ηόρνη αξηεξηαθήο πίεζεο. Είλαη ίδηνη ζε όινπο;

ηόρνη αξηεξηαθήο πίεζεο. Είλαη ίδηνη ζε όινπο;

Cardiovascular disease Europe s No. 1 killer Main cause of disease More than 4.3 million deaths/year 48% of all deaths Coronary heart disease most common cause of death in Europe 1.9 million deaths/year Stroke more than 5, deaths/year burden (23%) Cost to EU estimated at 192 billion per year Allender et al. European Heart Network 28

Hypertension: A Significant CV and Renal Disease Risk Factor Stroke CAD CHF LVH Hypertension Renal disease Peripheral vascular disease Morbidity Disability Arch Intern Med. 1993;153:186-28.

Hypertension Co-Morbidities % of patients with BP >14/9 mm Hg: 69% of patients with 1 st MI 77% of patients with 1 st stroke 74% of patients with HF Hypertension precedes HF in 91% of cases Hypertension is associated with a 2- to 3-times higher risk for HF - 8% of patients with CKD BP, blood pressure; HF, heart failure; MI, myocardial infarction. Thom T et al. Circulation. 26;113:e85-e151.

Long-Term Antihypertensive Therapy Significantly Reduces CV Events 9 8 7 6 5 Average reduction 4 in events (%) 3 2 1 1 2 3 4 5 Stroke 35%-4% Myocardial infarction 2%-25% 6 1ο Τρ. 2ο Τρ. 3ο Τρ. 4ο Τρ. Heart failure Ανατολή Δύση Βορράς >5% Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2;355:1955-1964.

27 ESH Guidelines for the Management of Hypertension. < 14 / 9 if low and moderate CV risk < 13 / 8 if high CV risk Diabetes Renal dysfunction Established CV disease Control of all cardiovascular risk factors

Historical Trends in HTN National Health and Nutrition Examination Survey Trends in awareness, treatment, and control of high blood pressure in adults ages 18-74 1976-198 1988-1991 1991-1994 1994-2 23-24 Awareness 51% 73% 68% 7% 75% Treatment 31% 55% 54% 59% 65% Control 1% 29% 27% 34% 33% SBP < 14 mmhg and DBP < 9 mmhg Hajjar I, et al. JAMA. 23;29:199-26. Ong KL et al Hypertension 27: 49;69-75

NHANES III: Poor Systolic BP Control Underlies Inadequate BP Control Overall 25 49.6% 16.1% 2 15 14 Only 34.3% Reach SBP Goal 1 73% Reach DBP Goal NHANES = National Health and Nutrition Examination Survey; SBP = systolic blood pressure; DBP = diastolic blood pressure. Burt VL et al. Hypertension. 1995;26:6-69. Whyte JL et al. J Clin Hypertens. 21;3:211-216. 5 9 23.6% 1.7% 5 1 15 DBP (mm Hg)

SBP (mmhg) Achieved SBP in Trials 16 15 14 13 12 11 148 13 Uncomplicated HT 15 149 146 142 14 138 137 13 BP Benefit Partial benefit SBP (mmhg) 19 18 17 16 15 14 13 PL Active 18 172 162 15 17 143 186 167 Elderly 165 161 16 156 151 151 159 144 148 145 147 138 BP Benefit Partial benefit No benefit 1 OS HDFP AUS MRC FEV 12 EW SHEP MRC S. China SCOPE CW STOP S. Eur HYVET JATOS SBP (mmhg) 17 16 15 14 13 12 PL Active 155 154 148 145 145 144 143 139 162 153 Diabetes 144 143 14 14 138 137 134 134 132 128 145 143 144 141 BP Benefit Partial benefit No benefit SBP (mmhg) 16 15 PL 14 Active 13 12 11 149 143 Stroke 15 15 141 132 14 136 Previous CVD 138 135 CHD 14 136 136 133 13 13 13 13 128 124 124 122 132 129 BP Benefit Partial benefit No benefit 11 HOT UKPDS S. Eur ADV ABCD IDNT IDNT REN SHEP HOPE PROG HT NT IR AM 1 PATS ACC PROG PROF HOPE CAM-AM PREV CAM-EN EU TR ACT PEA Zanchetti, Grassi, Mancia, J Hypertens 29; 27: 923-934

NEW TRIALS NEEDED Πξέπεη λα ρνξεγείηαη αληηππεξηαζηθή ζεξαπεία ζε όινπο ηνπο αζζελείο κε ππέξηαζε 1ζηαδηνπ αθόκα θαη κε ρακειό ε κέηξην ζπλνιηθό θθ θίλδπλν? Πξέπεη λα ρνξεγείηαη αληηππεξηαζηθή ζεξαπεία ζε ειηθησκέλνπο αζζελείο κε ππέξηαζε 1ζηαδηνπ? Πξέπεη ν ζηόρνο ηεο αληηππεξηαζηθήο ζεξαπείαο ζηνπο ειηθησκέλνπο λα είλαη< 14/9 mmhg? J of hypertension 29;27:2121 58

BP target in elderly patients No clear evidence for < 14 mmhg SBP HT in the elderly 19 186 18 18 17 16 PL 172 162 17 167 165 161 16 159 15 14 13 15 Active 143 156 151 151 144 148 145 147 138 12 EW SHEP MRC S. China SCOPE CW STOP S. Eur HYVET JATOS Conclude: No evidence to support lowering BP to<14 mmhg BP Benefit Partial benefit No benefit Zanchetti, Grassi, Mancia, J Hypertens 29; 27: 923-934

Ο ζηόρνο ηεο ΑΠ ζηνπο ειηθησκέλνπο αζζελείο Χσξίο ζαθή έλδεημε γηα < 14 mmhg ΑΠ «Δελ ππάξρνπλ ζηνηρεία γηα ειηθησκέλνπο ππεξηαζηθνύο αζζελείο, γηα ηνπο νπνίνπο ην όθεινο κείσζεο ηεο ΑΠ θάησ από 14 mmhg δελ έρεη πνηέ ειεγρζεί ζε ηπραηνπνηεκέλεο κειέηεο.» J of hypertension 29;27:2121 58

Initiation of Drug Treatment Recommendation to start drug treatment at BP 14/9 mmhg in the elderly is mainly based on - Post-hoc event data - Improvement of organ damage - Delayed treatment leads to irreversible organ damage / greater residual risk J of hypertension 29;27:2121 58

Major Clinical Trials Showing Benefit of Treating Isolated Systolic Hypertension Baseline SHEP (72yrs) Syst-Eur (7yrs) Syst-China (66yrs) (n=4736) (n=4695) (n=2394) SBP (mm Hg) 16-219 16-219 16-219 DBP (mm Hg) <9 <95 <95 BP reduction: 27/9 23/7 2/5 Drug therapy Chlorthalidone Nitrendipine Nitrendipine Atenolol Enalapril Captopril HCTZ HCTZ Outcomes (%) Stroke 33 42 38 CAD 27 3 27 CHF 55 29 All CVR disease 32 31 25 Journal of Clinical Hypertension Vol II, No. 5, page 336, September/October 2.

Αantihypertensive therapy in the elderly 1. Αantihypertensive therapy in the elderly is extremely useful. 2. Σhe benefit in patients > 65 yrs old is equally strong as in younger 3. Target BP <14/9 mmhg. (There is yet no trial in which a benefit was achieved for SBP averaged < 14 mmhg ) 4. Initial doses and subsequent dose titration should be more gradual because of a greater chance of undesirable effects 5. When we must start antihypertensive treatment? 6. What is the lower safe limit of BP IN THE ELDERLY? J of hypertension 29;27:2121 58

No. of events per 1 patients Incidence of Morbidity / Mortality in HYVET 8 7 6 5 4 3 2 1 7 6 All stroke Heart failure 2 1 Fatal stroke -3% 4-39% p =.55 3 p =.46 5 3 Total mortality Placebo 173/91 16/84 (mmhg) Active treatment 173/91 144/78 (mmhg) 5 4 3 2 1-64% 2 p <.1 p =.19 1-21% 1 2 3 4 Follow-up (yr) 1 2 3 4 Follow-up (yr)

Επιζημάνζεις Τα άηομα ηης μελέηης είταν καλύηερο επίπεδο σγείας από ηα ανηίζηοιτα ηοσ γενικού πληθσζμού Το όθελος για μείωζη ηης ΣΑΠ<16mmHg τρειάζεηαι περαιηέρω διερεύνηζη Η πίεζη-ζηότος ηης μελέηης ήηαν 15/8 mmhg όθελος από περαιηέρω μείωζη δεν έτει αποδειτθεί

Treatment in Patients Aged 8 Years Antihypertensive treatment is useful in patients > 8 yrs old. Evidence is now available from an outcome trial (HYVET) that antihypertensive treatment has benefits also in patients aged 8 years or more BP lowering drugs should thus be continued or initiated when patients turn 8, starting with monotherapy and adding a second drug if needed Target blood pressure? J of hypertension 29;27:2121 58

Major Take Home Message of Elderly Guidelines-Management The general recommended BP goal in uncomplicated hypertension is <14/9 mmhg but 14-145 is acceptable. However, this target for elderly hypertensives is based on expert opinion rather than data from RCTs. It is unclear if target SBP should be the same in 65 to 79 year olds as in patients >8 years Initial antihypertensive drugs should be started at the lowest dose and gradually increased, depending on BP response, to the maximum tolerated dose. An achieved SBP <14 mmhg, if tolerated, is recommended except for octogenarians. ACC/AHA Guidelines in Elderly 211- JACC

BP Treatment in the very elderly New evidence suggests that BP lowering reduces the risk of stroke, heart failure and death in people aged over 8yrs; Offer people aged >8yrs same treatment as people aged >55yrs, taking account of co-morbidities; Treat to a target of <15/9mmHg in people aged 8 and over <14/9 mmhg in people aged under 8 NICE clinical guideline 211

Diabetes and Hypertension SBP < 13 mmhg DBP < 8 mmhg SBP < 13 mmhg DBP < 85 mmhg 27 ESH Guidelines JNC-7 SBP < 13 mmhg DBP < 8 mmhg NICE 26

BP target in patients with diabetes melitus No clear evidence for < 13 mmhg SBP

BP question: does a therapeutic strategy targeting systolic blood pressure (SBP) <12 mmhg reduce CVD events compared to a strategy targeting SBP <14 mmhg in patients with type 2 diabetes at high risk for CVD events? Mean follow-up was 4.7 years.

Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3 Average after 1 st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2

Primary and secondary outcomes Intensive Events (%/yr) Standard Events (%/yr) HR (95% CI) P Primary 28 (1.87) 237 (2.9).88 (.73-1.6).2 Total Mortality 15 (1.28) 144 (1.19) 1.7 (.85-1.35).55 Cardiovascular Deaths 6 (.52) 58 (.49) 1.6 (.74-1.52).74 Nonfatal MI 126 (1.13) 146 (1.28).87 (.68-1.1).25 Nonfatal Stroke 34 (.3) 55 (.47).63 (.41-.96).3 Total Stroke 36 (.32) 62 (.53).59 (.39-.89).1 Also examined Fatal/Nonfatal HF (HR=.94, p=.67), a composite of fatal coronary events, nonfatal MI and unstable angina (HR=.94, p=.5) and a composite of the primary outcome, revascularization and unstable angina(hr=.95, p=.4)

Adverse Events Intensive N (%) Standard N (%) Serious AE 77 (3.3) 3 (1.3) <.1 Hypotension 17 (.7) 1 (.4) <.1 Syncope 12 (.5) 5 (.2).1 Bradycardia or Arrhythmia 12 (.5) 3 (.1).2 Hyperkalemia 9 (.4) 1 (.4).1 Renal Failure 5 (.2) 1 (.4).12 egfr ever <3 ml/min/1.73m 2 99 (4.2) 52 (2.2) <.1 Any Dialysis or ESRD 59 (2.5) 58 (2.4).93 Dizziness on Standing 217 (44) 188 (4).36 P Symptom experienced over past 3 days from HRQL sample of N=969 participants assessed at 12, 36, and 48 months post-randomization

Limitations of the ACCORD-BP Study 1. Only two SBP arms 2. Very large difference in SBP between arms (133.5 and 119.3 mmhg) 3. CVE incidence only half than expected (2% rather than 4% per year) Conclusions It cannot be excluded that the lower SBP target is accompanied by some benefit, or that there is an intermediate SBP level (between 134 and 119 mmhg) at which benefits are greater than at 134 and 119 mmhg (J-curve) A.Zanchetti Eur Heart J 21;31:2837-4

Meta-analyses examining SBP targets <14mmHg in patients with diabetes Included only trials that achieved SBPs < 14 mmhg Outcomes were mortality, CV mortality, MI, HF and stroke Bangalore et al. Circulation 211

Summary of new evidence in patients with diabetes and hypertension Diabetes and Hypertension: SBP <13 mmhg and DBP <8 mmhg ESH 29 NICE 211 A goal systolic blood pressure <13 mmhg is appropriate for most patients with diabetes (C) Based on patient characteristics and response to therapy, higher or lower systolic blood pressure targets may be appropriate (B) Patients with diabetes should be treated to a diastolic blood pressure <8 mmhg (B) American Diabetes Association 211 SBP lowering < 14 mmhg and DBP <8 mmhg appears beneficial with respect to all cause mortality and stroke SBP lowering below 135mmHg or 13 mmhg appears to confer significant benefit with respect to stroke As SBP decreases below 14 mmhg, the risk of SAEs increases but the absolute number of these events is low CHEP Recommendations Diabetes and Hypertension 212

For patients with hypertension and no diabetic chronic kidney disease ESH 27 Hypertension + Renal dysfunction Target BP is <13/8 mm Hg NICE 211 CHEP 212 For patients with no diabetic chronic kidney disease Target BP is <14/9 mm Hg (Grade B). For patient has both diabetes and CKD Target BP <13 8 mmhg

BP target in patients with previous CV disease No clear evidence for < 13 mmhg SBP

J hypertension 29;27:2121 58

Cardiac events (%) CV events (%) CV events (%) Adjusted HR 6 5 INVEST (CAD pts) 3 ONTARGET (high risk pts, mainly with CAD) 3 4 2 2 3 2 1 1 1 11 >11 to 12 to >12 13 to >13 14 to >14 15 to >15 16 >16 On-treatment SBP (mmhg) 112 121 126 13 133 136 14 144 149 16 On-treatment SBP (mmhg) 3 VALUE (High risk pts) CV Events at Different On-Treatment SBP in TNT a Lipid-Lowering Trial 2 1 < 12 >12 to 13 to >13 14 to >14 15 >15 >16 to 16 to 17 to >17 18 18 On-treatment SBP (mmhg) Bangalore S. et al, Eur Heart J, 21 J hypertension 29;27:2121 58

Example Framingham Study Note: J-curves have also been observed for stroke events

Incidence (%) of MI/Stroke Stroke / MI and DBP Strata:INVEST Sub-analysis: BP and Risk 2 MI Stroke 15 1 5 DBP (mm Hg) Messerli FH et al. Ann. Int. Med. July 26

Incidence (%) of Primary Outcome Estimated Hazard Ratio Incidence of Primary Composite Endpoint by Mean Diastolic Blood Pressure Categories: All Subjects ( TNT study CAD pts ) 1% 2 Primary Outcomes Hazard Ratio 18 8% 6% 4% 2% 16 14 12 1 8 6 4 2 % <= 6 > 6 to 7 > 7 to 8 > 8 to 9 > 9 to 1 > 1 to 11 > 11 Mean DBP (mmhg) Bangalore S, Messerli FH et al 21

Interaction of the J-Curve With Coronary Revascularization Messerli, F. H. et al. J Am Coll Cardiol 29;54:1827-1834

Overview of J Curve 23 clinical trials over the last 2 years in over 11, people QUESTION is there presence of a J curve on CV events. 12 studies showed a J curve with adverse CV outcomes at low diastolic BPs between 6-7 mmhg 8 of those 12 studies did NOT have a history of coronary artery disease events Messerli F and Panjrath G J Am Coll Cardiol, 29; 54:1827-1834

27 AHA Guidelines: Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease In achieving a target BP < 13/8 mmhg for secondary prevention, the BP should be lowered slowly and caution is advised in inducing falls of diastolic BP below 6mmg. Rosendorff C et al., Circulation 27,115:2761-2788.

The Dilemma of the J-curve In lack of evidence on the J-curve, recourse has been made to an indirect approach: incident outcomes in randomized trials are plotted against achieved BP, independently of the randomized group J-curve denied: HOT, PROGRESS, UKPDS J-curve found: IDNT, INVEST, ONTARGET J-curve found in both actively and placebo treated group: INDANA (7 trials) J-curve independent of antihypertensive therapy: TNT A.Zanchetti Eur Heart J 21;31:2837-4

Reappraisal of European Guidelines on hypertension management 29 < 14 / 9 if low and moderate CV risk < 13 / 8 if high CV risk Diabetes Renal dysfunction Established CV disease Control of all cardiovascular risk factors J of hypertension 29;27:2121 58

Σν θαηλόκελν ηεο θακπύιεο J Η έιιεηςε πξννπηηθώλ θαη αλαδξνκηθώλ κειεηώλ θαζώο θαη κεηαλαιπζεσλ νδεγεί ζηελ άπνςε, όηη γηα αζζελείο πςεινύ θαξδηαγγεηαθνύ θηλδύλνπ ππάξρνπλ ιόγνη αλεζπρίαο γηα ηπρόλ κείσζε ηεο ΑΠ <12/7mmHg Οη ηηκέο ΑΠ θάησ ησλ νπνίσλ απμάλνπλ ηα ζπκβάκαηα, θαίλεηαη λα είλαη δηαθνξεηηθέο γηα θάζε αζζελή, αλάινγα κε ηελ ειηθία/ηα θιηληθά θξηηήξηα/ θαη ηελ ηθαλόηεηα απηνξξύζκηζεο ηεο θπθινθνξίαο Οη ζπζηάζεηο γηα επηζεηηθή κείσζε ηεο ΑΠ ζε αζζελείο πςεινύ θηλδύλνπ πηζαλόλ ζα πξέπεη λα είλαη ιηγόηεξν απζηεξέο J hypertension 29;27:2121 58

Antihypertensive treatment starts too late The clock starts ticking before hypertension is diagnosed Not the lower the better but the earlier the better J of hypertension 29;27:2121 58

NEW TRIALS NEEDED Η αληηππεξηαζηθή ζεξαπεία ζηνπο δηαβεηηθνύο ε ζε αζζελείο κε ηζηνξηθό Ν ε ΑΕΕ πξέπεη λα αξρίδεη όηαλ ε ΑΠ είλαη αθόκα νξηαθή? Η πίεζε ζηόρνο ζε απηνύο ηνπο αζζελείο πξέπεη λα είλαη< 13/8? Πνηα είλαη ηα ρακειόηεξα αζθαιή επίπεδα ΑΠ ππό ζεξαπεία ζε δηαθνξεηηθέο θιηληθέο θαηαζηάζεηο? Οη πγηεηλνδηαηηεηηθέο παξεκβάζεηο πνπ κεηώλνπλ ηελ ΑΠ είλαη ηθαλέο λα ειαηηώζνπλ ηελ λνζεξόηεηα θαη ηελ ζλεζηκόηεηα ζηελ ππέξηαζε? J of hypertension 29;27:2121 58

Residual Risk in BP Lowering Trials Zanchetti J Hypertens 29

Η επίηεπμε ησλ ζεξαπεπηηθώλ ζηόρσλ είλαη θαζνξηζηηθήο ζεκαζίαο γηα ηελ πνξεία θαη ηελ πξόγλσζε ησλ ππεξηαζηθώλ αζζελώλ. Θεξαπεπηηθνί ζηόρνη < 14 mm Hg and < 9 mm Hg γηα ηνπο πεξηζζόηεξνπο αζζελείο θαη < 13 mm Hg and < 8 mm Hg γηα ηνπο πςεινύ θηλδύλνπ Σν θαηλόκελν ηεο θακπύιεο J θαίλεηαη λα ηζρύεη γηα αζζελείο πςεινύ θηλδύλνπ ηόζν γηα ηελ ΑΠ όζν θαη γηα ηελ ΔΑΠ. Not the lower the better but the earlier the better Ρύζκηζε όισλ ησλ παξαγόλησλ θθ-θηλδύλνπ THE GOAL IS THE CEILING, NOT THE FLOOR

Follow-up of blood pressure above targets Patients with blood pressure above target are recommended to be followed at least every 2nd month Follow-up visits are used to increase the intensity of lifestyle and drug therapy, monitor the response to therapy and assess adherence

Antihypertensive treatment in old elderly patiens 1. Antihypertensive treatment is useful in patients > 8 yrs old. 2. Subjects HYVET recruited were generally healthier than those within a general population so the results of HYVET can not be extended in weak subjects > 8 yrs old. 3. Initial doses and subsequent dose titration should be more gradual because of a greater chance of undesirable effects, especially in very old and frail subjects. 4.There is no reason for interrupting a successful and well tolerated therapy when a patient reaches 8 years of age. 5. BP lowering drugs should thus be continued or initiated when patients turn 8, starting with monotherapy and adding a second drug if needed. J of hypertension 29;27:2121 58

The European Society of Hypertension - Stroke in Hypertension Optimal Treatment Trial (ESH-SHOT Trial) Questions to be investigated: 1.The lower the BP the better for preventing recurrent stroke or does a J- shaped curve exist with more intensive BP lowering? 2. The lower the BP the better for preventing all cardiovascular outcomes? 3. The lower LDL-C the better for preventing recurrent stroke and all cardiovascular outcomes? Overall: Is intensive lowering of both BP and LDL-C the optimal treatment for preventing recurrent stroke, all cardiovascular outcomes and cognition decline in elderly patients after a stroke or TIA?

Incidence (%) of Primary Outcome Estimated Hazard Ratio Estimated Hazard Ratio DBP & Risk for Primary Outcome: INVEST Sub analysis 5 Nadir = 84.1 mm Hg 6 4 Primary Outcome Hazard Ratio 5 3 4 3 2 2 1 1 DBP (mm Hg) Total patients 176 2239 1136 7376 123 248 Messerli FH et al. Ann. Int. Med. July 26

Goals of Therapy Blood pressure target values for treatment of hypertension Condition Target SBP and DBP mmhg Isolated systolic hypertension <14 Systolic/Diastolic Hypertension Systolic BP Diastolic BP Diabetes Systolic Diastolic Non-DM CKD Systolic Diastolic < 14 < 9 < 13 < 8 <14 < 9 212 Canadian Hypertension Education Program Recommendations 51

JNC 7 blood pressure goals in hypertension subgroups Patient subgroup Goal systolic/diastolic BP, mm Hg Uncomplicated < 14/9 Black < 14/9 Elderly < 14/9 Diabetic < 13/85

Risk Factors Uncontrollable Sex Hereditary Race Age Controllable High blood pressure 14 /9mmHg High blood cholesterol Smoking Physical activity Obesity Diabetes Stress and anger

Lifestyle Modification Modification Approximate SBP reduction (range) Weight reduction 5 2 mmhg/1 kg weight loss Adopt DASH eating plan 8 14 mmhg Dietary sodium reduction 2 8 mmhg Physical activity 4 9 mmhg Moderation of alcohol consumption 2 4 mmhg

Selection of Antihypertensive Drug Level of blood pressure + Presence of other risk factors for CVD & target organ damage + Coexisting diseases Antihypertensive Therapy J hypertension 29;27:2121 58

BP target in elderly patients Πξέπεη λα ρνξεγείηαη αληηππεξηαζηθή ζεξαπεία ζε ειηθησκέλνπο αζζελείο κε ππέξηαζε 1ζηαδηνπ? Πξέπεη ν ζηόρνο ηεο αληηππεξηαζηθήο ζεξαπείαο ζηνπο ειηθησκέλνπο λα είλαη < 14/9 mmhg? J of hypertension 29;27:2121 58

Meta-analyses examining SBP targets <14mmHg in patients with diabetes Included only trials that achieved SBPs < 14 mmhg Included all anti-hypertensive trials Outcomes were mortality, CV mortality, MI, HF and stroke Outcomes were MI and stroke only Bangalore et al. Circ 211 Reboldi et al. J Hypertens 211

Meta-analyses examining SBP targets <14mmHg in patients with diabetes Bangalore et al, Circulation 211; 123:2799-281

Stroke Myocardial Infarction Reboldi et al, J of Hypertension 211, 29: 1253-1269

Changes in the Risk of Event (%) Vs. The Tertile 1 (Minimal or No Reduction) Adjusted Risk of a CV Event in Tertiles of SBP Reduction within Quartiles of Entry SBP 2 1-1 -2-3 -4-5 -6 2 1-1 -2-3 -4-5 -6 Baseline SBP > 154 Baseline SBP 143-154 Composite CV death MI Stroke -21 * -2 * -28 * -11-14 -18-2 +2-21 -25 2 1-1 -2-3 * * -4 * -38-39 * -45-5 * * * -51-6 +41 +16 * Baseline SBP 131-142 +17 * * Baseline SBP 13-32 * -19-27 -24-14 2 1-1 -2-3 -4-5 -6 Composite CV death MI Stroke -25-27 -33 +5-32 * Minimal SBP Intermediate SBP Maximal SBP Sleight, Verdecchia, Redón, Mancia, J Hypert 29-11 -5-25 -1-17 * = statistically significant

Unadjusted risk of events (%) Unadjusted risk of events (%) Unadjusted Risk of Events and Corresponding HR in Deciles of On-treatment SBP 3 Primary study outcome 3 3 Cardiovascular mortality 3 2 2 2 2 1 1 1 1 2 112 121 126 13 133 136 14 144 149 16 Myocardial infarction 2 HR (95% CI) 2 112 121 126 13 133 136 14 144 149 16 Stroke 6 HR (95% CI) 4 1 1 1 2 112 121 126 13 133 136 14 144 149 16 112 121 126 13 133 136 14 144 149 16 On-treatment SBP (mmhg) Sleight, Verdecchia, Redón, Mancia, J Hypert 29

Hazard Ratio INVEST Sub-analysis: SBP/DBP: Risk for Primary Outcome 6 6 Nadir =119.2mm Hg Nadir = 84.1 mm Hg 4 4 2 2 15 115 125 135 145 155 165 55 65 75 85 95 15 SBP (mm Hg) DBP (mm Hg) Messerli FH et al. Ann. Int. Med. July 26

Cardiac events (%) CV events (%) Adjusted HR CV events (%) CV events (%) Adjusted HR 6 5 INVEST (CAD pts) 3 ONTARGET (high risk pts, mainly with CAD) 3 4 2 2 3 2 1 1 1 11 >11 to 12 to >12 13 to >13 14 to >14 15 to >15 16 >16 On-treatment SBP (mmhg) 112 121 126 13 133 136 14 144 149 16 On-treatment SBP (mmhg) 3 VALUE (High risk pts) 35 TNT (CAD pts) 5 2 3 25 4 2 3 1 15 1 5 2 1 < 12 >12 to 13 >13 to 14 >14 to 15 >15 to 16 On-treatment SBP (mmhg) >16 to 17 to >17 18 18 6 61-7 71-8 81-9 91-1 > 1 On-treatment DBP (mmhg) J hypertension 29;27:2121 58

Challenges to Hypertension Management: Public Perceptions 44% of people could not identify a normal or a high blood pressure reading 8% of people were unaware of the association between hypertension and heart disease 63% believed that hypertension was not a serious condition 38% of people thought they could control high blood pressure without the help of a health professional Can J Cardiol 25;21:589-93.