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Ημερίδες Μεταβολισμού Αθήνα 15-18/5/2013

Οι νέες κατευθυντήριες οδηγίες στην αντιμετώπιση της αρτηριακής υπέρτασης

Κ.Τσιούφης A’ Πανεπιστημιακή Καρδιολογική Κλινική Ιπποκράτειο Γ.Ν.Α

New European Guidelines on HTN My Agenda
How to diagnose HTN/ assess BP reduction Target BP with treatment Is the principle of 1st step drugs still needed? Combination treatment How to treat resistant hypertension

How to Diagnose HT/Assess treatment effects
Should they still based on office BP BP? Should they rather be established or confirmed by ambulatory/home BP values?

WCH - Prevalence
WCH can account for up to 40-50% of the overall hypertensive population

CV and All Cause Mortality in WCH Diagnosed by 24h or Home Normality
CV mortality
Cumulative incidence
0.16 0.14 0.12 0.10 0.08 0.06 0.04

All cause mortality
Events: Cumulative incidence 48 (12.9%) 0.40

HT FU 16 years
P < 0.0001

0.35
0.30

Events: 112 (30.0%)

HT

0.25

FU 16 years
P < 0.0001

77 (19.7%)

WCH

21 (5.4%)

0.20 0.15 0.10

WCH
53 (6.4%)

0.02
0.00 0 2 4 6 8 10 12 14

NT8 (1.0%) 0.05
16 18

NT
2 4 6 8 10 12 14

0.00 0 20

16

18

20

Years

Years

Mancia et al., submitted

Should WCH be Regarded as Normotension?
More frequent organ damage / metabolic risk factors

In a number of studies CV risk increased Greater risk of new onset DM / established HT / LVH Out-of-office BP values higher than in true normotensives Beneficial effects of antihypertensive treatment never addressed by randomized trials
Patients with WCH well represented in several trials demonstrating the beneficial effects of treatment

Daytime or night time BP? Blood pressure variability

Increased nighttime blood pressure or nondipping profile for prediction of cardiovascular outcomes. Review article
 Our

findings suggest that nocturnal BP including

the phenotype of isolated nocturnal hypertension is better associated with CV target organ damage and 'hard end points' as compared with the nondipping pattern
 Tsioufis

C, et al.

J Hum Hypertens. 2011;25(5):281-93

Comparative prognostic role of nighttime blood pressure and nondipping profile on renal outcomes.
 These

findings underline the importance of nocturnal BP phenotypes, retrieved by ambulatory BP measurements, on age-dependent progressive kidney function decline and question whether, to what extent and in whom the reduced nocturnal BP or reverse nondipping BP profile to a normal pattern will be of benefit C, et al Am J Nephrol 2011;33:277-88

 Tsioufis

BP variability and CV risk
 Mancia

et al, J Hypertens 2001: BPV and TOD

 Rothwell

et al, Lancet 2010: BPV is an independent and strong predictor of CV events
et al, Hypertension 2011: Antihypertensive drugs not all equal to reduce BPV

 Zhang

11-Year Increase in Risk of CV Death for 10 mmHg Increase in SBP at Different Baseline SBP Values
5

Increase in risk of CV death (%)

4 3

Office Home 24h

4.5

2.4

2 1 0
0.9 0.6

1.8 1.3 1.1 0.8

2.0

120

130

140

Baseline SBP (mmHg) Sega, Facchetti, Bombelli, Corrao, Grassi, Mancia, Circulation 2005; 111: 1777-1783

Risk of CV Death as Predicted by SBP in PAMELA
 coeff. P< Goodness of fit

Office Home 24h Day Night

0.037 0.045 0.056 0.048 0.056

0.0001 0.0001 0.0001 0.0001 0.0001

46.26 57.63 37.31 28.76 44.66
Sega et al., Circulation 2005; 111: 1777

P significant for goodness of fit value of 3.7

ROC Curve Areas (AUC) for Prediction of CV Events by Different SBPs and SBP Combinations (PAMELA)
Sensitivity
1.0
0.9 0.8 0.7 0.6 0.5 0.76 0.742 Clinic 0.742 Clinic + 24h 0.753 * Clinic + Home 0.762 All three 0.764 Ref 0.5 0.6 0.7 0.8 0.9 0.78

Clinic AUC
0.80

Clinic + Home

Clinic + 24h

Clinic + Home + 24h

0.762 0.753

*

* ‡
0.764

0.4
0.3 0.2 0.1 0 0 0.1 0.2 0.3 0.4

0.74
*

AUC

0.72 1.0

1-Specificity

P significant vs: *

0.70

°

Zanchetti and Mancia, J Hypertens 2012; 30: 660-668

How to Diagnose HT/Assess treatment effects
Should they still based on office BP BP? yes Should they rather be established or confirmed by ambulatory/home BP values? If it is possible

Absolute values and differences between clinic and ambulatory BP at baseline and with different targets with treatment
160 130 S
139.0 ± 14.8

Baseline (n = 422)
128.3 125.5 ± 13.7 ± 13.9

On-T SBP < 140 mmHg (n = 515)
124.7 120.7 119.3 ± 10.0 ± 13.3 ± 13.3

On-T SBP < 130 mmHg (n = 296)
118.2 117.4 116.2 ± 8.4 ± 12.5 ± 12.7

On-T SBP < 120 mmHg (n = 135)
110.7 113.0 111.3 ± 6.1 ± 11.0 ± 10.5

mmHg

100

D
70 40 5
80.3 ± 9.3 75.0 ± 9.3
72.4 ± 8.6

Clinic Day
74.3 ± 8.9 71.8 ± 8.6 68.9 ± 8.2
71.5 ± 8.4 70.7 ± 8.2 68.6 ± 7.9

67.9 ± 8.3

68.9 ± 7.3

66.8 ± 6.8

24h

 from clinic
Day 24h Day 24h

 from clinic
Day 24h Day 24h

 from clinic
Day 24h
-0.8

+2.3

 from clinic
+0.6 +1.0

0

Day 24h
-0.8

-1.1

mmHg

-2.5

-2.0

Day 24h
-2.9

Day 24h

-5 -10 -15

-4.0 -5.3 -7.9 -10.7 -5.4

-3.5

S

-13.5

D

S

D

S

D

S D Mancia et al., Hypertension 2012; 60: 1400

ABP/HOME BP AS A GUIDE FOR TREATMENT No trial based on ABP/Home BP reduction

Superiority of ABP/Home BP in predicting degree of patient protection by treatment unproven
Target ABP/Home BP with treatment not established

Επίπεδα ΑΠ και καρδιαγγειακό όφελος

Για μείωση 10mmHg για την ΣΑΠ και 5 mmHg για την ΔΑΠ η υπολογιζόμενη μείωση της ΣΝ και των ΑΕΕ ήταν 22% και 41% αντίστοιχα, όμοια με την παρατηρούμενη στις επιδημιολογικές μελέτες μία αναλογική μείωση του κινδύνου που είναι σταθερή σε όλα τα επίπεδα της ΑΠ: Η ίδια για υψηλή και χαμηλή ΑΠ προ-θεραπείας, μέχρι το επίπεδο των 110/70mmHg , κάτω της οποίας τιμής δεν υπάρχουν δεδομένα
 The

 Υπήρχε

lower the better

Law et al, BMJ 2009

Hypertension Detection and Follow-up Program Επίδραση της μείωσης της ΑΠ στην πρόγνωση των ασθενών ανάλογα με την ύπαρξη ΒΟΣ.
S, stepped care group; U, usual care group.
(a) Ολική θνητότητα (b) ΒΟΣ ( -)
20 15,3

ΑΕΕ ΒΟΣ ( +)
18,7

ΒΟΣ ( -)

ΒΟΣ (+)

10 4,8 5,8 1,3 0 2,1 5,4

7,4

S

U

S

U

S

U

S

U

Journal of Hypertension 2009;27(8):1509-1520

Οφέλη από την μείωση της ΑΠ ανάλογα με το επίπεδο ΚΑΚ Συμπεράσματα

Τα ευρήματα αυτά δεν μειώνουν την αξία των θεραπευτικών παρεμβάσεων αλλά τονίζουν ότι ο προϋπάρχων υψηλός κίνδυνος

θέτει ένα όριο στο όφελος της θεραπείας
Αυτό σημαίνει ότι

καθυστερεί η έναρξη αντιυπερτασικής αγωγής έως ότου γίνει ήδη βλάβη οργάνων στόχων

και ότι η σύσταση για παρεμβάσεις μόνο στους ασθενείς με ολικό
καρδιαγγειακό κίνδυνο πάνω από 20% στη 10ετία (10% στη 5ετία) δεν είναι πλέον επιθυμητή.

Not ‘the lower the better’ but ‘the earlier the better’

ONTARGET: Adjusted risk of outcome events achieved by SBP divided into deciles.
H τιμή ΣΑΠ =130 mmHg αντιστοιχεί στο σημείο ανάκαμψης της καμπύλης J για όλα τα τελικά σημεία εκτός του ΑΕΕ

Journal of Hypertension 2009;27(7):1360-1369

INVEST Study Επίπτωση ΕΜ και ΑΕΕ ανάλογα με την ΔΑΠ κατά την θεραπεία

JACC 2009;54(20):1827-34

Αλληλεπίδραση της επαναγγείωσης με την ΔΑΠ κατά την θεραπεία στην έκβαση των ασθενών

INVEST Study

JACC 2009;54(20):1827-34

Μηχανισμοί του φαινομένου της καμπύλης J
Η χαμηλή ΔΑΠ

1. αποτελεί επιφαινόμενο υποκείμενης χρόνιας νόσου που οδηγεί σε αυξημένη νοσηρότητα και θνητότητα 2. οφείλεται σε αυξημένη πίεση σφυγμού λόγω αυξημένης αρτηριακής σκληρότητας αντανακλώντας αγγειακή νόσο

3. οφείλεται σε υπερβολική αντιυπερτασική θεραπεία και συνεπώς σε
υποάρδευση των στεφανιαίων και αύξηση των συμβάντων

<<ΔΕΝ ΕΧΕΙ ΑΠΟΔΕΙΧΘΕΙ ΑΙΤΙΟΛΟΓΙΚΗ ΣΧΕΣΗ>> Έχει σημασία η προ θεραπείας ΔΑΠ

Χαμηλή ΔΑΠ και καρδιαγγειακά επεισόδια
ΗΟΤ-INVEST-ACTION-Syst-Eur:

Υπάρχει μία σχέση τύπου J καμπύλης ανάμεσα στη ΔΑΠ κατά την θεραπεία (στα όρια 70-80mmHg) και την ΣΝ σε ασθενείς
υψηλού κινδύνου (ηλικιωμένοι, με YAK, με ΣΝ) χωρίς ενδείξεις επιβάρυνσης για τον εγκέφαλο ή τους νεφρούς.

BP Goals of Treatment
On the basis of current data, it may be prudent to recommend lowering BP within the range of 130-139 / 80-85 mmHg in all HTs, and possibly close to lower values in this range
Mancia et al., ESH Task Force, J Hypertens 2009; 27: 2121

First Choice Drugs - Guidelines Position
JNC 7 (2003) Thiazide D (TH)

WHO/ISH (2003)
NICE (2006) ESH/ESC (2003/2007) ESH Reappraisal (2009) JACC (2011, Elderly) NICE (2011) JNC 8

Low dose D (TH)
D / CCB / ACEI (ARB) D / CCB / ACEI / ARB / BB (choice dictated by individual factors) Classification of drugs into first / second / third … choice obsolete D / CCB / ACEI / ARB / BB (emphasis on choice by individual factors) ACEI (low cost ARB) / CCB  choice age-dependent (D 2nd choice / only chlorthalidone-indapamide) ?

The larger the number of therapeutic options the better

Is ranking antihypertensive agents in order of choice useful in clinical practice?

ESH Task Force, J Hypertens 2009

The principle of 1st choice drugs
 It

refers to an “average” patient which hardly

exists in clinical practice. In clinical practice no drug is ALWAYS 1st choice and no drug is
NEVER 1st choice.

Future Antihypertensive Treatment
 Approach

based on 1st / 2nd / n choice drugs

to be abandoned in favour of recommendations

on which drugs to use in which patients under which circumstances

Future Antihypertensive Treatment
 Guidelines

on hypertension (and design of

antihypertensive treatment trials) should move more and more towards an INDIVIDUALIZED treatment approach.

Καρδιο-αγγειο-νεφρο-προστασία
ΥΑΚ  Κολπική μαρμαρυγή  Πρόληψη, υποστροφή  Πρόληψη υποτροπών ACEI, ARB ACEI, ARB  Προηγούμενο ΕΜ  Έλεγχος συχνότητας BB, ACEI, ARB BB, μη διυδροπυριδίνες  Στηθάγχη προσπαθείας BB, CA Νεφρική δυσλειτουργία ACEI, ARB  Καρδιακή ανεπάρκεια Diuretics, BB, ACEI,

ARB,Antialdost.ant

BP-Lowering Regimens Based on Different Drug Classes and Total Major CV Events in Younger and Older Patients
No. of events/patients Difference in SBP/DBP (mmHg) 1st listed 2nd listed ACEI vs D or BB Age < 65 819/ 9448 Age ≥ 65 1795/10783 CA vs D or BB Age < 65 1165/20358 Age ≥ 65 2653/21204 ACEI vs CA Age < 65 548/ 5130 Age ≥ 65 1583/ 8170 ARB vs others Age < 65 183/ 742 Age ≥ 65 438/ 3167 Risk ratio (95%CI) Risk ratio (95%CI) P for homogeneity

1066/12012 2525/14429 1430/23236 3363/24981 568/ 4919 1608/ 8140 204/ 722 487/ 3171

1.3/0.1 2.0/0.5 1.1/-0.2 0.5/-0.4 0.9/0.6 1.0/1.0 -1.7/-0.3 -2.0/-1.2
0. 5 1.0

1.05 (0.96-1.14) 1.01 (0.95-1.06) 1.06 (0.98-1.14) 1.02 (0.97-1.06) 0.91 (0.78-1.06) 0.98 (0.92-1.05) 0.89 (0.75-1.05) 0.91 (0.81-1.02)
2.0

0.44 0.38 0.37 0.78

Favours 1st listed

Favours 2nd listed

BPLTTC, BMJ 2008; 336: 1121

Specific vs More General Treatment Strategies
Indications for specific drugs do not cover the whole hypertensive population In a residual large number of patients there is no reason to select one drug over another

Individual treatment can (regretfully) not apply to all patients Need for genetic/other markers of treatment efficacy(BP reduction/improvement of OD/event prevention )and safety in individuals

Choice of Antihypertensive Drugs

Effects on metabolic risk factors Effects on organ damage Presence / absence of diabetes / MS Presence / absence of CKD Presence / absence of CVD

Other disorders limiting particular drug use Cost of drugs 24h BP coverage Once-a-day administration Favorable side effect profile Previous patient’s experience with drug class

Monotherapy or combination therapy ?

Ratio of observed to expected incremental blood pressure-lowering effects* of adding a drug or doubling the dose according to the class of drug (n = 11000, 42 studies)
Incremental SBP reduction ratio of observed to expected additive effects
1.5
1.04 (0.88-1.20) 1.00 (0.76-1.24) 0.89 (0.69-1.09) 1.01 (0.90-1.12) 1.16 (0.93-1.39)

1.0

0.5
0.19 (0.08-0.30)

0.37 (0.29-0.45) 0.23 (0.12-0.34)

Adding a drug from another class (on average standard doses) Doubling dose of same drug (from standard dose to twice standard)
0.22 (0.19-0.25)

0.20 (0.14-0.26)

0.0

Thiazide

Betablocker

ACEinhibitor

Calcium channel blocker

All classes

* The expected incremental effect is the incremental blood pressure reduction of the added (or doubled drug), assuming an additive effect and allowing for the smaller reduction from 1 drug (or dose of 1 drug) given the lower pretreatment blood pressure because of the other

Wald DS et al., Am J Med 2009; 122: 290

Combination Antihypertensive Therapies
1950’s 1960’s 1970’s

1980’s

1990’s2000s

Ser-Ap-Es (reserpine/hydralazine/ hydrochlorothiazide) Methyldopa/thiazide

ACE inhibitor/thiazide

Butiserpine (reserpine/butalbital) Hyphex (hexamethonium/hydralazine) Hypotensin A, B, & C
(pentolinium/hydralazine/resperine) Renir (reserpine/ephedrine) Verapene (rauwolfia/veratrum)

Thiazide/K+-sparing diuretic  blocker/thiazide Clonidine/thiazide

ACE inhibitor/CCB ARB/thiazide//CCB DRI/ARB/thiazide/ /CCB Low-dose  blocker/thiazide

Combination Treatment in the 2009 ESH Reappraisal
ACEI / D
PROGRESS ADVANCE HYVET

ACEI / CA
Syst-Eur Syst-China INVEST ASCOT STAR ACCOMPLISH

CA / D
FEVER ELSA VALUE HOT

ARB / D
LIFE SCOPE RENAAL TRANSCEND

ARB / CA
RENAAL (?)

CA / BB
HOT (2nd used)

Diuretics RAS blocker + Angiotensin receptor antagonist Calcium antagonists
Calcium antagonist

Diuretic

ACE inhibitors
Mancia et al., J Hypert 2009; 27: 2121

Effects of Persistence or Adherence with Antihypertensive Drug Therapy on the Reduction in Hazard Ratio† of Coronary (n = 6665) and Cerebrovascular (n = 5351) Outcomes in 242.594 Patients Persistence category
0

Adherence level
0 -10 -20 -30 -40

Discontinuing use* (reference)

Continuing use

Very low (reference)

Low

Intermediate

High

Hazard ratio reduction (%)

-10 -20 -30 -40

-16% -21%
-24%-23%

-37% -36%
-50 -50

Coronary events Cerebrovascular events

Estimates are adjusted for gender, age, initial antihypertensive regimen, number of different classes of antihypertensive medications dispensed during FU, use of other drugs during FU, and categories of Charlson comorbidity index score. * At least 1 episode of no prescription coverage for > 90 days

Corrao, Parodi, Nicotra, Zambon, Merlino, Cesana, Mancia, J Hypert 2011; 29: 610-618

Promising therapeutic alternatives in hypertension
Novel drugs

Novel pharmacological classes New molecules from present pharmacological classes

New devices
CPAP Deep brain stimulation Device guided respiration Brainstem neurovascular decompression Renal artery stending Rheos device
 

New procedures Renal sympathetic denervation

Renal denervation

Renal denervation is a catheter-based ablation
procedure in which lesions are created along the walls of the renal arteries to disrupt the

sympathetic nerve network located within the
arterial adventitia

Interruption of both efferent and afferent renal fibers
Catheter Delivered Lesions

Rationale for renal sympathetic denervation in HTN

Current treatment barriers of
the hypertension management

Pathophysiological substrate of
activated renal sympathetic fibers in the pathogenesis of hypertension

Sympathetic overactivity in relation to the severity of hypertension

Severe hyprertensives

Mild to moderate hypertensives

normotensives

Activation of SNS in Resistant Hypertension

Tsioufis et al, International J Hypertension 2011

Essential HTN, SNS and Kidney A complex interrelationship

SNS

?

Kidney

HTN
• …..The renal sympathetic nerves probably serve as the critical link between the sympathetic nervous system and the kidney in hypertension….

DiBona, Curr

Opin Nephrol Hypertens 2002

Renal Sympathetic Efferent Nerve Activity

Krum H et al. Circulation 2011

Renal Sympathetic Afferent Activity

Mechanoreceptors chemoreceptors

Krum H et al. Circulation 2011

CV Mortality Risk Doubles with Each 20/10 mmHg Increment in SBP/DBP
Severe RH

CV mortality risk
8 6 4 2 0
1X risk 8X risk

4X risk 2X risk

115/75

135/85

155/95

175/105

SBP/DBP (mmHg)
Lewington et al. Lancet 2002;360:1903–13
*Individuals aged 40–69 years

 Severe

Resistant hypertension

Current indications
office BP ≥ 160 systolic or ≥ 100 mmHg diastolic (≥150/95 mmHg in type 2 diabetes) despite

treatment with ≥ 3 antihypertensive drugs of different types, including one diuretic.

Resistant Hypertension

Diagnosis
Diet

Drugs Devices

Resistant Hypertension - ESH Recommendations -

First step: Exclude
• False resistant hypertension (pseudoresistance) by using 24hour ABPM and home BP monitoring
• Secondary arterial hypertension • Causes which maintain high BP values and might be removed (obstructive sleep-apnea, high salt intake, BP raising drugs, severe obesity)
Schmieder,.........Tsioufis. J Hypertens. 2012;30:837-841.

Resistant Hypertension - ESH Recommendations -

Second step:
Optimize antihypertensive treatment with at least 3 (or better 4) tolerated drugs including a diuretic and an antialdosterone drug (if clinically possible, e.g after reevaluating renal function and the potential risk of hyperkaliemia) Check for effective BP control using ABPM before giving indication for RDN
Schmieder,.........Tsioufis. J Hypertens. 2012;30:837-841.

ESH : Renal sympathetic denervation
Schmieder ……Tsioufis. J Hypertens 2012;30:837-841

Exclusion criteria
Clinical eGFR<45 mL/min per 1.73 m 2  DM-I  history of a recent MI, unstable angina, or a cerebrovascular accident within 6 months,  Pregnacy Anatomical History of renal artery intervention (balloon angioplasty or stenting) Renal artery irregularities (stenosis >30%, aneurusm) multiple renal arteries (>20mm in diameter) main renal arteries of less than 4 mm in diameter or less than 20 mm in length

Discussing With Your Patients:

• Straightforward procedure

• In the cath lab, local anesthesia • No permanent implant
• Safe procedure • May experience some pain • Effect just after few weeks

• RDN is not a cure for resistant hypertension
- Reduction

of medication is not the primary

goal

Team for RSD
• Interventional Cardiologist

• (Interventional) Radiologist • Hypertension Specialist
(Nephrologist)

Centre selection for RDN

 

Centres should be specialized in the management of hypertension (ie ESH Hypertension Excellence Centers) with at least one hypertension expert being actively involved in the treatment and screening process. The interventions are performed by interventional cardiologists or angiologists who have been trained in performing this specific intervention and who are qualified to manage potential complications such as acute dissection of renal arteries by stent implantation Appropriate expertise could be assumed in centres with >25 renal interventions per year. Centers should enter their data into large registries to ensure proper quality control and to allow for an analysis of the procedural success acutely and at long-term follow up. Eur Heart J April 2013

RDN remains a blind procedure

Catheter Delivered Lesions

• How can we monitor ablation results?

• Pain? • Changes in renal haemodynamics? • Electrical stimulation at ostium of each renal artery?

Renal haemodynamics response acutely post RSD

Tsioufis et al, Int J Cardiol 2012

BLOOD PRESSURE RESPONSE BEFORE AND AFTER RF RENAL NERVE ABLATION

Chinushi et al (Hypertension. 2013;61:000-000)

Is there any sign of successful ablation ?

Treatment Procedure

Only the next days/weeks post procedure Renal Noradrenaline spillover MSNA BP reduction

RSD: The main issues.…
• 1. Not all patients respond to RDN-how can we identify those most likely to benefit? • Hypertension Phenotyping • 2. In patients who do not respond to RDN is the failure due to • -using the wrong treatment-pathophysiological failure? • - Technical failure of the denervation system? • Incomplete denervation • 3. At what time –point do we consider RDN therapy to have failed? • 4. Regeneration of renal fibers

Renal Denervation: 24 Mth Data

Change in Office BP vs Baseline

Patient initially diagnosed with “resistant hypertension” by general practitioner/internist/cardiologist/nephrologist
Referral or self-referral

Hypertension specialist Hypertension Center (preferably Hypertension Excellence Center)

Resistant hypertension confirmed and intensify therapy
(After exclusion of pseudoresistance, white-coat resistance, contributing lifestyle factors/substances and secondary hypertension)

Resistant hypertension not confirmed Controlled Hypertension

Standard conservative therapy

Consider for RSD
Resistant Hypertension Not controlled

Re-evaluation and implementation of current eligibility criteria (anatomical and clinical) for RSD therapy

Patient’s eligibility for RSD confirmed Specialized catheterization laboratory Center for RSD

Patient’s eligibility for RSD not confirmed

RSD therapy

Future Medicine

Personalized Medicine

Evidence based medicine
Experience

Individualized medicine “Medicine is an art based on science”