correspondence Since publication of his article, the author reports no further potential conflict of interest. 1. The EINSTEIN Investigators. Oral rivaroxaban for sympto-
matic venous thromboembolism. N Engl J Med 2010;363:2499510. 2. The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97.
3. Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban
versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013;11:21. 4. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799-808. DOI: 10.1056/NEJMc1313883
Macitentan and Pulmonary Arterial Hypertension To the Editor: Pulido et al. (Aug. 29 issue)1 report the results of the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN), an Actelion Pharmaceuticals–funded study of macitentan to treat pulmonary arterial hypertension. Although the article provides potentially good news for patients, the authors note that Actelion Pharmaceuticals conducted all the statistical analyses and hired a professional medical writer to assist. The acknowledgments thank these persons, thus meeting the standards of the International Committee of Medical Journal Editors.2 However, the blurred line between hired writing assistance and ghostwriting is unsettling. Disclosure is only beneficial when it provides enough information to evaluate the magnitude of risk for potential bias. We believe it is important to know who wrote the first draft of the manuscript and what exact role the paid writer had in drafting the article. History has warned us that studies completed and written entirely by entities who will benefit financially from the results warrant increased scrutiny.3,4 Disclosures that lack specificity make it impossible to understand the true risk of bias in the study. It is unclear how the authors can assert responsibility for the integrity of the data without further explanation of their roles and the roles of the persons who conducted all the analyses and assisted with the writing. Timothy S. Anderson, M.D. University of Pittsburgh Medical Center Pittsburgh, PA [email protected]
Chester B. Good, M.D., M.P.H. Walid F. Gellad, M.D., M.P.H. Veterans Affairs Pittsburgh Healthcare System Pittsburgh, PA No potential conflict of interest relevant to this letter was reported. 1. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and
morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809-18. 2. Drazen JM, Curfman GD. On authors and contributors. N Engl J Med 2002;347:55. 3. Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest authorship and ghostwriting in publications related to rofecoxib: a case study of industry documents from rofecoxib litigation. JAMA 2008;299:1800-12. 4. Blumenthal D, Campbell EG, Anderson MS, Causino N, Louis KS. Withholding research results in academic life science: evidence from a national survey of faculty. JAMA 1997;277: 1224-8. DOI: 10.1056/NEJMc1313112
To the Editor: Pulido et al. conclude that macitentan, a dual endothelin-receptor antagonist, reduced morbidity and mortality among patients with pulmonary arterial hypertension. The rate of death from any cause was not significantly different among the three groups; however, there was a suggestion that the rate of death due to pulmonary arterial hypertension was lower among patients who received 10 mg of macitentan once daily. We wonder how the independent clinical event committee adjudicated the cause of death, since we have recently reported on the difficulties of this determination.1 At the Cleveland Clinic, all deaths in patients with pulmonary arterial hypertension are reviewed within 7 days after the event by at least two physicians (including the treating physician) and a nurse. In our study, we noted that consensus was not achieved in a quarter of our patients, most commonly in those who died in the out-of-hospital setting or had clinically significant coexisting conditions. It would be very helpful and important to know how consensus about the cause of death was achieved in the study by Pulido et al. Adriano R. Tonelli, M.D. Raed A. Dweik, M.D. Cleveland Clinic Cleveland, OH [email protected] No potential conflict of interest relevant to this letter was reported.
n engl j med 370;1 nejm.org january 2, 2014
The New England Journal of Medicine Downloaded from nejm.org on November 3, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
81
The
n e w e ng l a n d j o u r na l
1. Tonelli AR, Arelli V, Minai OA, et al. Causes and circum-
stances of death in pulmonary arterial hypertension. Am J Respir Crit Care Med 2013;188:365-9.
of
m e dic i n e
tension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur Heart J 2010;31:2080-6. DOI: 10.1056/NEJMc1313112
DOI: 10.1056/NEJMc1313112
To the Editor: The results of the SERAPHIN trial raise several critical questions. First, although death was included as a component of the positive combined end point, the data suggest that the treatment effect on mortality in the two groups of patients who received macitentan was inconsistent (higher than placebo in the group that received 3 mg and similar to placebo in the group that received 10 mg). In addition, it is not clear how many deaths attributed to placebo at the end of the trial occurred in patients who were actually receiving open-label macitentan. Second, the claim of reduced morbidity coincides principally with a clinically insignificant (approximately 20-m) improvement in the 6-minute walk distance, which may not be a valid surrogate end point.1-3 Third, despite the fact that one of the authors has previously argued that pursuing long-term trials of agents against placebo in pulmonary arterial hypertension would be “unethical,” 4 the fact that these authors conducted this trial suggests an important change in beliefs. Is this change a reflection of uncertainty about the efficacy of therapies in pulmonary arterial hypertension? It seems so, because in this trial, some patients who were randomly assigned to placebo were receiving no background therapy. Alejandro Macchia, M.D. Fondazione Mario Negri Sud Santa Maria Imbaro, Italy [email protected]
Javier Mariani, M.D. Fundación Group de Estudio Sobre Investigación Clínica en Argentina Buenos Aires, Argentina
Gianni Tognoni, M.D. Fondazione Mario Negri Sud Santa Maria Imbaro, Italy No potential conflict of interest relevant to this letter was reported. 1. Savarese G, Paolillo S, Costanzo P, et al. Do changes of
6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol 2012;60:1192-201. 2. Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation 2012;126:349-56. 3. Macchia A, Marchioli R, Tognoni G, et al. Systematic review of trials using vasodilators in pulmonary arterial hypertension: why a new approach is needed. Am Heart J 2010;159:245-57. 4. Galiè N, Palazzini M, Manes A. Pulmonary arterial hyper-
82
The Authors Reply: Anderson et al. request clarification of the sponsor’s involvement in the data analysis in our study and in the manuscript preparation. Analyses were conducted by the sponsor according to a prespecified plan, and these analyses were reviewed by two independent statisticians and an external statistician who consulted at the request of the Journal. Medical writers assisted with the initial outline and first draft of the manuscript that was written jointly by the first and last authors; this complied with international guidelines for good publication practice.1-4 All authors contributed to subsequent versions and approved the final version of the manuscript. We maintain responsibility for the full content of the article. We agree with Tonelli and Dweik that the attribution of death in pulmonary arterial hypertension is challenging. The independent clinical event committee in our study consisted of three experts in pulmonary arterial hypertension who were unaware of the study-drug assignments; had full access to case-report and serious-adverseevent forms, hospital-discharge summaries, death certificates, and other supporting documents; and individually adjudicated whether death was related to pulmonary arterial hypertension. In cases of disparity, consensus had to be reached. Macchia et al. suggest an inconsistency between the two doses in the effect of macitentan on mortality. In interpreting the primary endpoint results, one must note that the end point was the time to the first occurrence of an event related to pulmonary arterial hypertension or death from any cause. In pulmonary arterial hypertension, death as a first event is uncommon and usually is preceded by disease worsening. It is also important to observe not only the number of deaths per group, but also the hazard ratio that takes into account the time to death; these results show no difference between placebo and macitentan at a dose of 3 mg, whereas there is a trend toward a reduction in mortality with macitentan at a dose of 10 mg versus placebo. With respect to death up to the end of the study, patients who were initially randomly assigned to placebo may have received open-label macitentan after a nonfatal event; this introduced a bias in favor of placebo.
n engl j med 370;1 nejm.org january 2, 2014
The New England Journal of Medicine Downloaded from nejm.org on November 3, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
As Macchia and colleagues highlight, our data Lewis J. Rubin, M.D. show that the change in 6-minute walk distance University of California, San Diego was not associated with long-term outcomes in La Jolla, CA pulmonary arterial hypertension. The observed Gérald Simonneau, M.D. reduction in morbidity was driven by a decrease Université Paris-Sud in the rate of worsening of pulmonary arterial Le Kremlin-Bicêtre, France hypertension, which was defined in great detail Since publication of their article, the authors report no furand required three criteria, not only a decrease ther potential conflict of interest. in the 6-minute walk distance. Our study was 1. Graf C, Battisti WP, Bridges D, et al. Research methods and approved by health authorities and ethics com- reporting: good publication practice for communicating committees. Background therapy for pulmonary ar- pany sponsored medical research: the GPP2 guidelines. BMJ terial hypertension, when available, was allowed, 2009;339:b4330. 2. AMWA position statement on the contribution of medical and we closely monitored patients for the need for writers to scientific publications. Rockville, MD: American additional treatment. In some countries, because Medical Writers Association (http://www.amwa.org). of the limited availability of approved targeted 3. Jacobs A, Wager E. European Medical Writers Association (EMWA) guidelines on the role of medical writers in developing therapies, a patient’s participation in a clinical peer-reviewed publications. Curr Med Res Opin 2005;21:317-22. trial may provide the only access to potential 4. Norris R, Bowman A, Fagan JM, et al. International Society treatment for pulmonary arterial hypertension. for Medical Publication Professionals (ISMPP) position statement: the role of the professional medical writer. Curr Med Res Tomás Pulido, M.D. Opin 2007;23:1837-40. Ignacio Chávez National Heart Institute Mexico City, Mexico
DOI: 10.1056/NEJMc1313112
Complement-Binding Anti-HLA Antibodies and Kidney Transplantation To the Editor: Loupy et al. (Sept. 26 issue)1 present data showing that the C1q-binding assay is more sensitive than the standard complementdependent microlymphocytotoxicity (CDL) assay for assessing the risk of graft loss. In their retrospective analysis of 1016 patients who had a negative CDL assay before transplantation, antibodymediated rejection developed in 7.4% during the first year. The authors predict that antibody-mediated rejection would have occurred in 3.7% of
patients (a 50% reduction) if the C1q-binding assay had been used. However, most laboratories use a more sensitive flow cytometric crossmatching (FCXM),2 not CDL alone. We have data from 11 patients who had low levels of donor-specific anti-HLA antibodies (mean fluorescence intensity [MFI],
matic venous thromboembolism. N Engl J Med 2010;363:2499510. 2. The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97.
3. Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban
versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013;11:21. 4. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799-808. DOI: 10.1056/NEJMc1313883
Macitentan and Pulmonary Arterial Hypertension To the Editor: Pulido et al. (Aug. 29 issue)1 report the results of the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN), an Actelion Pharmaceuticals–funded study of macitentan to treat pulmonary arterial hypertension. Although the article provides potentially good news for patients, the authors note that Actelion Pharmaceuticals conducted all the statistical analyses and hired a professional medical writer to assist. The acknowledgments thank these persons, thus meeting the standards of the International Committee of Medical Journal Editors.2 However, the blurred line between hired writing assistance and ghostwriting is unsettling. Disclosure is only beneficial when it provides enough information to evaluate the magnitude of risk for potential bias. We believe it is important to know who wrote the first draft of the manuscript and what exact role the paid writer had in drafting the article. History has warned us that studies completed and written entirely by entities who will benefit financially from the results warrant increased scrutiny.3,4 Disclosures that lack specificity make it impossible to understand the true risk of bias in the study. It is unclear how the authors can assert responsibility for the integrity of the data without further explanation of their roles and the roles of the persons who conducted all the analyses and assisted with the writing. Timothy S. Anderson, M.D. University of Pittsburgh Medical Center Pittsburgh, PA [email protected]
Chester B. Good, M.D., M.P.H. Walid F. Gellad, M.D., M.P.H. Veterans Affairs Pittsburgh Healthcare System Pittsburgh, PA No potential conflict of interest relevant to this letter was reported. 1. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and
morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809-18. 2. Drazen JM, Curfman GD. On authors and contributors. N Engl J Med 2002;347:55. 3. Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest authorship and ghostwriting in publications related to rofecoxib: a case study of industry documents from rofecoxib litigation. JAMA 2008;299:1800-12. 4. Blumenthal D, Campbell EG, Anderson MS, Causino N, Louis KS. Withholding research results in academic life science: evidence from a national survey of faculty. JAMA 1997;277: 1224-8. DOI: 10.1056/NEJMc1313112
To the Editor: Pulido et al. conclude that macitentan, a dual endothelin-receptor antagonist, reduced morbidity and mortality among patients with pulmonary arterial hypertension. The rate of death from any cause was not significantly different among the three groups; however, there was a suggestion that the rate of death due to pulmonary arterial hypertension was lower among patients who received 10 mg of macitentan once daily. We wonder how the independent clinical event committee adjudicated the cause of death, since we have recently reported on the difficulties of this determination.1 At the Cleveland Clinic, all deaths in patients with pulmonary arterial hypertension are reviewed within 7 days after the event by at least two physicians (including the treating physician) and a nurse. In our study, we noted that consensus was not achieved in a quarter of our patients, most commonly in those who died in the out-of-hospital setting or had clinically significant coexisting conditions. It would be very helpful and important to know how consensus about the cause of death was achieved in the study by Pulido et al. Adriano R. Tonelli, M.D. Raed A. Dweik, M.D. Cleveland Clinic Cleveland, OH [email protected] No potential conflict of interest relevant to this letter was reported.
n engl j med 370;1 nejm.org january 2, 2014
The New England Journal of Medicine Downloaded from nejm.org on November 3, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
81
The
n e w e ng l a n d j o u r na l
1. Tonelli AR, Arelli V, Minai OA, et al. Causes and circum-
stances of death in pulmonary arterial hypertension. Am J Respir Crit Care Med 2013;188:365-9.
of
m e dic i n e
tension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur Heart J 2010;31:2080-6. DOI: 10.1056/NEJMc1313112
DOI: 10.1056/NEJMc1313112
To the Editor: The results of the SERAPHIN trial raise several critical questions. First, although death was included as a component of the positive combined end point, the data suggest that the treatment effect on mortality in the two groups of patients who received macitentan was inconsistent (higher than placebo in the group that received 3 mg and similar to placebo in the group that received 10 mg). In addition, it is not clear how many deaths attributed to placebo at the end of the trial occurred in patients who were actually receiving open-label macitentan. Second, the claim of reduced morbidity coincides principally with a clinically insignificant (approximately 20-m) improvement in the 6-minute walk distance, which may not be a valid surrogate end point.1-3 Third, despite the fact that one of the authors has previously argued that pursuing long-term trials of agents against placebo in pulmonary arterial hypertension would be “unethical,” 4 the fact that these authors conducted this trial suggests an important change in beliefs. Is this change a reflection of uncertainty about the efficacy of therapies in pulmonary arterial hypertension? It seems so, because in this trial, some patients who were randomly assigned to placebo were receiving no background therapy. Alejandro Macchia, M.D. Fondazione Mario Negri Sud Santa Maria Imbaro, Italy [email protected]
Javier Mariani, M.D. Fundación Group de Estudio Sobre Investigación Clínica en Argentina Buenos Aires, Argentina
Gianni Tognoni, M.D. Fondazione Mario Negri Sud Santa Maria Imbaro, Italy No potential conflict of interest relevant to this letter was reported. 1. Savarese G, Paolillo S, Costanzo P, et al. Do changes of
6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol 2012;60:1192-201. 2. Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation 2012;126:349-56. 3. Macchia A, Marchioli R, Tognoni G, et al. Systematic review of trials using vasodilators in pulmonary arterial hypertension: why a new approach is needed. Am Heart J 2010;159:245-57. 4. Galiè N, Palazzini M, Manes A. Pulmonary arterial hyper-
82
The Authors Reply: Anderson et al. request clarification of the sponsor’s involvement in the data analysis in our study and in the manuscript preparation. Analyses were conducted by the sponsor according to a prespecified plan, and these analyses were reviewed by two independent statisticians and an external statistician who consulted at the request of the Journal. Medical writers assisted with the initial outline and first draft of the manuscript that was written jointly by the first and last authors; this complied with international guidelines for good publication practice.1-4 All authors contributed to subsequent versions and approved the final version of the manuscript. We maintain responsibility for the full content of the article. We agree with Tonelli and Dweik that the attribution of death in pulmonary arterial hypertension is challenging. The independent clinical event committee in our study consisted of three experts in pulmonary arterial hypertension who were unaware of the study-drug assignments; had full access to case-report and serious-adverseevent forms, hospital-discharge summaries, death certificates, and other supporting documents; and individually adjudicated whether death was related to pulmonary arterial hypertension. In cases of disparity, consensus had to be reached. Macchia et al. suggest an inconsistency between the two doses in the effect of macitentan on mortality. In interpreting the primary endpoint results, one must note that the end point was the time to the first occurrence of an event related to pulmonary arterial hypertension or death from any cause. In pulmonary arterial hypertension, death as a first event is uncommon and usually is preceded by disease worsening. It is also important to observe not only the number of deaths per group, but also the hazard ratio that takes into account the time to death; these results show no difference between placebo and macitentan at a dose of 3 mg, whereas there is a trend toward a reduction in mortality with macitentan at a dose of 10 mg versus placebo. With respect to death up to the end of the study, patients who were initially randomly assigned to placebo may have received open-label macitentan after a nonfatal event; this introduced a bias in favor of placebo.
n engl j med 370;1 nejm.org january 2, 2014
The New England Journal of Medicine Downloaded from nejm.org on November 3, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
As Macchia and colleagues highlight, our data Lewis J. Rubin, M.D. show that the change in 6-minute walk distance University of California, San Diego was not associated with long-term outcomes in La Jolla, CA pulmonary arterial hypertension. The observed Gérald Simonneau, M.D. reduction in morbidity was driven by a decrease Université Paris-Sud in the rate of worsening of pulmonary arterial Le Kremlin-Bicêtre, France hypertension, which was defined in great detail Since publication of their article, the authors report no furand required three criteria, not only a decrease ther potential conflict of interest. in the 6-minute walk distance. Our study was 1. Graf C, Battisti WP, Bridges D, et al. Research methods and approved by health authorities and ethics com- reporting: good publication practice for communicating committees. Background therapy for pulmonary ar- pany sponsored medical research: the GPP2 guidelines. BMJ terial hypertension, when available, was allowed, 2009;339:b4330. 2. AMWA position statement on the contribution of medical and we closely monitored patients for the need for writers to scientific publications. Rockville, MD: American additional treatment. In some countries, because Medical Writers Association (http://www.amwa.org). of the limited availability of approved targeted 3. Jacobs A, Wager E. European Medical Writers Association (EMWA) guidelines on the role of medical writers in developing therapies, a patient’s participation in a clinical peer-reviewed publications. Curr Med Res Opin 2005;21:317-22. trial may provide the only access to potential 4. Norris R, Bowman A, Fagan JM, et al. International Society treatment for pulmonary arterial hypertension. for Medical Publication Professionals (ISMPP) position statement: the role of the professional medical writer. Curr Med Res Tomás Pulido, M.D. Opin 2007;23:1837-40. Ignacio Chávez National Heart Institute Mexico City, Mexico
DOI: 10.1056/NEJMc1313112
Complement-Binding Anti-HLA Antibodies and Kidney Transplantation To the Editor: Loupy et al. (Sept. 26 issue)1 present data showing that the C1q-binding assay is more sensitive than the standard complementdependent microlymphocytotoxicity (CDL) assay for assessing the risk of graft loss. In their retrospective analysis of 1016 patients who had a negative CDL assay before transplantation, antibodymediated rejection developed in 7.4% during the first year. The authors predict that antibody-mediated rejection would have occurred in 3.7% of
patients (a 50% reduction) if the C1q-binding assay had been used. However, most laboratories use a more sensitive flow cytometric crossmatching (FCXM),2 not CDL alone. We have data from 11 patients who had low levels of donor-specific anti-HLA antibodies (mean fluorescence intensity [MFI],
