Risk Factors for Death in 632 Patients with Sickle Cell Anemia in the United States and United Kingdom

Abstract

3240 The role of pulmonary hypertension as a common and attributable cause of mortality in patients with sickle cell disease remains controversial. To assess this question and explore risk factors for death in patients with sickle cell disease we evaluated 632 patients in the Walk-PHASST pulmonary hypertension screening cohort, recruited from nine different study sites in the United States and one site in the United Kingdom. Methods: Patient characteristics and their associations with mortality were analyzed with Cox proportional hazards regression analysis. Based on data from three right heart catheterization screenings studies that have recently been published, we defined the presence of pulmonary hypertension for this analysis by a Doppler-echocardiographic measurement of the tricuspid regurgitant jet velocity (TRV) ≥ 3.0 m/s, which has a 67–75% positive predictive value for a mean pulmonary artery pressure ≥ 25 mm Hg by right heart catheterization. This therefore represents a very conservative threshold for a large population screening study. Among subjects with a measurable TRV (n=572), 64 (11.2%) had measurements of ≥ 3.0 m/sec. Among those with measurable NT-proBNP (n=582), 140 (24.1%) had measurements ≥160 pg/mL, a value associated with both pulmonary hypertension and mortality. A total of 39 (7.4%) had both high TRV (≥3.0 m/sec) and high NT-proBNP (≥160 pg/mL). Results: Over a median follow-up time of 29 months, we observed 22 deaths. 50% (N=11) of these patients had a TRV≥ 3.0 m/sec. At 24 months the cumulative survival was 83% for patients with TRV ≥ 3.0 m/sec and 98% for patients with TRV < 3.0 m/sec (p<0.0001). The unadjusted hazard ratios for death were 11.14 (95% CI 4.1–30.1; p<0.0001) for patients with TRV above and below 3.0 m/sec and 4.55 (95% CI 1.8–11.3; p=0.001) for patients with NT-proBNP above and below 160 pg/mL. For patients with both high TRV (≥ 3.0 m/sec) and high NT-proBNP (≥ 160 pg/mL), the unadjusted hazard ratio was 14.86 (95% CI 5.5–39.9; p<0.0001). Overall, an increased risk of death was observed for both age and gender, with males at higher risk relative to females (HR=2.48, 95% CI 1.0–6.1; p=0.05), and patients older than 47 years (HR=2.02, 95% CI 1.1–3.8; p=0.03). Associations with mortality were also observed for chronic transfusions (HR=3.00, 95% CI 1.2–7.8; p=0.02) and a NYHA/WHO class value or III or IV (HR=4.52, 95% CI 1.4–14.3; p=0.01). Other variables associated with mortality in our cohort included a high hemolytic component, aspartate aminotransferase (AST), ferritin, and creatinine. Variables not associated with mortality included current hydroxyurea use, SC disease, self-reported history of painful episodes, and six-minute walk distance. In stepwise multiple proportional hazards regression analysis, the association between TRV and mortality remained significant after adjustment for all other risk factors, including ferritin, AST, creatinine and even NT-proBNP (HR 4.27, 95%CI 1.3–14.1; p=0.04). Conclusions: Using a more conservative cut-off value of TRV ≥ 3.0 m/sec as defining PH in a large screening population of sickle cell disease patients, PH occurs in approximately 10% of unselected screened patients and is associated with the highest unadjusted and adjusted risk for death of any measured variable. Disclosures: Gladwin: Bayer Corp: Consultancy, Research Funding; NIH and NHLBI: Research Funding; Gilead Sciences: Research Funding. Barst:Ventripoint: Stock options Other; Actelion, Eli Lilly, Gilead, Glaxo Smith-Kline (GSK), Medtronics, Bayer, Ikaria, Pfizer, Novartis, VentriPoint: Consultancy, Honoraria. Girgis:NIH/NHLBI: Research Funding, Travel support Other. Rosenzweig:NIH: Research Funding. Badesch:NIH: Research Funding. Lanzkron:NIH: Research Funding.

The association between tricuspid regurgitation velocity and 5‐year survival in a North West London population of patients with sickle cell disease in the United Kingdom

“…Of the 164 patients included in our study, only 10 patients (6·1%) had a TRV value of 3·0 m/s or higher. Using the same time point as Gladwin et al () (24 months) we found similar survival estimates of 99% for TRV <3·0 m/s and 80% for TRV ≥3·0 m/s. Nonetheless, using a time point of 68 months, there was no significant difference ( P = 0·125) in the survival estimates: 95% for TRV <3·0 m/s and 80% for TRV ≥3·0 m/s.…”

“…Nonetheless, using a time point of 68 months, there was no significant difference ( P = 0·125) in the survival estimates: 95% for TRV <3·0 m/s and 80% for TRV ≥3·0 m/s. We also found that patients with higher TRV values had a higher risk of death (HR: 6·52; 95% CI 2·97–20·6; P = 0·001) when other factors are not considered (in comparison to a HR of 11·14 reported by Gladwin et al , ), however this risk disappears after adjustment for other variables associated with survival.…”

“…Powars et al () found a mean survival of 2·5 years in patients with chronic lung disease and elevated TRV. Recently, a large multinational study (Gladwin et al , ) of unselected 632 screened patients, which used a more conservative cut‐off value of TRV ≥3·0 m/s, showed that the association between TRV and mortality remained significant after adjustment for all other risk factors. In this study, 22 deaths were observed over median follow/up time of 29 months, of which 11 patients had TRV of at least 3·0 m/s.…”

“…The lower mortality in our United Kingdom cohort raises the possibility that we studied a lower risk group of patients. On the other hand, our patients were selected randomly from those at higher risk attending out‐patients clinics, whereas the patients studied by Gladwin et al () were recruited from the community through multimedia advertisements, community outreach, and regional clinics, and it was not certain if these patients were receiving comprehensive care for SCD. In the study reported by Castro et al () the selected patients were all hospitalized.…”

“…The ability to highlight a subgroup of patients with a high predicted mortality by use of a non‐invasive measurement, such as TRV, represents a significant clinical advance and has rightly generated a lot of research interest. Raised TRV, as assessed by Doppler echocardiography, whether or not associated with PAH, is commonly found in SCD (Ataga et al , ) and has been reported as a marker of mortality in several major studies from the United States (Ataga et al , ; Anthi et al , ; De Castro et al , ; Machado & Gladwin, ; Lorch et al , ; Gladwin et al , ). Raised TRV has been found in 32–42% of patients with SCD (Gladwin et al , ; Akgul et al , ; Liem et al , ; Fitzhugh et al , ; Parent et al , ).…”