Blood Pressure (mmHg)

Dott.ssa B. Bassi
Dr. G. Bondi
Dr. C. Camporesi
Dott.ssa L. Gardelli
Dr. F. Girelli
Dr. V. Mazzeo
Premessa
• Il principale obiettivo di una terapia è quello di
trarre il massimo beneficio e di ridurre al minimo
i rischi
• La terapia antiipertensiva, nel paziente diabetico e
nefropatico ha in particolare come obiettivo “in
primis” quello ridurre la mortalità e gli eventi CV,
ma anche quello potenziale di ridurre l’eventuale
incidenza e/o evoluzione delle complicanze microvascolari per il DM e prevenire e/o ritardare il
deterioramento della funzione renale
CHD and Stroke Mortality vs. Usual BP by Age
Systolic Blood Pressure
Diastolic Blood Pressure
Stroke Mortality
(Floating Absolute Risk and 95% CI)
IHD Mortality
(floating absolute risk and 95% CI)
Age at risk:
256
128
64
32
16
8
4
2
1
0
80-89 years
70-79 years
60-69 years
50-59 years
40-49 years
120
140
160
180
Age at risk:
256
128
64
32
16
8
4
2
1
0
80-89 years
70-79 years
60-69 years
50-59 years
120 140 160 180
Usual Systolic BP (mm Hg)
Age at risk:
256
128
64
32
16
8
4
2
1
0
256
128
64
32
16
8
4
2
1
0
80-89 years
70-79 years
60-69 years
50-59 years
40-49 years
70
CHD
80 90 100 110
Age at risk:
80-89 years
70-79 years
60-69 years
50-59 years
Stroke
70 80 90 100 110
Usual Diastolic BP (mm Hg)
Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.
Cumulative incidence of cv events in
subjects without hypertension
Vasan RS et al, NEJM 2001
Age-adjusted 16-year Incidence of all cause end-stage renal
disease by systolic and diastolic blood pressure in 300645 white
men and 20 222 African-American men
MRFIT Study
Klag M.J.JAMA. 1997;277:1293-1298
Relative risk for kidney disease progression based on current
level of systolic blood pressure and current urine protein
excretion.
A Patient-Level Meta-Analysis
Jafar TH Ann Intern Med. 2003;139:244-252.
HOT Study: significant benefit from
intensive treatment in the diabetic subgroup
Major cardiovascular
events/1,000 patient-years
25
20
15
p=0.005 for trend
10
5
0
90
85
80 mm Hg
Target Diastolic Blood Pressure
Hansson L et al. Lancet. 1998
UKPDS study
-37%
-24%
-32%
-21%
-44%
Any clinical end point, fatal
or non-fatal, related to
diabetes.
Less tight control:
154/87 mmHg
Tight control:
144/82 mmHg
Microvascular end points
(mostly retinal
photocoagulation), fatal or
non-fatal myocardial infarction
or sudden death, and fatal or
non-fatal strokes.
Mortality for disease related to
diabetes (myocardial infarction,
sudden death, stroke, peripheral
vascular disease, and renal
failure).
British Medical Journal Publishing Group et al. BMJ
1998;317:703-713
Cardiovascular death (%)
Blood pressure and cardiovascular death
10
8
Diabetics
n=3,305
death rate - 5.3%
6
4
Non-diabetics
n=88,257
death rate - 2.2%
2
0
<120
120-139
140-159
>160
Systolic blood pressure
(mmHg)
Asia-Pacific Cohort Studies Collaboration. Diabetes Care. 2004;27:2836-2842
I LIMITI DEGLI STUDI
✓ Uno studio osservazionale ci può dare interessanti
informazioni, ma è suscettibile di possibili errori, come quello
di selezione dei pazienti
✓ L’interpretazione dei risultati in studi “post hoc” in base
al target PA raggiunto, tradisce il principio della
randomizzazione e “intention to treat analysis”
✓ Comparare targets pressori raggiunti in diversi trials può
non essere appropriato (terapia concomitante, diverso profilo di
rischio cardiovascolare)
Estimated mean changes (SE) in glomerular filtration rate (GFR) (mL /min per 1.73
m2) from baseline through follow-up in the 2 blood pressure goal interventions
AASK Study
Usual BP
goal:
141/85
mmHg
P=0.24
Lower BP
goal:
128/78
mmHg
1094 African Americans aged 18 to 70 years
with hypertensive renal disease (GFR, 20-65 mL/min per 1.73m2
J.T. Wright et al. JAMA, November 20, 2002—Vol 288, No. 19
Estimated percentage changes in the urine protein/creatinine ratio
from baseline throughout follow-up by blood pressure
AASK study
Usual BP
goal: 141/85
mmHg
(P<0.001)
Lower BP
goal: 128/78
mmHg
1094 African Americans aged 18 to 70 years
with hypertensive renal disease (GFR, 20-65 mL/min
per 1.73m2
J.T. Wright et al. JAMA, November 20, 2002—Vol 288, No. 19
Cumulative probability of kidney failure (top) and cumulative probability of
the composite of kidney failure or all-cause mortality before kidney failure
(bottom).
MDRD Study
Usual BP :……..
p=0.00003
<140/90 mmHg
Low BP :
<125/75 mmHg
p= 0.0024
840 persons with predominantly nondiabetic kidney disease
and a glomerular filtration rate of 13 to 55 mL/minper 1.73 m2.
Samak M.J. et al. Ann Intern Med. 2005;142:342-351.
Fenomeno della curva J
Cruickshank JM. Cardiovasc Drugs Ther 2000;14(4):373—9.
Incidence of total MI and total stroke by DBP pressure strata in
patients with HBP and CAD enrolled in the INVEST
Messerli FH et Al, Ann Intern Med 2006;144:884-893
Studio PROGRESS: curva J non evidente
per l’ictus ischemico ed emorragico
(p = 0,0005)
(p < 0,0001)
Arima H, et al. J Hypertens 2006;24(6):1201—8.
Sintesi degli studi clinici favorevoli alla curva J
Dogma discusso: Un uso aggressivo degli agenti ipotensivanti
nei pazienti ipertesi con malattia coronarica può essere pericoloso?
Messerli F, Mancia G, et al. Ann Intern Med 2006
JNC VII
ESH/ESC 2007
< 140/90 mmHg
< 140/90 mmHg
< 130/80 mmHg nei
diabetici
< 130/80 mmHg nei
diabetici
< 130/80 mmHg nella
insufficienza renale
cronica
< 130/80 mmHg nella
insufficienza renale
cronica
JAMA 2003; 289:2560-2572
< 125/75 mmHg se
proteinuria > 1 g/die
J Hypertens 2007; 25:1105-1187
Effects of blood pressure lowering on death and macrovascular
and microvascular disease (coronary and renal) :
the ADVANCE Trial
Average BP during follow-up
Placebo arm: 140.3/77 mmHg
Perindopril-Indapamide arm: 134.7/74.8 mmHg
Advance collaborative Group Lancet 2007; 370: 829–40
Mortality and morbidity associated with lower vs standard blood pressure targets
(Review)
PAS 139.3 vs 143.2 Δ 3.9 mmHg
PAD 81.7 vs 85.1 Δ 3.4 mmHg
Seven trials (22,089 subjects)
AASK, ABCD (H), ABCD (N), HOT, MDRD, REIN-2, TOTO
Arguedas JA et al, Cochrane Database Syst Rev 2009: CD004349
Relative risk estimates of coronary heart disease events and stroke in
blood pressure difference trials according to pre-treatment diastolic and
systolic blood pressures
(taken as average in placebo group over course of trial).
Law, M R et al. BMJ 2009;338:b1665
Effects of active treatment vs. placebo on recurrent stroke in
patients with different baseline BP values in the PROGRESS trial
Arima H et al, J Hypertens 2006
Prognostic between changes in SBP from baseline to follow up of blood
pressure in patients with high vascular risk
ONTARGET STUDY
Quartile 1: baseline SBP  130 mmHg
Quartile 2: baseline SBP 131-142 mmHg
Quartile 3: baseline SBP 143-154 mmHg
Quartile 4 baseline: SBP > 154 mmHg
Sleight P. et al, Journal of Hypertension. 27(7):1360-1369, July 2009.
Blood Pressure Lowering and Cardiovascular
Prevention in Diabetes
170
50
162
160
155
154
153
34
SBP
Achieved
(mmHg)
150
40
40
34
30
148
31
25
145
144
145
143
140
140
138
139
137
20
%
CV event
reduction
134
132
130
10
128
8
0
0
120
0
S. Eur SHEP UK
DM
DM PDS
HOT HOPE ADV ABCD ABCD
DM
HT
NT
Zanchetti et al. J Hypertens 2009; 27: 923-934
Achieved SBP in patients randomized to a more active or
less active treatment in clinical trials in hypertension
Mancia G et al, J Hypertens 2009
ESH reappraisal 2009
< 140/90 mmHg in tutti i pazienti ipertesi
130-139/80-85 in tutti i pazienti ipertesi (possibilmente ai limiti
bassi di questo range)
< 130/80 mmHg nei diabetici e nei pazienti a rischio
molto elevato (pregressi eventi cardiovascolari)
(può essere una raccomandazione ‘saggia’, sebbene ‘non
supportata in misura consistente dai trials’)
J Hypertens 2009; 27:2121-2158
ACCORD study
N Engl J Med 2010;10.1056/NEJMoa1001286
Primary Outcome
Nonfatal MI, Nonfatal Stroke or CVD Death
Total Mortality
1
5
2
0
Patientsw
ithEvents(%
)
P
atientsw
ithE
vents(%
)
2
0
HR = 0.88
95% CI (0.73-1.06)
P 0.20
1
0
5
0
0
1
5
HR = 1.07
95% CI (0.85-1.35)
P 0.55
1
0
5
0
1
2
3
4
5
6
7
8
0
1
Y
e
a
r
sP
o
s
t
R
a
n
d
o
m
iz
a
t
io
n
2
3
4
5
6
7
8
Y
e
a
r
sP
o
s
t
R
a
n
d
o
m
iz
a
t
io
n
PAS : 119.3 mmHg
PAS: 133.5 mmHg
PatientswithEvents(%
)
2
0
1
5
HR = 1.06
95% CI (0.74-1.52)
P 0.74
1
0
CVD Deaths
5
0
0
1
2
3
4
5
6
7
Y
e
a
r
s
P
o
s
t
R
a
n
d
o
m
iz
a
t
io
n
8
ACCORD study
N Engl J Med 2010;10.1056/NEJMoa1001286
Non Fatal MI
Nonfatal Stroke
2
0
1
5
Patientsw
ithEvents(%
)
Patientsw
ithEvents(%
)
2
0
HR = 0.87
95% CI (0.68-1.10)
P 0.25
1
0
5
1
5
1
0
5
0
0
0
HR = 0.63
95% CI (0.41-0.96)
P 0.03
1
2
3
4
5
6
7
0
8
1
2
3
4
5
6
7
Y
e
a
r
sP
o
s
t
R
a
n
d
o
m
iz
a
t
io
n
Y
e
a
r
s
P
o
s
t
R
a
n
d
o
m
iz
a
t
io
n
PAS : 119.3 mmHg
PAS: 133.5 mmHg
Patientsw
ithEvents(%
)
2
0
HR = 0.59
95% CI (0.39-0.89)
P 0.01
1
5
Total Stroke
1
0
5
0
0
1
2
3
4
5
6
7
Y
e
a
r
sP
o
s
t
R
a
n
d
o
m
iz
a
t
io
n
8
8
ADVERSE EVENTES
ACCORD STUDY
Serious AE
Hypotension
Syncope
Bradycardia or
Arrhythmia
Hyperkalemia
Renal Failure
eGFR ever <30
mL/min/1.73m2
Any Dialysis or ESRD
Dizziness on Standing†
Intensive
N (%)
77 (3.3)
17 (0.7)
12 (0.5)
Standard
N (%)
30 (1.3)
1 (0.04)
5 (0.2)
<0.0001
<0.0001
0.10
12 (0.5)
3 (0.1)
0.02
9 (0.4)
5 (0.2)
1 (0.04)
1 (0.04)
0.01
0.12
99 (4.2)
52 (2.2)
<0.001
59 (2.5)
217 (44)
58 (2.4)
188 (40)
0.93
0.36
P
† Symptom experienced over past 30 days from HRQL sample of
N=969 participants assessed at 12, 36, and 48 months post-randomization
BP to intensive targets (< 130/80 mm Hg )
compared
BP to standard targets (< 140-160/85-100 mmHg)
Arch Intern Med. 2012;172(17):1296-1303.
Intensive and Standard Blood Pressure Targets in Patients With Type 2 Diabetes Mellitus
Systematic Review and Meta-analysis
RR 0.76;
95% CI, 0.55-1.05
Mortality
Myocardial
infarction
RR 0.93;
95%CI, 0.80-1.08)
RR 0.65;
95% CI, 0.48-0.86)
Stroke
Arch Intern Med. 2012;172(17):1296-1303.
Effects of intensive blood pressure lowering on progressive kidney failure.
HR overall: 0.82
(0.68-0.98)
HR overall: 0.79
(0.67-0.93)
Lv J et al. CMAJ 2013;185:949-957
©2013 by Canadian Medical Association
Subgroup analysis of the effect of intensive blood pressure lowering on kidney failure
in patients with proteinuria compared with those without proteinuria.
Lv J et al. CMAJ 2013;185:949-957
©2013 by Canadian Medical Association
Occurrence of Microalbuminuria during the 48-Month Follow-up Period
ROADMAP STUDY
Risk reduction in favour of Olmesartan: 23%
(p=0.01)
Risk reduction only in patients
with baseline SBP> 135 mmHg
(p=0.03)
Haller H. et al. N Engl J Med 2011;364:907-17.
ROADMAP Study
Haller H. N Engl J Med 2011;364:907-17.
I LIMITI DEGLI STUDI
✓ Uno studio osservazionale ci può dare interessanti
informazioni, ma è suscettibile di possibili errori, come
quello di selezione dei pazienti
✓ L’interpretazione dei risultati in studi “post hoc” in base
al target PA raggiunto, tradisce il principio della
randomizzazione e “intention to treat analysis”
✓ Comparare targets pressori raggiunti in diversi trials può
non essere appropriato (terapia concomitante, diverso profilo
di rischio cardiovascolare)
Adjusted incidence RRs (95% CI) for stroke, myocardial infarction (MI), and
other major cardiovascular (CV) events estimated based on mean level of
blood pressure control in the year after hypertension onset.
15,665 adults with diabetes but no diagnosed coronary or
cerebrovascular disease at baseline
mean 38-month follow-up period.
O’Connor P J et al. Dia Care 2013;36:322-327
2007
2009
2013
2007 ESH/ESC Guidelines: Initiation of Antihypertensive Treatment
Blood Pressure (mmHg)
Other risk
factors
OD or disease
No other risk
factors
Normal
SBP 120-129
or
DBP 80-84
No BP
intervention
High Normal
SBP 130-139
or
DBP 85-89
No BP
intervention
1-2 risk factors
Lifestyle
changes
≥ 3 Risk Factors,
MS or OD
Lifestyle
changes
Diabetes
Lifestyle
changes
Lifestyle
changes and
consider drug
treatment
Lifestyle
changes + Drug
treatment
Lifestyle
changes
+
Immediate drug
treatment
Lifestyle
changes
+
Immediate drug
treatment
Established CV
Established CV
or renal disease
or renal disease
Lifestyle
changes
Grade 1 HT
SBP 140-159
or
DBP 90-99
Grade 2 HT
SBP 160-179
or
DBP 100-109
Grade 3 HT
SBP ≥ 180
or
DBP ≥ 110
Lifestyle
changes for
several months
then drug
treatment if BP
uncontrolled
Lifestyle
changes for
several
weeks then drug
treatment if BP
uncontrolled
Lifestyle
changes for
several
weeks then drug
treatment if BP
uncontrolled
Lifestyle
changes for
several
weeks then drug
treatment if BP
uncontrolled
Lifestyle
changes
+
Drug treatment
Lifestyle
changes
+
Drug treatment
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
Lifestyle
changes
+
Immediate drug
treatment
2013 ESH/ESC Guidelines for the managment of arterial hypertension
Summary of recommendations on initiation of antihypertensive drug treatment
BP = blood pressure; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovascular disease;
DBP = diastolic blood pressure; HT = hypertension; OD = organ damage; RF = risk factor;
SBP = systolic blood pressure.
2013 ESH/ESC Guidelines for the management of arterial hypertension
Treatment strategies in patients with diabetes
2013 ESH/ESC Guidelines for the management of arterial hypertension
Therapeutic strategies in hypertensive patients with nephropathy
OBIETTIVI PRESSORI
(LG ESH/ESC 2013)
Obiettivo
Generale
< 140/90 mmHg
IA
Diabetici
< 140/85 mmHg
IA
Nefropatici
SBP < 140 mmHg
IIa B
SBP <130 mmHg
IIb B
Nefropatici
con franca proteinuria
Anziani
< 80 aa
Anziani < 80 aa
SBP 150-140 mmHg
SBP < 140 mmHg
IA
IIb C
In buone condizioni
Anziani > 80 aa
In buone condizioni
fisiche e mentali
SBP 150-140 mmHg
IB
 People with diabetes and hypertension should be treated to a
systolic blood pressure (SBP) goal of < 140 mmHg. B
 Lower systolic targets, such as <130 mmHg, may be appropriate for
certain individuals, such as younger patients, if it can be achieved without
undue treatment burden. C
 Patients with diabetes should be treated to a diastolic blood pressure
(DBP) < 80 mmHg. B
Clinical Practice Guidelines for the management of
blood pressure in chronic kidney diseases
Nefropatia diabetica e non
con albuminuria < 30 mg/24h
Nefropatia diabetica e non
con albuminuria fra 30 e 300
mg/24h o proteinuria franca
Nefropatia diabetica e non
≤ 140/90 mmHg
≤ 130/80 mmHg
ARB/ ACEi
con albuminuria fra 30 e 300
mg/24h o proteinuria franca
Kidney International supplements vol. 2, issue 5, Dec 2012
TAKE HOME MESSAGE
 Nel diabete mancano chiare evidenze di benefici nell’iniziare un trattamento
antiipertensivo per valori di PAS < 140 mmHg o addirittura <130 mmHg ed anzi una
riduzione troppo aggressiva e rapida potrebbe rivelarsi pericolosa
 La riduzione della proteinuria è globalmente considerata come un target
terapeutico (studi osservazionali da RCTsvariazioni della proteinuria sono
predittori di eventi CV e renali)
✓ Mancano comunque solide evidenze in gruppi randomizzati di una relazione fra
riduzione della proteinuria ed eventi CV e renali
✓ Malgrado ciò le ultime LG incoraggiano globalmente la riduzione della PAS < 130
mmHg nella nefropatia diabetica e non, in presenza di proteinuria franca.
✓ Obiettivi pressori più rigorosi potrebbero essere ricercati in pazienti selezionati
(ad alto rischio di ictus, diabete di recente insorgenza, assenza di coronaropatia)
✓ La letteratura più recente sembra infatti suggerire di spostare l’attenzione dal
“target pressorio” al “momento temporale” in cui questo obiettivo pressorio deve
essere raggiunto (importanza di una diagnosi tempestiva di ipertensione)
TAKE HOME MESSAGE (2)
 I farmaci più indicati per ridurre la PA nei pazienti diabetici e/o
nefropatici sono rappresentati dagli ACEi e sartani
 il doppio blocco con ACEi e sartani non è praticamente mai
indicato
✓ prudenza nell’associare ACEi e sartani con diuretici
antialdosteronici
<140/90?
<130/90?