Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC xTZ7gKQHC54xYHd9p79SJrk S0066-782X2019000700109 10.5935/abc.20190101 Letter to the Editor Prolonged PR Interval and Outcome in Cardiac Resynchronization Therapy 0000-0003-0959-5576 Kewcharoen Jakrin Kanitsoraphan Chanavuth University of Hawaii Internal Medicine Residency Program Honolulu HI USA University of Hawaii Internal Medicine Residency Program, Honolulu, HI - USA Mailing Address: Jakrin Kewcharoen • 1212 Nuuanu ave, Honolulu, HI, 96817 - USA Email address: jakrin@hawaii.edu 08 08 2019 07 2019 113 1 109 110 24 03 2019 24 04 2019 24 04 2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Keywords: Heart Failure Cardiac resynchronization Therapy/methods Meta-Analysis Atrioventricular Block Heart Conduction, System

Dear Editor

We read the article “Baseline Prolonged PR Interval and Outcome of Cardiac Resynchronization Therapy: A Systematic Review and Meta-analysis” by Rattanawong et al.1 with great interest. The authors investigated the effect of prolonged PR interval on composite outcome among patients who received cardio resynchronized therapy. The authors conclude that prolonged PR is associated with worse outcome in this population.

I would like to commend the authors for performing a systematic review and meta-analysis on this topic. The effect of prolonged PR interval was well-known in the general population. However, in this specific population, the answer is unclear and was in needed for answers, given almost half of the patients with cardiac resynchronization therapy (CRT) had 1st degree AV block.2 Although several previous studies reported a negative impact on the cardiovascular outcome, they were retrospective cohort and was limited by a relatively small number of participants. Nevertheless, the authors demonstrated a good systematic review and performed the random-effect model with statistical perfection.

However, as the authors mentioned in the article, this meta-analysis has a limitation regarding the number of the included studies. Also, there is a difference in the cut-point for prolonged PR interval among the included studies. Although the study by Friedman et al. was the only study that used the cut-point of 230 ms instead of 200 ms, they have the most included participants and has the most weight percentage in all three forest plots. We thought that this is a crucial point as a change in risk ratio of the study by Freidman et al.3 could potentially change the overall pooled RR of the meta-analysis.

There are two additional studies that we thought could be included in the meta-analysis that could affect the outcome of this meta-analysis. Studies by Stockburger et al.4 and Lin et al.5 evaluated the effect of PR interval in patients with CRT.

Stockburger et al.4 performed a post hoc analysis from the Multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy (MADIT-CRT) trial. The authors found that patients with CRT who had short PR interval (< 230 ms) generally had worse outcome regarding heart failure and all-cause mortality, regardless of the QRS duration, although the authors did not directly compare the prolonged PR interval to normal PR interval.

Another study by Lin et al.5 was based on the secondary analysis of The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial. The authors reported that the outcome of all-cause mortality was reduced in both normal and prolonged PR interval group when compared to medical therapy alone, but more so in the prolonged PR interval group. Moreover, in a multivariable Cox model, progressively longer baseline PR interval, as a continuous variable, was associated with an increasingly greater reduction in the primary outcome.

Given that results from these two studies reported a positive correlation between PR interval and cardiovascular outcome, including the data from the two studies could potentially change the outcome of this meta-analysis.

References 1 Rattanawong P, Prasitlumkum N, Riangwiwat T, kanjanahattaki N, Vuthikraivit W, Chongsathidkiat P, et al. Baseline Prolonged PR Interval and Outcome of Cardiac Resynchronization Therapy: A Systematic Review and Meta-analysis. Arq Bras Cardiol. 2018;111(5):710-9. Rattanawong P Prasitlumkum N Riangwiwat T kanjanahattaki N Vuthikraivit W Chongsathidkiat P Baseline Prolonged PR Interval and Outcome of Cardiac Resynchronization Therapy: A Systematic Review and Meta-analysis Arq Bras Cardiol 2018 111 5 710 719 2 Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. The New England journal of medicine. 2004;350(21):2140-50. Bristow MR Saxon LA Boehmer J Krueger S Kass DA De Marco T Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure The New England journal of medicine 2004 350 21 2140 2150 3 Friedman DJ, Bao H, Spatz ES, Curtis JP, Daubert JP, Al-Khatib SM. Association between a prolonged PR interval and outcomes of cardiac resynchronization therapy: a report from the National cardiovascular Data-Registry. Circulation. 2016;134(21):1617-28. Friedman DJ Bao H Spatz ES Curtis JP Daubert JP Al-Khatib SM Association between a prolonged PR interval and outcomes of cardiac resynchronization therapy: a report from the National cardiovascular Data-Registry Circulation 2016 134 21 1617 1628 4 Stockburger M, Moss AJ, Klein HU, Zareba W, Goldenberg I, Biton Y, et al.Sustained clinical benefit of cardiac resynchronization therapy in non-LBBB patients with prolonged PR-interval: MADIT-CRT long-term follow-up. Clin Res Cardiol. 2016;105(11):944-52. Stockburger M Moss AJ Klein HU Zareba W Goldenberg I Biton Y Sustained clinical benefit of cardiac resynchronization therapy in non-LBBB patients with prolonged PR-interval: MADIT-CRT long-term follow-up Clin Res Cardiol 2016 105 11 944 952 5 Lin J, Buhr KA, Kipp R. Effect of PR Interval on Outcomes Following Cardiac Resynchronization Therapy: A Secondary Analysis of the COMPANION Trial. J Cardiovasc Electrophysiol. 2017;28(2):185-91. Lin J Buhr KA Kipp R Effect of PR Interval on Outcomes Following Cardiac Resynchronization Therapy: A Secondary Analysis of the COMPANION Trial J Cardiovasc Electrophysiol 2017 28 2 185 191 Reply Pattara Rattanawong Narut Prasitlumkum Tanawan Riangwiwat Napatt Kanjanahattakij Wasawat Vutthikraivit

We appreciate the author’s comments on our original article “Baseline Prolonged PR Interval and Outcome of Cardiac Resynchronization Therapy: A Systematic Review and Meta-analysis”.1 We agree with the authors that the effect of PR interval in cardiac resynchronization therapy (CRT) population is unknown, and therefore we conducted a systematic review and meta-analysis on this topic.

We agree that the study by Friedman et al.2 has the most included participants and has the most percentage in all three forest plots. However, to evaluate the effect of Friedman et al.,2 we performed a sensitivity analysis by excluding one study at a time which is shown in Supplementary Document 2 in the original article.1 After excluding Friedman et al.,2 there was no significant change of the risk ratio of composite outcome (risk ratio = 1.19, 95% confidence interval: 1.04-1.36), all-cause mortality (risk ratio=1.53, 95% confidence interval: 1.23-1.91), and heart failure hospitalization (risk ratio = 1.6, 95% confidence interval: 1.06-2.42).1 The meta-analysis pooled result still has a statistically significant risk ratio even if we exclude the study by Friedman et al.2 Therefore, a prolonged PR interval still predicts the outcomes of CRT regardless of the results of the study by Friedman et al.2

We appreciate the author’s recommendation to include the study by Stockburger et al.3 and Lin et al.4 Both studies were included from our comprehensive search and both full-text articles were reviewed. However, both studies were excluded from our systematic review and meta-analysis for the following reasons.

The study by Lin et al.4 was excluded from our systematic review and meta-analysis due to an inappropriate comparison as demonstrated in Figure 1 of our original article.1 Their objective is to compare the outcomes between CRT and optimal pharmacologic therapy stratified by PR interval. Our meta-analysis compared the outcome of prolonged PR interval versus normal PR interval only in CRT patients.

Similarly, the study by Stockburger et al.3 was also excluded from our systematic review and meta-analysis due to an inappropriate comparator. Stockburger et al.3 reported that patients with prolonged PR interval derived clinical benefit with reduction in heart failure or death from CRT when compared to an implantable cardioverter defibrillator.3 Therefore, their comparison was different from our study, which was prolonged PR interval versus normal PR interval in CRT patients.

Our systematic review and meta-analysis used comprehensive search methodology and strict inclusion and exclusion criteria; therefore our results are robust. We showed that a prolonged PR interval in CRT patients is significantly associated with an increased risk for all-cause mortality, composite outcome, and HF hospitalization when compared to normal PR interval in CRT patients.1

References 1 Rattanawong P, Prasitlumkum N, Riangwiwat T, kanjanahattaki N, Vuthikraivit W, Chongsathidkiat P, et al. Baseline Prolonged PR Interval and Outcome of Cardiac Resynchronization Therapy: A Systematic Review and Meta-analysis. Arq Bras Cardiol. 2018;111(5):710-9. Rattanawong P Prasitlumkum N Riangwiwat T kanjanahattaki N Vuthikraivit W Chongsathidkiat P Baseline Prolonged PR Interval and Outcome of Cardiac Resynchronization Therapy: A Systematic Review and Meta-analysis Arq Bras Cardiol 2018 111 5 710 719 2 Friedman DJ, Bao H, Spatz ES, Curtis JP, Daubert JP, Al-Khatib SM. Association between a prolonged PR interval and outcomes of cardiac resynchronization therapy: a report from the National cardiovascular Data-Registry. Circulation. 2016;134(21):1617-28. Friedman DJ Bao H Spatz ES Curtis JP Daubert JP Al-Khatib SM Association between a prolonged PR interval and outcomes of cardiac resynchronization therapy: a report from the National cardiovascular Data-Registry Circulation 2016 134 21 1617 1628 3 Stockburger M, Moss AJ, Klein HU, Zareba W, Goldenberg I, Biton Y, et al.Sustained clinical benefit of cardiac resynchronization therapy in non-LBBB patients with prolonged PR-interval: MADIT-CRT long-term follow-up. Clin Res Cardiol. 2016;105(11):944-52. Stockburger M Moss AJ Klein HU Zareba W Goldenberg I Biton Y Sustained clinical benefit of cardiac resynchronization therapy in non-LBBB patients with prolonged PR-interval: MADIT-CRT long-term follow-up Clin Res Cardiol 2016 105 11 944 952 4 Lin J, Buhr KA, Kipp R. Effect of PR Interval on Outcomes Following Cardiac Resynchronization Therapy: A Secondary Analysis of the COMPANION Trial. J Cardiovasc Electrophysiol. 2017;28(2):185-91. Lin J Buhr KA Kipp R Effect of PR Interval on Outcomes Following Cardiac Resynchronization Therapy: A Secondary Analysis of the COMPANION Trial J Cardiovasc Electrophysiol 2017 28 2 185 191 Carta ao Editor Intervalo PR Prolongado e Desfecho na Terapia de Ressincronização Cardíaca 0000-0003-0959-5576 Kewcharoen Jakrin Kanitsoraphan Chanavuth University of Hawaii Internal Medicine Residency Program, Honolulu, HI - USA Mailing Address: Jakrin Kewcharoen • 1212 Nuuanu ave, Honolulu, HI, 96817 - USA Email: jakrin@hawaii.edu Palavras-chave: Insuficiência Cardíaca Terapia de Ressincronização Cardíaca/métodos Metanálise Bloqueio Atrioventricular Sistema de Condução Cardíaca

Caro editor

Lemos com grande interesse o artigo “Intervalo PR Basal Prolongado e Desfecho da Terapia de Ressincronização Cardíaca: Revisão Sistemática e Meta-Análise” de Rattanawong et al.,1 Os autores investigaram o efeito do intervalo PR prolongado no desfecho composto nos pacientes que receberam terapia de ressincronização cardíaca. Os autores concluem que o PR prolongado está associado a uma pior evolução nessa população.

Eu gostaria de elogiar os autores por realizar uma revisão sistemática e metanálise sobre este tópico. O efeito do intervalo PR prolongado era bem conhecido na população em geral. No entanto, nesta população específica, a resposta não era clara e precisava de respostas, pois quase metade dos pacientes com terapia de ressincronização cardíaca (TRC) apresentava bloqueio atrioventricular (BAV) de primeiro grau.2 Embora vários estudos anteriores tenham relatado um impacto negativo no desfecho cardiovascular, eles utilizaram coortes retrospectivas, sendo limitados por um número relativamente pequeno de participantes. Ainda assim, os autores demonstraram uma boa revisão sistemática e realizaram o modelo de efeito aleatório com perfeição estatística.

No entanto, como os autores mencionaram no artigo, essa metanálise tem uma limitação quanto ao número de estudos incluídos. Além disso, há uma diferença no ponto de corte para o intervalo PR prolongado nos estudos incluídos. Embora o estudo de Friedman et al. tenha sido o único estudo que utilizou o ponto de corte de 230 ms no lugar de 200 ms, eles têm o maior número de participantes incluídos e o maior percentual de peso nos três gráficos Forest Plot. Nós achamos que este é um ponto crucial, pois a mudança na taxa de risco do estudo de Freidman et al.,3 poderia potencialmente alterar os RRs (riscos relativos) agrupados globais da metanálise.

Existem dois estudos adicionais que, em nossa opinião, poderiam ser incluídos na metanálise com potencial para afetar o resultado do estudo. Os estudos de Stockburger et al.,4 e Lin et al.,5 avaliaram o efeito do intervalo PR em pacientes com TRC.

Stockburger et al.,4 realizaram uma análise post hoc do estudo multicêntrico de implante de desfibrilador automático com terapia de ressincronização cardíaca (MADIT-CRC, (Multicenter Automatic Desfibrillator Implantation Trial). Os autores verificaram que pacientes com TRC que tinham intervalo PR curto (< 230 ms) normalmente apresentaram pior evolução em relação à insuficiência cardíaca e mortalidade por todas as causas, independentemente da duração do QRS, embora os autores não tenham comparado diretamente o intervalo PR prolongado com intervalo PR normal.

Outro estudo, de Lin et al.,5 foi baseado na análise secundária do estudo “The Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure” (COMPANION). Os autores relataram que o desfecho da mortalidade por todas as causas foi reduzido tanto no grupo com intervalo PR normal quanto no de PR prolongado, quando comparado ao tratamento clínico isolado; porém, ainda mais no grupo com intervalo PR prolongado. Além disso, em um modelo multivariado de Cox, o intervalo PR basal progressivamente mais longo, como variável contínua, foi associado a uma redução cada vez maior no desfecho primário.

Considerando que os resultados destes dois estudos relataram uma correlação positiva entre o intervalo PR e o desfecho cardiovascular, a inclusão dos dados dos dois estudos poderia potencialmente alterar o desfecho desta meta-análise.

Carta-resposta Pattara Rattanawong Narut Prasitlumkum Tanawan Riangwiwat Napatt Kanjanahattakij Wasawat Vutthikraivit

Agradecemos os comentários do autor em nosso artigo original “Intervalo PR Basal Prolongado e Desfecho da Terapia de Ressincronização Cardíaca: Revisão Sistemática e Meta-Análise”.1 Concordamos com os autores que o efeito do intervalo PR na população submetida à terapia de ressincronização cardíaca (CRT) é desconhecido e, portanto, realizamos uma revisão sistemática e meta-análise sobre este tópico.

Concordamos que o estudo de Friedman et al.,2 tem o maior número de participantes incluídos e tem o maior percentual em todos os três gráficos Forest Plot. No entanto, para avaliar o efeito de Friedman et al.,2 realizamos uma análise de sensibilidade excluindo um estudo por vez, que é mostrado no Documento Suplementar 2 no artigo original.1 Após excluir Friedman et al.,2 não houve mudança significativa da razão de risco do desfecho composto (razão de risco = 1,19, intervalo de confiança de 95%: 1,04-1,36), mortalidade por todas as causas (razão de risco = 1,53, intervalo de confiança de 95%: 1,23-1,91) e hospitalização por insuficiência cardíaca = 1,6, intervalo de confiança de 95%: 1,06-2,42).1 O resultado agrupado da meta-análise ainda tem uma razão de risco estatisticamente significativa, mesmo se excluirmos o estudo de Friedman et al.,2 Portanto, um intervalo PR prolongado ainda prediz os desfechos de TRC, independentemente dos resultados do estudo de Friedman et al.2

Agradecemos a recomendação do autor de incluir o estudo de Stockburger et al.,3 e Lin et al.,4 Ambos os estudos foram incluídos em nossa pesquisa abrangente e ambos os artigos completos foram revisados. No entanto, ambos os estudos foram excluídos da nossa revisão sistemática e metanálise pelas seguintes razões.

O estudo de Lin et al.,4 foi excluído de nossa revisão sistemática e metanálise devido a uma comparação inadequada, conforme demonstrado na Figura 1 do nosso artigo original.1 Seu objetivo é comparar os resultados entre TRC e terapia farmacológica otimizada estratificada pelo intervalo PR. Nossa metanálise comparou o desfecho do intervalo PR prolongado versus o intervalo PR normal apenas em pacientes com TRC.

Da mesma forma, o estudo de Stockburger et al.,3 também foi excluído de nossa revisão sistemática e metanálise devido a um comparador inadequado. Stockburger et al., 3 relataram que pacientes com intervalo PR prolongado tiveram benefício clínico com redução da insuficiência cardíaca ou morte por TRC quando comparados a um desfibrilador cardioversor implantável.3 Portanto, sua comparação foi diferente do nosso estudo, que foi intervalo PR prolongado versus intervalo PR normal em pacientes com TRC.

Nossa revisão sistemática e meta-análise utilizou metodologia abrangente de pesquisa e critérios rígidos de inclusão e exclusão; portanto, nossos resultados são robustos. Mostramos que um intervalo PR prolongado em pacientes com TRC está significativamente associado a um risco aumentado de mortalidade por todas as causas, desfecho composto e hospitalização por IC, quando comparado ao intervalo PR normal em pacientes com TRC.1

References 1 Rattanawong P, Prasitlumkum N, Riangwiwat T, kanjanahattaki N, Vuthikraivit W, Chongsathidkiat P, et al. Baseline Prolonged PR Interval and Outcome of Cardiac Resynchronization Therapy: A Systematic Review and Meta-analysis. Arq Bras Cardiol. 2018;111(5):710-9. Rattanawong P Prasitlumkum N Riangwiwat T kanjanahattaki N Vuthikraivit W Chongsathidkiat P Baseline Prolonged PR Interval and Outcome of Cardiac Resynchronization Therapy: A Systematic Review and Meta-analysis Arq Bras Cardiol 2018 111 5 710 719 2 Friedman DJ, Bao H, Spatz ES, Curtis JP, Daubert JP, Al-Khatib SM. Association between a prolonged PR interval and outcomes of cardiac resynchronization therapy: a report from the National cardiovascular Data-Registry. Circulation. 2016;134(21):1617-28. Friedman DJ Bao H Spatz ES Curtis JP Daubert JP Al-Khatib SM Association between a prolonged PR interval and outcomes of cardiac resynchronization therapy: a report from the National cardiovascular Data-Registry Circulation 2016 134 21 1617 1628 3 Stockburger M, Moss AJ, Klein HU, Zareba W, Goldenberg I, Biton Y, et al.Sustained clinical benefit of cardiac resynchronization therapy in non-LBBB patients with prolonged PR-interval: MADIT-CRT long-term follow-up. Clin Res Cardiol. 2016;105(11):944-52. Stockburger M Moss AJ Klein HU Zareba W Goldenberg I Biton Y Sustained clinical benefit of cardiac resynchronization therapy in non-LBBB patients with prolonged PR-interval: MADIT-CRT long-term follow-up Clin Res Cardiol 2016 105 11 944 952 4 Lin J, Buhr KA, Kipp R. Effect of PR Interval on Outcomes Following Cardiac Resynchronization Therapy: A Secondary Analysis of the COMPANION Trial. J Cardiovasc Electrophysiol. 2017;28(2):185-91. Lin J Buhr KA Kipp R Effect of PR Interval on Outcomes Following Cardiac Resynchronization Therapy: A Secondary Analysis of the COMPANION Trial J Cardiovasc Electrophysiol 2017 28 2 185 191