Trial to Reduce Cardiovascular Events with Aranesp* Therapy John J.V. McMurray, Hajime Uno, Petr Jarolim, Akshay S. Desai, Dick de Zeeuw, Kai-Uwe Eckardt, Peter Ivanovich, Andrew S. Levey, Eldrin F. Lewis, Janet B. McGill, Patrick Parfrey, Hans- Henrik Parving, Robert M Toto, Scott D. Solomon & Marc A. Pfeffer for the TREAT investigators* *darbepoetin alfa Disclosures: This study was sponsored by Amgen. All investigators received research funding and some received consulting fees from the sponsor. A full list of disclosures is publicly released.
Outline of presentation The clinical problem Summary of TREAT Cardiovascular risk modelling- standard variables Cardiovascular risk modelling- addition of cardiac biomarkers Discussion and conclusions
Survival Probability (All-Cause Mortality) Incremental Risk of CKD and Anaemia in relation to Mortality in Subjects With Diabetes 1.0 ARIC, Cardiovascular Health Study, Framingham Heart Studies. n = 3015 subjects with DM.90.80.70 DM DM, Anaemia DM, CKD.60.50 Hypothesis Anemia+, CKD+, (71) HR: 2.84 (2.05 to 3.91) Anemia+, CKD-, (174) HR: 1.21 (0.89 to 1.65) Anemia-, CKD+, (344) HR: 1.51 (1.25 to 1.82) Anemia-, CKD-, (2426) HR: 1 In patients with type 2 diabetes, chronic kidney disease not requiring dialysis, and concomitant anaemia, raising haemoglobin with darbepoetin alfa would lower the rates of death and cardiovascular morbidity and/or death and end-stage renal disease..20.10 0 0 2 4 6 8 10 Years Since Baseline Vlagopoulos PT et al. J Am Soc Nephrol 16: 3403 3410, 2005 DM, CKD, Anaemia
TREAT: Trial to Reduce Cardiovascular Events with Aranesp (Darbepoetin alfa) Therapy International (24) multi-centre (623), double-blind, placebo-controlled randomized trial Study Population Type 2 DM CKD egfr 20-60 L/min/1.73 m 2 Anaemia Hb 11 g/dl transferrin saturation 15% N = 2012 Darbepoetin Group (Target Hemoglobin 13 g/dl) randomized (1:1), double blind, placebo-controlled N = 2026 Placebo Group Event-driven: 1203 patients with events 2 composite primary endpoints (adjudicated): Cardiovascular : death, MI, myocardial ischaemia, CHF or stroke. Renal: death or ESRD.
Baseline Characteristics Variable Darbepoetin alfa N = 2012 Placebo N = 2026 P-value Age (years) 68 68 0.22 Women 58.5 56.0 0.10 BMI (kg/m 2 ) 30.5 30.1 0.11 CVD history 64.0 66.9 0.05 CAD 43.2 45.5 0.16 Heart failure 31.5 35.2 0.01 Myocardial infarction 18.4 18.3 0.95 Stroke 11.5 10.7 0.41 PAD 21.2 20.8 0.73 Systolic BP (mmhg) 136 135 0.25 Diastolic BP (mmhg) 71 70 0.55 LDL mmol/l (mg/dl) 2.2 (84) 2.2 (85) 0.41
Baseline Characteristics Variables Darbepoetin alfa N = 2012 Placebo N = 2026 P-value Serum creatinine µmol/l (mg/dl) 159 (1.8) 168 (1.9) 0.01 egfr (ml/min/1.73 m 2 ) 34 33 0.03 Protein to creatinine ratio (g/g creatinine) 0.4 0.4 0.73 Hemoglobin A1c (%) 7.0 6.9 0.02 Baseline Hb (g/dl) 10.5 10.4 0.15 Insulin % 48.7 49.8 0.49 Oral hypoglycemic agents % 57.5 56.1 0.36 ACE inhibitor or ARB % 79.7 80.0 0.82 Beta blocker % 49.9 48.7 0.43 Statin or other lipid lowering % 64.6 64.0 0.72 Aspirin or other antiplatelet % 48.0 48.6 0.68
Patients With Events (%) Primary CV endpoint: Death, MI, Myocardial Ischemia,HF, Stroke 50 Median 2.4 yr follow-up 40 Darbepoetin alfa 632 (31.4%) Placebo 602 (29.7%) 30 20 HR: 1.05 (0.94-1.17) P = 0.41 10 0 Hb Median: 10.6 IQR [9.9 11.3] Hb Median: 12.5 IQR [12.0 12.8] 0 6 12 18 24 30 36 42 48 Months
Primary Composite and Component Endpoints Endpoint Darbepoetin alfa N = 2012 Placebo N = 2026 HR (95% CI) P- value CV Composite 632 (31.4) 602 (29.7) 1.05 (0.94-1.17) 0.41 Death 412 (20.5) 395 (19.5) 1.05 (0.92-1.21) 0.48 Heart Failure 205 (10.2) 229 (11.3) 0.89 (0.74-1.08) 0.24 MI 124 (6.2) 129 (6.4) 0.96 (0.75-1.22) 0.73 Stroke 101 (5.0) 53 (2.6) 1.92 (1.38-2.68) <0.001 Myocardial Ischaemia 41 (2.0) 49 (2.4) 0.84 (0.55-1.27) 0.40 Renal Composite 652 (32.4) 618 (30.5) 1.06 (0.95-1.19) 0.29 ESRD 338 (16.8) 330 (16.3) 1.02 (0.87-1.18) 0.83
TREAT: Trial conclusions In patients with Type 2 DM, CKD and anaemia a strategy to treat anemia with darbepoetin alfa: 1 : Did not reduce either primary composite endpoint of: Death and CV events or Death and ESRD Reduced RBC transfusion (24.5% vs. 14.8%. HR:0.56 (0.49-0.65) P < 0.001) Fact-Fatigue modestly improved Higher stroke rates were documented Supports data from cancer studies of higher mortality For many, these risks will outweigh the rather modest potential benefits
Outline of presentation The clinical problem Summary of TREAT Cardiovascular risk modelling- standard variables Cardiovascular risk modelling- addition of cardiac biomarkers Discussion and conclusions
Cardiovascular risk modelling standard variables Post-hoc composite outcome of cardiovascular death myocardial infarction, stroke or hospitalization for heart failure or myocardial ischaemia Univariate analysis of candidate variables Step 1: Individual multivariable models using age, sex, race in each and related candidate variables e.g. diabetes complications Step 2: Final multivariable model including predictors from Step1plus egfr, BP, HR and randomized treatment (darbepoetin/placebo).
Patients With Events (%) CV death, MI, myocardial ischaemia, HF or stroke 50 Median 2.4 yr follow-up 40 Darbepoetin alfa 518 (25.7%) Placebo 492 (24.3%) 30 20 10 HR: 1.04 (0.92-1.18) P = 0.54 0 0 12 24 36 48 Months
Baseline variables included in models variables not predictive Demographics/exam. Age Sex Smoking history HR BP BMI History Coronary heart disease Cerberovascular disease Heart failure Arrhythmia (AF/VT/VF/ICD/PM) PAD Hypertension Diabetes complications Lung disease GI bleeding Blood transfusion Gout/hyperuricaemia Treatment Insulin Loop diuretic Haematology/iron indices Hb Reticulocytes Ferritin TSAT WBC Platelets Blood chemistry TC/LDL/TG Potassium GFR (MDRD estimated) BUN Albumin CRP (not hscrp) HbA1c Urine Protein/creatinine ratio ECG (Echocardiogram)
Predictive model for CV mortality and morbidity ranked by chi-square ( 2 ) Variable (category/per unit increase) HR (95% CI) 2 P-value Heart failure (yes) 1.74 (1.51-2.01) 55.8 <.0001 Age (year) 1.03 (1.02-1.04) 46.1 <.0001 Urine prot/cr ratio (log g/g) 1.19 (1.13-1.26) 39.2 <.0001 CRP (g/dl) >6.6 >3.0-6.6 1.44 (1.23-1.69) 1.20 (1.02-1.41) 20.6 4.6 <.0001.0312 Abnormal ECG (yes) 1.42 (1.21-1.66) 19.2 <.0001 Albumin (g/dl) 0.70 (0.59-0.83) 16.7 <.0001 Coronary heart disease (yes) 1.32 (1.15-1.52) 15.0.0001 Cardiac arrhythmia (yes) 1.33 (1.13-1.56) 11.9.0006 Haemoglobin A1c (%) 1.07 (1.02-1.12) 8.2.0042 Reticulocytes (%) 1.11 (1.03-1.20) 7.8.0053 BUN (mg/dl) 1.06 (1.01-1.11) 5.8.0164 Insulin (yes) 1.22 (1.06-1.40) 7.3.0068 Cerebrovascular disease (yes) 1.21 (1.03-1.41) 5.5.0192 Loop diuretic (yes) 1.18 (1.02-1.37) 4.6.0312 Male 1.16 (1.01-1.34) 4.3.0381 Race (other vs. white) (black vs. white) 0.80 (0.65-0.99) 0.92 (0.77-1.09) 4.2 1.0.0417.3303
Additional prognostic information from combining urinary protein/cr ratio and CRP Adjusted HR* Cardiovascular mortality and morbidity 3 2.5 2 1.5 1 0.5 0 5.7% 20.2% <3.0 3.0-6.6 >6.6 T1 T2 T3 UPCR CRP *Age, sex, race, history CVD, abnormal ECG, HbA1c, egfr, BUN, serum albumin, retics, insulin Tx, loop diuretic Tx
Outline of presentation The clinical problem Summary of TREAT Cardiovascular risk modelling- standard variables Cardiovascular risk modelling- addition of cardiac biomarkers Discussion and conclusions
Cardiovascular risk modelling cardiac biomarker cohort First 1000 patients enrolled in TREAT had a baseline measurement of plasma cardiac biomarkers Troponin T (Roche; 99% upper reference limit 0.010 ng/ml) N terminal-pro B-type natriuretic peptide (Roche; pg/ml) Best CV risk model (developed using standard variables) was run in cardiac biomarker cohort This model was the re-run with NT-pro BNP (as log concentration) and TnT (3 categories undetectable, detectable median [0.028ng/mL] and detectable >median) added
Number of Patients NT-proBNP, TREAT baseline (n=1000) NT-proBNP Q1 Q2 Q3 Q4 < 273 pg/ml 273-601 pg/ml 602-1521 pg/ml > 1521 pg/ml 60% 450 pg/ml 38% 900 pg/ml 100 1000 10000 100000 NT-proBNP (logarithmic scale)
Troponin T, TREAT baseline (n=1000) 45% detectable TnT (>0.01ng/mL) Median detectable TnT = 0.028 ng/ml 0.01 0.02 0.04 0.06 0.08 0.10 ng/ml
CV risk model in cardiac biomarker cohort model with biomarkers Variable (category/per unit increase) HR (95% CI) 2 NT probnp (log pg/ml) 1.30 (1.15-1.46) 18.3 Age (yr) 1.03 (1.01-1.04) 16.1 Heart Failure (yes) 1.54 (1.19-2.00) 10.5 CRP (g/dl) + >6.6 >3.0-6.6 1.65 (1.22-2.23) 1.55 (1.16-2.08) 10.4 8.7 Abnormal ECG (yes) 1.45 (1.09-1.92) 6.5 Smoking (vs. current) former never TnT (ng/ml) + > 0.028 (median) 0.028 0.67 (0.41-1.09) 0.55 (0.33-0.91) 1.50 (1.06-2.13) 1.42 (1.05-1.93) 2.6 5.3 5.2 5.4 Urine prot/cr ratio (log g/g) 1.13 (1.02-1.25) 5.2
Additional prognostic information from combining NT-pro BNP and TnT Adjusted HR* Cardiovascular mortality and morbidity 3 2.5 2 1.5 1 0.5 0 4.7% <0.01 0.01-0.028 >0.028 T1 TnT 30.2% *Age, sex, race, history CVD, abnormal ECG, HbA1c, egfr, BUN, serum albumin, retics, insulin Tx, loop diuretic Tx and CRP + UPCR T2 T3 NT- BNP
Conclusions from CV risk modelling In this population with the triad of type-2 DM, CKD and anaemia, many conventional risk factors were not predictive of CV events e.g. lipids, blood pressure CRP and urinary protein/creatinine ratio were independent predictors of CV outcome This ambulatory population also had markedly abnormal cardiac biomarkers NT-pro BNP and TnT added important prognostic information to conventional risk markers In addition to aiding risk stratification, these plasma and urinary biomarkers may help understanding of the mechanisms underlying cardiac risk and suggest new therapeutic strategies in this population.