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Giovambattista Desideri

Università degli Studi dell’Aquila

Il ruolo della terapia di

combinazione nel controllo

dell’ipertensione

51

7368

72

31

55 54

61

10

29 27

35

0

10

20

30

40

50

60

70

80

90

100

NHANESII1976-1980 NHANESIII(fase1)1988-1991

NHANESIII(fase2)1991-1994

NHANESIV1999-2004

Pazien

(%)

Consapevoli Tra a Controlla

Chobanian AV. New Engl J Med 2009;361:878-87

La proporzione dei pazienti con ipertensione non controllata è

rimasta sostanzialmente immodificata negli anni

68%

47% 50%43%

Achievement of treatment goals for primary prevention of CVD

disease in clinical practice across Europe: the EURIKA study

*If diabetes: blood pressure ,130/80 mmHg, total cholesterol ,4.5 mmol/L, and LDL cholesterol ,2.5 mmol/L.

Banegas JR et al. European Heart Journal (2011) 32, 2143–2152

Modified from Kathib R et al. January 2014 | Volume 9 | Issue 1 | e84238

Patient and Healthcare Provider Barriers to Hypertension

Awareness, Treatment and Follow Up: A Systematic Review and

Meta-Analysis of Qualitative and Quantitative Studies

Modified from Kathib R et al. January 2014 | Volume 9 | Issue 1 | e84238

Patient and Healthcare Provider Barriers to Hypertension

Awareness, Treatment and Follow Up: A Systematic Review and

Meta-Analysis of Qualitative and Quantitative Studies

The doctor(inertia)

The patient(adherence)

The drug

Efficacy

Tolerability

Simplicity

Efficacy

Tolerability

Simplicity

2013 ESH-ESC Guidelines, J Hypertens 2013

2013 ESH/ESC Guidelines: Summary of recommendations on

antihypertensive treatment strategies

the major mechanism of the benefits of anti-hypertensive

therapy is lowering of BP per se

the effects on cause specific outcomes of the various agents

are similar or differ by only a minor degree

the type of outcome in a given patient is unpredictable

all classes of antihypertensive agents have their advantages

but also contraindications

Should antihypertensive agents be ranked in order of choice?

Use of BP lowering drugs in the prevention of CV disease:

meta-analysis of 147 randomised trials

Law MR et al. BMJ 2009

Raddoppio della dose di un farmaco(dalla dose standard a quella doppia)

1.0

0.8

0.6

0.4

0.2

0

1.2

1.4

Tiazidici Beta bloccanti ACEI CCB Tutte le classi

Aggiunta di un farmacodi un’altra classe

ACEI, inibitori dell’angiotensin-converting enzyme; CCB, calcio antagonisti

0.190.23

0.20

0.37

1.04 1.00

0.89 1.01

0.22

1.16

Wald et al. Am J Med 2009;122:290-300.

Rap

po

rto

tra

rid

uzi

on

ep

ress

ori

ain

crem

enta

leo

sser

vat

ae

rid

uzi

on

ep

ress

ori

aat

tesa

Razionale per la terapia di combinazione:

due farmaci sono più efficaci di uno

AASK MAP <92

Target BP (mm Hg)Average number of antihypertensive agents

1

UKPDS DBP <85

ABCD DBP <75

MDRD MAP <92

HOT DBP <80

Trial 2 3 4

IDNT SBP/DBP 135/85

DBP, diastolic BP; SBP, systolic BP; MAP, mean arterial pressure; UKPDS, United Kingdom Prospective Diabetes Study; ABCD, Appropriate Blood Pressure Control in Diabetes; MDRD, Modification of Diet in Renal Disease; HOT, Hypertension Optimal Treatment; AASK, African American Study of Kidney Disease; IDNT, Irbesartan Diabetic Nephropathy Trial

Bakris GL et al. Am J Kidney Dis 2000;36:646–661

Multiple antihypertensive agents are needed to achieve target BP

Percentage of People in Outcomes Trials of the Elderly Taking 2 or More Antihypertensive Medications

JACC Vol. 57, No. 20, 2011

Hypertension in the Elderly May 17, 2011:2037–114

The issue is not whether combination therapy is useful,

but whether it should always be preceded by an

attempt to use monotherapy, or whether - and when -

combination therapy may be the initial approach.

Monotherapy and combination therapy:

Pros and cons of the two approaches

Monotherapy allows to

ascribe effectiveness and

adverse events

Finding an alternative

monotherapy may be a

painstaking process and

discourage adherence

Increasing dose of one drug

is less effective than

combination therapy

Prompert response in a larger

numerbe of patients

Greater probability of

achieving the target BP

Lower probabily of drop-out

Physiological and

pharmacological synergies

Fewer side effects

Value of low dose combination treatment with blood

pressure lowering drugs: analysis of 354 randomised trials

Law MR et al. 2003;326:1427

Adverse effects of drugs: percentage of people with one or more symptoms attributable to

treatment*, according to category of drug and dose, in randomised trials

Effect of Renin-Angiotensin System Blockade on Calcium Channel Blocker-Associated Peripheral Edema:

25 RCT with 17.206 patients

Makani H et al. The American Journal of Medicine (2011) 124, 128-135

Per

cen

tage

0%

1%

2%

3%

4%

5%

6%

7%

Incidence of peripheral

edema

Withdrawl due to

peripheral edema

CCB monotherapy

CCB/RAS blocker

combination

*

*

-60%

-50%

-40%

-30%

-20%

-10%

0%

CCB-ACE vs

CCB

CCB-ARB vs

CCB

-54%

P<0.0001

-21%

P=0.02

Incidence of peripheral edema

Incidence of cough in patients with single, double or triple

therapy including an ACE-inhibitor

0

2

4

6

8

10

12

14

ACE-I ACE-I + CCB ACE-I + CCB

+ DIUR

0

2

4

6

8

10

12

14

ACE-I ACE-I + CCB ACE-I + CCB

+ DIUR

Sato A et al. Clin Exp Hypertens. 2015;37(7):563-8

Male Female


Monotherapy vs drug combination strategies to achieve target blood

pressure. 2013 ESH/ESC Guidelines

Moving from a less intensive to a more intensive therapeutic strategy should be done whenever blood pressure target is not achieved.

Volpe M, Agabiti Rosei E, Ambrosioni E, Cottone S, Cuspidi C, Borghi

C, De Luca N, Fallo F, Ferri C, Morganti A, Muiesan ML, Sarzani R,

Sechi L, Virdis A, Tocci G, Trimarco B, Filippi A, Mancia G.

RAS Blockade

Condition

Prevention of

HR Diseases

Subclinical TOD

Improvement

Cause-specific

Event Prevention

CHF (?)

Stroke (?)

Renal

dysfunction

LVH

Proteinuria /

MA

Asympt.

atherosclerosis

Cogntive

dysfunction (?)

MS DM

D / nonD

nephropathy

Previous

MI CHF

ESRD AF New onset

DM

MS New onset

HT (?)

2013 ESH/ESC Guidelines

Use of RAS Blockers as Preferred Drugs


Composite outcome

%

0,11

0,7

0,5

0,9

OR

Cardiovascular death

%

0,11

0,7

0,5

0,9

Myocardial infarction

%

0,11

0,7

0,5

0,9

New heart failure onset

%

0,11

0,7

0,5

0,9

All-cause death

%

0,11

0,7

0,5

0,9

OR

Stroke

%

0,11

0,7

0,5

0,9*

** *

*

New diabetes onset

%

0,11

0,7

0,5

0,9

*

** *

ACE-Is

ARBs

outcome significantly reduced as compared to placebo* Savarese G et al, JACC 2013

Effect of ACE-Is or ARBs on outcomes in 108,212 high

risk patients

Comparison of RAAS blockers for a same BP effect

Rela

tive r

isk r

eduction

(%)

-48%

-20%

-35%

-53%

-25%

NS

STROKECHD HEART FAILURE

For a similar blood pressure reduction (10/5 mm Hg SBP/DBP reduction):

ACE INHIBITORS

ARBs N=100 959 patients

Mean follow-up: 4 years

Thomopoulos C. J Hypertens. 2015;33:195-211.

Van Vark LC et al. Eur Heart J 2012; 33:2088-97.

ACE inhibitors reduce mortality in hypertension: a meta-analysis of

RCT of (RAAS) inhibitors involving 158.998 patients.

0.90 (0.84-0.97)

0.99 (0.94-1.04)

All-cause mortality: effect of ACE inhibitors

ASCOT-BPLA

ADVANCE

HYVET

Overall

1.03 (0.90-1.15)

0.90 (0.75-1.09)

0.99 (0.62-1.58)

1.32 (0.61-2.86)

0.89 (0.81-0.99)

0.86 (0.75-0.98)

0.79 (0.65-0.95)

0.90 (0.84-0.97)

ACE inhibitor better Control better

Random effects model HR (95% CI) P

N= 76 6150.50 0.75 1.33 2.01HR (log scale)

0.03

0.03

0.02

0.87(0.81-0.93)

0.004

<0.001

ALLHAT (lisinopril)

ANBP-2 (enalapril)

pilot HYVET (lisinopril)

JMIC-B (lisinopril, enalapril)

(perindopril)

Van Vark LC et al. Eur Heart J 2012; 33:2088-97.

Ceconi C, et al. Eur J Pharmacol. 2007

Comparative affinity of ACE inhibitors to

bradykinin vs angiotensin I binding sites of ACE

1.00

trandolaprilatquinaprilat enalaprilatramiprilatperindoprilat

1.44

1.16

1.09 1.081.00

1.10

1.20

1.30

1.40

1.50

BK

/An

g I s

elec

tivi

ty r

atio

P<0.01

P<0.001

Differential affinity for tissue ACE

Ferrari R, Exp Rev Cardiovasc Ther 2005

0

2

4

6

Perindopril Quinalapril Ramipril Enalapril Fosinopril Captopril

BK, bradykinin; Ang I, angiotensin I

Dominiczak A and Unger T (Editors) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997)

Renin-angiotensin systems

Long-term effectsand tissue homeostasis

Local "tissue-bound" system

90%

Classical "circulating" systemAcute and short-term effectsand blood pressure control

10%

Ang II

Ang I

Angiotensinogen

Aldosterone

Na+-retentionK+-lossACE

BPNa+

SNSRenin

BDK

Inactive fragments

Ang I

Angiotensinogen

Ang II

specific cellularresponse

specific cellularresponse

B1 B2

Renin

AT1 AT2

ACEChymases

Cathepsin GCAGE

Confidence Study: dose-dependent blood pressure

lowering effect of Perindopril

70

90

110

130

150

170

190

Blo

od

Pre

ssu

re (

mm

Hg)

182.4

159.3*

144.8*

133.6*

146.7*

154.5

99.1

90.6

90.0*

86.3*

80.8*

80.3*

Perindopril 4 mg Perindopril 8 mg

Severely hypertensive population (n=193)Overall hypertensive population (n=1943)

SBP

DBP

* p<0.05 or less vs baseline

Tsoukas G et al. Am J Cardiovasc Drugs 2011



Possible combinations of classes of antihypertensive drugs.

Sever PS et al. European Heart Journal 2011;32, 2499-2506

Complementarietà del meccanismo di azione di inbitori del sistema

renina-angiotensina, diuretici e calcioantagonisti

Crosstalk intracellulare tra Angiotensina II Ed Insulina

Sharma AM, et al. Hypertension 2002;40: 609-611

IRS1

PI3K

p-Ser

p-Ser

p-Ser

Akt

GLUT-4

Sintesi di glicogeno,

proteine e lipidi

Crescita e

differenzione

cellulare

Metabolismo

glucosio

JAK2

IRS1

PI3K

p-Tyr

p-Tyr

ERK

JNK

X

X X

NADPH ossidasi

ROS

Ang II

Crosstalk intracellulare tra Angiotensina II Ed Insulina

Sharma AM, et al. Hypertension 2002;40: 609-611

IRS1

PI3K

p-Thyr p-Thyr

p-Thyr

Akt

GLUT-4

Sintesi di glicogeno,

proteine e lipidi

Crescita e

differenzione

cellulare

Metabolismo

glucosio

JAK2

IRS1

PI3K

p-Tyr

p-Tyr

ERK

JNK

NADPH ossidasi

ROS

X

XX

X

Ang IIX

Curve di Kaplan Meyer per l’incidenza di diabete mellito nei

pazienti arruolati nello studio ASCOT-BPLA distinti in base ai

quartili di rischio di sviluppare diabete

Gupta AK et al. Diabetes Care. 2008;31(5):982-8.

By the end of the trial, 78% of patients were taking at least two antihypertensive agents

Treatment algorithm in the Anglo-Scandinavian Cardiac Outcomes

Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)

Dahlof B, et al. Lancet 2005; 366:895–906

BP over time by group in the Anglo-Scandinavian Cardiac Outcomes

Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)


Superiorità della combinazione amlodipina/perindopril rispetto

alla combinazione atenololo/diuretico tiazidico nel prevenire gli

eventi nello studio ASCOT-BPLA


N Engl J Med 2008;359:2417-28.

“Three or four drugs may be required in many cases”

Mancia et al., J Hypert, 2007 ESH/ESC GLs

“In no less than 15-20% of the patients control cannot

be achieved by a two drug combination”

Mancia et al., J Hypert, 2009 ESH Reappraisal)

“If the (blood pressure) target is not achieved by a two

drug combination ... a third drug can be added”

Mancia et al., J Hypert, 2013 ESH/ESC GLs)

How Frequently should 3 or More Drugs be

Used in Clinical Practice?

Value of low dose combination treatment with blood

pressure lowering drugs: analysis of 354 randomised trials

Law MR et al. 2003;326:1427

-25

-20

-15

-10

-5

0

SBP DBP

1 drug 2 drugs 3 drugs-80

-60

-40

-20

0

Stroke IHD

1 drug 2 drugs 3 drugs

Reduction of the incidence of stroke and IHD

events (%) when durg are used separately and

in combination at half standard dose

Efficacy: blood pressure lowering effects

(mmHg) of drugs when used at half standard

dose separately and in combination

Systolic Blood Pressure in the Two Treatment

Groups over the Course of the Trial: SPRINT

N Eng J Med 2015

average BP difference of 14.8 mm Hg

136.2 mmHg

121.4 mmHg

Utilization of Antihypertensive Medication Classes

at Most Recent Visit: SPRINT

N Eng J Med 2015



Possible combinations of classes of antihypertensive drugs.

Step 4

Summary of

antihypertensive

drug treatment

Step 1

Step 2

Step 3

Key

A – ACE inhibitor or low-cost angiotensin II

receptor blocker (ARB)1

C – Calcium-channel blocker (CCB)

D – Thiazide-like diuretic

Aged over 55 years or

black person of African or

Caribbean family origin of

any age

Aged under

55 years

C2A

A + C2

A + C + D

Resistant hypertension

A + C + D + consider further diuretic3, 4 or

alpha- or

beta-blocker5

Consider seeking expert advice

Diuretics

…Diuretics have remained the cornerstoneof antihypertensive treatment since atleast the first Joint National Committee(JNC) report in 1977 [412] and the firstWHO report in 1978 [413], and still, in 2003,they were classified as the only first-choicedrug by which to start treatment, in boththe JNC-7 [264] and the WHO/InternationalSociety of Hypertension Guidelines [55,264].

…It has also been argued that diuretics suchas chlorthalidone or indapamide should beused in preference to conventional thiazidediuretics, such as hydrochlorothiazide [271].

…D: Thiazide-like Diuretics likeChlortalidone (12.5-25 mg once daily) orIndapamide (2.5 or 1.5 SR mg oncedaily) rathre than thiazide diuretics suchas Bendroflumethiazide orHydrocholorothiazide.

Pharmacological profile of Diuretics

HCTZ (Thiazide-Type)(Kaplan NM, 2000)

o Diuretic effect

o Reduction of ECV (short-term)

o Reduction of PVR (long-term)

Indapamide(Bataillard A et al, 1999)

Diuretico effect

Reductiono of ECV (short-term)

Reductiono of PVR (long-term)

Downregulationo SNS

Ca++ o channel blocker effect

Increaseo of PGI2

Antioxidanto effect

Relationship between the risk ratio of CVE and HF and the BP

difference between treatment and control in patients treated with

thiazide-type and thiazide-like diuretics

Olde Engberinck RHG et al, Hypertension 2015

Risk reduction TL vs TT

12% p=0.049

Risk reduction TL vs TT

21% p=0.023

Roush G. et al. Hypertension. 2015 Mar 2

Metaanalysis comparing hydrochlorothiazide (HCTZ) and

indapamide (INDAP) in patients with HTN: effect of BP

Roush G. et al. Hypertension. 2015 Mar 2

Metaanalysis comparing hydrochlorothiazide (HCTZ) and

indapamide (INDAP) in patients with HTN: effect of K+

P<0.001

Changes in renal function in patients with renal failure

and hypertension treated with Indapamide or Thiazides

Madkour H et al, Am J Cardiol 1996

Baseline 24 months

Long-term (9 months) Metabolic profile of Indapamide

SR in patients with hypertension. Pooled results of 3 RCT

Weidmann P et al, Drug Safety 2001

Riduzione della pressione arteriosa sistolica con la triplice

combinazione perindopril/indapamide/amlodipina in ipertesi a

rischio elevato o molto elevato: studio PIANIST

Toth K; et al. Am J Cardiovasc Drugs. 2014;14(2):137-45.

Riduzione della pressione arteriosa sistolica con la triplice

combinazione perindopril/indapamide/amlodipina in ipertesi a

rischio elevato o molto elevato: studio PIANIST

Toth K; et al. Am J Cardiovasc Drugs. 2014;14(2):137-45.

Paz

ienti

con p

ress

ione

a ta

rget

(%

)

Pre

ssio

ne

sist

oli

ca (

mm

Hg

)

Effetto del trattamento con la combinazione fissa perindopril/indapamide

sugli eventi CV maggiori e sulla mortalita in relazione al concomitante

trattamento con CA all’inizio dello studio ADVANCE

Chalmers J et al.

Hypertension. 2014;63(2):259-64.

Effetto del trattamento con la combinazione fissa perindopril/indapamide

sugli eventi CV maggiori e sulla mortalita in relazione al concomitante

trattamento con CA in una qualsiasi fase dello studio ADVANCE

Chalmers J et al.

Hypertension. 2014;63(2):259-64.

Combination therapy is a real

need in hypertension

The patient would take 12 separate medications with a

medication complexity score of 14. This regimen requires 19

doses per day, taken at 5 times during a typical day,

assuming that albuterol “as needed” is taken twice daily, plus

weekly alendronate.

Effect of fixed-dose combination vs free-drug combination

on the risk of medication non-compliance in hypertensives

Bangalore S et al. The American Journal of Medicine (2007) 120, 713-719

Corrao G et al. Hypertension 2011;58:566-572

Odds ratios of nonfatal CV outcomes as a whole, CHD, or

cerebrovascular events associated with an initial combination of

blood pressure-lowering agents, with respect to initial monotherapy

Conclusioni

La terapia di combinazione rappresenta un prezioso

strumento per raggiungere il controllo pressorio

nella maggioranza degli ipertesi

La combinazione di un ACE-inibitore, un calcio

antagonista e un diuretico è razionale dal punto di

vista farmacologico

La protezione del trattamento antipertensivo

dipende soprattutto dalla riduzione pressoria:

tuttavia..

Perindopril ed amlodipina, nell’ambito delle

relative classi famacologiche, hanno la migliore

evidenza di protezione dagli eventi mentre tra i

diuretici, indapamide ha una letteratura scientifica

superiore rispetto all’idroclorotiazide

La combinazione fissa di Perindopril/Amlodipina/

Indapamide è attualmente l’unica triplice terapia di

combinazione attualmente disponibile per il

trattemento dei pazienti ipertesi

Conclusioni

…..poca teoria e molta sostanza, cose che servono

per migliorare la professione del medico

Patient-Centered Care

More health benefits worldwide would result from

improving (use of and) adherence to existing treatments

than developing any new medical treatment*

*Sabate, E. Adherence to long-term therapies: Evidence for action. Geneva, Switzerland: World Health Organization; 2003.

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