- Email: [email protected]
The TRINITY study: Twitter discussion from a respirology journal club
Correspondence
The TRINITY study: Twitter discussion from a respirology journal club We had the pleasure of discussing the TRINITY trial 1 at our Twitterbased journal club (@respandsleepjc, #rsjc) on April 20, 2017. This trial assessed whether treatment with a single-inhaler delivery of triple therapy (long-acting muscarinic agonist [LAMA], long-acting β agonist [LABA], and inhaled corticosteroid [ICS]— ie, glycopyrronium bromide plus formoterol fumarate plus extrafine beclometasone dipropionate) was beneficial in patients with chronic obstructive pulmonary disorder (COPD) who were at risk of moderate-to-severe exacerbations, compared with monotherapy with a LAMA (tiotropium), or a combination of LABA and ICS (formoterol fumarate plus extrafine beclometasone dipropionate) with a LAMA (tiotropium), in a second inhaler. After discussing the Article, we were left with a few uncertainties. First, we are unclear what the term “open triple” meant for the control group. Did this mean that they received open-label treatment?2 If so, this would essentially nullify blinding and bias the results. Furthermore, since the study showed that fixed triple therapy was more efficacious at reducing exacerbations (adjusted rate ratio of 0·7) in patients with one exacerbation or more in the previous 12 months (compared with the open triple therapy group), perhaps non-adherence is an important mechanism underlying the increased frequency of exacerbations in some patients with COPD. 3 Since the
www.thelancet.com/respiratory Vol 5 July 2017
open-triple group seems to have been included precisely because adherence was an important issue, why did the investigators choose to measure it by self-report instead of a more objective method?4 Figure 2B in the Article suggests that the effect of triple therapy on reduced exacerbation rate, compared with LAMA monotherapy, mainly occurred during the first 4 weeks of treatment. Could this have been related to a steroid-withdrawal effect? The run-in period of 2 weeks on LAMA monotherapy might have been too short to mitigate this,5 since the median time to exacerbation after steroid withdrawal has previously been observed as 6 weeks.6 A subgroup analysis of exacerbation rate based on baseline treatment would have been helpful.7 The results were also consistent with previous observations8 that patients with increased eosinophil levels might derive more benefit from ICS in terms of reduction of exacerbations, compared with no ICS therapy.9 It was also reassuring to note the minimal risk of pneumonia with triple therapy, which could be due to the reduced ICS dose (table 3).10 Overall, the study results showed that LAMA monotherapy is suboptimal for patients with GOLD D COPD, but since most of the patients studied were white, the results might not be generalisable to settings with large multicultural populations, such as Canada. 11 We must await the results of ongoing trials to know whether triple therapy will be more beneficial than LABA/LAMA combined. We declare no competing interests.
Melissa Brijbassi,*Anju Anand, Matthew Stanbrook [email protected] University of Toronto, Toronto, ON, Canada (MB, AA, MS); St Michael’s Hospital, Toronto, ON, Canada (AA); and Toronto Western Hospital, Toronto, ON, Canada (MS) 1
Vestbo J, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic-obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet 2017; 389: 1919–29. 2 Stanbrook, Matthew (drstanbrook). Wish Dr Vestbo could explain why he called 3rd group “open triple”—did they get open label Tx? Seems not. April 20, 2017, 2052 h EDT. Tweet. 3 Stanbrook, Matthew (drstanbrook). Fixed triple beat open triple, perhaps this means that non-adherence is an issue causing increased frequency of exacerbations? April 20, 2017, 2108 h EDT. Tweet. 4 Stanbrook, Matthew (drstanbrook). Since they put an extra arm to look at compliance, you’d think they would measure this better than self-report. April 20, 2017, 2105 h EDT. Tweet. 5 Resp&Sleep JC (respandsleepjc). Discussing run in period of trial-some pt actually “step”down but excl pt hat flared in run in-what about duratn of monitoring this? April 20, 2017, 1808 h EDT. Tweet. 6 van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med 2002; 166: 1358–63. 7 Stanbrook, Matthew (drstanbrook). Fig2B: exacerbation difference all happens in first 4 weeks. Steroid withdrawal? No analysis by baseline Tx done. April 20, 2017, 2100 h EDT. Tweet. 8 Barnes NC, Sharma R, Lettis S, Calverley PM. Blood eosinophils as a marker of response to inhaled corticosteroids in COPD. Eur Respir J 2016; 47: 1374–82. 9 Stanbrook, Matthew (drstanbrook). Once again, eosinophils seem to predict ICS benefit in #COPD. Interesting. April 20, 2017, 2106 h EDT. Tweet. 10 Stanbrook, Matthew (drstanbrook). Minimal pneumonia risk with triple therapy suggests this is mitigated with lower ICS doses, in contrast to older RCTs. April 20, 2017, 2110 h EDT. Tweet. 11 Resp&Sleep JC (respandsleepjc). What about generalizability in this trial for our popn in Canada? 1826 h EDT. Tweet.
e25
The TRINITY study: Twitter discussion from a respirology journal club We had the pleasure of discussing the TRINITY trial 1 at our Twitterbased journal club (@respandsleepjc, #rsjc) on April 20, 2017. This trial assessed whether treatment with a single-inhaler delivery of triple therapy (long-acting muscarinic agonist [LAMA], long-acting β agonist [LABA], and inhaled corticosteroid [ICS]— ie, glycopyrronium bromide plus formoterol fumarate plus extrafine beclometasone dipropionate) was beneficial in patients with chronic obstructive pulmonary disorder (COPD) who were at risk of moderate-to-severe exacerbations, compared with monotherapy with a LAMA (tiotropium), or a combination of LABA and ICS (formoterol fumarate plus extrafine beclometasone dipropionate) with a LAMA (tiotropium), in a second inhaler. After discussing the Article, we were left with a few uncertainties. First, we are unclear what the term “open triple” meant for the control group. Did this mean that they received open-label treatment?2 If so, this would essentially nullify blinding and bias the results. Furthermore, since the study showed that fixed triple therapy was more efficacious at reducing exacerbations (adjusted rate ratio of 0·7) in patients with one exacerbation or more in the previous 12 months (compared with the open triple therapy group), perhaps non-adherence is an important mechanism underlying the increased frequency of exacerbations in some patients with COPD. 3 Since the
www.thelancet.com/respiratory Vol 5 July 2017
open-triple group seems to have been included precisely because adherence was an important issue, why did the investigators choose to measure it by self-report instead of a more objective method?4 Figure 2B in the Article suggests that the effect of triple therapy on reduced exacerbation rate, compared with LAMA monotherapy, mainly occurred during the first 4 weeks of treatment. Could this have been related to a steroid-withdrawal effect? The run-in period of 2 weeks on LAMA monotherapy might have been too short to mitigate this,5 since the median time to exacerbation after steroid withdrawal has previously been observed as 6 weeks.6 A subgroup analysis of exacerbation rate based on baseline treatment would have been helpful.7 The results were also consistent with previous observations8 that patients with increased eosinophil levels might derive more benefit from ICS in terms of reduction of exacerbations, compared with no ICS therapy.9 It was also reassuring to note the minimal risk of pneumonia with triple therapy, which could be due to the reduced ICS dose (table 3).10 Overall, the study results showed that LAMA monotherapy is suboptimal for patients with GOLD D COPD, but since most of the patients studied were white, the results might not be generalisable to settings with large multicultural populations, such as Canada. 11 We must await the results of ongoing trials to know whether triple therapy will be more beneficial than LABA/LAMA combined. We declare no competing interests.
Melissa Brijbassi,*Anju Anand, Matthew Stanbrook [email protected] University of Toronto, Toronto, ON, Canada (MB, AA, MS); St Michael’s Hospital, Toronto, ON, Canada (AA); and Toronto Western Hospital, Toronto, ON, Canada (MS) 1
Vestbo J, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic-obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet 2017; 389: 1919–29. 2 Stanbrook, Matthew (drstanbrook). Wish Dr Vestbo could explain why he called 3rd group “open triple”—did they get open label Tx? Seems not. April 20, 2017, 2052 h EDT. Tweet. 3 Stanbrook, Matthew (drstanbrook). Fixed triple beat open triple, perhaps this means that non-adherence is an issue causing increased frequency of exacerbations? April 20, 2017, 2108 h EDT. Tweet. 4 Stanbrook, Matthew (drstanbrook). Since they put an extra arm to look at compliance, you’d think they would measure this better than self-report. April 20, 2017, 2105 h EDT. Tweet. 5 Resp&Sleep JC (respandsleepjc). Discussing run in period of trial-some pt actually “step”down but excl pt hat flared in run in-what about duratn of monitoring this? April 20, 2017, 1808 h EDT. Tweet. 6 van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med 2002; 166: 1358–63. 7 Stanbrook, Matthew (drstanbrook). Fig2B: exacerbation difference all happens in first 4 weeks. Steroid withdrawal? No analysis by baseline Tx done. April 20, 2017, 2100 h EDT. Tweet. 8 Barnes NC, Sharma R, Lettis S, Calverley PM. Blood eosinophils as a marker of response to inhaled corticosteroids in COPD. Eur Respir J 2016; 47: 1374–82. 9 Stanbrook, Matthew (drstanbrook). Once again, eosinophils seem to predict ICS benefit in #COPD. Interesting. April 20, 2017, 2106 h EDT. Tweet. 10 Stanbrook, Matthew (drstanbrook). Minimal pneumonia risk with triple therapy suggests this is mitigated with lower ICS doses, in contrast to older RCTs. April 20, 2017, 2110 h EDT. Tweet. 11 Resp&Sleep JC (respandsleepjc). What about generalizability in this trial for our popn in Canada? 1826 h EDT. Tweet.
e25