research paper
Estimated pulmonary artery systolic pressure and sickle cell disease: a meta-analysis and systematic review
Melissa C. Caughey,1 Charles Poole,2 Kenneth I. Ataga1 and Alan L. Hinderliter1 1
Department of Medicine, University of North
Carolina at Chapel Hill, and 2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Received 5 January 2015; accepted for publication 2 March 2015 Correspondence: Melissa C. Caughey, Ph.D., UNC Center for Heart and Vascular Care, Campus Box 7310, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7075, USA. E-mail: [email protected]
Summary Many studies report estimated pulmonary artery systolic pressure (ePASP) in patients with sickle cell disease (SCD) screened by echocardiography. To better understand the prevalence and outcomes of elevated ePASP in clinically stable SCD patients, we conducted a random-effects meta-analysis. A total of 45 studies, representing 15 countries and including 6109 individuals, met our inclusion criteria. In most (70%) studies, elevated ePASP was defined by a tricuspid regurgitant velocity of 25 m/s. The prevalence of elevated ePASP was 21% (17–26%) in children and 30% (26–35%) in adults. After adjustment for sex, SCD genotype, haemoglobin, hydroxycarbamide (hydroxyurea) treatment, country and publication year, age remained associated with elevated ePASP, yielding a 12% (04–23%) higher adjusted prevalence in adults. Few studies reported 6-min walk tests or mortality outcomes, and estimates were highly heterogeneous. In random effects meta-analyses, patients with elevated ePASP walked an estimated 304 (69–539) metres less than those without elevated ePASP and had an associated mortality hazard ratio of 49 (24–97). Keywords: sickle cell disease, pulmonary hypertension, echocardiography, meta-analysis.
The American Thoracic Society (ATS) recommends screening patients with sickle cell disease (SCD) every 1–3 years by echocardiography, for the detection of possible pulmonary hypertension (PHT) and increased mortality risk (Klings et al, 2014). Although right heart catheterization remains the gold standard for PHT detection, echocardiography is non-invasive and relative inexpensive, making it suitable for prospective screenings and implementation in less developed countries. To assess pulmonary artery systolic pressure (PASP) by echocardiography, the tricuspid regurgitant jet velocity (TRV) is quantified and PASP is estimated with the modified Bernoulli equation: ePASP = 4 9 (TRV)2 + right atrial pressure (with 5 or 10 mmHg generally assumed for the right atrial pressure). Numerous echocardiography screening programmes of patients with SCD have been initiated worldwide, but to date, the prevalence and outcomes of elevated ePASP associated with SCD have not been assessed by a formal meta-analysis.
Methods Literature search Published articles were identified using MEDLINE (PubMed) and BIOSIS (Web of Science) search engines, by
First published online 09 April 2015 doi: 10.1111/bjh.13447
entering the key term ‘sickle’ with ‘tricuspid’, ‘pulmonary hypertension’ or ‘echocardiography’. Our initial search retrieved 757 articles published between 1964 and 2014. Reviews, duplicate citations, non-human studies, highly selected study populations and articles written in languages other than English were excluded. To avoid elevated pulmonary pressures due to vaso-occlusive pain crisis or acute chest syndrome (Machado et al, 2007), we omitted studies with hospitalized patients, patients presenting with cardiopulmonary symptoms and retrospective chart reviews of hospital records. We limited our analysis to steady-state prospective screenings, and publications not specifying clinically stable conditions during echocardiography were excluded. Publications reporting mean, rather than categorized, TRV values were omitted, as no prevalence estimates of elevated ePASP could be deduced. Multiple publications arising from the same study population were narrowed down to a single publication with the most complete information. Prevalence estimates from open cohorts were based on the latest publication. Studies examining associations between elevated ePASP and 6-min walk tests (6MWTs) or mortality outcomes were identified by the same search criteria, with PASP estimated during clinically stable conditions. ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 416–424
Pulmonary Hypertension and Sickle Cell Disease
Prevalence of elevated estimated PASP For the purposes of this analysis, elevated ePASP was defined by the TRV or ePASP cut-off points implemented in the published literature. We did not require ePASP values to be confirmed by right heart catheterization, nor did we distinguish between elevations in ePASP arising from pulmonary arterial hypertension or pulmonary venous hypertension. We considered the elevated ePASP prevalence of each study to be the number of elevated ePASP cases divided by the total number of patients imaged by echocardiography. In most instances, our definition of elevated ePASP prevalence was identical to the published result; however, some studies reported elevated ePASP prevalence relative to the number of echocardiograms with measureable TRV. Because TRV can usually be quantified by echocardiography in patients with PHT (Berger et al, 1985), we considered the absence of a measureable velocity to indicate no elevated ePASP, and recalculated elevated ePASP prevalence out of the total number of patients screened. In the few studies reporting TRV or ePASP values in categories, rather than dichotomies, the prevalence of elevated ePASP was calculated by collapsing the higher value categories into a single designation.
Covariate abstraction We abstracted the year of publication and country of origin for all studies included in our analysis. When available in the published results, the mean age, gender percentages, SCD genotype distributions, mean haemoglobin and per cent treated by hydroxycarbamide (previously termed hydroxyurea) were also abstracted. For the purposes of our analysis, SCD genotypes were dichotomized into clinically severe (HbSS and HbS/b0 thalassaemia) and less severe (HbSC and HbS/b+ thalassaemia). Study populations were dichotomized into paediatric or adult based on the mean age, with 18
21 22
12 32
Proportion of females (%)
≤51% >51%
21 20
45% 59%
Geographical Locale Proportion with HbSS or HbSb0 (%)
Western Non-Western ≤84% >84%
31 16 20 19
N/A N/A 70% 99%
Mean haemoglobin (g/l)
≤88 >88
19 18
84 93
Proportion treated by hydroxycarbamide (%)
≤36% >36%
17 15
17% 51%
Publication year
≤2011 >2011
26 19
2009 2013
Mean prevalence of elevated ePASP (95% CI) 21% (17–26%) 30% (26–35%) 20 year increase† 23% (19–28%) 30% (26–35%) Increase of 14%† 26% (22–31%) 26% (20–31%) 27% (22–32%) 23% (18–28%) Increase of 29%† 28% (23–33%) 29% (23–34%) 90 g/l increase† 24% (19–29%) 28% (23–34%) Increase of 34%† 26% (22–30%) 26% (21–32%) 4 year increase†
D in prevalence of elevated ePASP (95% CI) 0 9% (2–15%) 6% (1–12%) 0 7% (0–13%) 2% ( 3% to 7%) 0 0% ( 6% to 8%) 0 4% ( 11% to 3%) 3% ( 10% to 3%) 0 1% ( 8% to 6%) 0% ( 5% to 5%) 0 4% ( 3% to 12%) 5% ( 1% to 11%) 0 0% ( 7% to 7%) 3% ( 9% to 2%)
ePASP, estimated pulmonary artery systolic pressure; 95% CI, 95% confidence interval. *All continuous variables except for age dichotomized by the median value. †Difference in category means.
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Pulmonary Hypertension and Sickle Cell Disease
Fig 1. Random-effects meta-analysis of the prevalence of elevated estimated pulmonary artery systolic pressure in adult patients with sickle cell disease. Horizontal lines = width of 95% confidence interval, diamond = mean of random effects distribution, diamond width = width of 95% confidence interval, horizontal lines surrounding diamond = 95% predictive interval. ePASP, estimated pulmonary artery systolic pressure; TRV, tricuspid regurgitant jet velocity; BMI, body mass index.
Fig 2. Random-effects meta-analysis of the prevalence of elevated estimated pulmonary artery systolic pressure in paediatric patients with sickle cell disease. Horizontal lines = width of 95% confidence interval, diamond = mean of random effects distribution, diamond width = width of 95% confidence interval, horizontal lines surrounding diamond = 95% predictive interval. ePASP, estimated pulmonary artery systolic pressure; TRV, tricuspid regurgitant jet velocity.
bers of events, and confidence intervals were implausibly broad (Table IV). Interestingly, in sequential analyses (2004, 2005, 2007) of a National Institutes of Health open cohort, the risk of death was halved, from a hazard ratio of 101–51, as more participants were screened and a greater amount of follow-up time was accrued. It is noteworthy that the confidence limit ratio decreased by two-thirds, from 214 to 67, indicating much better precision with the latter estimate. ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 416–424
Probably the most convincing estimate of risk associated with ePASP is an analysis involving 542 SCD patients who were followed for a mean of 93 years (Elmariah et al, 2014). In this multisite registry, elevated ePASP was associated with twice the risk of death (hazard ratio = 23), with a confidence limit ratio of 32. In our random effects meta-analysis (Fig 4), the pooled hazard ratio of death associated with elevated ePASP was 49 (24–97); however the 95% PI ranged 419
M. C. Caughey et al Table III. Mean distances walked in 6 minutes, stratified by elevated estimated pulmonary artery systolic pressure cut-off points or categories. Reference Aliyu et al (2008) TRV < 25 m/s TRV 25–29 m/s TRV ≥ 30 m/s Minniti et al (2009) TRV < 26 m/s TRV ≥ 26 m/s Parent et al (2011) TRV < 25 m/s TRV ≥ 25 m/s Sachdev et al (2011) TRV < 27 m/s TRV 27–29 TRV ≥ 30 m/s Fonseca et al (2012) TRV < 25 m/s TRV ≥ 25 m/s Marouf et al (2014) TRV < 25 m/s TRV ≥ 25 m/s Agha et al (2014) TRV < 25 m/s TRV ≥ 25 m/s
N
Mean distance (m SE)
120 32 7
388 7 380 13 370 29
202 29
441 70 457 60
289 72
520 88 527 62
258 120 52
458 91 438 98 409 96
48 32
515 148 475 131
49 8
381 70 394 90
57 23
425 40 334 35
TRV, tricuspid regurgitant jet velocity; SE, standard error.
from a hazard ratio of 06–399, indicating substantial heterogeneity.
Discussion This meta-analysis of the published literature formally examines the prevalence of elevated ePASP in clinically stable SCD patients screened by echocardiography. As might be expected,
we observed substantial heterogeneity across the studies. Among the potential demographical and clinical covariates that may influence pulmonary artery pressures, only age showed a clear association, with adult study populations associated with a 9% higher crude prevalence of elevated ePASP and 12% higher prevalence of elevated ePASP after adjustments for covariates. Estimates of functional status and mortality risk varied widely from study to study, with elevated ePASP associated with both decreased 6MWT distances and survival. Evidence of pulmonary vasculopathy in SCD patients has been noted in autopsy reports, with medial hypertrophy, intimal hyperplasia and fibrosis of the pulmonary artery detected in 75–100% of SCD cases (Adedeji et al, 2001; Haque et al, 2002). Although autopsy series are based on highly selected populations, this meta-analysis confirms a high prevalence of elevated ePASP in both paediatric and adult SCD populations examined in the steady-state by echocardiography. The aetiology of elevated ePASP is probably a combination of anaemia-induced increases in cardiac output as well as pulmonary vasculopathy. SCD-related haemolyis, releasing nitric oxide scavenging free haemoglobin, is hypothesized to produce endothelial dysfunction and intimal hyperplasia of the pulmonary artery (Kato et al, 2009). Left ventricular diastolic dysfunction, often observed in SCD patients (Sachdev et al, 2007), may also contribute to medial hypertrophy of the pulmonary artery by inducing pulmonary congestion and downstream venous hypertension. In addition, splenectomy, thromboembolism and sleep-disordered breathing have been associated with elevated ePASP in SCD patients (Gladwin & Sachdev, 2012). Even in the absence of SCD, pulmonary artery pressures are known to increase with age. Ageing is accompanied by increased pulmonary vascular resistance, contributing to pulmonary arterial hypertension and diminished left ventricular compliance, augmenting pulmonary venous hypertension. In
Fig 3. Random-effects meta-analysis of distance walked in 6 min comparing sickle cell disease patients with elevated estimated pulmonary artery systolic pressure to those without. Horizontal lines = width of 95% confidence interval, diamond = mean of random effects distribution, diamond width = width of 95% confidence interval, horizontal lines surrounding diamond = 95% predictive interval. ePASP, estimated pulmonary artery systolic pressure; TRV, tricuspid regurgitant jet velocity RHC = right heart catheterization. *Categories compared to patients with a TRV < 25 m/s.
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Pulmonary Hypertension and Sickle Cell Disease Table IV. Hazard ratios of death associated with elevated pulmonary artery systolic pressure estimated by echocardiography in patients with sickle cell disease.
Reference
N
Gladwin et al (2004)* Morris et al (2005)* Sachdev et al (2007)* Ataga et al (2006)
195 222 232 93
Cabrita et al (2013) Elmariah et al (2014) Gladwin et al (2014)
164 542 572
ePASP cut-off value
Follow-up (mean, years)
Deaths (n)
Hazard ratio (95% CI)
CLR
TRV ≥ 25 TRV ≥ 25 TRV ≥ 25 Age and sex ePASP ranges TRV ≥ 25 TRV ≥ 25 TRV ≥ 30
15 n/a n/a 26
n/a 18 20 10
101 74 51 93
(22–470) (24–224) (20–133) (12–733)
214 93 67 611
57 93 24
15 128 22
45 (10–198) 23 (13–41) 111 (41–301)
198 32 73
ePASP, estimated pulmonary artery systolic pressure; 95% CI, 95% confidence interval; CLR, confidence limit ratio; TRV, tricuspid regurgitant jet velocity; n/a, not available. *Continuation of the same cohort.
Fig 4. Random-effects meta-analysis of hazard ratios of death associated with elevated estimated pulmonary artery systolic pressure in sickle cell disease patients. Horizontal lines = width of 95% confidence interval, diamond = mean of random effects distribution, diamond width = width of 95% confidence interval, horizontal lines surrounding diamond = 95% predictive interval. (e) PASP, (estimated) pulmonary artery systolic pressure; TRV, tricuspid regurgitant jet velocity; BMI, body mass index.
a chart review examining 3790 clinically normal echocardiograms with measurable tricuspid regurgitation, ePASP was observed to increase ~ 1 mmHg per decade of age (McQuillan et al, 2001). The correlation of ePASP with age has prompted some to advocate age-specific reference ranges for the diagnosis of possible PHT. Nonetheless, the ATS guidelines recommend a TRV value of 25 m/s as a convenient cut-off point to identify mortality risk in SCD patients, with follow-up testing by right heart catheterization in those with TRV ≥ 30 m/s. As with the general population, in the 45 studies screening SCD patients, we observed a trend for higher prevalence of elevated ePASP among older study patients. Other than the association with age, there were no correlations between the prevalence of elevated ePASP and demographical or study characteristics assessed by multivariate meta-regression. No changes in the prevalence of elevated ePASP were observed with publication year; however, it is noteworthy that all studies were conducted during the ‘hydroxycarbamide era’. The earliest report that we included was published in 2005, well after the US Food and Drug administration approved hydroxycarbamide for the treatment ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 416–424
of SCD in 1998. Interestingly, hydroxycarbamide, which would be expected to lower pulmonary pressures in SCD patients by decreasing haemolysis and levels of endothelin-1 (Ataga et al, 2006), was not associated with lower prevalence of elevated ePASP. This may simply reflect confounding by indication, as patients with the most severe SCD-related complications and possibly PHT are more likely to receive hydroxycarbamide treatment. There was also no association between elevated ePASP and geography, comparing Western to non-Western countries, with the latter expected to have limited access to medical care. Perhaps most surprisingly, we observed no associations between elevated ePASP and SCD severity, indicated by HbSS/HbSb0 genotypes and haemoglobin levels. This suggests that the heterogeneity in the prevalence of elevated ePASP that we observed between studies may be more strongly related to unmeasured factors – possibly quality of the imaging equipment or skill of the sonographers – than the clinical characteristics of the study populations. We acknowledge the controversy surrounding the use of TRV cut-off points for assessing possible PHT in SCD populations. Although a TRV value of 25 m/s is recommended 421
M. C. Caughey et al by the ATS guidelines for risk stratification, the American Society of Echocardiography (ASE) considers a TRV value of 28 or 29 m/s suggestive of PHT (Rudski et al, 2010). Of note, the ASE guidelines were derived from data from the general population, which may not capture mortality risk in SCD patients. In this meta-analysis, the vast majority of studies defined elevated ePASP by a TRV cut-off point of 25 m/s. However, in invasive procedures, a mean pulmonary artery pressure of 25 mmHg is generally considered indicative of PHT. When compared to standard right heart catheterization cut-off points, a TRV cut-off of 25 m/s detects PHT in SCD patients with only a 25% positive predictive value, which increases to 64% when a TRV cut-off of 29 m/ s is used (Parent et al, 2011). Our study has some limitations. Though every effort was made to analyse unique study populations, independence was not always possible to discern. SCD is a rare disease in the US, and it is conceivable that multisite registries may have shared some patients in common with publications from individual study sites. We were also unable to consider BMI, a known determinant of ePASP in the general population (McQuillan et al, 2001), as most studies did not report this
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Acknowledgements Melissa Caughey designed the research study, abstracted the data, performed the analysis, and wrote the paper. Charles Poole, Kenneth Ataga, and Alan Hinderliter interpreted the data and revised the paper critically. No funding sources went into the making of this paper.
Competing interests The authors have no competing interests.
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Estimated pulmonary artery systolic pressure and sickle cell disease: a meta-analysis and systematic review
Melissa C. Caughey,1 Charles Poole,2 Kenneth I. Ataga1 and Alan L. Hinderliter1 1
Department of Medicine, University of North
Carolina at Chapel Hill, and 2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Received 5 January 2015; accepted for publication 2 March 2015 Correspondence: Melissa C. Caughey, Ph.D., UNC Center for Heart and Vascular Care, Campus Box 7310, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7075, USA. E-mail: [email protected]
Summary Many studies report estimated pulmonary artery systolic pressure (ePASP) in patients with sickle cell disease (SCD) screened by echocardiography. To better understand the prevalence and outcomes of elevated ePASP in clinically stable SCD patients, we conducted a random-effects meta-analysis. A total of 45 studies, representing 15 countries and including 6109 individuals, met our inclusion criteria. In most (70%) studies, elevated ePASP was defined by a tricuspid regurgitant velocity of 25 m/s. The prevalence of elevated ePASP was 21% (17–26%) in children and 30% (26–35%) in adults. After adjustment for sex, SCD genotype, haemoglobin, hydroxycarbamide (hydroxyurea) treatment, country and publication year, age remained associated with elevated ePASP, yielding a 12% (04–23%) higher adjusted prevalence in adults. Few studies reported 6-min walk tests or mortality outcomes, and estimates were highly heterogeneous. In random effects meta-analyses, patients with elevated ePASP walked an estimated 304 (69–539) metres less than those without elevated ePASP and had an associated mortality hazard ratio of 49 (24–97). Keywords: sickle cell disease, pulmonary hypertension, echocardiography, meta-analysis.
The American Thoracic Society (ATS) recommends screening patients with sickle cell disease (SCD) every 1–3 years by echocardiography, for the detection of possible pulmonary hypertension (PHT) and increased mortality risk (Klings et al, 2014). Although right heart catheterization remains the gold standard for PHT detection, echocardiography is non-invasive and relative inexpensive, making it suitable for prospective screenings and implementation in less developed countries. To assess pulmonary artery systolic pressure (PASP) by echocardiography, the tricuspid regurgitant jet velocity (TRV) is quantified and PASP is estimated with the modified Bernoulli equation: ePASP = 4 9 (TRV)2 + right atrial pressure (with 5 or 10 mmHg generally assumed for the right atrial pressure). Numerous echocardiography screening programmes of patients with SCD have been initiated worldwide, but to date, the prevalence and outcomes of elevated ePASP associated with SCD have not been assessed by a formal meta-analysis.
Methods Literature search Published articles were identified using MEDLINE (PubMed) and BIOSIS (Web of Science) search engines, by
First published online 09 April 2015 doi: 10.1111/bjh.13447
entering the key term ‘sickle’ with ‘tricuspid’, ‘pulmonary hypertension’ or ‘echocardiography’. Our initial search retrieved 757 articles published between 1964 and 2014. Reviews, duplicate citations, non-human studies, highly selected study populations and articles written in languages other than English were excluded. To avoid elevated pulmonary pressures due to vaso-occlusive pain crisis or acute chest syndrome (Machado et al, 2007), we omitted studies with hospitalized patients, patients presenting with cardiopulmonary symptoms and retrospective chart reviews of hospital records. We limited our analysis to steady-state prospective screenings, and publications not specifying clinically stable conditions during echocardiography were excluded. Publications reporting mean, rather than categorized, TRV values were omitted, as no prevalence estimates of elevated ePASP could be deduced. Multiple publications arising from the same study population were narrowed down to a single publication with the most complete information. Prevalence estimates from open cohorts were based on the latest publication. Studies examining associations between elevated ePASP and 6-min walk tests (6MWTs) or mortality outcomes were identified by the same search criteria, with PASP estimated during clinically stable conditions. ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 416–424
Pulmonary Hypertension and Sickle Cell Disease
Prevalence of elevated estimated PASP For the purposes of this analysis, elevated ePASP was defined by the TRV or ePASP cut-off points implemented in the published literature. We did not require ePASP values to be confirmed by right heart catheterization, nor did we distinguish between elevations in ePASP arising from pulmonary arterial hypertension or pulmonary venous hypertension. We considered the elevated ePASP prevalence of each study to be the number of elevated ePASP cases divided by the total number of patients imaged by echocardiography. In most instances, our definition of elevated ePASP prevalence was identical to the published result; however, some studies reported elevated ePASP prevalence relative to the number of echocardiograms with measureable TRV. Because TRV can usually be quantified by echocardiography in patients with PHT (Berger et al, 1985), we considered the absence of a measureable velocity to indicate no elevated ePASP, and recalculated elevated ePASP prevalence out of the total number of patients screened. In the few studies reporting TRV or ePASP values in categories, rather than dichotomies, the prevalence of elevated ePASP was calculated by collapsing the higher value categories into a single designation.
Covariate abstraction We abstracted the year of publication and country of origin for all studies included in our analysis. When available in the published results, the mean age, gender percentages, SCD genotype distributions, mean haemoglobin and per cent treated by hydroxycarbamide (previously termed hydroxyurea) were also abstracted. For the purposes of our analysis, SCD genotypes were dichotomized into clinically severe (HbSS and HbS/b0 thalassaemia) and less severe (HbSC and HbS/b+ thalassaemia). Study populations were dichotomized into paediatric or adult based on the mean age, with 18
21 22
12 32
Proportion of females (%)
≤51% >51%
21 20
45% 59%
Geographical Locale Proportion with HbSS or HbSb0 (%)
Western Non-Western ≤84% >84%
31 16 20 19
N/A N/A 70% 99%
Mean haemoglobin (g/l)
≤88 >88
19 18
84 93
Proportion treated by hydroxycarbamide (%)
≤36% >36%
17 15
17% 51%
Publication year
≤2011 >2011
26 19
2009 2013
Mean prevalence of elevated ePASP (95% CI) 21% (17–26%) 30% (26–35%) 20 year increase† 23% (19–28%) 30% (26–35%) Increase of 14%† 26% (22–31%) 26% (20–31%) 27% (22–32%) 23% (18–28%) Increase of 29%† 28% (23–33%) 29% (23–34%) 90 g/l increase† 24% (19–29%) 28% (23–34%) Increase of 34%† 26% (22–30%) 26% (21–32%) 4 year increase†
D in prevalence of elevated ePASP (95% CI) 0 9% (2–15%) 6% (1–12%) 0 7% (0–13%) 2% ( 3% to 7%) 0 0% ( 6% to 8%) 0 4% ( 11% to 3%) 3% ( 10% to 3%) 0 1% ( 8% to 6%) 0% ( 5% to 5%) 0 4% ( 3% to 12%) 5% ( 1% to 11%) 0 0% ( 7% to 7%) 3% ( 9% to 2%)
ePASP, estimated pulmonary artery systolic pressure; 95% CI, 95% confidence interval. *All continuous variables except for age dichotomized by the median value. †Difference in category means.
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Pulmonary Hypertension and Sickle Cell Disease
Fig 1. Random-effects meta-analysis of the prevalence of elevated estimated pulmonary artery systolic pressure in adult patients with sickle cell disease. Horizontal lines = width of 95% confidence interval, diamond = mean of random effects distribution, diamond width = width of 95% confidence interval, horizontal lines surrounding diamond = 95% predictive interval. ePASP, estimated pulmonary artery systolic pressure; TRV, tricuspid regurgitant jet velocity; BMI, body mass index.
Fig 2. Random-effects meta-analysis of the prevalence of elevated estimated pulmonary artery systolic pressure in paediatric patients with sickle cell disease. Horizontal lines = width of 95% confidence interval, diamond = mean of random effects distribution, diamond width = width of 95% confidence interval, horizontal lines surrounding diamond = 95% predictive interval. ePASP, estimated pulmonary artery systolic pressure; TRV, tricuspid regurgitant jet velocity.
bers of events, and confidence intervals were implausibly broad (Table IV). Interestingly, in sequential analyses (2004, 2005, 2007) of a National Institutes of Health open cohort, the risk of death was halved, from a hazard ratio of 101–51, as more participants were screened and a greater amount of follow-up time was accrued. It is noteworthy that the confidence limit ratio decreased by two-thirds, from 214 to 67, indicating much better precision with the latter estimate. ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 416–424
Probably the most convincing estimate of risk associated with ePASP is an analysis involving 542 SCD patients who were followed for a mean of 93 years (Elmariah et al, 2014). In this multisite registry, elevated ePASP was associated with twice the risk of death (hazard ratio = 23), with a confidence limit ratio of 32. In our random effects meta-analysis (Fig 4), the pooled hazard ratio of death associated with elevated ePASP was 49 (24–97); however the 95% PI ranged 419
M. C. Caughey et al Table III. Mean distances walked in 6 minutes, stratified by elevated estimated pulmonary artery systolic pressure cut-off points or categories. Reference Aliyu et al (2008) TRV < 25 m/s TRV 25–29 m/s TRV ≥ 30 m/s Minniti et al (2009) TRV < 26 m/s TRV ≥ 26 m/s Parent et al (2011) TRV < 25 m/s TRV ≥ 25 m/s Sachdev et al (2011) TRV < 27 m/s TRV 27–29 TRV ≥ 30 m/s Fonseca et al (2012) TRV < 25 m/s TRV ≥ 25 m/s Marouf et al (2014) TRV < 25 m/s TRV ≥ 25 m/s Agha et al (2014) TRV < 25 m/s TRV ≥ 25 m/s
N
Mean distance (m SE)
120 32 7
388 7 380 13 370 29
202 29
441 70 457 60
289 72
520 88 527 62
258 120 52
458 91 438 98 409 96
48 32
515 148 475 131
49 8
381 70 394 90
57 23
425 40 334 35
TRV, tricuspid regurgitant jet velocity; SE, standard error.
from a hazard ratio of 06–399, indicating substantial heterogeneity.
Discussion This meta-analysis of the published literature formally examines the prevalence of elevated ePASP in clinically stable SCD patients screened by echocardiography. As might be expected,
we observed substantial heterogeneity across the studies. Among the potential demographical and clinical covariates that may influence pulmonary artery pressures, only age showed a clear association, with adult study populations associated with a 9% higher crude prevalence of elevated ePASP and 12% higher prevalence of elevated ePASP after adjustments for covariates. Estimates of functional status and mortality risk varied widely from study to study, with elevated ePASP associated with both decreased 6MWT distances and survival. Evidence of pulmonary vasculopathy in SCD patients has been noted in autopsy reports, with medial hypertrophy, intimal hyperplasia and fibrosis of the pulmonary artery detected in 75–100% of SCD cases (Adedeji et al, 2001; Haque et al, 2002). Although autopsy series are based on highly selected populations, this meta-analysis confirms a high prevalence of elevated ePASP in both paediatric and adult SCD populations examined in the steady-state by echocardiography. The aetiology of elevated ePASP is probably a combination of anaemia-induced increases in cardiac output as well as pulmonary vasculopathy. SCD-related haemolyis, releasing nitric oxide scavenging free haemoglobin, is hypothesized to produce endothelial dysfunction and intimal hyperplasia of the pulmonary artery (Kato et al, 2009). Left ventricular diastolic dysfunction, often observed in SCD patients (Sachdev et al, 2007), may also contribute to medial hypertrophy of the pulmonary artery by inducing pulmonary congestion and downstream venous hypertension. In addition, splenectomy, thromboembolism and sleep-disordered breathing have been associated with elevated ePASP in SCD patients (Gladwin & Sachdev, 2012). Even in the absence of SCD, pulmonary artery pressures are known to increase with age. Ageing is accompanied by increased pulmonary vascular resistance, contributing to pulmonary arterial hypertension and diminished left ventricular compliance, augmenting pulmonary venous hypertension. In
Fig 3. Random-effects meta-analysis of distance walked in 6 min comparing sickle cell disease patients with elevated estimated pulmonary artery systolic pressure to those without. Horizontal lines = width of 95% confidence interval, diamond = mean of random effects distribution, diamond width = width of 95% confidence interval, horizontal lines surrounding diamond = 95% predictive interval. ePASP, estimated pulmonary artery systolic pressure; TRV, tricuspid regurgitant jet velocity RHC = right heart catheterization. *Categories compared to patients with a TRV < 25 m/s.
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Pulmonary Hypertension and Sickle Cell Disease Table IV. Hazard ratios of death associated with elevated pulmonary artery systolic pressure estimated by echocardiography in patients with sickle cell disease.
Reference
N
Gladwin et al (2004)* Morris et al (2005)* Sachdev et al (2007)* Ataga et al (2006)
195 222 232 93
Cabrita et al (2013) Elmariah et al (2014) Gladwin et al (2014)
164 542 572
ePASP cut-off value
Follow-up (mean, years)
Deaths (n)
Hazard ratio (95% CI)
CLR
TRV ≥ 25 TRV ≥ 25 TRV ≥ 25 Age and sex ePASP ranges TRV ≥ 25 TRV ≥ 25 TRV ≥ 30
15 n/a n/a 26
n/a 18 20 10
101 74 51 93
(22–470) (24–224) (20–133) (12–733)
214 93 67 611
57 93 24
15 128 22
45 (10–198) 23 (13–41) 111 (41–301)
198 32 73
ePASP, estimated pulmonary artery systolic pressure; 95% CI, 95% confidence interval; CLR, confidence limit ratio; TRV, tricuspid regurgitant jet velocity; n/a, not available. *Continuation of the same cohort.
Fig 4. Random-effects meta-analysis of hazard ratios of death associated with elevated estimated pulmonary artery systolic pressure in sickle cell disease patients. Horizontal lines = width of 95% confidence interval, diamond = mean of random effects distribution, diamond width = width of 95% confidence interval, horizontal lines surrounding diamond = 95% predictive interval. (e) PASP, (estimated) pulmonary artery systolic pressure; TRV, tricuspid regurgitant jet velocity; BMI, body mass index.
a chart review examining 3790 clinically normal echocardiograms with measurable tricuspid regurgitation, ePASP was observed to increase ~ 1 mmHg per decade of age (McQuillan et al, 2001). The correlation of ePASP with age has prompted some to advocate age-specific reference ranges for the diagnosis of possible PHT. Nonetheless, the ATS guidelines recommend a TRV value of 25 m/s as a convenient cut-off point to identify mortality risk in SCD patients, with follow-up testing by right heart catheterization in those with TRV ≥ 30 m/s. As with the general population, in the 45 studies screening SCD patients, we observed a trend for higher prevalence of elevated ePASP among older study patients. Other than the association with age, there were no correlations between the prevalence of elevated ePASP and demographical or study characteristics assessed by multivariate meta-regression. No changes in the prevalence of elevated ePASP were observed with publication year; however, it is noteworthy that all studies were conducted during the ‘hydroxycarbamide era’. The earliest report that we included was published in 2005, well after the US Food and Drug administration approved hydroxycarbamide for the treatment ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 416–424
of SCD in 1998. Interestingly, hydroxycarbamide, which would be expected to lower pulmonary pressures in SCD patients by decreasing haemolysis and levels of endothelin-1 (Ataga et al, 2006), was not associated with lower prevalence of elevated ePASP. This may simply reflect confounding by indication, as patients with the most severe SCD-related complications and possibly PHT are more likely to receive hydroxycarbamide treatment. There was also no association between elevated ePASP and geography, comparing Western to non-Western countries, with the latter expected to have limited access to medical care. Perhaps most surprisingly, we observed no associations between elevated ePASP and SCD severity, indicated by HbSS/HbSb0 genotypes and haemoglobin levels. This suggests that the heterogeneity in the prevalence of elevated ePASP that we observed between studies may be more strongly related to unmeasured factors – possibly quality of the imaging equipment or skill of the sonographers – than the clinical characteristics of the study populations. We acknowledge the controversy surrounding the use of TRV cut-off points for assessing possible PHT in SCD populations. Although a TRV value of 25 m/s is recommended 421
M. C. Caughey et al by the ATS guidelines for risk stratification, the American Society of Echocardiography (ASE) considers a TRV value of 28 or 29 m/s suggestive of PHT (Rudski et al, 2010). Of note, the ASE guidelines were derived from data from the general population, which may not capture mortality risk in SCD patients. In this meta-analysis, the vast majority of studies defined elevated ePASP by a TRV cut-off point of 25 m/s. However, in invasive procedures, a mean pulmonary artery pressure of 25 mmHg is generally considered indicative of PHT. When compared to standard right heart catheterization cut-off points, a TRV cut-off of 25 m/s detects PHT in SCD patients with only a 25% positive predictive value, which increases to 64% when a TRV cut-off of 29 m/ s is used (Parent et al, 2011). Our study has some limitations. Though every effort was made to analyse unique study populations, independence was not always possible to discern. SCD is a rare disease in the US, and it is conceivable that multisite registries may have shared some patients in common with publications from individual study sites. We were also unable to consider BMI, a known determinant of ePASP in the general population (McQuillan et al, 2001), as most studies did not report this
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characteristic. However, even in Western countries with predominant obesity, most patients with SCD are characterized by small body habitus. Despite these limitations, our study has several notable strengths. This meta-analysis encompasses 45 studies selected by objective criteria, represents 15 countries and, to date, is the largest examination of the prevalence and outcomes of elevated ePASP among SCD patients around the world.
Acknowledgements Melissa Caughey designed the research study, abstracted the data, performed the analysis, and wrote the paper. Charles Poole, Kenneth Ataga, and Alan Hinderliter interpreted the data and revised the paper critically. No funding sources went into the making of this paper.
Competing interests The authors have no competing interests.
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