Although shown to improve mortality compared with medical therapy,1,2 the use of left ventricular assist devices (LVADs) is still associated with a high frequency of device-related complications including pump thrombosis, infection, stroke, and gastrointestinal (GI) bleeding.2–5 There are a number of risk predictive markers and models proposed to evaluate a patient’s candidacy for an LVAD for mortality,6–9 but fewer have comprehensively studied nonmortality outcomes after LVAD implant.10–13
The red blood cell distribution width (RDW) is a measure of red blood cell size variability.14 Felker et al.15 described RDW elevation as independently associated with cardiovascular death, hospitalization, and all-cause mortality in patients with heart failure (HF). They found the RDW to be more strongly associated with these outcomes than traditional parameters such as ejection fraction, renal function, and New York Heart Association functional class.15 The prognostic value of RDW elevation in HF has subsequently been validated in several other cohorts16,17 and meta-analyses.18,19 However, the relationship between RDW and post-LVAD outcomes remains unexplored.
RDW elevation is associated with oxidative stress, a pro-inflammatory state, and tissue hypoxia.20–23 Because of these mechanisms and the close association between LVAD complications and the hematologic system,24,25 one might postulate that a hematologic marker such as RDW would provide unique insight into prognosis in this population. In this study, we assess the association of preimplant RDW with discrete clinical outcomes, including mortality, GI bleed, stroke, pump thrombosis, and infection.
Materials and Methods
The medical records of all subjects aged 18 years or older that underwent care for continuous flow LVAD (HeartMate II [Thoratec, Pleasanton, CA] or HeartWare Framingham, MA]) at the Johns Hopkins Hospital between January 1, 2004 and June 30, 2014 were reviewed. Of the 196 patients identified, eight underwent LVAD implantation at an outside facility or had a preimplant biventricular assist device and were excluded, leaving a total of 188 patients in the final analysis. This study was approved by the Johns Hopkins Hospital Institutional Review Board.
Red Blood Cell Distribution Width Definition
RDW values assigned were all from within 24 hours before LVAD implant and represent the last value before implant for each patient. Complete blood cell counts, including RDW values, were measured using a Sysmex XN series analyzer (Sysmex Corporation, Kobe, Japan). Individuals were separated into tertiles with the preimplant tertile 1 defined as less than 15.7%, tertile 2 defined as 15.7% to 18%, and tertile 3 defined as greater than or equal to 18.1%. The RDW normal reference range at our institution is 11.5% to 14.5%.
All records were reviewed for five discrete clinical outcomes more than 1 year of follow-up with all-cause mortality being our primary outcome and GI bleeding, LVAD-associated infection, stroke, and pump thrombosis our secondary outcomes. Gastrointestinal bleeding was defined as an admission for GI bleed in the medical record with confirmation by endoscopy. Left ventricular assist device-associated infection was defined as a driveline infection, pump pocket infection, or sepsis of unknown source documented in the medical record. Pump thrombosis was defined as a pump thrombosis documented in the medical record requiring enhanced anticoagulation or need for pump exchange. Stroke was defined as a new ischemic or hemorrhagic stroke in the medical record with corroborating imaging.
Patient records were assessed for demographic variables, including age (years), sex, race (white; nonwhite), diabetes, body mass index (BMI) at the time of implant, LVAD type (Thoratec HeartMate II; HeartWare), cardiomyopathy etiology (ischemic; nonischemic), preoperative ventilator, and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1–3 (yes; no). Laboratory values were generally from within 24 hours before LVAD implant and included hemoglobin, mean corpuscular volume (MCV), white blood cell (WBC) count, total bilirubin, estimated glomerular filtration rate (GFR), albumin, and international normalized ratio (INR).
The distributions of demographic and clinical characteristics were compared by RDW tertile using χ2 for categorical variables and t-tests for continuous variables. Laboratory values including hemoglobin, MCV, albumin, INR, and total bilirubin were analyzed as continuous variables, and WBC (<4.5 × 109/L and ≥11 × 109/L vs. 4.5 × 109/L to <11 × 109/L) and GFR (<60 ml/min/1.73 m2vs. ≥60 ml/min/1.73 m2) were analyzed as binary values.
Cox proportional hazard models were used to assess the association between all-cause mortality and secondary clinical outcomes with RDW assessed by two methods, RDW tertiles and continuously. Tertiles were chosen because of similarity of the reference (tertile 1) with normal, physiologic RDW values (as assigned by our institution’s laboratory) as well as to preserve power. Patients that were transplanted before 1 year were censored from analyses. The proportional hazard assumptions were checked with the use of Schoenfeld residuals and graphic methods. We tested for trend across the median of RDW tertiles. Analyses were adjusted for demographic variables and comorbidities shown in previous cohorts to predict adverse outcomes (age, sex, race, diabetes, BMI, and INTERMACS profile) and then further adjusted for laboratory values typically included in LVAD risk scores (hemoglobin, MCV, total bilirubin, estimated GFR, albumin, and INR).7 We included hemoglobin and MCV to assess isolated RDW as an independent hematologic marker of risk.
To tailor our analyses and prevent being overfit, each secondary outcome was adjusted for known preimplant risk factors. Gastrointestinal bleed was adjusted for age, BMI, and cardiomyopathy type.26 Stroke was adjusted for age, race, and diabetes.26 Pump thrombosis was adjusted for age, estimated GFR, and BMI.26,27 Finally, infection was adjusted for age, BMI, diabetes, LVAD type, and INTERMACS profile.28
We additionally modeled the association of continuous RDW with all-cause mortality using a restricted cubic spline model with knots at the 5th, 35th, 65th, and 95th percentiles to assess for linearity. Sensitivity analyses for implant strategy (bridge to transplant vs. destination therapy) and implant era (pre or post 2010) were completed.
All reported p values were based on two-sided tests, and p < 0.05 was considered statistically significant. Statistical analysis was performed using Stata SE 13.1 (StataCorp, College Station, TX).
Characteristics of the study population overall and by RDW tertile are described in Table 1. The average age of individuals was 53.0 years with 22.3% women and 45.7% blacks. The etiology of HF was classified as ischemic in 31.9% and nonischemic in 68.1% of individuals. The HeartMate II device was used in 87.8% of implants with the HeartWare comprising the remaining 12.2% of the population. Roughly, 80% of patients had an INTERMACS profile of 1–3. At the time of LVAD implant, the average BMI was 28.3 kg/m2, 44.7% of patients had diabetes, and 44.2% of individuals had an estimated GFR less than 60 ml/min/1.73 m2. More than 1 year of follow-up, there were a total of 56 deaths, 31 incident GI bleeds, 63 incident LVAD-associated infections, 21 strokes, and 12 episodes of pump thrombosis. The 3 and 12 month mortality in our population was 23.4% and 29.8%, respectively. All baseline characteristics were similar between the tertiles except that individuals in tertile 3 were more likely than tertile 1 to have diabetes, an elevated total bilirubin, a lower albumin, and to be on preoperative inotropic support.
Compared with reference (tertile 1), both tertiles 2 (HR 6.95 [2.67–18.10]) and 3 (HR 4.61 [1.74–12.21]) showed a significantly greater risk of all-cause mortality (p < 0.005), which persisted after adjusting for demographic data, cardiovascular, and laboratory values (Table 2). Results in Table 2 are shown with only combined adjustment (demographic, cardiovascular disease, and laboratory), as results were similar throughout. We did not find statistically significant associations with RDW tertiles and the secondary clinical outcomes tested.
Figure 1A shows a Kaplan–Meier survival analysis for mortality by RDW tertile. Tertiles 2 and 3 overlap and separate steeply from tertile 1 early after implant (log-rank p value < 0.001). Individuals in tertile 1 with a preimplant RDW less than 15.7% exhibited approximately 10% mortality at 1 year compared with those in higher RDW tertiles, which demonstrated approximately 40% mortality. Figure 1B–E shows our secondary clinical outcomes, which did not reach statistical significance for infection (Figure 1C), stroke (Figure 1D), or pump thrombosis (Figure 1E). In log-rank analysis, GI bleed (Figure 1B) showed an association (p = 0.02) with RDW. Notably, tertile 2 had the greatest survival from GI bleed, and tertile 3 had the worst. Figure 2 shows the continuous association of RDW with mortality using an adjusted restricted cubic spline model and demonstrates that mortality risk was not linearly associated with RDW.
In sensitivity analyses, there were no interactions for both implant strategy and implant era (p > 0.05).
In this retrospective study, we found that preimplant RDW was strongly associated with mortality more than follow-up of 1 year after adjustment for demographic, cardiovascular, and laboratory variables. The relationship between RDW and mortality was similar between tertiles 2 and 3, suggesting a threshold effect. We did not find that increasing RDW was associated with any of our secondary outcomes.
The RDW reflects heterogeneity in the corpuscular volume of a population of red blood cells14 and is a robust prognostic marker in heart failure15–19 as well as several other disease states, including coronary artery disease.22,29 The biologic mechanism explaining these observations remains poorly defined. However, RDW is associated with a pro-inflammatory state and oxidative stress and has been found to be independently associated with other serologic markers of inflammation such as erythrocyte sedimentation rate and C-reactive protein levels.20 It is thought that oxidative stress impairs the membrane fluidity of erythrocytes, reducing the life span of the red blood cells and leading to anisocytosis, marked by elevated RDW.21 Furthermore, an elevated RDW has been shown to be associated with impaired microvascular perfusion and hypoxia even in patients without anemia.22 With other studies noting an association between RDW and inflammation and microvascular disease,20–22 the observed association between RDW and post-LVAD mortality is biologically plausible.
In patients with chronic kidney disease and HF, recent studies have found that RDW is independently associated with altered catabolism of fibroblast growth factor 23 (FGF23),30 which is a direct cardiotropic hormone involved in mineral metabolism and associated with endothelial dysfunction.31,32 Elevated serum concentrations of FGF23 have been associated with heart failure and mortality.33–35 This mechanism is thought to be because of the direct effects of FGF23 on cardiomyocyte cell signaling and activation of fetal growth pathways.31 As a surrogate for FGF23 elevation, an elevated preimplant RDW may signify a population with more myocardial and endothelial dysfunction, and thus higher risk postimplant.
Prior studies have found that changes in RDW over a relatively brief period of time (during a hospital admission) predict outcomes in patients with heart failure. In 229 consecutive patients admitted with acute decompensated heart failure, Uemura et al.36 found that patients whose RDW levels increased during hospitalization had significantly higher all-cause and cardiac mortality than those whose RDW levels decreased. This raises the question of whether changes in RDW levels in LVAD patients (either preimplant or postimplant) could be used to predict adverse events.
Several risk prediction models, such as the HeartMate II Risk Score (HMRS), have tried to assess postimplant LVAD survival. The HMRS incorporated four readily available variables to predict 90 day mortality. It was found to improve risk discrimination compared with the Destination Therapy Risk Score and Model for End-Stage Liver Disease.7 Although we stress that our results are hypothesis generating and must be validated, RDW could offer clinicians an easily obtainable and potent variable for LVAD risk prediction. Further, a larger cohort should assess for improved risk discrimination when RDW is added to currently available risk scores.
Our study needs to be interpreted in light of its limitations. The single-center nature of our study calls for evaluation of RDW in larger, multicenter LVAD populations with a focus not only on mortality but also on discrete postimplant adverse events. Our population may not match the average patient sample in the United States, which limits generalizability. Notably, our analyses were limited to 1 year of follow-up, which represents a relatively short follow-up in a group of patients nearing survival rates of 4 years.37 It may be that preoperative blood transfusions affected the preimplant RDW. However, our retrospective study was unable to accurately capture preoperative transfusion timing and amount for each patient, although it is more likely that patients would have been transfused postoperatively instead of preoperatively. Furthermore, by including hemoglobin and MCV, we attempted to “double” control for anemia as a possible confounder, and our results persisted after adjustment for these factors. We did not adjust for measures of right heart function because of a smaller sample size with this information available but was also notably not included in the HMRS. This study also has several strengths including the novel application of RDW to the LVAD population, robust multivariable adjustment, and a well-described population with 100% outcome ascertainment for patients implanted at our institution.
Preimplant RDW is strongly associated with mortality more than 1 year in patients supported with an LVAD in those with an elevated RDW. This relationship persisted despite adjustment for multiple risk factors. Given the association with inflammation and oxidative stress, an elevated RDW may represent a sicker population of patients. These results require further study as the RDW could offer a readily available adjunctive marker for risk stratification. Future studies should investigate whether short-term changes in RDW signal an LVAD patient population more prone to complications and would therefore necessitate closer monitoring.
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