MEDICAL TREATMENT OF HYPERTENSION: STATE OF THE

ART

Luis M Ruilope

Cardiology Update

Davos, february 14, 2011

Number of deaths (000s)

0 2000 4000 6000 8000

Occupational risk factors for injury

Unsafe health care injections

Vitamin A deficiency

Zinc deficiency

Urban air pollution

Iron deficiency

Indoor smoke from solid fuels

Unsafe water, sanitation, and hygiene

Alcohol

Physical inactivity

High Body Mass Index

Deficient fruit and vegetable intake

Unsafe sex

Underweight

Cholesterol

Tobacco

Blood pressure

WHO Health Report 2002

World’s #1 killer: High blood pressure (HBP) and its consequences

BENEFIT OF BP CONTROL

•A fixed amount of

benefit corresponds

to a fixed amount of

drop in BP

J Hypertens 2009; 27:673–679.

New concepts even in the

presence of a good BP control• USUAL BP- True BP can not be measured with total

precision.

• MEAN BP- Average of several readings (ABPM, HBPM)

• BP VARIABILITY- The variation of BP with time. Can be

measured over minutes or over days, weeks or months.

• BP INSTABILITY- Transient fluctuations in BP usually in

response to a specific stimulus (posture, stress, pain).

Contributes to BP variability

• Peter M Rothwell, Lancet 2010, 375:938

7 26-MAY-2010

ROADMAP: Percentage of patients reaching BP goal§P

ati

en

ts r

ea

ch

ing

BP

go

al*

(%

)

Months

0 3 6 12 18 24 30 36 42 48

Olmesartan* Placebo*

§ BP goal: <130/80 mmHg

* Additional antihypertensive treatment except RAAS blockers at physician´s discretion, CCBs diuretics, BBs allowed to reach target BP goal

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

Documento del Grupo de Trabajo de la European Society of Hypertension

Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M,

Caulfield MJ, Cifkova R, Clément D, Coca A, Dominiczak A, Erdine S,

Fagard R, Farsang C, Grassi G, Haller H, Heagerty A, Kjeldsen SE,

Kiowski W, Mallion JM, Manolis A, Narkiewicz K, Nilsson P, Olsen

MH, Rahn KH, Redon J, Rodicio J, Ruilope L, Schmieder RE,

Struijker-Boudier HA, van Zwieten PA, Viigimaa M, Zanchetti A.

Reappraisal of European Guidelines on Hypertension

Management: a European Society of Hypertension Task Force

document.

J Hypertens. 2009;27:2121-2158.

ESHESC and JNC 7 Guidelines Recommend Target BP Goals of <140/90 mmHg

for Uncomplicated Hypertension and <130/80 mmHg for Complicated Hypertension1

Type of hypertension BP goal (mmHg)

Uncomplicated <140/90

Complicated

Diabetes mellitus <130/80

Kidney disease <130/80*

Other high risk (stroke, myocardial

infarction)

<130/80

1. Task Force of ESH–ESC. J Hypertens 2007;25:110587

2. Chobanian et al. Hypertension 2003;42:1206–52

*Lower if proteinuria is >1 g/day

11

Reproduced with permission from: Mancia G. Eur Heart J 2007;28:1462–536.

Mancia G, et al. J Hypertens 2009;27:2121–58

Continuous lines show two-drug

combinations that have been found

to be well tolerated and effective

CCBs and ARBs are recommended as preferred

combination therapy partners

Diuretics

ACE inhibitors

CCBs

ARBsβ-blockers

1-blockers

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

betterAtenolol-based

better

Valsartan and Amlodipine: Cardiovascular Endpoints in High-risk

Hypertension1,2

0.5 2

Primary cardiac composite

endpoint

Cardiac mortality

Cardiac morbidity

All MI

All congestive heart failure

All stroke

All-cause death

New-onset diabetes

1

VALUE trial2

Favors

valsartan

Favors

amlodipine

Development of diabetes

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

A)- THE EVIDENCE SUGGESTS THAT TO IMPROVE

CV OUTCOMES WE REQUIRE A NEW PARADIGM

THAT EMPHASIZES RAPID ACHIEVEMENT OF BP

CONTROL (1).

B)- BP CONTROL SHOULD BE ATTAINED PREFERABLY

WITHIN 3 MONTHS OF INITIATING THERAPY (2)

1- Basile J. J Clin Hypertens 2008

2- Berlowitz DR & Franklin S. J Clin Hypertens 2010

BP CONTROL

Initiating therapy with the combination of

nifedipine GITS/telmisartan reduced office SBP

as early as 2 weeks

Re

du

cti

on

in

SB

P f

rom

ba

se

lin

e (

mm

Hg

)

Nifedipine GITS 20mg + telmisartan 80mg

Nifedipine GITS 20mg Nifedipine GITS 20mg + telmisartan 80mg

Telmisartan 80mg Nifedipine GITS 20mg + telmisartan 80mg

A

B

C

0 weeks 8 weeks 24 weeks

p=0.003

p=0.024

* * * * * * * * * * * *

*p<0.001 vs baseline

A B C A B CA B CA B C

Based on least-squared (LS) mean ± standard error of the mean (SE) data

Mancia G., et al. Blood pressure control by the nifedipine GITS-telmisartan combination in

patients at high cardiovascular risk. The TALENT Study. Manuscript in preparation. 2010

Primary composite endpoint of the LIFE

stratified by time-varying albuminuria.

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

Intensive vs standard BP lowering strategies

on albuminuria in ACCORD-BP

ACCORD Study Group. N Engl J Med 2010.

P=0.13

Intensive

0

4

8

12

16

20

24

28

32

36

Pa

tie

nts

(%

)

Microalbuminuria Macroalbuminuria

Standard

32.3%30.2%

P=0.009

8.7%6.6%

Albuminuria GroupsN (%)

Baseline Year 1 Year 2 Year 3 p

Total

Normal

High-Normal

Micro

Macro

970 (67.7)171 (11.9)

234 (16.3)

58 (4.0)

862 (60.2)

213 (14.9)

267 (18.6)

91 (6.4)

754 (54.1)

256 (18.4)

291 (20.9)

94 (6.7)

766 (54.9)223 (16.0)

302 (21.6)

104 (7.5)

0.004

No DM

Normal

High-Normal

Micro

Macro

906 (70.0)148 (11.4)

198 (15.3)

43 (3.3)

789 (63.0)

184 (14.7)

217 (17.3)

62 (5.0)

669 (56.1)

222 (18.6)

235 (19.7)

67 (5.6)

682 (58.2)184 (15.7)

238 (20.3)

67 (5.7)

0.005

DM

Normal

High-Normal

Micro

Macro

64 (46.4)23 (16.7)

36 (26.1)

15 (10.9)

73 (40.3)

29 (16.0)

50 (27.6)

29 (16.0)

85 (42.1)

34 (16.8)

56 (27.7)

27 (13.4)

84 (37.5)39 (17.4)

64 (28.6)

37 (16.5)

0.002

p DM <0.001 <0.001 <0.001 <0.001

Ruilope LM et al. In press 2011.

Development of new-onset microalbuminuria

among hypertensive patients according to

previous cardiovascular events

Ruilope LM et al. In press 2011.

New-onset microalbuminuria was seen in 9.9% of patients without a previous event

and in 17.2% (p=0.003) of those with a previous event.

Survival function

Time (months)

Previous CVD

events

No events

Events

% P

atie

nts

fre

e o

f m

icro

alb

um

inu

ria

CONCLUSIONS• Albuminuria appears and progresses under RAS

suppression either with ACEi or ARB.

• Renal function, severity of hypertension and glycemic

control are independent factors related with the increased

urinary albumin excretion.

• We need to know whether the capacity of RAS

suppression is finished or can be improved in order to

improve the outcome of our patients.

• New ways for RAS suppression have to be investigated in

these cohort of patients (dual blockade with ACEi-ARBs

plus Aliskiren, plus spironolactone).

Schematic differences between ACE/NEP inhibition (as with

omapatrilat) and angiotensin receptor blockade/NEP inhibition (as

with LCZ696).

ACE angiotensin-converting enzyme; Ang II angiotensin II; ARBs angiotensin receptor blockers;

AT1 angiotensin II type 1; NEP neprilysin; NPs natriuretic peptides

Segura J, Ruilope LM. Curr Hypertens Rep 2011; 13:74–78.

Change in placebo-subtracted mean sitting systolic blood pressure (A) and

mean sitting diastolic blood pressure (B) during the 8-week treatment period

Patients who discontinued the study drug without a blood pressure measurement after randomisation were excluded.

CONCLUSION

• Early BP control is desirable (increased use of

combinations). Initial BP is lower than it was

years ago.

• Other means of measuring BP different from

office BP measurement have to be used. This

could include BP variability.

• Trials with different combinations reflect

different outcomes.

• Long-term RAAS suppression could not impede

the development of cardiorenal damage