Improving risk prediction focusing on intermediate endpoints. Arterial stiffness. Pr. Stéphane LAURENT, MD, PhD, FESC

Improving risk prediction focusing on intermediate endpoints Arterial stiffness Pr. Stéphane LAURENT, MD, PhD, FESC Pharmacology Department, Hôpital Européen Georges Pompidou, Paris Cardiovascular Research Center (P.A.R.C.C.), INSERM U970 Université Paris Descartes, Assistance Publique-Hôpitaux de Paris

DISCLOSURE Stéphane LAURENT, MD, PhD Potential conflict of interest: Research grant, advisory board, honorarium as speaker or chairman Drug companies ASTRA-ZENECA BAYER-SCHERING BOEHRINGER-INGELHEIM CHIESI DAICHII-SANKYO ESTEVE MENARINI MSD NEGMA NOVARTIS PFIZER RECORDATI SERVIER Manufacturers ALAM MEDICAL ATCOR ESAOTE-PIE MEDICAL HEMO SAPIENS OMRON TENSIOMED

Circulation 2011 Genetic and Environmental Risk factors Subclinical disease Imaging biomarkers (arterial stiffness, )

Clinical application of imaging biomarkers as. Intermediate endpoint or Surrogate endpoint?

NIH Biomarkers Definitions Working Group, Clin Pharmacol Therap, 2001;69:89-95 Definition A surrogate end point - is a subset of biomarkers - is «a biomarker that is intended to substitute for a clinical end point» and not for a marker. Thus, the term «surrogate marker» has been discouraged. - is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiological, therapeutic, pathophysiologic, or other scientific evidence. - applies primarily to therapeutic intervention trials

NIH Biomarkers Definitions Working Group, Clin Pharmacol Therap, 2001;69:89-95 Definition A surrogate end point - is a subset of biomarkers - is «a biomarker that is intended to substitute for a clinical end point» and not for a marker. Thus, the term «surrogate marker» has been discouraged. - is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiological, therapeutic, pathophysiologic, or other scientific evidence. - applies primarily to therapeutic intervention trials

Circulation 2009 1. Proof of concept 2. Prospective validation 6 steps to be completed 3. Incremental value 4. Clinical utility, reclassification? 5. Clinical outcomes. Reduction translates to less CV events 6. Cost-effectiveness

Carotid-femoral pulse wave velocity: the Gold standard for the measurement of aortic stiffness Laurent S et al. Eur Heart J 2006 L dp PWV. t. Bramwell and Hill, 1922 V dv Pulse wave velocity is the speed (4-12 m/sec) with which the pressure wave, generated by cardiac ejection, is propagated along the arterial tree. 1 2 3 4 5 6 7 8 9 10

Carotid-femoral pulse wave velocity: the Gold standard for the measurement of aortic stiffness the «foot-to-foot method» Laurent S et al. Eur Heart J 2006 L dp PWV. t. V dv t L

Step 1: Proof of concept: Clinical conditions associated with an increased arterial stiffness Aging Menopausal status CV risk factors Lack of physical activity Obesity Smoking Hypertension Hypercholesterolemia Impaired glucose tolerance Metabolic syndrome Type 1 diabetes Type 2 diabetes Hyperhomocyteinemia High CRP level Genetic background Parental history of hypertension Parental history of diabetes Parental history of myocardial infarction Genetic polymorphisms CV Diseases Coronary Heart Disease Congestive Heart Failure Fatal stroke Primarily non CV diseases End-stage renal disease (ESRD) Moderate chronic kidney disease Rheumatoid arthritis Systemic vasculitis Systemic lupus erythematosus

AHA Guidelines: Phases of evaluation of a novel risk marker 1. Proof of concept 2. Prospective validation Arterial stiffness 1.00 Hlatky MA et al. Circulation 2009 Arterial stiffness and total mortality in 1980 hypertensives Low PWV Survival 0.90 0.80 +/- 0.70? Kaplan-Meier P<0.0001 0 5 10 15 20 Follow-up (years) Medium PWV High PWV Laurent S et al., Hypertension 2001

Meta-analysis of the predictive value of aortic stiffness (carotid-femoral PWV) for CV events 17 studies, 15,877 subjects, FU 7.7 yrs Vlachopoulos et al. JACC 2010 Total CV events CV mortality All-cause mortality RR 1.47 [1.31-1.64] RR 1.47 [1.29-1.66] RR 1.42 [1.29-1.58] RR for 1 SD

Meta-analysis in individual data: independent predictive value of aortic stiffness for CV events (16,358 subjects) Age-specific HRs for CVD, per 1SD increase in log cf-pwv Y Ben Schlomo et al. ARTERY 11, Oct 2011 Category ES (95% CI) Age_Group <50 years 51-60 years 61-70 years >70 years 1.83 (1.33, 2.52) 1.67 (1.40, 1.99) 1.37 (1.17, 1.61) 1.25 (1.09, 1.43).8 1 1.4 1.8 2.2 2.6 Hazard Ratio (95% CI) 14 studies including 16,358 subjects with 1700 combined CVD events. z-scores of log transformed cf-pwv (pooled SD = 3.3m/s). Higher predictive value in younger subjects: (p-value for trend = 0.0095).

99 patients (63±12 yrs) with acute ischemic stroke. PWV measured at 7 days. PWV = dd/t x 0.8 Functional recovery after stroke measured at 90 days using the modified Rankin scale. Multivariate analysis Gasecki et al. Stroke 2012 Age (10 years) NIHSS Previous stroke P=0.067 P=0.010 P=0.049 cf-pwv ( 9.4 m/s) P=0.021 OR 0.20 0.40 0.60 0.80 1.00 1.20 Reduces fonctional outcome Increases functional outcome

Aortic stiffness measurement improves the prediction of asymptomatic CAD in Stroke/TIA patients beyond classical CV risk factors Calvet D et al. Int J Stroke 2012, pending revision 300 patients (45-75 yrs) with non cardioembolic stroke or TIA and no prior history of CAD 64-section CT coronary angiography (asymptomatic CAD = at least one stenosis 50%) PWV = dd/t x 0.8, Multivariate analysis FRS-predicted 10 years risk of CHD (%) < 10% 10-19% P<0.0001 20% Severity of cervicocephalic stenosis No atherosclerosis < 50% stenosis P=0.005 50% stenosis cf-pwv (m/s) 10 m/s P=0.018 > 10 m/s Adjusted OR 1.0 2.0 4.0 6.0 8.0

Aortic stiffness predicts CV outcome independently of other risk factors in CKD patients NEPHROTEST cohort, n=439 CKD (stage 2-5), mean age 59.8 yrs GFR measured with 51 Cr-EDTA; mean FU = 4.7 years PWV= dd/t CV events= CV deaths, non fatal MI, coronary revascularization, and stroke Statistical analysis: Fine and Gray competing risks models Karras et al. Hypertension 2012, pending revision cf-pwv (1 SD=3.4 m/s) mgfr (10 ml/min/1.73 m²) Age (10 years) SBP (10 mmhg) Diabetes (no/yes) Active smoking (no/yes) History of CV events P=0.021 P=0.0055 P=0.11 P=0.54 P=0.24 P=0.071 P=0.00052 RR 0.60 1.00 1.40 1.80 2.20 2.60 Decreases risk Increases risk

Aortic stiffness predicts CV outcome after renal transplantation, independently of other risk factors (age, gender, CRP) Verbecke et al. Hypertension 2011 n=512 renal transplant recipients mean FU = 5 years PWV= dd/t x 0.8 CV events= MI, coronary revascularization, acute pulmonary oedema, stroke, TIA, revascularization for PAD or aortic aneurysm, and sudden death PWV CAI CAP CAP= central augmentation pressure CAI = central augmentation index

The independent predictive value of aortic stiffness has been demonstrated for various outcomes in various populations Outcomes Populations - Total mortality - CV mortality - Coronary events - Asymptomatic CAD - Stroke - Functional outcome after stroke - Onset of dialysis - Onset of hypertension - - general population - elderly - hypertensives - diabetics (T2D) - CAD - after acute stroke - stroke/tia - chronic kidney disease (CKD): moderate, severe, ESRD - renal transplant recipients -

AHA Guidelines: Phases of evaluation of a novel risk marker 1. Proof of concept 2. Prospective validation 3. Incremental value vs SCORE, FRS Arterial stiffness +/-? Hlatky MA et al. Circulation 2009 C statistics

AHA Guidelines: Phases of evaluation of a novel risk marker 1. Proof of concept Arterial stiffness Hlatky MA et al. Circulation 2009 COPENHAGEN study: additive predictive value of PWV to SCORE 2. Prospective validation 3. Incremental value vs SCORE, FRS +/- 8 7 6 5 4 3 2 1 0 Sehestedt et al. Eur Heart J 2010 LVH Plaque PWV>12 m/s * UACR>90th? SCORE > 5% SCORE < 5%

AHA Guidelines: Phases of evaluation of a novel risk marker 1. Proof of concept 2. Prospective validation 3. Incremental value vs SCORE, FRS 4. Clinical utility - Reclassification Arterial stiffness +/-? Hlatky MA et al. Circulation 2009 Framingham study Mitchell et al. Circulation 2010 14.3% of intermediate risk individuals were reclassified into higher risk for CV events, when PWV was added to standard CV RF.

AHA Guidelines: Phases of evaluation of a novel risk marker 1. Proof of concept 2. Prospective validation 3. Incremental value vs SCORE, FRS 4. Clinical utility - Reclassification Arterial stiffness +/-? Hlatky MA et al. Circulation 2009 Framingham study Mitchell et al. Circulation 2010 14.3% of intermediate risk individuals were reclassified into higher risk for CV events Meta-analysis in individual data Ben Schlomo et al. in preparation 19% of intermediate risk individuals were reclassified into higher or lower quartiles of risk for CHD (p<0.001) 22% were reclassified for stroke outcomes respectively (both p<0.001)

AHA Guidelines: Phases of evaluation of a novel risk marker 1. Proof of concept 2. Prospective validation Arterial stiffness Hlatky MA et al. Circulation 2009 Framingham study Mitchell et al. Circulation 2010 14.3% of intermediate risk individuals were reclassified into higher risk for CV events 3. Incremental value vs SCORE, FRS 4. Clinical utility - Reclassification Nephrotest cohort +/- Karras et al. Hypertension, submitted 29 % of patients were reclassified into lower or higher risk for all-cause? mortality Meta-analysis in individual data Ben Schlomo et al. in preparation 19% of intermediate risk individuals were reclassified into higher or lower quartiles of risk for CHD (p<0.001) 22% were reclassified for stroke outcomes respectively (both p<0.001)

2013 ESH-ESC Guidelines for the management of hypertension A novel cut-off value of PWV for the prediction of CV events Subclinical organ damage Electrocardiographic LVH (Sokolow-Lyon > 38 mm; Cornell > 2440 mm*ms) or Echocardiographic LVH (LVMI M 125 g/m 2, W 110 g/m 2 ) Carotid wall thickening (IMT > 0.9 mm) or plaque Carotid-femoral pulse wave velocity > 12 m/s >10 m/s # 12 m/s x 0.8 Ankle/Brachial BP index < 0.9 Slight increase in plasma creatinine: M: 115-133 mol/l (1.3-1.5 mg/dl); W: 107-124 mol/l (1.2-1.4 mg/dl) Low estimated glomerular filtration rate (< 60 ml/min/1.73m 2 ) or creatinine clearance (< 60 ml/min) Microalbuminuria 30-300 mg/24h or albumin-creatinine ratio: 17 (M); 25(W) mg/g creatinine

Metrics of cf-pwv: standardisation of methods PWV = Distance / t Common carotid Distance (aortic pathway at MRI) should be Sternal notch L car-ster - either direct distance x 0.8 - or substracted distance = L ster-fem - L car-ster Direct distance Vermeersch S et al. J Hypertens 2009 Boutouyrie P et al. Eur Heart J 2010 Van Bortel et al. J Hypertens 2012 L subtracted L ster-fem Common femoral

Nomal and reference values for aortic stiffness Reference Value for Arterial Stiffness Collaboration 23 000 subjects (PWV=dD/t x0.8) Boutouyrie, Vermeersch et al. Eur Heart J 2010 25 20 PWV m/s PWV m/s 10 m/s corresponds to the 90 th percentile of the 50-59 years decade 15 10 5 20 30 40 50 60 70 yrs 20 30 40 50 60 70 yrs Reference values Normal values 8,400 untreated subjects with CV risk factors and no T2D 1,344 healthy subjects with no CV risk factors

AHA Guidelines: Phases of evaluation of a novel risk marker 1. Proof of concept 2. Prospective validation 3. Incremental value vs SCORE, FRS 4. Clinical utility - Reclassification 5. Clinical outcomes. The reduction in aortic stiffness translates to the reduction in CV events Arterial stiffness +/-? Hlatky MA et al. Circulation 2009

Clinical outcome study: the SPARTE study Laurent et al. Hypertension 2012 Guidelines driven therapeutic strategy French Ministry of Health, French Foundation for Research in Hypertension 1 500 hypertensive patients per group Arterial stiffness driven i.e. 3 000 patients therapeutic strategy FU: 4 years, PROBE design 40 investigation centers in France Inclusion criteria: Medium to very-high added CV risk (ESH 2007) and no T2D 10 yrs risk of CV morbidity-mortality (Framingham) >15 % (median CV risk: 20%) Primary end-point = combined end-point (median CV risk: 10% per year) stroke+mi+angioplasty+cabg+pad (angioplasty, bypass,amputation)+chf hosp.+af+aortic dissection+doubling of creatinin+esrd+sudden death Arterial stiffness driven therapeutic strategy: high recommended dose of ACEI or ARB, aldosterone blockers, CCB+ARB combination, vasodilating BB Expected nb of events: 480 vs 600

AHA Guidelines: Phases of evaluation of a novel risk marker Arterial stiffness Hlatky MA et al. Circulation 2009 1. Proof of concept 2. Prospective validation 3. Incremental value vs SCORE, FRS 4. Clinical utility - Reclassification 5. Clinical outcomes. The reduction in aortic stiffness translates to the reduction in CV events 6. Cost-effectiveness +/-?

Conclusion: arterial stiffness for improving risk prediction 1. Carotid-femoral PWV is a direct method for measuring aortic stiffness 2. cf-pwv measurement is a simple and robust method, easy to implement in clinical practice 3. cf-pwv has demonstrated an added predictive value for CV events in various populations, beyond ESC-SCORE, ESH-ESC Risk Chart, and Framingham risk score 4. cf-pwv is listed among subclinical organ damage by the ESH-ESC Guidelines for the management of hypertension 5. The cut-off value is 10 m/s for the prediction of CV events 6. Its value as surrogate end-point remains to be demonstrated by therapeutic intervention trials

Artery 12 www.arterysociety.org 18 th 20 th October 2012 Tech Gate Vienna, Austria Endorsed by: Supported by:

Normalization of arterial stiffness 1. Through the reduction of BP preferentially without beta-blockers 2. Through mechanisms independent of acute BP lowering - targeting long-term arterial remodeling (several years ) - using drugs preferentially acting on fibrosis, collagen, and extra-cellular matrix In clinical practice: - highest recommended doses of RAAS blockers - combinations of RAS blockers + CCB (central PP) - ACEI, ARB, aldosterone antagonists (spironolactone, eplerenone) - using nitrates and NO donors 3. Through intensified intervention on other CV risk factors - Anti-platelet, lipid-lowering, and anti-diabetic drugs when indicated - Physical exercise, weight reduction, salt reduction, alcohol

cf Pulse Wave Velocity (m/s) 5 10 15 20 25 30 Long-term normalization of aortic stiffness Changes in PWV, in 97 hypertensives during a 5.3 yrs FU Ait Oufella et al. J Hypertens 2010-0.61 ± 0.06 m/s/yr, P<0.001 T0 T1 T2 2.9 ± 1.2 yrs 5.3 ± 1.3 yrs PWV 14.2 ± 4.2 m/s 11.3 ± 2.7 m/s 11.0 ± 2.4 m/s MBP 93 ± 10 mmhg 91 ± 9 mmhg 89 ± 8 mmhg

Clinical outcome study Guidelines driven therapeutic strategy Arterial stiffness driven therapeutic strategy P<0.001 Guidelines driven Arterial stiffness driven? Pletcher MJ et al. Circulation 2011