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Noninvasive echocardiographic markers of pulmonary artery pressure have been associated with early mortality in some studies in adults with sickle cell disease (SCD),1,2 but considerable controversy remains regarding the prevalence of pulmonary hypertension and its contribution to mortality.3 We assessed survival in a cohort of patients with SCD with pulmonary hypertension documented by right heart catheterization (RHC).
Patients provided written informed consent to protocols approved by the institutional review board at the National Institutes of Health. All adults with stable SCD seen consecutively in the outpatient clinic at the National Institutes of Health were screened with no exclusion criterion applied. Those who underwent RHC between March 13, 2002, and June 8, 2010, with elevated tricuspid regurgitant velocity (TRV) on echocardiography (≥2.8 m/s) and clinical suspicion of pulmonary hypertension (6-minute walk distance <500 m, unexplained dyspnea or desaturation, or both) were included. Pulmonary hypertension was defined as mean pulmonary artery pressure of 25 mm Hg or greater. Life status was ascertained from clinical records, the Social Security Death Index, state death certificates, and contact with the patient or family as of June 8, 2010. All causes of death were considered for survival analysis. Survival rates (estimated by the Kaplan-Meier method) were compared between (1) those with pulmonary hypertension documented by RHC, (2) those without pulmonary hypertension documented by RHC, and (3) those who did not undergo RHC. Hazard ratios (HRs) were calculated based on Cox proportional hazards regression. Statistical tests were 2-sided and performed using the statistical language R version 2.13.1. P < .05 was considered statistically significant.
Of 531 patients screened by echocardiography, 84 (15.8%) underwent RHC. Right heart catheterization was performed in 81 of 243 patients with a TRV of 2.5 m/s or greater, 67 of 128 with a TRV of 2.8 m/s or greater, 58 of 88 with a TRV of 3 m/s or greater, and 56 of 63 with both a TRV of 2.8 m/s or greater and a 6-minute walk distance of less than 500 m. Fifty-five patients had pulmonary hypertension (65.5% of those who underwent RHC and 10.4% of the total population) and 29 did not. Patients with pulmonary hypertension were older than those who did not undergo RHC and had lower levels of hematocrit and higher serum levels of lactate dehydrogenase, aspartate aminotransferase, direct bilirubin, and ferritin (Table). Patients with pulmonary hypertension demonstrated significantly abnormal cardiopulmonary markers and exercise capacity.
The median follow-up time since enrollment was 4.4 years, with a maximum of 9.6 years. A total of 73 deaths were observed. The overall mortality was worse in the pulmonary hypertension group (20 deaths, 6-year mortality of 37% [95% CI, 20%–50%]) than in either the group without pulmonary hypertension (3 deaths, 6-year mortality of 13% [95% CI, 0%–26%]; age-adjusted HR, 3.43 [95% CI, 1.02–11.55]; P = .047) or the group without RHC (50 deaths, 6-year mortality of 17% [95% CI, 12%–21%]; age-adjusted HR, 2.14 [95% CI, 1.25–3.67]; P = .006) (Figure, part A). Estimated median survival time was 6.8 years after ascertainment of pulmonary hypertension. Patients with SCD and pulmonary hypertension also died at a younger age than the group without RHC (Figure, part B).
This is, to our knowledge, the largest cohort of adults with SCD and pulmonary hypertension detected using RHC consensus diagnostic criteria, and for the first time, an association has been shown between mortality and mean pulmonary artery pressure documented by RHC. This finding suggests a role for pulmonary hypertension in SCD mortality, previously suspected from noninvasive echocardiographic screening studies.1,2 Our pulmonary hypertension prevalence is similar to 1 recent study4 but higher than another,5 which may relate to differences in study exclusion criteria and population characteristics. This was a retrospective, observational study with inherent limitations. Approximately 1.3% of patients screened had indications for catheterization but did not undergo RHC, projecting to an estimate of 5 missed cases of pulmonary hypertension in the group without RHC. Our results therefore represent a conservative estimate of the prevalence and mortality of pulmonary hypertension in SCD.
Pulmonary hypertension mortality in SCD is high, and effective treatment approaches targeting this population are needed.
Funding/Support: This research was supported by grants 1ZIAHL006011, 1ZIAHL006015, and 1ZIAHL006012 from the Division of Intramural Research of the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr Gladwin receives research support from the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania and from National Institutes of Health grants R01HL098032, RO1HL096973, RC1DK085852, and PO1HL103455. Dr Machado receives research support from National Institutes of Health grant K23HL098454.
Role of the Sponsors: The funding organizations had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Gladwin reported that grant money was paid to his institution by Bayer Corporation and INO Therapeutics and money was paid by the US government to his institution for patents in which he is the co-inventor and coauthor. No other author reported disclosures.
Author Contributions: Dr Kato 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. Drs Mehari and Gladwin contributed equally. Drs Machado and Kato (senior authors) contributed equally.Study concept and design: Gladwin, Machado, Kato.
Acquisition of data: Mehari, Gladwin, Machado, Kato.
Analysis and interpretation of data: Mehari, Gladwin, Tian, Machado, Kato.
Drafting of the manuscript: Mehari, Gladwin, Tian, Machado, Kato.
Critical revision of the manuscript for important intellectual content: Mehari, Gladwin, Tian, Machado, Kato.
Statistical analysis: Mehari, Tian.
Obtained funding: Kato.
Administrative, technical or material support: Gladwin.
Study supervision: Machado, Kato.
Additional Contributions: The following 9 collaborators are acknowledged for their contributions to this study: Shoaib Alam, MD, James G. Taylor VI, MD, Vandana Sachdev, MD, Caterina P. Minniti, MD, and Catherine Seamon, RN (acquisition of data and critical revision of the manuscript for important intellectual content), Dihua Xu, PhD (data analysis), all with the National Heart, Lung, and Blood Institute, Bethesda, Maryland; Michael J. Cuttica, MD (acquisition of data and critical revision of the manuscript for important intellectual content), Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Christopher F. Barnett, MD (acquisition of data and critical revision of the manuscript for important intellectual content), Division of Cardiology, University of California, San Francisco; and Patricia Adams-Graves, MD (acquisition of data and critical revision of the manuscript for important intellectual content). We thank additional National Institutes of Health personnel, including Mary K. Hall, CIP, for expert protocol management; and additional Protocol Coordinators James Nichols, RN, Wynona Coles, RT, and Lori Hunter, RN. None of these personnel received outside compensation for this study. This research could not have been possible without all the patients with sickle cell disease who participated.