1. Blood pressure parameters and pulse wave velocity for cardiovascular-renal prevention Jacques Blacher Unité HTA, prévention et thérapeutique cardiovasculaires Centre de diagnostic et de thérapeutique, Hôtel-Dieu, Paris May 2015

2. Disclosures Jacques Blacher ∙No financial participation in the capital of a healthcare company. ∙No permanent interest (work contract, regular remuneration...) in a healthcare company. ∙Occasional direct and indirect interests (clinical trials, scientific work, scientific committees, expert reports, conferences, colloquia, training courses, participation at various symposia, writing of brochures...), remunerated where appropriate, for most companies that market cardiovascular drugs or other medicinal products used in my areas of expertise ( ARDIX-THERVAL, AMGEN, ASTRAZENECA, BAYER, BMS, BOUCHARA RECORDATI, DAÏCHI SANKYO, DANONE, EUTHERAPIE, GSK, IPSEN, MENARINI, MERCK SERONO, MSD, NOVARTIS, PIERRE FABRE, PILEJE, ROCHE, SANOFI, SERVIER, TAKEDA ).

3. Risk assessment strategies

4. Systolic versus diastolic ? Pulse pressure versus systolic ? Young versus old ? Central versus peripheral ? PWV versus BP ? Comparison of different biomarkers - problem of intercorrelations

6. Risk of CHD Death According to Systolic BP and Diastolic BP in MRFIT Stamler et al. Arch Intern Med. 1993;153:598-615. <112112-118-121-125-129-132-137-142-? 151 Systolic BP (mm Hg) 0 1 2 3 4 12345678910 Systolic Diastolic (Lowest 10%) (Highest 10%) Adjusted Relative Risk Decile <7171-76-79-81-84-86-89-92-? 98 Diastolic BP (mm Hg)

7. Risk assessment strategies Systolic versus diastolic ? Pulse pressure versus systolic ? Young versus old ? Central versus peripheral ? PWV versus BP ? Comparison of different biomarkers - problem of intercorrelations

8. Darné B et al. Pulsatile versus steady component of blood pressure: a cross-sectional analysis and a prospective analysis on cardiovascular mortality. Hypertension 1989;13:392-400 Blood pressure divided into 2 components: pulse and mean, rather than systolic and diastolic 18 336 men + 9351 women aged 40-69 Follow-up: 9.5 years Strong correlation between PP and MAP Principal component analysis = 2 independent parameters Relation between pulsatile component and LVH Relation between steady component index and CV death in both sexes Relation between pulsative component index and death from CHD in women > 55

9. Blacher et al. Arch Intern Med. 2000;160. Pulse Pressure Predicts Risk Best In Older Hypertensives - A Meta-Analysis 2-Year Risk Of End Point Systolic Blood Pressure (mm Hg) Diastolic Pressure (mm Hg) EWPHE (N=840) Syst-Eur (N=4695) Syst-China (N=2394)

10. Mortality Rates (per 10000 person-years) in the 9 groups of patients Cardiovascular Mortality Benetos A. et al. Hypertens. 1999; 33: 44-52.

11. Risk assessment strategies Systolic versus diastolic ? Pulse pressure versus systolic ? Young versus old ? Central versus peripheral ? PWV versus BP ? Comparison of different biomarkers - problem of intercorrelations

12. Franklin S, et al. Hemodynamic Patterns of Age-Related Changes in Blood Pressure. The Framingham Heart Study. Circulation 1997; 96: 308-315.

13. Franklin S. Does the relation of blood pressure to coronary heart disease risk change with aging ? Circulation.2001; 103: 1245-9. Relative cardiovascular risk associated with SBP, DBP and PP Single BP Components* HR (95 % CI)† Age < 50 y SBP 1.14(1.06-1.24)++ DBP 1.34(1.18-1.51)+++ PP 1.02(0.89-1.17) Age 50-59 y SBP 1.08(1.02-1.15)+ DBP 1.11(0.99-1.24) PP 1.11(1.02-1.22)+ Age  60 y SBP1.17(1.11-1.24)+++ DBP1.12(0.99-1.27) PP1.24(1.16-1.33)+++ * SBP, DBP and PP were entered in separate models, adjusted for age, sex, body mass index, cigarette smoking, diabetes mellitus, and ratio of total to HDL cholesterol † HR was associated with 10 mm Hg increase in BP + p<0.05, ++p<0.01, +++ p<0.001

14. Risk assessment strategies Systolic versus diastolic ? Pulse pressure versus systolic ? Young versus old ? Central versus peripheral ? PWV versus BP ? Comparison of different biomarkers - problem of intercorrelations

16. Probabilities of survival in the study population according to the level of central PP divided into tertiles. Comparison between survival curves was highly significant (p<0.001) Safar et al. Hypertension 2002

17. Duration of follow-up (months) Cardiovascular survival Augmentation Index (AIX) and CV survival London and al. Hypertension 2001

19. Jankowski P, et al. Hypertension 2008 ; 51 : 848-55.

20. Risk assessment strategies Systolic versus diastolic ? Pulse pressure versus systolic ? Young versus old ? Central versus peripheral ? PWV versus BP ? Comparison of different biomarkers - problem of intercorrelations

24. Risk assessment strategies Systolic versus diastolic ? Pulse pressure versus systolic ? Young versus old ? Central versus peripheral ? PWV versus BP ? Comparison of different biomarkers - problem of intercorrelations

25. Systolic Diastolic MeanPulse Peripheral Central

26. Area under ROC curves, crude and adjusted HRs per 1 SD increment 1.2 (0.9-1.6) 1.5 (1.2-1.8) 0.68±0.11172±46LV mass index 1.3 (1.0-1.7)2.1 (1.7-2.6) 0.83±0.1111.7±3.1Aortic PWV 0.5 (0.3-0.8)0.2 (0.1-0.4) 0.85±0.11110±16Bra./carot. PP 1.4 (1.1-1.8)2.2 (1.7-2.7) 0.84±0.1168±25Carotid PP 1.2 (0.9-1.5) 1.8 (1.5-2.3) 0.78±0.1173±23Brachial PP 0.7 (0.9-1.2)0.8 (0.7-1.1)0.50±0.09108±17MBP 0.8 (0.6-1.0) 0.5 (0.4-0.7) 0.65±0.1083±15DBP 1.2 (0.8-1.4) 1.6 (1.2-2.1) 0.71±0.11152±29Carotid SBP 1.1 (0.8-1.3) 1.3 (1.0-1.7) 0.64±0.10156±28Brachial SBP Adjusted HRCrude HRAUCMean±SDVariable

28. Hypertension 2009

31. Relative Integrated Discrimination Improvement (RIDI%) : major cardiovascular events 4%20%7%13%-7%-13% -15 -5 5 15 25 DBP vs SBP PP vs SBP MAP vs SBP PP vs DBP MAP vs DBP PP vs MAP RIDI (%)

32. From risk assessment to risk reduction strategies

33. Residual risk Systolic versus diastolic ? BP versus PWV ? Peripheral BP versus central BP ? Young versus old versus oldest old Prevention of CAD versus prevention of stroke ? Prêt-à-porter versus haute couture

36. From risk assessment to risk reduction strategies Residual risk Systolic versus diastolic ? BP versus PWV ? Peripheral BP versus central BP ? Young versus old versus oldest old Prevention of CAD versus prevention of stroke ? Prêt-à-porter versus haute couture

38. From risk assessment to risk reduction strategies Residual risk Systolic versus diastolic ? BP versus PWV ? Peripheral BP versus central BP ? Young versus old versus oldest old Prevention of CAD versus prevention of stroke ? Prêt-à-porter versus haute couture

39. IMPACT OF AORTIC STIFFNESS ATTENUATION ON SURVIVAL OF PATIENTS IN END-STAGE RENAL FAILURE 1st step: dry weight 2nd step: ACE inhibitor or calcium antagonist 3rd step: calcium antagonist or ACE inhibitor (if not well tolerated) 4th step: ACE inhibitor or calcium antagonist + beta-blocker 5th step: ACE inhibitor + calcium antagonist + beta-blocker Guérin et al. Circulation 2001;103:987-992

40. Survivors Inclusion At target BP End of follow up 14 13 9 12 10 11 Inclusion At target BP End of follow up 14 13 9 12 10 11 120 100 110 Non Survivors 120 100 110 PWV (m/s) Guerin and al. Impact of aortic stiffness attenuation on survival of patient in end stage renal failure. Circulation. 2001; 103:987-992 Changes of Mean Blood Pressure and aortic PWV MBP (mmHg)

41. From risk assessment to risk reduction strategies Residual risk Systolic versus diastolic ? BP versus PWV ? Peripheral BP versus central BP ? Young versus old versus oldest old Prevention of CAD versus prevention of stroke ? Prêt-à-porter versus haute couture

44. From risk assessment to risk reduction strategies Residual risk Systolic versus diastolic ? BP versus PWV ? Peripheral BP versus central BP ? Young versus old versus oldest old Prevention of CAD versus prevention of stroke ? Prêt-à-porter versus haute couture

45. ARTERIAL HYPERTENSION LVH Atrial fibrillation Heart failure Ischemic stroke Dementia Hypertensive encephalopathy Blindness Aortic aneurism Peripheral arterial disease Chronic renal insufficiency Cerebral haemorrhage Coronary artery disease Pre-eclampsia/ eclampsia Myocardial infarction Hypertension : complications

46. From risk assessment to risk reduction strategies Residual risk Systolic versus diastolic ? BP versus PWV ? Peripheral BP versus central BP ? Young versus old versus oldest old Prevention of CAD versus prevention of stroke ? Prêt-à-porter versus haute couture

48. From risk assessment to risk reduction strategies Residual risk Systolic versus diastolic ? BP versus PWV ? Peripheral BP versus central BP ? Young versus old versus oldest old Prevention of CAD versus prevention of stroke ? Prêt-à-porter versus haute couture

49. From risk assessment to risk reduction strategies CONCLUSION Reliable BP measurements Better understanding of the patho-physiology Meta-analysis of observational studies and therapeutic trials (structural models): Association of different BP parameters to CV risk Association of different BP parameters to CV risk reduction Dedicated therapeutic trials Focussing on one parameter versus another Difficult to interpret because of collinearity

50. Systolic Diastolic MeanPulse Peripheral Central