Οι β αποκλειστές αποτελούν ... · BP Reduction and CV Events in LIFE Dahlöf...

Δρ. Δημήτρης Π. Παπαδόπουλος-FESC

Υπεύθυνος Αντιυπερτασικού Ιατρείου

Καρδιολογικής Κλινικής Π.Γ.Ν.Α. «ΛΑΪΚΟ»

Clinical Assist. Professor George Washington University

Clinical Hypertension Specialist ESH``

Οι β-αποκλειστές αποτελούν

πρώτη θεραπευτική επιλογή για

την αρτηριακή υπέρταση?

0

20

40

60

80

100

120

140

160

180

0

20

40

60

80

100

120

140

160

180 Men

Women

Number of People with Hypertension Aged 20 Years and Older

by World Region and Sex in 2000 and 2025

2000

2025

Nu

mb

er o

f p

eop

le w

ith

hy

per

ten

sio

n (

mil

lio

ns)

Establishedmarket

countries

Formersocialist

economies

India LatinAmericaand the

Caribbean

Middleeasterncrescent

China OtherAsia andislands

Sub-Saharian

Africa

Overall(developed +

developingcountries)

116.2123.3

40.652.5

60.4 57.8 60.054.3

35.9 37.9

98.5

83.1

38.433.0 38.2

41.6972 million

(333 + 639)

147.9

161.8

44.0

59.7

107.3106.2 102.1 98.5

72.280.4

151.7147.5

67.362.1

73.6 77.1

1.56 billion

Kearney et al Lancet 2005;365:217-23

TIA = transient ischemic attack; LVH = left ventricular hypertrophy; CHD = coronary heart disease;

HF = heart failure.

Cushman WC. J Clin Hypertens. 2003;5(Suppl):14-22.

Renal

failurePeripheral vascular

disease

Complications of Hypertension:

LVH, CHD,

HF

TIA, stroke

Hypertension

is a risk factor

• Η βξαβεπκέλε κε Nobel αλαθάιπςε ησλ β-

αλαζηνιέσλ ήηαλ έλαο από ηνύο ζξηάκβνπο

ηεο ζύγρξνλεο θαξκαθνινγίαο.

• Εθηνηε νη β-αλαζηνιείο έρνπλ θαζηεξσζεί ζαλ

αλαγθαία θαη απνηειεζκαηηθά θάξκαθα γηα

πνιιέο θαξδηαγγεηαθέο παζήζεηο, όπσο ε

ΑΤ, ε θαξδηαθή αλεπάξθεηα, ε ζηεθαληαία

λόζνο, ε πξόιεςε ηνπ αηθλίδηνπ ζάλαηνπ,

θαη δηάθνξεο αξξπζκίεο.

Καξδηαθή ζπρλόηεηα θαη

πξνζδόθηκν

δσήο

Καλόλαο:

3 ζπζηνιέο ιηγόηεξεο αλά ιεπηό

παξάηαζε δσήο θαηά 3 ρξόληα

GOALS OF ANTIHYPERTENSIVE

TREATMENT

BP reduction

Risk

Factors

HT

Prevention

TOD

regression/

prevention

NOD

PreventionESRDAF

PreventionCHD StrokeCHF Cognitive

Dysfunction

Dementia

LVH

IMT

Microalbuminaria

Arterial stiffness

Endotheliadysfunction

Cardiacfibrosis

BP Reduction and CV Events in LIFE

Dahlöf B et al Lancet 2002; 359: 995-1003

0 6 12 18 24 30 36 42 48 54

Study Month

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

Systolic

Diastolic

Mean Arterial

mmHg

Atenolol 145.4 mmHg*

Losartan 144.1 mmHg*

Atenolol 80.9 mmHg*

Losartan 81.3 mmHg*

* Mean BP at last visit

Atenolol 102.4 mmHg*

Losartan 102.2 mmHg*

0

2

4

6

8

10

12

14

16

Pro

po

rtio

n o

f p

ati

ents

wit

h f

irst

even

t (%

)

Composite of CV death, stroke and MI

Losartan

Atenolol

Study Month

0 6 12 18 24 30 36 42 48 54 60 66

Losartan 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901Atenolol 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876

Adjusted Risk Reduction 13.0%, p=0.021

Unadjusted Risk Reduction 14.6%, p=0.009

Number

at Risk

BP

Ακινδηπίλε ± Πεξηλδνπξίιε

vs.

β-απνθιεηζηή ± Γηνπξεηηθό

Ακινδηπίλε 5-10 mg Αηελνιόιε 50-100 mg

Πεξηλδνπξίιε 4-8 mgBFZ-K

1.25-2.5 mg

Δνμαδνζίλε GITS 4-8 mg

+

+ +

Άιια θάξκαθα π.ρ. κνμνληδίλε/ζπηξνλνιαθηόλε

+

Αλγόριθμος μείωζης ηης ΑΠΑλγόριθμος μείωζης ηης ΑΠ << 140/90 140/90

mmmm HgHg ή <130/80ή <130/80 mmmm HgHg ζε ζε

διαβηηικούς αζθενείςδιαβηηικούς αζθενείς

DahlDahlööf B et alf B et al. Lancet. 2005;366:895. Lancet. 2005;366:895--906. 906.

-14%

-10%

-16%

-14%

-12%

-10%

-8%

-6%

-4%

-2%

0%

ALL CAUSE MORTALITY PRIMARY END POINT

ASCOT: Preliminary results

p=0,005

p=0,12

REASON FOR STOPPING THE

TRIAL

ASCOT Trial: Endpoints for amlodipine and perindopril

versus atenolol and thiazide

-13%

-16%

-24%

-16%

-34%

-29%

-24%

-19%

-14%

-9%

-4%

-13%-11%

-23%

Total

coronary

endpoint

Non-fatal myocardial

infarction

(excluding silent)

and fatal coronary

heart disease

Total

cardiovascular

events and

proceduresAll-cause

mortality

Cardiovascular

mortality

Fatal and

non-fatal

heart failure

Fatal and

non-fatal

stroke

Beta-Blockers in Hypertension - Disadvantages

Dysmetabolic effects

Protection against subclinical organ

damage

Side effects

Less central BP reduction?

Less prevention of stroke?

Less BP reduction / CVD protection in the

elderly?

Potential Adverse Metabolic Effects

of β-blockers

Insulin-resistance

P-insulin levels

P-glucose levels

LDL/HDL

Triglycerides

Antihypertensive Treatments and Incidence of New Onset Diabetes

Lancet 1999;353:611-16. Lancet 2003;362:759-66. JAMA 2003;290:2805-2816. Lancet 2000;356:366-72. Lancet 2002;359:995-1003. JAMA 2002;288:2981-97. N Engl J Med 2000;342:145-53. J Hypertension 2003;21:1563-1574.

Study% Higher Incidence in Patients Using

Diuretics, b-Blockers

CAPPP diuretics, b-blockers 13% vs. captopril

CHARM placebo ± SOC 16% vs. candesartan ± SOC

INVESTatenolol ± HCTZ or trandolapril

17%vs. atenolol ± HCTZ or trandolapril

INSIGHT co-amiloride ± b-blocker 30% vs. nifedipine GITS

LIFE atenolol 33% vs. losartan

ALLHAT chlorthalidone18%

43%

vs. amlodipine

vs. lisinopril

HOPE placebo ± SOC 50% vs. ramipril ± SOC

ALPINE HCTZ ± atenolol 720%vs. candesartan ± felodipine

From Elliott WJ, Lancet 2007; 369: 201

Results of a Meta-analysis for Incident Diabetes -

Twenty-two Clinical Trials of 143,153 Hypertensive Patients

ARB

ACE inhibitor

CCB

Placebo

Beta-blocker

Diuretic

0.57 (0.46-0.72) p < 0.0001

0.67 (0.56-0.80) p < 0.0001

0.75 (0.62-0.90) p = 0.002

0.77 (0.63-0.94) p = 0.009

0.90 (0.75-1.09) p = 0.30

Referent

50 70 90 126

Odds ratio of incident diabetes Incoherence = 0.000017

ύκθσλα κε ηηο λέεο επξσπατθέο νδεγίεο:

►Οη β-αλαζηνιείο εμαθνινπζνύλ λα απνηεινύλ κία από ηηο πξώηεο επηινγέο ηνπ ηαηξνύ ηόζν γηα έλαξμε όζν θαη γηα ζπλέρηζε ηεο ζεξαπείαο

►Επεηδή νη β-αλαζηνιείο έρνπλ αξλεηηθή επίδξαζε ζε ζεκαληηθέο κεηαβνιηθέο παξακέηξνπο, δελ πξέπεη λα πξνηηκνύληαη ζε ππεξηαζηθνύο κε κεηαβνιηθό ζύλδξνκν ή ηα επηκέξνπο πξνβιήκαηα απηνύ

2007 Guidelines for the Management of Arterial Hypertension:

European Heart Journal, June 11, 2007

►Αυτό μπορεί να μην ισχύει για τους

αγγειοδιασταλτικούς β-αναστολείς, όπως

η καρβεδιλόλη και η νεμπιβολόλη, οι

οποίοι έχουν λιγότερη ή καθόλου

δυσμενή επίπτωση στις μεταβολικές

παραμέτρους και εμφανίζουν λιγότερα

περιστατικά νέου διαβήτη συγκριτικά με

τους κλασικούς β-αναστολείς

2007 Guidelines for the Management of Arterial Hypertension:

European Heart Journal, June 11, 2007

Propranolol

Metoprolol

Atenolol

Pindolol

Carvedilol

Percentage change (%)

20-20-40 0-10-30 10

Jacob S et al. Am J Hypertens 1998

Effects of b Blockers on Insulin Sensitivity

Nebivolol

Επίδραζη ζε μεηαβολικές παραμέηροσς

-30

-20

-10

0

10

20

30

carvedilol

atenolol

metoprolol

Εσαιζθηζία ζηην

ινζοσλίνηΤριγλσκερίδια HDL

+13%

-22% -21%

0%

+18%

+30%

0%

-9% -7%

Jacob S et al, Am J Hypertens 1998;11:1258-65

Επηβεβαίσζε : Μειέηε

GEMINI

► Καξβεδηιόιε – Μεηνπξνιόιε

► 1235 αζζελείο

► Δηαβεηηθνί ηύπνπ 2, Τπεξηαζηθνί

► ΑΠ>130mmHg, ΔΑΠ>80mmHg)

► ε ΑΜΕΑ / ΑΣ-Ι

► ηαζεξνπνηεκέλε αληηδηαβεηηθή ζεξαπεία

γηα 3 κήλεο

► ηαζεξνπνηεκέλε αληηππεξηαζηθή

ζεξαπεία γηα 1 κήλα

Bakris G et al. JAMA 2004;292:2227-2236

Αξηεξηαθή Πίεζε : θαξβεδηιόιε + ΑΜΕΑ/ΑΣ-Ι

87

131.3

77.1

149.4

-40

10

60

110

160

ΑΠ ΔΑΠ

Έλαξμε

Μήλαο 5

(n=454) (n=454)


GEMINI

mmHg

Αληίζηαζε ζηελ ηλζνπιίλε

5.6

5.7

5.8

5.9

6

6.1

6.2

6.3

Καξβεδηιόιε Μεηνπξνιόιε

Έλαξμε

Μήλαο 5

p=0,004

p=0,48

p=0,004

↑↑

(n=371) (n=540)


GEMINI

HOMA-IR

Μεηαβνιή ζηε γιπθνδπιησκέλε αηκνζθαηξίλε

7

7.1

7.2

7.3

7.4

7.5

Καξβεδηιόιε Μεηνπξνιόιε

Έλαξμε

Μήλαο 5

p=0,65

p<0,001

p=0,004

Μέζ

ε H

bA

1c

(%

)

↑

(n=454) (n=657)


GEMINI

Change in Insulin and HOMA Index Induced by Nebivolol and Metoprolol

after 24 Wks in HTN

Insulin κU/ml

0

2

4

6

8

10

12

* p< 0.006

Nebivolol

16

18

14

Placebo Placebo Metoprolol

HOMA index

0

1

2

* p< 0.008

Nebivolol

4

3

Placebo Placebo Metoprolol

Celik et al. J Hypertens 2006

Changes in Lipids Induced by Nebivolol and Metoprolol after 24 Wks in HTN

-4.6

-20

-15

-10

-5

0

5

10

15

20

-2.4

-10.1

-2.7

-11.5

+8.7

-2.0

+16.3

TC LDL-C LDL-C/HDL-C TG

Nebivolol (5 mg)

Atenolol (50 mg)

Pesant et al. Amer J Therap 1999

%

Reappraisal of European Guidelines on Hypertension Management:

an ESH Task Force Document

Journal of Hypertension 2009

…when discussing β-blockers, however, it should not be

ignored that they are no homogeneous class, and that

vasodilating β-blockers such as carvedilol and nebivolol

appear not to share some of the negative properties

described for other compounds


15805 M



damage

Side effects




elderly?

Η ΠΡΟΛΗΦΗ ΣΗ ΒΛΑΒΗ ΣΧΝ ΟΡΓΑΝΧΝΣΟΥΧΝ ΑΠΟΣΕΛΕΙ ΕΠΙΠΡΟΘΕΣΟΜΕΛΗΜΑ / ΚΟΠΟ ΠΕΡΑΝ ΣΗ ΡΤΘΜΙΗΣΗ ΑΠ, ΓΙΑ ΣΗ ΒΕΛΣΙΧΗ ΣΗΠΡΟΓΝΧΗ ΣΧΝ ΑΘΕΝΧΝ

B. Dahlof Eur H J 2003;5:SF(F33-F39).

“Specific” Protective Effects of Antihypertensive Drugs

on Subclinical Organ Damage

Diuretics

Beta-

blockers

CCB

ACEI

ARB

Arterial thickening /

Atherosclerosis

Endothelial

dysfunction

Arterial stiffening

Coronary Ca++

depletion

Arteriolar remodelling

Diastolic

dysfunction?

Cognitive

dysfunction /

Dementia

LVH

Nephroprotection

MA / Proteinuria

Mancia G, 2006

Proportion of patients

with first event (%)

0

2

4

6

8

10

12

14

16

0 6 12 18 24 30 36 42 48 54 60 66

Adjusted Risk Reduction:

13.0%, p = 0.021

Time (months)

Change from baseline (%)

in LVH determined by electrocardiography

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

p < 0.0001

p < 0.0001

4.4%

10.2%

15.3%

9.0%

Atenolol

Losartan

Dahlöf B et al. Lancet 2002;359:995–1003.

LIFE: Παπόμοια μείωζη ΑΠ Τποζηποθή

ΤΑΚ

Atenolol

Losartan

CornellVoltage-Duration

Product

Sokolow-LyonVoltage

Composite of CV Death, stroke and MI

Μετα-ανάλσση μελετών σποστρουής ΥΑΚ στην σπέρταση

Schmieder RE et al. Am J Med 2003; 115:41-6.

-16

-14

-12

-10

-8

-6

-4

-2

0Diuretics b-blockers

Ca-antagonist

ACE-inhibitors ARBs

-8%

-6%

-11%-10%

-13%

LV massreduction

(%)

80 Μελέηερ;4,113 αζθενείρ

Έζσ θαξσηίδα (IC)Έμσ θαξσηίδα (EC)

Δέξκα

Κνληηλό

ηνίρσκα

Μαθξηλό

ηνίρσκα

1.0 cm

0.5-1.0 cm

1.0 cm

CBMmax

Μέζνο όξνο ηνπ κέγηζηνπ

IMT από 4 καθξηλά

ηνηρώκαηα (+ 4 θνληηλά

ηνηρώκαηα)

ζε CC θαη Bif,

ακθνηεξόπιεπξα

Δηραζκόο (Bif)

Κνηλή

θαξσηίδα (CC)

Ορισμός του πάχους του έσω –μεσου

χιτωνα (ΙΜΤ)

Μειέηε

PREVENT

PART-2

SECURE

BCAPS

MIDAS ns

VHAS ns

INSIGHT

DAPHNE

ELSA

Αζζέλεηα

CHD

VD

Υς.Κίλδ.

VD

HT

HT

HT

HT

HT

Θεξαπεπηηθέο αγσγέο

Ακινδηπίλε έλαληη Placebo

Ρακηπξίιε έλαληη Placebo

Ρακηπξίιε έλαληη Placebo

Μεηνπξνιόιε έλαληη Placebo

Ιζξαδηπίλε έλαληη HCTZ

Βεξαπακίιε έλαληη

Χισξνζαιηδόλεο

Νηθεδηπίλε GITS έλαληη

Cν-Ακηινδίδεο

Γνμαδνζίλε έλαληη HCTZ

Λαζηδηπηλε - Αηελνινιε

Μέηξεζε

IMT

Mmax

CC-IMT

Mmax

Bif

Mmax

Mmax

CC-IMT

C + Fem

IMT-CBM

Αζζελείο

(n)

373

617

732

793

833

498

324

80

2255

Πξόζθαηεο Μειέηεο Αληηππεξηαζηθώλ Παξαγόλησλ ζην Καξσηηδηθό IMT

Beta-blockers in Patients with Intermittent Claudication and Arterial Hypertension:

Results from the Nebivolol or Metoprolol in Arterial Occlusive Disease Trial

Espinola-Klein C et al. Hypertension 2011; June ahead print

Results:

After a 48-week treatment period, ABI and absolute

claudiacation distance improved significantly in both

groups (p<0.05 for both)

A significant increase 39% of initial claudication distance

was found in Nebivolol group (p< 0.003)

vs 16.6% in Metoprolol group (p: NS)

Nebivolol but not Atenolol Reduces

Arterial Stiffness

McEniery, et al. Hypertension 2004;44:305

3.0

3.3

3.7

4.0

Atenolol

* p<0.05 vs baseline

Nebivolol

** p<0.01 vs baseline

n=12

3.1

3.2

3.4

3.5

3.6

3.8

3.9 *

Saline 250 500

Dose (nmol/min)

**

PW

V (

m/s

ec)

BB and Subclinical Organ Damage

ESH Task Force Document, J Hypertens 2009

Increased LVM

Carotid IMT thickening

Aortic stiffness

Increased small artery wall/lumen ratio

“…BBs have been shown to be less powerful than other agents

in studies using subclinical organ damage as an endpoint”




damage

Side effects




elderly?

CAFÉ Study Circulation 2006

Differential Effect of β-bl/D and

ACE-I/CCB’s On BP in ASCOT




damage

Side effects




elderly?

Beta-blockers (BB) and Withdrawal from Side Effects -

Data from 15 Placebo-controlled Trials (n > 35000)

12512 M Ko DT et al., JAMA 2002; 288: 351

0

1

2

3

Placebo

BB

%

Depression Fatigue Sexual dysfunction

0.94

(0.44-2.01)

2.63

(1.16-5.94)

4.89

(2.98-8.03)

RR

0.50.4

0.5

2.4

1.3

0.3

Cumulative Incidence of Discontinuation of Initial Antihypertensive Monotherapy

over 1 Year (Lombardia Data-base; n = 445356)

0.

5

1.

0

2.

0

Diuretics

Beta-blockers

Alpha-blockers

Calcium channel blockers

ACE-inhibitors

Angiotensin-receptorblockers

1.83 (1.81-1.85)

1.64 (1.62-1.67)

1.23 (1.20-1.27)

1.08 (1.06-1.09)

0.92 (0.90-0.94)

- +

Corrao, Zambon, Parodi, Poluzzi, Baldi, Merlino, Cesana, Mancia, J Hypert 2008; 26: 819-824




damage

Side effects




elderly?

Diuretic b-Blocker Placebo

Total stroke 7.3* 9.0 10.8

Total coronary heart disease 7.7* 12.8 12.7

Total cardiovascular disease 17.4* 24.6 25.2

Total mortality 21.3 26.4 24.7

* significantly better than placebo

MEDICAL RESEARCH COUNCIL TRIAL (MRC)

Treating Elderly with Diuretic and Beta Blockers Is Beneficial(1992)

MRC Working Party. Br Med J 1992; 304:405




damage

Side effects




elderly?

13 ηςσαιοποιημένερ μελέηερ (n=105.591) :

β- blockers vs other antihypertensive

7 ηςσαιοποιημένερ μελέηερ (n=27.433) :

β - blockers vs placebo

Aνάλςζη έγινε για όλοςρ ηοςρ β αναζηολείρ και για 3 ςποομάδερ αςηών:

> non atenolol b-blockers

> Mixed b-blockers and diuretics (>50% of pts started on a b blocker)

Atenolol

Eξεηάζθηκε η επίδπαζη ζε ΑΕΕ, ΕΜ, θνηηόηηηα όλων ηων αιηιών

The Lancet Vol 366 October 29

2005

Reappraisal of European Guidelines on Hypertension Management

A European Society of Hypertension (ESH) Task Force Document

ESH Task Force:

G. Mancia, Co-Chairperson (Italy), S. Laurent, Co-Chairperson (France),

E. Agabiti-Rosei (Italy), E. Ambrosioni (Italy), M. Burnier (Switzerland),

R. Cifkova (Czech Republic), D. Clement (Belgium), A. Coca (Spain),

A. Dominiczak (UK), S. Erdine (Turkey), R. Fagard (Belgium), C. Farsang (Hungary), G.

Grassi (Italy), SE. Kjeldsen (Norway), W. Kiowski (Switzerland),

A. Manolis (Greece), K. Narkiewicz (Poland), P. Nilsson (Sweden), M. Olsen

(Denmark), J. Redón (Spain), J. Rodicio (Spain), L. Ruilope (Spain), RE. Schmieder

(Germany), HAJ. Struijker-Boudier (The Netherlands), P. van Zwieten (The Netherlands),

Mancia G. et al., J Hypert, Nov 2009

M. Viigimaa (Estonia), A. Zanchetti (Italy)

< 140 / 90 if low and moderate CV risk

< 130 / 80 if high CV risk

Diabetes

Renal dysfunction

Established CV disease

2007 ESH Guidelines for the Management of Hypertension.

J of hypertension 2009;27:2121–58

2007 Blood pressure targets

2003 ESH/ESC Guidelines

Evidence of CV protection with 5 drug classes

- Diuretics

- Beta-blockers

- ACE-inhibitors

- Calcium channel blockers

- Angiotensin II antagonists

All above classes suitable for initiation / maintenance of

antihypertensive treatment

Effective BP fundamental

2009 ESH/ESC Guidelines

Combinations between Some Classes of Antihypertensive Drugs

Thiazide diuretics

ACE inhibitors

Calcium

antagonists

ß-

blockers

AT1-

receptor

antagonists

α-blockers

Thiazide diuretics

ACE inhibitors

Calcium

antagonists

AT1-

receptor

antagonists

• Pronounced antihypertensive

effect

• CV protection

• Optimal tolerability

ACCOMPLISH

ADVANCE

HYVET

ASCOT

ONTARGET

Beta blockers are still first line

therapy in arterial hypertension???

Yes for individual patients and

vasodilatory agents

Οι β αποκλειστές αποτελούν ... · BP Reduction and CV Events in LIFE Dahlöf...

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