Reply: Practice Guideline for Pulmonary Hypertension in Sickle Cell: Direct Evidence Needed before Universal Adoption
Authors: Elizabeth S. Klings, Roberto F. Machado, Claudia R. Morris, Victor R. Gordeuk, Gregory J. Kato, Kenneth I. Ataga, Oswaldo Castro, Lewis Hsu, Marilyn J. Telen, Lakshmanan Krishnamurti, Martin H. Steinberg, Mark T. Gladwin
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Committee placed on concern for early mortality predicted by these parameters.These recommendations are problematic for several reasons:1.No guidance is given regarding the indication for or timing of screening echocardiography to assess mortality risk.2. There is no direct evidence that disease-modifying therapies have an effect on mortality for those with elevated TRV or NT-proBNP, or proven PH. 3.Although an elevated TRV may be found in 10 to 20% of children, the cited evidence suggests increased morbidity, not mortality, among children 8 years of age or older.Yet, the Guideline calls for initiating disease-modifying therapy without age limitation, even though mortality in children with elevated TRV has not been demonstrated.This seems inconsistent with the Committee's justification of intervention, despite potential harms, based on reduction in early mortality.4. The majority of evidence reviewed by the Committee includes individuals with HbSS/Sb 0 thalassemia; little information is provided or available for HbSC/Sb 1 thalassemia.The term "SCD" is used throughout the paper without distinguishing among sickle genotypes.Approximately 40% of the z90,000 individuals in the U.S. sickle cell population (2) have these milder forms of sickle cell disease with less sickling, anemia, and hemolysis, for which hydroxyurea therapy is not currently recommended, given a paucity of evidence demonstrating benefits.The authors note 10 to 25% of these individuals may have a TRV greater than 2.5 m/s, representing up to 9,000 individuals.Although listed as a "weak" recommendation, implementation of the Guideline calls for initiation of lifelong transfusion therapy for these patients.Chronic exchange transfusion will be required because baseline hemoglobin values are too high to permit simple transfusion, which results in a three-to fourfold increase in the amount of blood required (3) and attendant risks of alloimmunization and complications of indwelling lines typically required for indefinite transfusion therapy.There may also be significant adverse impact on school and/or work attendance.Importantly, the risk of early mortality in these individuals is not clear, calling into question the justification for and benefits of this costly intervention.5.The Guideline recommends initiation of lifelong diseasemodifying therapy solely for NT-proBNP greater than or equal to 160 pg/ml.Unlike the discussion providing context for TRV determination, no guidance is given about how or when to measure NT-proBNP.Transient acute elevation in TRV described in the paper could be associated with a similarly transient elevation in NT-proBNP, which is also affected by renal insufficiency.There are no data regarding impact on mortality risk of NT-proBNP values determined in these settings, but per the Guideline they could be used to justify initiation of hydroxyurea or chronic transfusion.Furthermore, the evidence cited is for patients with HbSS/Sb thalassemia, not HbSC disease.The concerns raised by the Guideline emphasize the need for research into causes of death associated with elevated TRV or NT-proBNP.Clinical trials are necessary to demonstrate benefits outweigh risks before recommending universal application of disease-modifying therapies based on these findings and for those with catheterization-proven PH.