA, Davies MW. Humidified high flow nasal cannulae: current practice in Australasian nurseries, a survey. J Paediatr Child Health 2012;48:106-13. 5. Lampland AL, Plumm B, Meyers PA, Worwa CT, Mammel MC. Observational study of humidified high-flow nasal cannula compared with nasal continuous positive airway pressure. J Pediatr 2009;154:177-82. DOI: 10.1056/NEJMc1314238

Calcium Supplements and Fracture Prevention To the Editor: Bauer (Oct. 17 issue)1 misrepresents the rationale for the reanalysis of the results of the Women’s Health Initiative (WHI) trial. Because 54% of the participants were already taking calcium supplements at baseline, the trial effectively compared higher versus lower doses of calcium and cannot answer the question 386

of whether taking calcium supplements alters the risk of cardiovascular events.2 My colleagues and I addressed this question by restricting analyses to participants who were not taking calcium supplements at baseline, and we reported that the use of calcium (with vitamin D) increased cardiovascular risk.2

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High-flow nasal cannulae in very preterm infants after extubation.

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