Red Cell Distribution Width RDW as a Novel

Red Cell Distribution Width (RDW) as a Novel Prognostic Marker in Heart Failure: Data from the CHARM Program and the Duke Databank

Study Objective n To identify prognostic biomarkers from a wide range of routine laboratory measures in symptomatic heart failure patients Ø Derivation Dataset: CHARM Ø Replication Dataset: Duke Databank

Derivation Dataset n CHARM North American Cohort l N=2679 l Enrollment March 1999 - March 2001 l Median follow-up of 34 months l Major enrollment criteria included: Ø Symptomatic chronic HF > 4 weeks duration Ø Serum Cr < 3 mg/dl, K < 5. 5 mmol/L Ø Absence of MI or stroke in the prior 4 weeks Ø Absence of non-cardiac disease judged to limit 2 year survival

Methods n Blood samples were collected at time of randomization l n=1085 CHARM-Preserved (EF > 40%) l n=931 CHARM-Added (concurrent ACEI + EF ≤ 40%) l n=663 CHARM-Alternative (ACEI intolerance + EF ≤ 40%) n 36 measures: l Chemistry: BMP, Ca/Mg/P, LFTs, lipids, CK, uric acid l Hematology: CBC, differential, Hb. A 1 c n CV death and HF hospitalizations were the 1º 1 endpoint n Cox proportional hazards modeling

Clinical Variables by HF Hosp or CV Death Baseline Characteristics No event Event (N=1727) (N=952) History Age (year) 64. 1 67. 4 Etiology (ischemic) 65. 0% 71. 5% NYHA Class III 56. 1% 70. 1% NYHA Class IV 1. 3% 5. 5% Prior hospitalization for HF 62. 4% 77. 7% Ejection Fraction 0. 40 0. 35 Stroke 9. 4% 12. 7% Diabetes Mellitus 30. 8% 48. 8% Atrial fibrillation 25. 3% 35. 2% Physical Exam Systolic BP (mm. Hg) 129. 1 126. 5 Pulmonary crackles 10. 5% 16. 8% Cardiomegaly 8. 4% 20. 1%

Key Laboratory Parameters by Outcome CV Death or HF Hospitalization No event (N=1727) Mean Event (N=952) Mean SD Sodium (mmol/l) 140. 4 Urea nitrogen (mg/dl) Creatinine (mg/dl)1. 1 2. 9 140. 0 3. 2 25 12 32 0. 4 1. 3 0. 9 Albumin (g/dl) 4. 15 Bilirubin Total (mg/dl) Uric Acid (mg/dl) 6. 7 Cholesterol (mg/dl) 0. 31 4. 07 0. 33 0. 61 0. 32 0. 72 2. 0 7. 6 2. 3 197 46 189 50 2. 1 7. 6 23. 6 2. 3 SD White cell count (103/mm 3) 7. 2 Lymphocytes (%) 26. 5 Hemoglobin (g/dl) 13. 7 1. 5 RDW (%) 14. 4 1. 6 Glycohemoglobin A 1 C (%) 6. 8 8. 4 13. 4 15. 2 3. 1 1. 4 7. 3 17 0. 47 8. 7 2. 0 1. 6

Multivariable Model for CV Death or HF Hosp CHARM – Laboratories HR* RDW 1. 17 Bilirubin Total Lymphocyte % Uric Acid 1. 13 Hb. A 1 C 1. 12 Hemoglobin Creatinine 1. 13 95%CI 1. 10 -1. 25 24. 78 1. 14 1. 08 -1. 21 20. 72 0. 86 0. 80 -0. 93 15. 09 1. 06 -1. 21 12. 20 1. 04 -1. 22 8. 46 0. 90 0. 84 -0. 97 8. 15 1. 03 -1. 23 6. 79 *HR for continuous variables shown as standardized HR (HR per 1 SD) Χ 2

Multivariable Model for CV Death or HF Hosp CHARM – All Variables HR* 95%CI Χ 2 Age (per 10 yr >60) 1. 32 1. 21 -1. 44 41. 32 Cardiomegaly 1. 56 1. 33 -1. 84 28. 15 RDW 1. 17 1. 10 -1. 25 24. 78 HF Hosp < 6 mo 1. 53 1. 28 -1. 84 21. 11 Bilirubin Total 1. 14 1. 08 -1. 21 20. 72 NYHA Class IV 2. 09 1. 52 -2. 89 20. 43 NYHA Class III 1. 42 1. 21 -1. 66 18. 88 EF (per 5% ↓<45%) 1. 59 1. 29 -1. 97 18. 24 *HR for continuous variables shown as standardized HR (HR per 1 SD)

Red Cell Distribution Width? n RDW = the variation in red blood cell volume (anisocytosis) n Elevated in variety of diseases l Iron deficiency l Malnutrition l Chronic kidney disease n Calculated automatically on every CBC

Adjusted Hazard Ratio CHARM Adjusted HR by quintile of RDW for CV Death or HF Hospitalization Events = 952 RDW Quintiles

Adjusted Hazard Ratio CHARM Adjusted HR by quintile of RDW for All-Cause Mortality Events = 625 RDW Quintiles

Replication Dataset – Duke Databank n Duke Databank for Cardiovascular Disease (DDCD) l Registry of all patients undergoing cardiac cath at Duke since 1969 l Mortality follow up >96% n Limited dataset for this analysis l 1999 -2003 l Symptomatic HF (NYHA II-IV) at enrollment Irrespective of LVEF l RDW value available 0 -30 days prior to enrollment n Multivariable Cox model was constructed identifying the relationship of baseline variables (including RDW) to all-cause mortality

Multivariable Model for All-Cause Death Duke - All Predictors HR* 95%CI Χ 2 Age 1. 49 1. 32 -1. 69 39. 17 RDW 1. 29 1. 16 -1. 43 21. 65 Hemoglobin 0. 79 0. 71 -0. 88 17. 74 # Diseased Vessels 1. 19 1. 08 -1. 30 13. 31 Non-CV Charlson Index# 1. 14 1. 05 -1. 23 11. 02 Systolic Blood Pressure 0. 85 0. 76 -0. 95 8. 75 Ejection Fraction 0. 88 0. 78 -0. 98 5. 30 History of Hypertension 0. 78 0. 62 -0. 99 4. 33 Male 1. 27 1. 01 -1. 60 4. 10 *Hazard ratios for continuous variables shown as standardized hazard rations (HR per 1 SD); #Charlson index is a combined measure of non-cardiac comorbidity

Adjusted Hazard Ratio Duke Adjusted HR by quintile of RDW for All-Cause Mortality Events = 368 RDW Quintiles

Conclusions n Among 36 routine laboratory measures in a large HF trial database, higher RDW showed the greatest association with CV death and HF hospitalization n This finding was replicated in a large registry, where RDW continued to be strongly associated with mortality n Understanding how and why this marker is associated with outcome may provide l Improved targeting of HF therapies l Increased understanding HF pathophysiology