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

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

3. 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:  Symptomatic chronic HF > 4 weeks duration  Serum Cr < 3 mg/dl, K < 5.5 mmol/L  Absence of MI or stroke in the prior 4 weeks  Absence of non-cardiac disease judged to limit 2- year survival

4. Methods n 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 n 36 measures: l l Chemistry: BMP, Ca/Mg/P, LFTs, lipids, CK, uric acid l l Hematology: CBC, differential, HbA1c n n CV death and HF hospitalizations were the 1º endpoint n n Cox proportional hazards modeling

5. Clinical Variables by HF Hosp or CV Death Baseline CharacteristicsNo event Event (N=1727) (N=952) (N=1727) (N=952) History Age (year)64.167.4 Etiology (ischemic)65.0%71.5% NYHA Class III56.1%70.1% NYHA Class IV1.3%5.5% Prior hospitalization for HF62.4%77.7% Ejection Fraction0.400.35 Stroke9.4%12.7% Diabetes Mellitus30.8%48.8% Atrial fibrillation25.3%35.2% Physical Exam Systolic BP (mmHg)129.1126.5 Pulmonary crackles10.5%16.8% Cardiomegaly8.4%20.1%

6. Key Laboratory Parameters by Outcome Mean SD Sodium (mmol/l)140.4 2.9 140.0 3.2 Urea nitrogen (mg/dl)25 12 32 17 Creatinine (mg/dl)1.1 0.4 1.3 0.9 Albumin (g/dl)4.15 0.31 4.07 0.33 Bilirubin Total (mg/dl)0.61 0.32 0.72 0.47 Uric Acid (mg/dl)6.7 2.0 7.6 2.3 Cholesterol (mg/dl)197 46 189 50 White cell count (10 3 /mm 3 )7.2 2.1 7.6 2.3 Lymphocytes (%)26.5 8.4 23.6 8.7 Hemoglobin (g/dl)13.7 1.5 13.4 3.1 RDW (%)14.4 1.6 15.2 2.0 Glycohemoglobin A1C (%)6.8 1.4 7.3 1.6 CV Death or HF Hospitalization Event (N=952) Event (N=952) No event (N=1727) No event (N=1727)

7. Multivariable Model for CV Death or HF Hosp CHARM – LaboratoriesHR*95%CI Χ 2 RDW1.171.10-1.2524.78 Bilirubin Total1.141.08-1.2120.72 Lymphocyte %0.860.80-0.9315.09 Uric Acid1.131.06-1.2112.20 HbA1C1.121.04-1.228.46 Hemoglobin0.900.84-0.978.15 Creatinine1.131.03-1.236.79 *HR for continuous variables shown as standardized HR (HR per 1 SD)

8. Multivariable Model for CV Death or HF Hosp CHARM – All VariablesHR*95%CI Χ 2 Age (per 10yr >60)1.321.21-1.4441.32 Cardiomegaly1.561.33-1.8428.15 RDW1.171.10-1.2524.78 HF Hosp < 6 mo1.531.28-1.8421.11 Bilirubin Total1.141.08-1.2120.72 NYHA Class IV2.091.52-2.8920.43 NYHA Class III1.421.21-1.6618.88 EF (per 5% ↓<45%)1.591.29-1.9718.24 *HR for continuous variables shown as standardized HR (HR per 1 SD)

9. 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

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

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

12. 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

13. Multivariable Model for All-Cause Death Duke - All Predictors HR*95%CI Χ 2 Age1.491.32-1.6939.17 RDW1.291.16-1.4321.65 Hemoglobin0.790.71-0.8817.74 # Diseased Vessels1.191.08-1.3013.31 Non-CV Charlson Index # 1.141.05-1.2311.02 Systolic Blood Pressure0.850.76-0.958.75 Ejection Fraction0.880.78-0.985.30 History of Hypertension0.780.62-0.994.33 Male1.271.01-1.604.10 *Hazard ratios for continuous variables shown as standardized hazard rations (HR per 1 SD); #Charlson index is a combined measure of non-cardiac comorbidity

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

15. 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