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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
2013 ESH-ESC Guidelines, J Hypertens 2013
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
2013 ESH-ESC Guidelines, J Hypertens 2013
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
2013 ESH-ESC Guidelines, J Hypertens 2013
2013 ESH/ESC Guidelines
Possible combinations of classes of antihypertensive drugs.
2013 ESH-ESC Guidelines, J Hypertens 2013
2013 ESH/ESC Guidelines
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)
Dahlof B, et al. Lancet 2005; 366:895–906
Superiorità della combinazione amlodipina/perindopril rispetto
alla combinazione atenololo/diuretico tiazidico nel prevenire gli
eventi nello studio ASCOT-BPLA
Dahlof B, et al. Lancet 2005; 366:895–906
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
2013 ESH-ESC Guidelines, J Hypertens 2013
2013 ESH/ESC Guidelines
Possible combinations of classes of antihypertensive drugs.
2013 ESH-ESC Guidelines, J Hypertens 2013
2013 ESH/ESC Guidelines
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.
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.