High red cell distribution width associated with adverse outcomes in patients with coronary artery disease

January 6, 2008 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org] Alberta

The red cell distribution width (RDW) is a measure of the variability of size in the red cell population. It is a numerical measure of anisocytosis, computed as the standard deviation of the distribution of red cell widths divided by the mean corpuscular volume. RDW is often elevated in clinical practice by nutrient deficiencies, which lead to heterogeneous red cell populations. A large number of reticulocytes can also increase the RDW, as can lab errors from red cell clumping or counting of large platelets or schistocytes. Recently, data from the CHARM study of heart failure patients reported an association between elevated RDW and mortality among heart failure patients (1). Now, researchers have investigated the prognostic value of elevated RDW in coronary artery disease patients.

The CARE (Cholesterol And Recurrent Events) study was a randomized, placebo-controlled trial of pravastatin in patients with hyperlipidemia and a history of myocardial infarction. Patients from both the control and pravastatin arm (n=4111) were divided into quartiles based on baseline RDW values. Mean follow up was almost 60 months. Patients with higher RDW were older (mean 61 years in Q4 vs. 57 years in Q1), more were of black race (6% vs. 1.6%), current smokers (16.7 vs 12.1), with lower glomerular filtration rate (69 vs. 74 ml/min/m^2) and hemoglobin concentration (14.4 vs. 15.0). Medication use also differed significantly across quartiles, with ACE-inhibitors more common and aspirin less common in higher quartiles. Randomization to pravastatin did not differ across quartiles.

In unadjusted analyses, increasing RDW was associated with every adverse outcome measured, including increased mortality (HR 1.2 per percent increase in RDW, CI 1.12 to 1.29, p<0.001), fatal coronary disease or non-fatal myocardial infarction, stroke, fatal or non-fatal myocardial infarction, and symptomatic heart failure. After adjustment for a long list of covariates including hemoglobin level and MCV, the association between high RDW and these adverse events remained (mortality HR 1.14 per percent increase in RDW, CI 1.05 to 1.24; Symtomatic heart failure HR 1.15 per percent increase in RDW, CI 1.05 to 1.26). The risk was graded; those with lowest (<12.6%) RDW were the lowest-risk, and risk increased across RDW quartiles. Those in the highest RDW quartile had almost 80% increase in adjusted risk of death compared to those in the lowest quartile (HR 1.78, CI 1.28 to 2.47).

The association between high RDW and poor outcome is significant and substantial. Most patients have RDW measured as part of a complete blood cell count, and most physicians ignore this measure. Given the interest in novel biomarkers to predict adverse coronary heart disease outcomes, more attention should be paid to this readily available data. While empirically useful, the mechanism by which high RDW is associated with cardiovascular risk is unclear. The investigators included hemoglobin concentration and MCV in their multivariate analyses, suggesting that anemia and nutritional deficiencies might not be the cause. However, normal MCV does not rule out a nutritional deficiency, as often elevated RDW is seen prior to MCV elevation. The authors propose that high RDW might reflect a general inflammatory state causing ineffective erythropoiesis in addition to vascular disease progression. Future prospective studies should investigate this association with close attention to factors known to associate with elevated RDW and inflammation, as well as data from peripheral smears.