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Red blood cell distribution width predicts one-year mortality following transcatheter aortic valve implantation
International Journal of Cardiology 172 (2014) 456–536
Contents lists available at ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Letters to the Editor
Red blood cell distribution width predicts one-year mortality following transcatheter aortic valve implantation Caroline J. Magri 1, Alaide Chieffo ⁎,1, Azeem Latib 1, Matteo Montorfano 1, Francesco Maisano 1, Michela Cioni 1, Eustachio Agricola 1, Remo Daniel Covello 1, Chiara Gerli 1, Annalisa Franco 1, Pietro Spagnolo 1, Ottavio Alfieri 1, Antonio Colombo 1 Interventional Cardiology Unit, San Raffaele Scientific Institute, 60, Via Olgettina, Milan, Italy
a r t i c l e
i n f o
Article history: Received 18 November 2013 Accepted 29 December 2013 Available online 8 January 2014 Keywords: Red blood cell distribution width Transcutaneous aortic valve implantation Mortality Body mass index Percutaneous coronary intervention Chronic kidney disease
Transcatheter aortic valve implantation (TAVI) is an effective alternative in high-risk patients with severe symptomatic aortic stenosis (AS). Risk stratification in TAVI is a relevant issue. The available risk models, such as the EuroSCORE, have shown several limitations, including poor performance in the elderly population. There is a need to identify new prognosticators that are simple, costeffective and widely available. Red blood cell distribution width (RDW), routinely reported in automated complete blood counts (CBC), is a numerical measure of the size variation of the erythrocytes. Clinical studies have shown a strong and independent association between RDW and cardiovascular disease. The current study sought to determine whether higher RDW levels are associated with increased risk of death in high-risk elderly subjects undergoing TAVI. The study population comprised 250 consecutive patients with severe symptomatic AS who were referred to San Raffaele Scientific Institute, Milan, Italy for TAVI from November 2007 to January 2011. Patients were evaluated by a multidisciplinary Heart Team. Past medical history and cardiovascular risk factors were noted. The transfemoral approach was the standard technique used; the transaxillary, the transapical or the transaortic access was utilized
⁎ Corresponding author. E-mail address: [email protected] (A. Chieffo). 1 This author takes responsibility for all aspects of reliability and freedom from bias of the data presented and their discussed interpretation.
when the peripheral vascular anatomy was not suitable. The devices used were the Edwards-SAPIEN/SAPIEN XT (ESV) and the Medtronic CoreValve ReValving Technology (MCV). Blood samples were drawn at baseline. The normal reference range for RDW is between 11.5% and 14.5%. The primary end-point investigated was all-cause mortality at one year. Informed consent was obtained from each patient. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. Data were analysed using SPSS version 21.0. The following covariates were investigated for association with one-year mortality in univariate analysis: age, sex, body mass index (BMI), logistic EuroSCORE, STSPROM, previous myocardial infarction (MI), coronary artery bypass grafting, or percutaneous coronary intervention (PCI), coronary artery disease (CAD), hypertension, chronic obstructive pulmonary disease, diabetes mellitus, peripheral vascular disease, chronic kidney disease (CKD), cerebrovascular disease, ejection fraction b35%, aortic annulus diameter, access site, sheath size, white cell count, haemoglobin, red cell count, RDW, mean corpuscular volume, platelet count and mean platelet volume. Significant determinants (p b 0.1) identified from univariate analysis were studied in a forward stepwise Cox regression model. Receiver–operator curve (ROC) analysis was used to define the optimal cut-off value for the RDW in predicting mortality. The baseline demographic characteristics of the patients studied are reported in Table 1. 59.2% of the procedures were performed using ESV. 26 mm valves were most commonly used (49.6%) while 48.8% of the procedures were performed using an 18 French sheath. The overall procedural outcomes were satisfactory, with a device success rate of 91.2%, and a low procedural complication rate (valve embolization in 2.8% of patients; shock in 11.2% of patients; cardiac tamponade in 3.2%), Bleeding events were the commonest complications with life-threatening bleeding noted in 28.8%, major bleeding in 36% while minor bleeding occurred in 8.8%. Major vascular complications were observed in 18%. The in-hospital complication rates were low: 7 patients experienced a transient ischaemic attack (TIA), 2 patients had a stroke, 4 patients sustained a MI and 13 patients (5.2%) died. The event rate at 30 days was similarly low: 6 patients had a TIA, 1 patient sustained a stroke while 3 had a MI. 30-day mortality was noted in 13 patients (5.2%) while 36 patients (14.4%) died within one year. Of these, cardiovascular mortality was noted in 24 patients. Also, at 1 year, 5 patients had sustained a stroke and 5 had sustained a MI.
Letters to the Editor Table 1 Baseline characteristics of study population.
457
Table 2 1-year all-cause mortality in TAVI patients, univariate analysis and multivariate analysis.
Patient characteristics (n = 250)
Values
Age, years † Male: female (n) Body mass index, kg/m2* Body surface area, m2* Previous myocardial infarction (n (%)) Previous percutaneous coronary intervention (n (%)) Previous coronary artery bypass grafting (n (%)) Coronary artery disease (n (%)) Diabetes mellitus (n (%)) Current smoker (n (%)) Hypertension (n (%)) Hyperlipidaemia (n (%)) LV ejection fraction b35% (n (%)) Cerebrovascular disease (n (%)) Chronic kidney disease (n (%)) Pulmonary hypertension (n (%)) Chronic obstructive airways disease (n (%)) Peripheral arterial disease (n (%)) Logistic Euroscore† STS-PROM † Aortic annulus diameter, mm † Mean aortic gradient, mm Hg Access site (TF:Tap:Tax:TA) (n) Sheath size, mm † White cell count, × 109/L† Red cell count, × 1012/L† Haemoglobin, g/dL* Mean corpuscular volume, fL † Red blood cell distribution width, %† Platelet count, × 109/L † Mean platelet volume, fL*
81 (76–85) 135:115 26.13 ± 4.58 1.77 ± 0.17 57 (22.8%) 50 (20%) 56 (22.4%) 102 (40.8%) 75 (30%) 9 (3.6%) 177 (70.8%) 150 (60%) 39 (15.6%) 44 (17.6%) 85 (34%) 37 (14.8%) 95 (38%) 73 (29.2%) 21.03 (11.99–32.31) 5.90 (4.1–9.08) 24 (22–24.5) 52.91 ± 17.04 205:18:26:1 19 (18–22) 6.7 (5.48–8.22) 4.21 (3.88–4.57) 12.1 ± 1.78 89.2 (85.4–92.8) 14.7 (13.7–16.1) 192 (151–236) 10.8 ± 1.06
Values are expressed as mean ± SD* or median (IQR)† or number (% of patients). Abbreviations: STS-PROM = Society of Thoracic Surgeons Predicted Risk of Mortality; TF = transfemoral: Tap = transapical; Tax = trans-axillary; TA = trans-aortic.
The predictors of 1-year all-cause mortality (Table 2) were previous PCI, CKD, low BMI and high RDW. In ROC analysis, an RDW value of 15.15% was an effective cut-off point of the 1-year all-cause mortality (area under curve = 0.65, 95% CI: 0.55–0.75), yielding a sensitivity of 65.7% and a specificity of 63.3%. This is the first report demonstrating the prognostic significance of RDW in TAVI patients. Given that RDW is routinely reported as a component of the complete blood count, is inexpensive, and not affected by renal function, understanding its prognostic significance could be very valuable for risk stratification in clinical decisionmaking. In countries with limited funds, RDW can help identify subjects who will benefit most from TAVI. On the other hand, it can also help detect those patients who need to be monitored more carefully to improve longevity. RDW is a measure of deviation of the volume of RBCs, and not directly the diameter. The underlying mechanisms linking RDW with increasing mortality both in CAD and in our TAVI population is still unknown, particularly whether RDW is an independent cardiovascular risk factor or a marker of underlying comorbidities. Possibly, high RDW could be an indicator of altered red blood cell rheological properties, as suggested by its association with increased total blood viscosity [1], red blood cell agglutination and fragmentation [2], resulting in significant changes in the microcirculation and occlusion [3]. Oxidative stress and chronic inflammation might also contribute, as suggested by the association of RDW with hsCRP and pro-inflammatory cytokines [4]; these might attenuate erythropoietin activity resulting in ineffective erythropoiesis [5] while oxidative stress promotes haemolysis [6] leading
0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.216
Univariable
Multivariable
Variable
P value
Odds ratio (95% CI)
P value
Previous PCI Coronary artery disease LV Ejection fraction b 35% Chronic kidney disease Access site (TF:Tap:Tax:TA) Body mass index, kg/m2 Logistic Euroscore STS-PROM RDW, %
0.042 0.043 0.005 b0.001 0.01 0.002 0.003 0.003 0.005
2.24 (1.10–4.56)
0.036
2.60 (1.29–5.21)
0.004
0.85 (0.78–0.94)
0.001
1.20 (1.06–1.35)
0.036
Abbreviations: PCI = percutaneous coronary intervention; RDW = red blood cell distribution width; STS-PROM = Society of Thoracic Surgeons Predicted Risk of Mortality; TF = transfemoral: Tap = transapical; Tax = trans-axillary; TA = transaortic.
to elevated RDW [5]. Neurohumoral activation might play a role by stimulating erythropoietin release [7]. Iron, vitamin B12 and folate deficiency might adversely influence erythropoiesis [8]; however, the fact that mean corpuscular volume was not found to be an important contributor to mortality goes against this hypothesis. Alternatively, RDW is a surrogate of overall cellular membrane integrity [9] or a marker of unstable plaque disease. Previous PCI, CKD and low BMI were also independent predictors of 1-year mortality. Subjects with previous PCI probably represent those with more diffuse atherosclerosis. Similarly, CKD leads to accelerated atherosclerosis. The obesity paradox shown has been previously observed [10]; possible mechanisms include malnutrition– inflammation complex syndrome, endotoxin–lipoprotein hypothesis, survival bias and reverse causation. Our findings provide impetus for further studies to explain the underlying pathophysiological mechanisms linking RDW with mortality following TAVI with improved outcomes in this high-risk elderly population.
References [1] Savov Y, Antonova N, Zvetkova E, Gluhcheva Y, Ivanov I, Sainova I. Whole blood viscosity and erythrocyte hematometric indices in chronic heroin addicts. Clin Hemorheol Microcirc 2006;35:129–33. [2] Bessman JD, Gilmer Jr PR, Gardner FH. Improved classification of anemias by MCV and RDW. Am J Clin Pathol 1983;80:322–6. [3] Cavusoglu E, Chopra V, Gupta A, et al. Relation between red blood cell distribution width (RDW) and all-cause mortality at two years in an unselected population referred for coronary angiography. Int J Cardiol 2010;141:141–6. [4] Lippi G, Targher G, Montagnana M, et al. Relation between red blood cell distribution width and inflammatory biomarkers in a large cohort of unselected outpatients. Arch Pathol Lab Med 2009;133:628–32. [5] Tsuboi S, Miyauchi K, Kasai T, et al. Impact of red blood cell distribution width on long-term mortality in diabetic patients after percutaneous coronary intervention. Circ J 2013;77(2):456–61. [6] Marinkovic D, Zhang X, Yalcin S, et al. Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J Clin Invest 2007;117:2133–44. [7] Eschbach JW. Anemia management in chronic kidney disease: role of factors affecting epoetin responsiveness. J Am Soc Nephrol 2002;13:1412–4. [8] Montagnana M, Cervellin G, Meschi T, Lippi G. The role of red blood cell distribution width in cardiovascular and thrombotic disorders. Clin Chem Lab Med 2012;50(4):635–41. [9] Goldstein MR, Mascitelli L, Pezzetta F. Is red blood cell distribution width a marker of overall membrane integrity? Arch Intern Med 2009;169(16):1539–40. [10] van der Boon RM, Chieffo A, Dumonteil N, et al. Effect of body mass index on shortand long-term outcomes after transcatheter aortic valve implantation. Am J Cardiol Jan 15 2013;111(2):231–6.
Contents lists available at ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Letters to the Editor
Red blood cell distribution width predicts one-year mortality following transcatheter aortic valve implantation Caroline J. Magri 1, Alaide Chieffo ⁎,1, Azeem Latib 1, Matteo Montorfano 1, Francesco Maisano 1, Michela Cioni 1, Eustachio Agricola 1, Remo Daniel Covello 1, Chiara Gerli 1, Annalisa Franco 1, Pietro Spagnolo 1, Ottavio Alfieri 1, Antonio Colombo 1 Interventional Cardiology Unit, San Raffaele Scientific Institute, 60, Via Olgettina, Milan, Italy
a r t i c l e
i n f o
Article history: Received 18 November 2013 Accepted 29 December 2013 Available online 8 January 2014 Keywords: Red blood cell distribution width Transcutaneous aortic valve implantation Mortality Body mass index Percutaneous coronary intervention Chronic kidney disease
Transcatheter aortic valve implantation (TAVI) is an effective alternative in high-risk patients with severe symptomatic aortic stenosis (AS). Risk stratification in TAVI is a relevant issue. The available risk models, such as the EuroSCORE, have shown several limitations, including poor performance in the elderly population. There is a need to identify new prognosticators that are simple, costeffective and widely available. Red blood cell distribution width (RDW), routinely reported in automated complete blood counts (CBC), is a numerical measure of the size variation of the erythrocytes. Clinical studies have shown a strong and independent association between RDW and cardiovascular disease. The current study sought to determine whether higher RDW levels are associated with increased risk of death in high-risk elderly subjects undergoing TAVI. The study population comprised 250 consecutive patients with severe symptomatic AS who were referred to San Raffaele Scientific Institute, Milan, Italy for TAVI from November 2007 to January 2011. Patients were evaluated by a multidisciplinary Heart Team. Past medical history and cardiovascular risk factors were noted. The transfemoral approach was the standard technique used; the transaxillary, the transapical or the transaortic access was utilized
⁎ Corresponding author. E-mail address: [email protected] (A. Chieffo). 1 This author takes responsibility for all aspects of reliability and freedom from bias of the data presented and their discussed interpretation.
when the peripheral vascular anatomy was not suitable. The devices used were the Edwards-SAPIEN/SAPIEN XT (ESV) and the Medtronic CoreValve ReValving Technology (MCV). Blood samples were drawn at baseline. The normal reference range for RDW is between 11.5% and 14.5%. The primary end-point investigated was all-cause mortality at one year. Informed consent was obtained from each patient. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. Data were analysed using SPSS version 21.0. The following covariates were investigated for association with one-year mortality in univariate analysis: age, sex, body mass index (BMI), logistic EuroSCORE, STSPROM, previous myocardial infarction (MI), coronary artery bypass grafting, or percutaneous coronary intervention (PCI), coronary artery disease (CAD), hypertension, chronic obstructive pulmonary disease, diabetes mellitus, peripheral vascular disease, chronic kidney disease (CKD), cerebrovascular disease, ejection fraction b35%, aortic annulus diameter, access site, sheath size, white cell count, haemoglobin, red cell count, RDW, mean corpuscular volume, platelet count and mean platelet volume. Significant determinants (p b 0.1) identified from univariate analysis were studied in a forward stepwise Cox regression model. Receiver–operator curve (ROC) analysis was used to define the optimal cut-off value for the RDW in predicting mortality. The baseline demographic characteristics of the patients studied are reported in Table 1. 59.2% of the procedures were performed using ESV. 26 mm valves were most commonly used (49.6%) while 48.8% of the procedures were performed using an 18 French sheath. The overall procedural outcomes were satisfactory, with a device success rate of 91.2%, and a low procedural complication rate (valve embolization in 2.8% of patients; shock in 11.2% of patients; cardiac tamponade in 3.2%), Bleeding events were the commonest complications with life-threatening bleeding noted in 28.8%, major bleeding in 36% while minor bleeding occurred in 8.8%. Major vascular complications were observed in 18%. The in-hospital complication rates were low: 7 patients experienced a transient ischaemic attack (TIA), 2 patients had a stroke, 4 patients sustained a MI and 13 patients (5.2%) died. The event rate at 30 days was similarly low: 6 patients had a TIA, 1 patient sustained a stroke while 3 had a MI. 30-day mortality was noted in 13 patients (5.2%) while 36 patients (14.4%) died within one year. Of these, cardiovascular mortality was noted in 24 patients. Also, at 1 year, 5 patients had sustained a stroke and 5 had sustained a MI.
Letters to the Editor Table 1 Baseline characteristics of study population.
457
Table 2 1-year all-cause mortality in TAVI patients, univariate analysis and multivariate analysis.
Patient characteristics (n = 250)
Values
Age, years † Male: female (n) Body mass index, kg/m2* Body surface area, m2* Previous myocardial infarction (n (%)) Previous percutaneous coronary intervention (n (%)) Previous coronary artery bypass grafting (n (%)) Coronary artery disease (n (%)) Diabetes mellitus (n (%)) Current smoker (n (%)) Hypertension (n (%)) Hyperlipidaemia (n (%)) LV ejection fraction b35% (n (%)) Cerebrovascular disease (n (%)) Chronic kidney disease (n (%)) Pulmonary hypertension (n (%)) Chronic obstructive airways disease (n (%)) Peripheral arterial disease (n (%)) Logistic Euroscore† STS-PROM † Aortic annulus diameter, mm † Mean aortic gradient, mm Hg Access site (TF:Tap:Tax:TA) (n) Sheath size, mm † White cell count, × 109/L† Red cell count, × 1012/L† Haemoglobin, g/dL* Mean corpuscular volume, fL † Red blood cell distribution width, %† Platelet count, × 109/L † Mean platelet volume, fL*
81 (76–85) 135:115 26.13 ± 4.58 1.77 ± 0.17 57 (22.8%) 50 (20%) 56 (22.4%) 102 (40.8%) 75 (30%) 9 (3.6%) 177 (70.8%) 150 (60%) 39 (15.6%) 44 (17.6%) 85 (34%) 37 (14.8%) 95 (38%) 73 (29.2%) 21.03 (11.99–32.31) 5.90 (4.1–9.08) 24 (22–24.5) 52.91 ± 17.04 205:18:26:1 19 (18–22) 6.7 (5.48–8.22) 4.21 (3.88–4.57) 12.1 ± 1.78 89.2 (85.4–92.8) 14.7 (13.7–16.1) 192 (151–236) 10.8 ± 1.06
Values are expressed as mean ± SD* or median (IQR)† or number (% of patients). Abbreviations: STS-PROM = Society of Thoracic Surgeons Predicted Risk of Mortality; TF = transfemoral: Tap = transapical; Tax = trans-axillary; TA = trans-aortic.
The predictors of 1-year all-cause mortality (Table 2) were previous PCI, CKD, low BMI and high RDW. In ROC analysis, an RDW value of 15.15% was an effective cut-off point of the 1-year all-cause mortality (area under curve = 0.65, 95% CI: 0.55–0.75), yielding a sensitivity of 65.7% and a specificity of 63.3%. This is the first report demonstrating the prognostic significance of RDW in TAVI patients. Given that RDW is routinely reported as a component of the complete blood count, is inexpensive, and not affected by renal function, understanding its prognostic significance could be very valuable for risk stratification in clinical decisionmaking. In countries with limited funds, RDW can help identify subjects who will benefit most from TAVI. On the other hand, it can also help detect those patients who need to be monitored more carefully to improve longevity. RDW is a measure of deviation of the volume of RBCs, and not directly the diameter. The underlying mechanisms linking RDW with increasing mortality both in CAD and in our TAVI population is still unknown, particularly whether RDW is an independent cardiovascular risk factor or a marker of underlying comorbidities. Possibly, high RDW could be an indicator of altered red blood cell rheological properties, as suggested by its association with increased total blood viscosity [1], red blood cell agglutination and fragmentation [2], resulting in significant changes in the microcirculation and occlusion [3]. Oxidative stress and chronic inflammation might also contribute, as suggested by the association of RDW with hsCRP and pro-inflammatory cytokines [4]; these might attenuate erythropoietin activity resulting in ineffective erythropoiesis [5] while oxidative stress promotes haemolysis [6] leading
0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.216
Univariable
Multivariable
Variable
P value
Odds ratio (95% CI)
P value
Previous PCI Coronary artery disease LV Ejection fraction b 35% Chronic kidney disease Access site (TF:Tap:Tax:TA) Body mass index, kg/m2 Logistic Euroscore STS-PROM RDW, %
0.042 0.043 0.005 b0.001 0.01 0.002 0.003 0.003 0.005
2.24 (1.10–4.56)
0.036
2.60 (1.29–5.21)
0.004
0.85 (0.78–0.94)
0.001
1.20 (1.06–1.35)
0.036
Abbreviations: PCI = percutaneous coronary intervention; RDW = red blood cell distribution width; STS-PROM = Society of Thoracic Surgeons Predicted Risk of Mortality; TF = transfemoral: Tap = transapical; Tax = trans-axillary; TA = transaortic.
to elevated RDW [5]. Neurohumoral activation might play a role by stimulating erythropoietin release [7]. Iron, vitamin B12 and folate deficiency might adversely influence erythropoiesis [8]; however, the fact that mean corpuscular volume was not found to be an important contributor to mortality goes against this hypothesis. Alternatively, RDW is a surrogate of overall cellular membrane integrity [9] or a marker of unstable plaque disease. Previous PCI, CKD and low BMI were also independent predictors of 1-year mortality. Subjects with previous PCI probably represent those with more diffuse atherosclerosis. Similarly, CKD leads to accelerated atherosclerosis. The obesity paradox shown has been previously observed [10]; possible mechanisms include malnutrition– inflammation complex syndrome, endotoxin–lipoprotein hypothesis, survival bias and reverse causation. Our findings provide impetus for further studies to explain the underlying pathophysiological mechanisms linking RDW with mortality following TAVI with improved outcomes in this high-risk elderly population.
References [1] Savov Y, Antonova N, Zvetkova E, Gluhcheva Y, Ivanov I, Sainova I. Whole blood viscosity and erythrocyte hematometric indices in chronic heroin addicts. Clin Hemorheol Microcirc 2006;35:129–33. [2] Bessman JD, Gilmer Jr PR, Gardner FH. Improved classification of anemias by MCV and RDW. Am J Clin Pathol 1983;80:322–6. [3] Cavusoglu E, Chopra V, Gupta A, et al. Relation between red blood cell distribution width (RDW) and all-cause mortality at two years in an unselected population referred for coronary angiography. Int J Cardiol 2010;141:141–6. [4] Lippi G, Targher G, Montagnana M, et al. Relation between red blood cell distribution width and inflammatory biomarkers in a large cohort of unselected outpatients. Arch Pathol Lab Med 2009;133:628–32. [5] Tsuboi S, Miyauchi K, Kasai T, et al. Impact of red blood cell distribution width on long-term mortality in diabetic patients after percutaneous coronary intervention. Circ J 2013;77(2):456–61. [6] Marinkovic D, Zhang X, Yalcin S, et al. Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J Clin Invest 2007;117:2133–44. [7] Eschbach JW. Anemia management in chronic kidney disease: role of factors affecting epoetin responsiveness. J Am Soc Nephrol 2002;13:1412–4. [8] Montagnana M, Cervellin G, Meschi T, Lippi G. The role of red blood cell distribution width in cardiovascular and thrombotic disorders. Clin Chem Lab Med 2012;50(4):635–41. [9] Goldstein MR, Mascitelli L, Pezzetta F. Is red blood cell distribution width a marker of overall membrane integrity? Arch Intern Med 2009;169(16):1539–40. [10] van der Boon RM, Chieffo A, Dumonteil N, et al. Effect of body mass index on shortand long-term outcomes after transcatheter aortic valve implantation. Am J Cardiol Jan 15 2013;111(2):231–6.