Letters
The lack of significant change in most adverse events may reflect the low baseline rate of such occurrences, making it harder to detect temporal change. This study is the first, to our knowledge, to quantify US ART-associated patient risks. A 1984-2008 report from the Netherlands found a higher ART-related maternal death rate (42.5/100 000 pregnancies) compared with our study (peak of 14.2/100 000 pregnancies).5 Underreporting of complications remains an inherent limitation of surveillance systems 6 and must be considered when interpreting our findings. Additionally, our outcomes are cycle-based rather than patient-based, validation does not include complication variables, and available data do not explain the noted trends. Increased awareness of the most common complication, OHSS, may prompt additional study to characterize predictors of this and other adverse events to inform the development of effective approaches necessary to decrease complication occurrence. Jennifer F. Kawwass, MD Dmitry M. Kissin, MD, MPH Aniket D. Kulkarni, MBBS, MPH Andreea A. Creanga, MD, PhD Donna R. Session, MD William M. Callaghan, MD, MPH Denise J. Jamieson, MD, MPH for the National ART Surveillance System (NASS) Group Author Affiliations: Division of Reproductive Endocrinology and Infertility, Emory University School of Medicine, Atlanta, Georgia (Kawwass, Session); Division of Reproductive Health, US Centers for Disease Control and Prevention, Atlanta, Georgia (Kissin, Kulkarni, Creanga, Callaghan, Jamieson). Corresponding Author: Jennifer F. Kawwass, MD, 550 Peachtree St, Atlanta, GA 30308 ([email protected]). Author Contributions: Dr Kawwass had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kawwass, Kissin, Kulkarni, Session, Callaghan, Jamieson. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Kawwass, Creanga, Callaghan, Jamieson. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Kulkarni, Creanga. Administrative, technical, or material support: Kissin, Creanga. Study supervision: Kissin, Session, Jamieson. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Group Information: The NASS Group is composed of the following additional members (all with the Division of Reproductive Health, US Centers for Disease Control and Prevention [CDC]) who contributed to the data collection but received no financial compensation: Sheree Boulet, DrPH, MPH, Jeani Chang, MPH, Sara Crawford, PhD, Allison Mneimneh, MPH, CPM, Mithi Sunderam, PhD, and Yujia Zhang, PhD. Pedro Moro, MD, MPH (Division of Healthcare Quality Promotion, CDC), participated in the critical revision of the manuscript but did not receive any financial compensation.
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2. de Ziegler D, Gambone JC, Meldrum DR, Chapron C. Risk and safety management in infertility and assisted reproductive technology (ART): from the doctor’s office to the ART procedure. Fertil Steril. 2013;100(6):1509-1517. 3. Adashi EY, Wyden R. Public reporting of clinical outcomes of assisted reproductive technology programs: implications for other medical and surgical procedures. JAMA. 2011;306(10):1135-1136. 4. Centers for Disease Control and Prevention; Society for Assisted Reproductive Technology. 2010 Assisted Reproductive Technology Fertility Clinic Success Rates Report. Atlanta, GA: US Dept of Health and Human Services; 2012. 5. Braat DDM, Schutte JM, Bernardus RE, Mooij TM, van Leeuwen FE. Maternal death related to IVF in the Netherlands 1984-2008. Hum Reprod. 2010;25(7): 1782-1786. 6. Schoendorf KC, Branum AM. The use of United States vital statistics in perinatal and obstetric research. Am J Obstet Gynecol. 2006;194(4):911-915.
COMMENT & RESPONSE
Management of Patients With Sickle Cell Disease To the Editor The Special Communication reporting a summary of the National Heart, Lung, and Blood Institute expert panel report on the management of patients with sickle cell disease (SCD)1 distilled best practice recommendations from the extensive sickle cell anemia literature. However, the recommendation that chelation therapy should be standard for patients with SCD and iron overload failed to consider an important aspect of the problem. The value of iron unloading with chelating agents in children with thalassemia is unquestioned. The expert panel suggested that this should be extrapolated to the management of patients with SCD and iron overload. But in thalassemia, unlike SCD, hepcidin production ranges from undetectable to diminished. 2 Recent animal experiments have demonstrated that in the absence of hepcidin, (1) iron entering the liver is incorporated into lysosomes, (2) the lysosomes are damaged and release proteases, and (3) nonferritinbound iron in the lysosomes supports the production of free radicals.3 The pathophysiology of liver disease in human patients with thalassemia may be similar; however, it may not be for patients with SCD. Considering these differences, and without evidence that treating iron overload improves morbidity or mortality in patients with SCD, chelation treatment with deferasirox (outside of a controlled study) seems questionable. Deferasirox can be hepatotoxic, nephrotoxic, and sometimes lethal.4 The cost of the intervention also must be considered; chelation can cost up to $40 000 per year. Simeon Pollack, MD Author Affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York. Corresponding Author: Simeon Pollack, MD, Department of Medicine, Albert Einstein College of Medicine, 5 Wooddale Ave, Croton on Hudson, NY 10520 ([email protected]).
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
1. Wang J, Sauer MV. In vitro fertilization (IVF): a review of 3 decades of clinical innovation and technological advancement. Ther Clin Risk Manag. 2006;2(4): 355-364.
1. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048.
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2. Porter J, Garbowski,M. Consequences and management of iron overload in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2013;2013:447456. 3. Lunova M, Goehring C, Kuscuoglu D, et al. Hepcidin knockout mice fed with iron-rich diet develop chronic liver injury and liver fibrosis due to lysosomal iron overload. J Hepatol. 2014;61(3):633-641. 4. Kontoghiorghes GJ. A record number of fatalities in many categories of patients treated with deferasirox: loopholes in regulatory and marketing procedures undermine patient safety and misguide public funds? Expert Opin Drug Saf. 2013;12(5):605-609.
To the Editor As members of the guideline committee sponsored by the American Thoracic Society on the diagnosis and treatment of pulmonary hypertension in patients with SCD,1 we would like to emphasize several important differences between our guidelines and the pulmonary hypertension recommendations made by Dr Yawn and colleagues.2 We concur that an echocardiogram is an essential part of the evaluation of patients with SCD and unexplained dyspnea and that right heart catheterization is required for diagnosis of pulmonary hypertension. However, the prevalence of pulmonary hypertension defined by right heart catheterization in SCD (10%) is comparable with other disorders such as systemic sclerosis, in which the accepted standard of care is to screen for pulmonary hypertension by echocardiography.3 Patients with an elevated tricuspid regurgitant jet velocity are often asymptomatic and pulmonary hypertension may be advanced by the time that dyspnea is recognized by clinicians,4 supporting the use of echocardiography screening for both mortality risk assessment and early diagnosis of pulmonary hypertension in patients with SCD.5 It remains unproven whether screening of asymptomatic patients changes outcomes, but it is well documented that echocardiography identifies a group of high-risk patients with SCD who may have treatable contributory factors such as chronic thromboembolism, sleep-disordered breathing, or exercise and nocturnal hypoxemia.1 Furthermore, stratification of high-risk patients with echocardiography, elevated levels of plasma N-terminal brain natriuretic peptide, or pulmonary hypertension defined by right heart catheterization could identify a group of patients whose SCD treatment could be intensified using proven effective therapies such as hydroxyurea or chronic transfusion. It was the consensus of the American Thoracic Society expert committee that an intensive clinical evaluation of high tricuspid regurgitant jet velocity is indicated in patients with SCD aged 18 years or older due to the documented risk of high mortality. Screening echocardiography prior to age 18 years may be considered; however, there is no consensus for routine use of echocardiography in asymptomatic children and adolescents. Although the risk of pulmonary arterial hypertension is mentioned in the guideline document by Yawn et al,2 pulmonary venous hypertension is also prevalent in patients with SCD and associated with increased mortality, particularly in those with high transpulmonary pressure gradients. There is a strong need for additional large-scale clinical trials of SCD on which treatment recommendations can be based.
Elizabeth S. Klings, MD Gregory J. Kato, MD Mark T. Gladwin, MD Author Affiliations: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts (Klings); Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (Kato); Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Gladwin). Corresponding Author: Elizabeth S. Klings, MD, Pulmonary Center, Department of Medicine, Boston University School of Medicine, 72 E Concord St, Boston, MA 02118 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Klings reported being a consultant on an acute chest syndrome adjudication committee for a clinical trial for Pfizer. Dr Gladwin reported receiving grants from the National Heart, Lung, and Blood Institute, the Department of Defense, Gilead Sciences, and Bayer Corp; receiving personal fees from Bayer Corp; having funding agreements with the University of Pittsburgh from ITxM and HCWP; receiving royalties from a patent for nitrite salts for cardiovascular indications; and receiving royalties from a textbook for medical students from Medmaster Publishing. No other disclosures were reported. Additional Information: All 3 of the authors were members of the clinical guideline committee sponsored by the American Thoracic Society on the diagnosis and treatment of pulmonary hypertension in patients with sickle cell disease. 1. Klings ES, Machado RF, Barst RJ, et al; American Thoracic Society Ad Hoc Committee on Pulmonary Hypertension of Sickle Cell Disease. An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med. 2014;189(6):727-740. 2. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048. 3. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25)(suppl):D42-D50. 4. Klings ES, Anton Bland D, Rosenman D, et al. Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression. Am J Hematol. 2008;83(7):547-553. 5. Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA. 2012;307(12):12541256.
In Reply Dr Pollack is concerned about the lack of evidence for deferasirox therapy in people with SCD and iron overload, as well as potential adverse effects and high costs. He refers to recent advances in the understanding of hepatic pathophysiology in handling iron and comments that this may apply to people with thalassemia, correctly pointing out that it is not clear if those data also apply to patients with SCD.1 In patients with SCD, it is the hepatic consequences of transfusion-related iron overload that are of greatest concern.2,3 Transfusion therapy represents a highly effective diseasemodifying treatment for many patients, but without chelation therapy it can result in hepatic fibrosis within 2 years of transfusion initiation.2 The panel’s moderate strength recommendation was based on direct evidence of harm from iron overload and indirect evidence of benefit with chelation therapy. We agree that further prospective studies of the epidemiology of iron overload in patients with SCD as well as the ben-
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efits and risks of chelation therapy in this patient population are necessary. But like Porter and Garbowski,1 the panel was concerned that the evidence from randomized trials of chelation therapy in patients with SCD receiving transfusion therapy may require up to 2 decades to test end points such as death or hepatic cirrhosis. It is not clear that such randomization would even be considered feasible or ethical. Based on this information, the panel chose to make a moderate strength recommendation to consider chelation therapy in patients with SCD and signs of iron overload. Dr Klings and colleagues address the serious problem of pulmonary hypertension in patients with SCD. Even though our guidelines differ from those of the American Thoracic Society for screening asymptomatic patients with SCD for pulmonary hypertension, we strongly support their recommendation for the conduct of prospective outcome studies of tricuspid regurgitant jet velocity screening accompanied by evaluation of pharmacological intervention in patients in whom cardiac catheterization confirms a diagnosis of pulmonary arterial hypertension or pulmonary venous hypertension.4 We do agree that no evidence exists to demonstrate that the screening of asymptomatic patients changes outcomes. We hope that continued consideration will also be given to quantifying the currently unknown number of asymptomatic individuals with treatable contributory factors as well as further clarification of the benefits and harms of screening to allow risk stratification. We agree with Klings and colleagues that there is continued underuse of SCD-specific therapies. One of the primary goals of our guideline sponsored by the National Heart, Lung, and Blood Institute was to enhance the availability of hydroxyurea and transfusion therapy for all SCD treatment candidates, in agreement with Klings et al. Barbara P. Yawn, MD, MSc, MSPH George Buchanan, MD Kathryn Hassell, MD Author Affiliations: Department of Research and Education, Olmsted Medical Center, Rochester, Minnesota (Yawn); University of Texas Southwestern Medical Center, Dallas (Buchanan); University of Colorado, Denver (Hassell). Corresponding Author: Barbara P. Yawn, MD, MSc, MSPH, Department of Research and Education, Olmsted Medical Center, 210 Ninth St SE, Rochester, MN 55904 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hassell reported receiving individual payment for serving on advisory boards for Pfizer, ApoPharma, the Foundation for Women and Girls with Blood Disorders, and PFO Research Foundation; receiving consultant fees from AGA Medical Corp; receiving individual and institutional grant support from Terumo, GlycoMimetics, and Emmaus; and serving on the board of directors for Mount Evans Home Health & Hospice. No other disclosures were reported. 1. Porter J, Garbowski M. Consequences and management of iron overload in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2013;2013:447456. 2. Olivieri NF. Progression of iron overload in sickle cell disease. Semin Hematol. 2001;38(1)(suppl 1):57-62. 92
3. Brown K, Subramony C, May W, et al. Hepatic iron overload in children with sickle cell anemia on chronic transfusion therapy. J Pediatr Hematol Oncol. 2009;31(5):309-312. 4. Klings ES, Machado RF, Barst RJ, et al; American Thoracic Society Ad Hoc Committee on Pulmonary Hypertension of Sickle Cell Disease. An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med. 2014;189(6):727-740.
Reanalyses of Trial Results To the Editor We agree with Dr Ebrahim and colleagues1 that reanalyses of clinical trial data provide an important opportunity to better understand trial results and that more independent reanalyses are needed. However, the estimate of the number of reanalyses published prior to March 9, 2014, reported by Ebrahim et al1 is incorrect, possibly by a substantial margin. Ebrahim et al1 reported that their MEDLINE search identified 37 reanalyses of data from previously published randomized clinical trials. However, the authors limited their search to manuscripts categorized as a clinical trial in MEDLINE. This is problematic because many reanalyses are given the more general classification of journal article and so are not identified in searches restricted to clinical trial articles. Examples of this can be found among the reanalyses of the data from the trial of tissue plasminogen activator for ischemic stroke sponsored by the National Institute of Neurological Disorders and Stroke (NINDS). The original analysis was published in 1995.2 A recent Cochrane review3 identified at least 7 reanalyses of the data from the NINDS trial. Each of these reanalyses meets the criteria defined by Ebrahim et al1; however, none was identified using their search method. Five of these reanalyses are not classified within MEDLINE as clinical trials. The same problem may be true of other reanalyses. As noted by IBM Quality Manager H. James Harrington, “measurement is the first step that leads to control and eventually improvement.”4 Obtaining an accurate measure of the number of reanalyses being published and defining a search method that can consistently generate this number is essential to assess whether new policies (such as those called for by Krumholz and Peterson5) result in the increase in reanalyses needed to optimize understanding of trial results. A search unrestricted by publication type should provide a more accurate measure of the number of reanalyses but adds considerably to the workload of the search. Steps to improve the consistency of classification of articles by publication type within MEDLINE may provide a long-term solution to this challenge. Timothy F. Platts-Mills, MD, MSc Christopher W. Jones, MD Author Affiliations: Department of Emergency Medicine, University of North Carolina, Chapel Hill (Platts-Mills); Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, New Jersey (Jones). Corresponding Author: Timothy F. Platts-Mills, MD, MSc, Department of Emergency Medicine, University of North Carolina, 170 Manning Dr, Chapel Hill, NC 27599 ([email protected]).
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The lack of significant change in most adverse events may reflect the low baseline rate of such occurrences, making it harder to detect temporal change. This study is the first, to our knowledge, to quantify US ART-associated patient risks. A 1984-2008 report from the Netherlands found a higher ART-related maternal death rate (42.5/100 000 pregnancies) compared with our study (peak of 14.2/100 000 pregnancies).5 Underreporting of complications remains an inherent limitation of surveillance systems 6 and must be considered when interpreting our findings. Additionally, our outcomes are cycle-based rather than patient-based, validation does not include complication variables, and available data do not explain the noted trends. Increased awareness of the most common complication, OHSS, may prompt additional study to characterize predictors of this and other adverse events to inform the development of effective approaches necessary to decrease complication occurrence. Jennifer F. Kawwass, MD Dmitry M. Kissin, MD, MPH Aniket D. Kulkarni, MBBS, MPH Andreea A. Creanga, MD, PhD Donna R. Session, MD William M. Callaghan, MD, MPH Denise J. Jamieson, MD, MPH for the National ART Surveillance System (NASS) Group Author Affiliations: Division of Reproductive Endocrinology and Infertility, Emory University School of Medicine, Atlanta, Georgia (Kawwass, Session); Division of Reproductive Health, US Centers for Disease Control and Prevention, Atlanta, Georgia (Kissin, Kulkarni, Creanga, Callaghan, Jamieson). Corresponding Author: Jennifer F. Kawwass, MD, 550 Peachtree St, Atlanta, GA 30308 ([email protected]). Author Contributions: Dr Kawwass had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kawwass, Kissin, Kulkarni, Session, Callaghan, Jamieson. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Kawwass, Creanga, Callaghan, Jamieson. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Kulkarni, Creanga. Administrative, technical, or material support: Kissin, Creanga. Study supervision: Kissin, Session, Jamieson. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Group Information: The NASS Group is composed of the following additional members (all with the Division of Reproductive Health, US Centers for Disease Control and Prevention [CDC]) who contributed to the data collection but received no financial compensation: Sheree Boulet, DrPH, MPH, Jeani Chang, MPH, Sara Crawford, PhD, Allison Mneimneh, MPH, CPM, Mithi Sunderam, PhD, and Yujia Zhang, PhD. Pedro Moro, MD, MPH (Division of Healthcare Quality Promotion, CDC), participated in the critical revision of the manuscript but did not receive any financial compensation.
90
2. de Ziegler D, Gambone JC, Meldrum DR, Chapron C. Risk and safety management in infertility and assisted reproductive technology (ART): from the doctor’s office to the ART procedure. Fertil Steril. 2013;100(6):1509-1517. 3. Adashi EY, Wyden R. Public reporting of clinical outcomes of assisted reproductive technology programs: implications for other medical and surgical procedures. JAMA. 2011;306(10):1135-1136. 4. Centers for Disease Control and Prevention; Society for Assisted Reproductive Technology. 2010 Assisted Reproductive Technology Fertility Clinic Success Rates Report. Atlanta, GA: US Dept of Health and Human Services; 2012. 5. Braat DDM, Schutte JM, Bernardus RE, Mooij TM, van Leeuwen FE. Maternal death related to IVF in the Netherlands 1984-2008. Hum Reprod. 2010;25(7): 1782-1786. 6. Schoendorf KC, Branum AM. The use of United States vital statistics in perinatal and obstetric research. Am J Obstet Gynecol. 2006;194(4):911-915.
COMMENT & RESPONSE
Management of Patients With Sickle Cell Disease To the Editor The Special Communication reporting a summary of the National Heart, Lung, and Blood Institute expert panel report on the management of patients with sickle cell disease (SCD)1 distilled best practice recommendations from the extensive sickle cell anemia literature. However, the recommendation that chelation therapy should be standard for patients with SCD and iron overload failed to consider an important aspect of the problem. The value of iron unloading with chelating agents in children with thalassemia is unquestioned. The expert panel suggested that this should be extrapolated to the management of patients with SCD and iron overload. But in thalassemia, unlike SCD, hepcidin production ranges from undetectable to diminished. 2 Recent animal experiments have demonstrated that in the absence of hepcidin, (1) iron entering the liver is incorporated into lysosomes, (2) the lysosomes are damaged and release proteases, and (3) nonferritinbound iron in the lysosomes supports the production of free radicals.3 The pathophysiology of liver disease in human patients with thalassemia may be similar; however, it may not be for patients with SCD. Considering these differences, and without evidence that treating iron overload improves morbidity or mortality in patients with SCD, chelation treatment with deferasirox (outside of a controlled study) seems questionable. Deferasirox can be hepatotoxic, nephrotoxic, and sometimes lethal.4 The cost of the intervention also must be considered; chelation can cost up to $40 000 per year. Simeon Pollack, MD Author Affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York. Corresponding Author: Simeon Pollack, MD, Department of Medicine, Albert Einstein College of Medicine, 5 Wooddale Ave, Croton on Hudson, NY 10520 ([email protected]).
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
1. Wang J, Sauer MV. In vitro fertilization (IVF): a review of 3 decades of clinical innovation and technological advancement. Ther Clin Risk Manag. 2006;2(4): 355-364.
1. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048.
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2. Porter J, Garbowski,M. Consequences and management of iron overload in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2013;2013:447456. 3. Lunova M, Goehring C, Kuscuoglu D, et al. Hepcidin knockout mice fed with iron-rich diet develop chronic liver injury and liver fibrosis due to lysosomal iron overload. J Hepatol. 2014;61(3):633-641. 4. Kontoghiorghes GJ. A record number of fatalities in many categories of patients treated with deferasirox: loopholes in regulatory and marketing procedures undermine patient safety and misguide public funds? Expert Opin Drug Saf. 2013;12(5):605-609.
To the Editor As members of the guideline committee sponsored by the American Thoracic Society on the diagnosis and treatment of pulmonary hypertension in patients with SCD,1 we would like to emphasize several important differences between our guidelines and the pulmonary hypertension recommendations made by Dr Yawn and colleagues.2 We concur that an echocardiogram is an essential part of the evaluation of patients with SCD and unexplained dyspnea and that right heart catheterization is required for diagnosis of pulmonary hypertension. However, the prevalence of pulmonary hypertension defined by right heart catheterization in SCD (10%) is comparable with other disorders such as systemic sclerosis, in which the accepted standard of care is to screen for pulmonary hypertension by echocardiography.3 Patients with an elevated tricuspid regurgitant jet velocity are often asymptomatic and pulmonary hypertension may be advanced by the time that dyspnea is recognized by clinicians,4 supporting the use of echocardiography screening for both mortality risk assessment and early diagnosis of pulmonary hypertension in patients with SCD.5 It remains unproven whether screening of asymptomatic patients changes outcomes, but it is well documented that echocardiography identifies a group of high-risk patients with SCD who may have treatable contributory factors such as chronic thromboembolism, sleep-disordered breathing, or exercise and nocturnal hypoxemia.1 Furthermore, stratification of high-risk patients with echocardiography, elevated levels of plasma N-terminal brain natriuretic peptide, or pulmonary hypertension defined by right heart catheterization could identify a group of patients whose SCD treatment could be intensified using proven effective therapies such as hydroxyurea or chronic transfusion. It was the consensus of the American Thoracic Society expert committee that an intensive clinical evaluation of high tricuspid regurgitant jet velocity is indicated in patients with SCD aged 18 years or older due to the documented risk of high mortality. Screening echocardiography prior to age 18 years may be considered; however, there is no consensus for routine use of echocardiography in asymptomatic children and adolescents. Although the risk of pulmonary arterial hypertension is mentioned in the guideline document by Yawn et al,2 pulmonary venous hypertension is also prevalent in patients with SCD and associated with increased mortality, particularly in those with high transpulmonary pressure gradients. There is a strong need for additional large-scale clinical trials of SCD on which treatment recommendations can be based.
Elizabeth S. Klings, MD Gregory J. Kato, MD Mark T. Gladwin, MD Author Affiliations: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts (Klings); Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (Kato); Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Gladwin). Corresponding Author: Elizabeth S. Klings, MD, Pulmonary Center, Department of Medicine, Boston University School of Medicine, 72 E Concord St, Boston, MA 02118 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Klings reported being a consultant on an acute chest syndrome adjudication committee for a clinical trial for Pfizer. Dr Gladwin reported receiving grants from the National Heart, Lung, and Blood Institute, the Department of Defense, Gilead Sciences, and Bayer Corp; receiving personal fees from Bayer Corp; having funding agreements with the University of Pittsburgh from ITxM and HCWP; receiving royalties from a patent for nitrite salts for cardiovascular indications; and receiving royalties from a textbook for medical students from Medmaster Publishing. No other disclosures were reported. Additional Information: All 3 of the authors were members of the clinical guideline committee sponsored by the American Thoracic Society on the diagnosis and treatment of pulmonary hypertension in patients with sickle cell disease. 1. Klings ES, Machado RF, Barst RJ, et al; American Thoracic Society Ad Hoc Committee on Pulmonary Hypertension of Sickle Cell Disease. An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med. 2014;189(6):727-740. 2. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048. 3. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25)(suppl):D42-D50. 4. Klings ES, Anton Bland D, Rosenman D, et al. Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression. Am J Hematol. 2008;83(7):547-553. 5. Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA. 2012;307(12):12541256.
In Reply Dr Pollack is concerned about the lack of evidence for deferasirox therapy in people with SCD and iron overload, as well as potential adverse effects and high costs. He refers to recent advances in the understanding of hepatic pathophysiology in handling iron and comments that this may apply to people with thalassemia, correctly pointing out that it is not clear if those data also apply to patients with SCD.1 In patients with SCD, it is the hepatic consequences of transfusion-related iron overload that are of greatest concern.2,3 Transfusion therapy represents a highly effective diseasemodifying treatment for many patients, but without chelation therapy it can result in hepatic fibrosis within 2 years of transfusion initiation.2 The panel’s moderate strength recommendation was based on direct evidence of harm from iron overload and indirect evidence of benefit with chelation therapy. We agree that further prospective studies of the epidemiology of iron overload in patients with SCD as well as the ben-
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Letters
efits and risks of chelation therapy in this patient population are necessary. But like Porter and Garbowski,1 the panel was concerned that the evidence from randomized trials of chelation therapy in patients with SCD receiving transfusion therapy may require up to 2 decades to test end points such as death or hepatic cirrhosis. It is not clear that such randomization would even be considered feasible or ethical. Based on this information, the panel chose to make a moderate strength recommendation to consider chelation therapy in patients with SCD and signs of iron overload. Dr Klings and colleagues address the serious problem of pulmonary hypertension in patients with SCD. Even though our guidelines differ from those of the American Thoracic Society for screening asymptomatic patients with SCD for pulmonary hypertension, we strongly support their recommendation for the conduct of prospective outcome studies of tricuspid regurgitant jet velocity screening accompanied by evaluation of pharmacological intervention in patients in whom cardiac catheterization confirms a diagnosis of pulmonary arterial hypertension or pulmonary venous hypertension.4 We do agree that no evidence exists to demonstrate that the screening of asymptomatic patients changes outcomes. We hope that continued consideration will also be given to quantifying the currently unknown number of asymptomatic individuals with treatable contributory factors as well as further clarification of the benefits and harms of screening to allow risk stratification. We agree with Klings and colleagues that there is continued underuse of SCD-specific therapies. One of the primary goals of our guideline sponsored by the National Heart, Lung, and Blood Institute was to enhance the availability of hydroxyurea and transfusion therapy for all SCD treatment candidates, in agreement with Klings et al. Barbara P. Yawn, MD, MSc, MSPH George Buchanan, MD Kathryn Hassell, MD Author Affiliations: Department of Research and Education, Olmsted Medical Center, Rochester, Minnesota (Yawn); University of Texas Southwestern Medical Center, Dallas (Buchanan); University of Colorado, Denver (Hassell). Corresponding Author: Barbara P. Yawn, MD, MSc, MSPH, Department of Research and Education, Olmsted Medical Center, 210 Ninth St SE, Rochester, MN 55904 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hassell reported receiving individual payment for serving on advisory boards for Pfizer, ApoPharma, the Foundation for Women and Girls with Blood Disorders, and PFO Research Foundation; receiving consultant fees from AGA Medical Corp; receiving individual and institutional grant support from Terumo, GlycoMimetics, and Emmaus; and serving on the board of directors for Mount Evans Home Health & Hospice. No other disclosures were reported. 1. Porter J, Garbowski M. Consequences and management of iron overload in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2013;2013:447456. 2. Olivieri NF. Progression of iron overload in sickle cell disease. Semin Hematol. 2001;38(1)(suppl 1):57-62. 92
3. Brown K, Subramony C, May W, et al. Hepatic iron overload in children with sickle cell anemia on chronic transfusion therapy. J Pediatr Hematol Oncol. 2009;31(5):309-312. 4. Klings ES, Machado RF, Barst RJ, et al; American Thoracic Society Ad Hoc Committee on Pulmonary Hypertension of Sickle Cell Disease. An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med. 2014;189(6):727-740.
Reanalyses of Trial Results To the Editor We agree with Dr Ebrahim and colleagues1 that reanalyses of clinical trial data provide an important opportunity to better understand trial results and that more independent reanalyses are needed. However, the estimate of the number of reanalyses published prior to March 9, 2014, reported by Ebrahim et al1 is incorrect, possibly by a substantial margin. Ebrahim et al1 reported that their MEDLINE search identified 37 reanalyses of data from previously published randomized clinical trials. However, the authors limited their search to manuscripts categorized as a clinical trial in MEDLINE. This is problematic because many reanalyses are given the more general classification of journal article and so are not identified in searches restricted to clinical trial articles. Examples of this can be found among the reanalyses of the data from the trial of tissue plasminogen activator for ischemic stroke sponsored by the National Institute of Neurological Disorders and Stroke (NINDS). The original analysis was published in 1995.2 A recent Cochrane review3 identified at least 7 reanalyses of the data from the NINDS trial. Each of these reanalyses meets the criteria defined by Ebrahim et al1; however, none was identified using their search method. Five of these reanalyses are not classified within MEDLINE as clinical trials. The same problem may be true of other reanalyses. As noted by IBM Quality Manager H. James Harrington, “measurement is the first step that leads to control and eventually improvement.”4 Obtaining an accurate measure of the number of reanalyses being published and defining a search method that can consistently generate this number is essential to assess whether new policies (such as those called for by Krumholz and Peterson5) result in the increase in reanalyses needed to optimize understanding of trial results. A search unrestricted by publication type should provide a more accurate measure of the number of reanalyses but adds considerably to the workload of the search. Steps to improve the consistency of classification of articles by publication type within MEDLINE may provide a long-term solution to this challenge. Timothy F. Platts-Mills, MD, MSc Christopher W. Jones, MD Author Affiliations: Department of Emergency Medicine, University of North Carolina, Chapel Hill (Platts-Mills); Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, New Jersey (Jones). Corresponding Author: Timothy F. Platts-Mills, MD, MSc, Department of Emergency Medicine, University of North Carolina, 170 Manning Dr, Chapel Hill, NC 27599 ([email protected]).
JAMA January 6, 2015 Volume 313, Number 1
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