PROGNOSTIC VALUE OF OSTEOPROTEGERIN IN CHRONIC HEART FAILURE: THE GISSI-HF TRIAL

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1 PROGNOSTIC VALUE OF OSTEOPROTEGERIN IN CHRONIC HEART FAILURE: THE GISSI-HF TRIAL Ragnhild Røysland MD 1,2, Serge Masson PhD 3, Torbjørn Omland MD, PhD, MPH 1,2, Valentina Milani MS 3, Mette Bjerre PhD 4, Allan Flyvbjerg MD, PhD 4, Giuseppe Di Tano MD 5, Gianfranco Misuraca MD 6, Aldo P. Maggioni MD 7, Gianni Tognoni MD 8, Luigi Tavazzi MD 9, Roberto Latini MD 3 on behalf of the GISSI-HF Investigators. 1 Division of Medicine, Akershus University Hospital, Lørenskog, Norway, 2 Center for Heart Failure Research, University of Oslo, Norway, 3 Department of Cardiovascular Research, Istituto Mario Negri, Milan, Italy, 4 Department of Endocrinology and Internal Medicine & the Medical Research Laboratories, Clinical Institute, Aarhus University Hospital, Aarhus C, Denmark, 5 U.O. di Cardiologia, Azienda Istituti Ospitalieri di Cremona, Cremona, Italy, 6 Division of Cardiology, Ospedale Santissima Annunziata, Cosenza, Italy, 7 ANMCO Research Center, Florence, Italy, 8 Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy, 9 GVM Hospitals of Care and Research, Cotignola, Italy

2 DISCLOSURES GISSI-HF: GISSI is endorsed by Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), Florence, Italy; by Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; and by Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy; SPA, Pfizer, Sigma Tau and AstraZeneca concurred to fund the study. SPA provided the experimental treatment. R Røysland: None

3 OSTEOPROTEGERIN (OPG) TO PROTECT BONE a secreted glycoprotein First described in 1997 Member of the TNF reseptor superfamily Decoy receptor for RANKL and TRAIL Inhibits osteoclast activity Knockout: osteoporosis and arterial calcification Wilde-type mouse OPG knockout mouse Bucay et al. Genes Dev. 1998; 12(9):

4 OPG EXPRESSION IN MANY TISSUES OPG mrna expression in in human myocardium Mouse tissue Human tissue Mouse embryo Simonet et al. Cell. 1997; 89(2):

5 THE HEART A SOURCE OF CIRCULATING OPG? Heart tissue from nonfailing donor Heart tissue from patient with end-stage HF Ueland et al. Circulation 2005;111:

6 OPG IS ASSOCIATED WITH: LV mass & LV systolic function in the general population Hospitalisation for heart failure and mortality after ACS Omland et al. J Am Coll Cardiol. 2008; 51(6):

7 INFLAMMATION & HEART FAILURE Inflammation associated with progression of heart failure Increased circulating levels of proinflammatory cytokines is associated with adverse outcome However... The prognostic value of OPG in CHF is unknown The effect of statin therapy on circulating OPG level is unknown

8 OBJECTIVE Primary: To assess the prognostic value of OPG in CHF Secondary: To identify independent predictors of circulating OPG in CHF To assess the effect of statin therapy on OPG levels in CHF

9 THE GISSI-HF TRAIL A RCT (GRUPPO ITALIANO PER LO STUDIO DELLA SOPRAVVIVENZA NELL INFARTO MIOCARDICO HEART FAILURE) GISSI HF - Conducted in Italy, in 31 clinical centres - Patients included from GISSI-HF trial N = 6975 CHF of any etiology OPG sub study N = 1229 n-3 PUFA or placebo rosuvastatin or placebo Follow-up time: 3.9 years

10 METHODS Biomarker sub-study within clinical trial 1229 patients Samples collection: Randomisation 3 months Biomarker analysis ELISA using commercially available monoclonal antibodies (DY085E from R&D Systems, Abingdon, UK) Samples analysed in a single batch Primary endpoints was all-cause mortality the composite all-cause mortality or hospitalisation for CV causes EDTA blood samples

11 BASELINE CHARACTERISTICS RESULTS T1 ( ng/l) T2 ( ng/l) T3 ( ng/l) N OPG (range, ng/l) 252-1,209 1,210-1,922 1,923-6,848 Age (year) 60.4± ± ±8.2 < Females (%) < BMI (kg/m 2 ) 27.1± ± ± Heart rate (bpm) 69.8± ± ± SBP (mmhg) 123.3± ± ± DBP (mmhg) 77.0± ± ± NYHA class III-IV (%) < Ischemic etiology of HF (%) LVEF (%) 32.6± ± ± History of diabetes (%) < Serum creatinine (mg/dl) 1.00 [ ] 1.10 [ ] 1.20 [ ] < BNP (ng/l) 112 [45-209] 129 [55-291] 191 [85-368] < hscrp (mg/l) 1.78 [ ] 2.21 [ ] 3.22 [ ] < P

12 INDEPENDENT DETERMINANTS OF ELEVATED BASELINE OPG RESULTS Variable OR 95% CI p Age (y, continuous) < Serum creatinine (mg/dl, continuous) < Baseline BNP (ng/l, continuous) Serum fibrinogen (mg/dl, continuous) History of diabetes (yes) Gender (males) Prescription of spironolactone (yes) LVEF (continuous) History of paroxystic AF (yes) SBP (mmhg, continuous) Variables entered into the model (p<0.05 at univariate analysis) but not statistically significant in the multivariable model were: NYHA class, heart rate, ischemic etiology of HF, history of COPD, prescription of ACEI, ARB, β-blockers, diuretics and digitalis, baseline serum concentrations of LDL-cholesterol, baseline plasma concentration of hscrp.

13 Estimated probability of death ALL-CAUSE MORTALITY BY BASELINE TERTILES OF OPG RESULTS The OPG substudy: 332 patients died Median follow-up time: 3.9 years OPG 1923 ng/l OPG ng/l 0.1 OPG <1210 ng/l Time (year) Kaplan Meier curves for mortality.

14 OPG IS ASSOCIATED WITH ALL-CAUSE MORTLITY - A COX REGRESSION MODEL RESULTS a) with tertiles of OPG All-cause mortality Univariate models Multivariable models Hazard Ratio 95% CI P Hazard Ratio 95% CI P T1 [252-1,209 ng/l] 16.9% 1 (referent) 1 (referent) T2 [1,210-1,922 ng/l] 25.4% T3 [1,923-6,848 ng/l] 38.8% < b) with continuous OPG concentration 1 SD increment < Variables entered into the multivariable models: Model (a) with tertiles of OPG: Variable significant in the multivariable model (by decreasing order of chi-square): age, prescription of digitalis, LVEF, history of COPD, prescription of beta-blockers, history of diabetes. Variables entered into the multivariable model but not significant (by decreasing order of chi-square): history of atrial fibrillation, BMI, prescription of diuretics, ischemic etiology of HF. Model (b) with continuous OPG: Variable significant in the multivariable model (by decreasing order of chi-square): serum creatinine, NYHA class, age, LVEF, prescription of digitalis, history of COPD, systolic blood pressure, serum triglycerides, prescription of beta-blockers, history of diabetes. Variables entered into the multivariable model but not significant (by decreasing order of chi-square): serum bilirubin, hear rate, history of atrial fibrillation, serum fibrinogen, prescription of diuretics, diastolic blood pressure, ischemic etiology of HF.

15 EFFECT OF THERAPY? NO CHANGE IN OPG CONCENTRATION FROM BASELINE TO 3-MONTH Baseline OPG Median [Q1-Q3]), ng/l 3-month OPG Median [Q1-Q3]), ng/l RESULTS Absolute difference Median [Q1-Q3]), ng/l P* R1 (n-3 PUFA vs placebo) 0.51 Placebo 1,523 [1,124-2,233] 1,598 [1,129-2,307] +46 [ ] n-3 PUFA 1,506 [1,080-2,140] 1,539 [1,130-2,191] +25 [ ] R2 (rosuvastatin vs placebo) 0.80 Placebo 1,509 [1,143-2,289] 1,607 [1,159-2,303] +6 [ ] Rosuvastatin 1,512 [1,088-2,180] 1,596 [1,124-2,338] +57 [ ] * P for ANCOVA adjusted for baseline concentration.

16 CONCLUSION In chronic heart failure: OPG is an independent predictor of all-cause mortality OPG is most strongly associated with kidney function (serum creatinin), hx of diabetes and female gender No effect of n-3 PUFA or rosuvastatin on OPG levels within the first 3 months of treatment

17 ACKNOWLEDGEMENT Co-authors GISSI HF group Serge Masson Valentina Milani Giuseppe Di Tano Gianfranco Misuraca Aldo P. Maggioni Gianni Tognoni Luigi Tavazzi Roberto Latini Aarhus Mette Bjerre Allan Flyvbjerg Torbjørn Omland

18 THANK YOU!

19 NET RECLASSIFICATION IMPROVEMENT (NRI) - ADDING OPG TO A CLINICAL RISK MODEL TO PREDICT ALL-CAUSE MORTALITY Model with clinical risk factors and OPG Model with clinical risk factors alone <18% 18-36% >36% Total Patients who died Reclassified to higher risk (n) Reclassified to lower risk (n) Net correct reclassification (%) <18% 31 (93.9) 2 (6.1) 0 (0.0) % 3 (4.2) 67 (93.0) 2 (2.8) 72 >36% 0 (0.0) 5 (3.0) 164 (97.0) 169 Total Patients alive <18% 288 (93.2) 21 (6.80) 0 (0.0) % 18 (6.7) 238 (88.5) 13 (4.8) 269 >36% 0 (0.0) 15 (9.0) 152 (91.0) 167 Total Net reclassification improvement (%) -1.6 (p=0.34)

20 ALL CAUSE MORTALITY AND CV EVENTS BY BASELINE TERTILES OF OPG Kaplan Meier curves for mortality and CV events.

21 ALL-CAUSE MORTLITY AND CV EVENTS - A COX MODELS FOR BASELINE OPG CONSENTRATION All-cause mortality or hospitalizations for CV reasons Univariate model Multivariable model Hazard Ratio 95% CI P Hazard Ratio 95% CI P T1 [252-1,209 ng/l] 57.0% 1 (referent) 1 (referent) T2 [1,210-1,922 ng/l] 64.4% T3 [1,923-6,848 ng/l] 71.2% <

22 SELECTED BASELINE CHARACTERISTICS Variable Category N OPG (median [Q1-Q3]) p Age < 70 y [ ] < y [ ] NYHA II [ ] < egfr III-IV [ ] <60 ml/min/1.73 m [ ] < [ ] [ ] BMI <25 kg/m [ ] [ ] [ ]