P H Y S I C I A N S ’ A C A D E M Y F O R C A R D I O V A S C U L A R E D U C A T I O N

Hypertension:Does it matter how to lower blood pressure?

Luis Ruilope, MDHospital 12 de Octubre,Madrid, Spain

Cardio Diabetes Master ClassOctober 15-17, 2010, Dublin

Slide lecture prepared and held by:

CARDIORENAL CONTINUUM

1- CVRF2- ASYMPTOMATIC TOD3- SYMPTOMATIC TOD

DiabetesNo diabetes

CVD

dea

th ra

te(p

er 1

0,00

0 pe

rson

-yea

r)250

0

200

150

100

50

Systolic blood pressure (mmHg)

< 120 120–139 140–159 160–179 180–199 200

‘Double jeopardy’: type 2 diabetes and hypertension and cardiovascular risk

1

2

3

75 %

25 %

COST

%EVENTS

Treatment is effective

Mean-DBP at randomisation 99 mm Hg, mean difference 5-6 mm Hg, n=37 000, mean time to event 2-3 years

Collins et al. Lancet 1990;335:827

•Results of antihypertensive therapy in randomised controlled trials

BENEFIT OF BP CONTROL

•A fixed amount of benefit corresponds to a fixed amount of drop in BP

BPLTTC Lancet 2003; 362: 1527– 35; Arch I ntern 1995;155:701-9

23% RR stroke

15% RR major CV events

Beneficios de pequeños descensos de PA

Risk Stratification

Other CVRF. OD or Disease

NormalSBP 120-129 orDBP 80-84

High Normal

SBP 130-139 or

DBP 85-89

Grade 1 HTSBP 140-159

or DBP 90-99

Grade 2 HT

SBP 160-179or

DBP 100-109

Grade 3 HT

SBP≥ 180or

DBP≥ 110

No other CVRF Average risk Average risk Low added

riskModerate added risk

High added risk

1-2 CVRF Low added risk

Low added risk

Moderate added risk

Moderate added risk

Very high added risk

3 or more CVRF, MS, OD or DM

Moderate added risk

High added risk

High added risk

High added risk

Very high added risk

Established CV or renal disease

High added risk

Very high added risk

Very high added risk

Very high added risk

Very high added risk

Initiation of antihypertensive treatment

Other CVRF. OD or Disease

NormalSBP 120-129 orDBP 80-84

High NormalSBP 130-139

orDBP 85-89

Grade 1 HTSBP 140-159

or DBP 90-99

Grade 2 HTSBP 160-179

or DBP 100-109

Grade 3 HTSBP≥ 180

orDBP≥ 110

No other CVRF No BP intervention

No BP intervention

Lifestyle changes for several months

then drug treatment if BP

uncontrolled

Lifestyle changes for several weeks

then drug treatment if BP uncontrolled

Lifestyle changes

+Immediate

drug treatment

1-2 CVRF Lifestyle changes

Lifestyle changes

Lifestyle changes for several weeks

then drug treatment if BP

uncontrolled

Lifestyle changes for several weeks

then drug treatment if BP uncontrolled

Lifestyle changes

+Immediate

drug treatment

3 or more CVRF, MS or OD

Lifestyle changes

Lifestyle changes and consider drug

treatment Lifestyle changes+

Drug treatment

Lifestyle changes+

Drug treatment

Lifestyle changes

+Immediate

drug treatmentDiabetes Lifestyle

changesLifestyle

changes +Drug treatment

Established CV or renal disease

Lifestyle changes

+Immediate

drug treatment

Lifestyle changes

+Immediate drug

treatment

Lifestyle changes+

Immediate drug treatment

Lifestyle changes+

Immediate drug treatment

Lifestyle changes

+Immediate

drug treatment

0 25 50 100 mg Losartan0 80 160 320 mg Valsartan0 75 150 300 mg Irbesartan

Reduction in diastolic BP (mmHg)

LosartanValsartanIrbesartan

-10

-8

-6

-4

-2

-0

Elmfeldt et al 2002

Meta-Analysis based on US New Drug Application Evaluation Reports

Candesartan

0 4 8 16 mg Candesartan

Non-fatal MI (excluding silent) + fatal CHD

Total coronary endpoint

Total CV events and procedures

All-cause mortality

CV mortality

Fatal/non-fatal stroke

Fatal/non-fatal HF

Development of renal impairment

0.5 1 2

ASCOT BPLA1

Amlodipine-based better

Atenolol-based better

Valsartan and Amlodipine: Cardiovascular Endpoints in High-risk Hypertension1,2

0.5 2

Primary cardiac compositeendpoint

Cardiac mortality

Cardiac morbidity

All MI

All congestive heart failure

All stroke

All-cause death

New-onset diabetes

1

VALUE trial2

Favorsvalsartan

Favorsamlodipine

Development of diabetes

1. Dahlöf et al. Lancet 2005;366:895–906; 2. Julius et al. Lancet 2004;363:2022–31

Amlodipine/Valsartan Provides Powerful BP Reductions Across Hypertension Severities1,2

Ad hoc analysis¶DBP 9099 mmHg, SBP 140159 mmHg‡DBP ≥100 mmHg, SBP ≥160 mmHgBP = blood pressure; DBP = diastolic BP; SBP = systolic BP; MSSBP = mean sitting SBP

1. Smith et al. J Clin Hypertens 2007;9:355–64 (Dose 10/160 mg)2. Poldermans et al. Clin Ther 2007;29:279–89 (Dose 5–10/160 mg)

Mild HTN1¶

Mea

n ch

ange

in M

SSB

Pfr

om b

asel

ine

(mm

Hg)

0

–10

–20

–30

–40

–50

n=69 n=140 n=15

–20

–43

–30

Moderate HTN1‡Baseline SBP≥180 mmHg2

0

–10

–20

–30

–40

–50

Prevent CKD

Prevent ESRD

Prevent Microalbuminuria

PreventStroke/CVD

PreventCVD/Stroke

Hypertension

Diabetes

Micro-albuminuria

Chronic Kidney Disease

OBJECTIVES:• BP <130/80 mmHg (<125/75 mmHg if U/prot >1

g/24h) with ACEi, ARBs, CCB’s, diuretics• Start with 2 drug-fixed dose combination if SBP

>20 mmHg and/or DBP >10 mmHg above target• Reduce proteinuria using ACEi, ARBs, Aldo-

antagonists ndCCBs (dCCBs may increase proteinuria)

• Slow GFR decline with ACEi, ARBs (dCCBs may not alter GFR decline, in the absence of an ACEi/ARB)

• Reduce CV Risk with ACEi• ACEi, ARBs and diuretics reduce CHF, ACEi and

ARBs do not worsen IR

OBJECTIVES:• BP goal <140/90

mmHg with ACEi, ARBs, CCB’s

• Other CVRF control, lipid profile

• Spot urine albumin/creatinine ratio

OBJECTIVES: • Intensive diabetes control

(HbA1c <6.5% or lower, PG fasting, postprandial)

• Intensive BP control <130/80mmHg

• RAS blockade• Lipid profile: TChol, LDL, HDL,

TGL goals…• Microalbuminuria - Proteinuria• Serum creatinine, GFR• Eye examination, ECG

OBJECTIVES:• BP goal <130/80 mmHg • ACEi, ARBs, combination• Treat other CRFs• Monitor urine Alb/Cr ratio

annually

Pre-Hypertension

IGTMetabolic Syndrome

Prevent

Prevent

Ruilope et al, Blood Press 2007rR Ruilope et al, Blood Press 2007

Baseline BP predicts progression to hypertension 4 year hypertension incidence rates,

adjusted for sex, age, BMI, and baseline BP

Age 35-64

5,3

17,6

37,3

0

10

20

30

40

50

60

Optimal Normal HighNormal

4 Ye

ar H

yper

tens

ion

Inci

denc

e %

Age 65-94

16

25,5

49,5

0

10

20

30

40

50

60

Optimal Normal High Normal

Optimal = <120/80 mm Hg Normal = 120-130/80-85 mm Hg High Normal = 130-139/85-89 mm Hg

Vasan RS Lancet 2001

Impact of high-normal BP on CV risk

Cumulativeincidence ofCV events(%)

PreHTN

PreHTN

Vasan RS et al. N Engl J Med 2001;345:1291-7

1210

86420

14

1210

86420

0 2 4 6 8 10 12Years

Optimal BP

High-normal BP

Normal BP

High-normal BP

Optimal BP

Normal BP

Women

Men

Optimal BP: <120/80 mmHgNormal BP: 120-129/80-84 mmHgHigh-normal BP: 130-139/85-89 mmHg

16

Cumulativeincidence ofCV events(%)

Kaplan-Meier curves of clinical hypertension in the two groups

Numbers under the graph refer to hypertension-free individuals

0 1 2 3 4

Years in study

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

% C

umul

ativ

e in

cide

nce Candesartan

Placebo

Candesartan 391 356 309 191 128Placebo 381 269 184 118 85

CONFIDENTIAL

ROADMAP BP goal (ie. < 130/80 mmHg):

0

10

20

30

40

50

60

70

80

90

100

Screening Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10

% pts reaching goal BP <130/80mmHg% pts reaching BP <140/90mmHg

1 y 2 y 3 y6 mo3 mo1 moRand.

ALPINE

New-onset diabetes (n=362)

0123456789 p<0.05

No ofpatients

Lindholm LH, J Hypertens 2003

HCTZCandesartan

NormalLV structure and function

Hypertension HF

Overt heart failure

SmokingDyslipidaemiaDiabetes

ObesityDiabetes

LV remodelling

LVH

MISystolic

dysfunction

Diastolicdysfunction

Subclinical LV

dysfunction

Time: decades Time: months

Death

Progression from hypertension to heart failure

DN = diabetic nephropathy.Adler et al. Kidney Int. 2003;63:225-232.

Annual Transition Rates Through Stages of DN

No nephropathy

Microalbuminuria

Macroalbuminuria

Elevated plasma creatinine or Renal replacement therapy

2.0%(1.9% to 2.2%)

2.8%(2.5% to 3.2%)

2.3%(1.5% to 3.0%)

1.4%(1.3% to 1.5%)

3.0%(2.6% to 3.4%)

4.6%(3.6% to 5.7%)

19.2%(14.0% to 24.4%)

Hallan, S. I. et al. J Am Soc Nephrol 2009;20:1069-1077

HR (95% CI) for ESRD associated with urine albumin excretion

Primary composite endpoint of the LIFE stratified by time-varying albuminuria.

Ibsen H et.al J Hypertension 2004;22:1805

23

GUARD trial BP Results SBP

DBP

-20.49*

-13.05*

*P<0.0001 vs baseline; †P=0.0176 vs benazepril/amlodipine

-18.75*

-9.97*†

Cha

nge

in B

P fr

om b

asel

ine

Bakris G et.al. Kidney International 19 March 2008;doi:10.1038/ki.2008.102

PREVALENCE AND TREATMENT OF HYPERTENSION IN EUROPE

44% ( > 140/90 mmHg), age and sex adjusted

> 200 million europeans are actually treated

ACEi/ARB are the most widely used classes (30-50%)

ESH-ESC Guidelines recomend ACEi/ARB as initial therapy whenever there is a high added risk

Wolf-Maier et al, JAMA 2003; Wang et al, Arch Intern Med 2007; Falaschetti et al, Hypertension 2009; Corrao et al, J Hypertens 2008; Mancia et al, J Hypertens 2007.

ONTARGETONTARGET: Changes in urinary albumin excretion

0

0,5

1

1,5

2

2,5

UAE initial(mg/mmol)

Second yearRatio to initial

FinalRatio to initial

Ramipril Telmisartan Ram+Telm

<0.0001 0.0009

Occurrenceproteinuria

0.019

Mann J et al. Lancet 2008

Evolución de la proteinuria a lo largo del estudio

J Am Soc Nephrol 2005;16:3038-3045

CARDIORENAL CONTINUUM

1- CVRF2- ASYMPTOMATIC TOD3- SYMPTOMATIC TOD

Systolic Pressures (mean + 95% CI)

Average : 133.5 Standard vs. 119.3 Intensive, Delta = 14.2

Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3

Systolic Blood Pressure Over Timem

m H

g

N=5723

N=5700

Month

130.0 mmHg

129.3 mmHg

ACEI/HCTZ N=5762

ACEI/CCB N=5744

Jamerson K et.al. N Engl J Med 2008;359:2417-28

Blood pressure control according to clinic-based measurement and ambulatory monitoring

Clinic-based Control = 23.6%

Ambulatory monitoring control = 51.6%

Clinic-based control

Controlled(<140/90 mmHg)

No controlled (140/90 mmHg)

Ambulatory monitoring

control

Controlled (<135/85 mmHg)

18.2% 33.4%

No controlled(135/85 mmHg)

5.4% 43%

Banegas JR, Segura J, Sobrino J, Ruilope LM, et al. Hypertension 2007;49:62-68.

Am J Med 2009, december

Discrepancies between office and ambulatory blood pressure: clinical implications

José R. Banegas,a MD; Franz H. Messerli,b MD; Bernard Waeber,c MD; Fernando Rodríguez-Artalejo,a Alex de la Sierra,d MD; Julián Segura,e MD; Alex Roca-Cusachs,f MD; Pedro Aranda,g MD; Luis M. Ruilope,e MD

aDepartment of Preventive Medicine and Public Health. Universidad Autónoma de Madrid, and CIBER en Epidemiología y Salud Pública (CIBERESP), Spain. bDivision of Cardiology, St Luke's-Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, USA. cDivision of Clinical Pathophysiology, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland.dHypertension Unit, Clinic Hospital, Barcelona, Spain. eHypertension Unit, Doce de Octubre Hospital, Madrid, Spain. fHypertension Unit, Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. gNephrology Department, Hospital Regional Universitario Carlos Haya, Málaga, Spain.

Am J Med 2009; in press.

Office BP (mmHg) CHD Stroke Diabetes

<120/80 129 (88.4) 68 (82.9) 144 (81.8)

120-129/80-84 130 (75.6) 90 (73.2) 228 (74.3)

130-139/85-89 224 (65.1) 123 (59.7) 408 (57.1)

140-159/90-99 401 (45.2) 260 (43.0) 1142 (43.2)

≥160/100 205 (25.3) 126 (23.7) 624 (22.3)

Total 1089 (46.1) 667 (43.1) 2546 (38.3)

P for trend <0.001 <0.001 <0.001

N=4,729

Number and percentage of treated high-risk hypertensive patients whose 24-h ambulatory blood pressure is controlled (<130/80 mm Hg),

according to office blood pressure and type of associated disease