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Κώστας ΤσιούφηςΚαθηγητής Καρδιολογίας ΕΚΠΑPresident of European Society of Hypertension (ESH)(2017-19)Πρόεδρος ΕΚΕ (2017-18)

Δήλωση σύγκρουσης συμφερόντων

✓Εχω λάβει υποστήριξη συμμετοχής σε συνέδρια ή ερευνητική υποστήριξη ή τιμητική

αμοιβή ομιλίας από Medtronic, St. Jude Medical, Bayer, Novartis, Astra-Zeneca,

Boehringer In, Pfizer, Chiesi, Pharmanel, Sanofi, Vianex, Win-Medica, Elpen

✓49 year old male

✓Diagnosed with hypertension 6 months ago

✓Obese with a BMI:37.2 kg/m2, Waist =112 cm

✓Hx: hyperlipidemia, Office BP:157/95 mmHg, (3 readings, automated

device, appropriate cuff, both arms, sitting and standing position)

✓Heart rate : 68 bpm

• Home BP readings : 150/90-95 mmHg

• Physical examination : unremarkable

The Story

✓No drugs for hypertension

✓Other drugs:

• For high cholesterol: Atorvastatin.

• For high uric acid: Allopurinol

Therapy

✓ HCT: 44.1%, WBC: 10,3 , PLT: 341

✓ HbA1C=6.3%, Serum K+=4.9mEq/l

✓ eGFR: 68 ml/min/1,73m2, ACR: 40 mg/g

✓ ECG and echo : normal

➢Retinal: grade I

➢High salt intake

Laboratory and TOD data

Classification of blood pressure

Recommendation Class Level

It is recommended that BP be classified as

optimal, normal, high-normal, or grades 1–3

hypertension, according to office BP.

I C

Classification of office BP and definitions of hypertension grade

Category Systolic (mmHg) Diastolic (mmHg)

Optimal < 120 and < 80

Normal 120–129 and/or 80–84

High normal 130–139 and/or 85–89

Grade 1 hypertension 140–159 and/or 90–99

Grade 2 hypertension 160–179 and/or 100–109

Grade 3 hypertension ≥ 180 and/or ≥ 110

Isolated systolic hypertension ≥ 140 and < 90

Categories of BP in Adults*

*Individuals with SBP and DBP in 2 categories should be

designated to the higher BP category.

BP indicates blood pressure (based on an average of ≥2

careful readings obtained on ≥2 occasions, as detailed in

DBP, diastolic blood pressure; and SBP systolic blood

pressure.

BP Category SBP DBP

Normal <120 mm Hg and <80 mm Hg

Elevated 120–129 mm Hg

and <80 mm Hg

Hypertension

Stage 1 130–139 mm Hg

or 80–89 mm Hg

Stage 2 ≥140 mm Hg or ≥90 mm Hg

Definitions of hypertension according to office, ambulatory, and home BP levels

Category Systolic (mmHg) Diastolic (mmHg)

Office BP ≥ 140 and/or ≥ 90

Ambulatory BP

Daytime (or awake) mean ≥ 135 and/or ≥ 85

Night-time (or asleep) mean ≥ 120 and/or ≥ 70

24-h mean ≥ 130 and/or ≥ 80

Home BP mean ≥ 135 and/or ≥ 85

Screening and diagnosis of hypertension

Out-of-Office and Self-Monitoring of BP

COR LOERecommendation for Out-of-Office and Self-Monitoring

of BP

I ASR

Out-of-office BP measurements are recommended to confirm the diagnosis of hypertension and for titration of BP-lowering medication, in conjunction with telehealth counseling or clinical interventions.

SR indicates systematic review.

Case Baseline ABPM

Clinical indications for HBPM or ABPM

Conditions in which white-coat hypertension is more common, for example:

• Grade I hypertension on office BP measurement

• Marked office BP elevation without HMOD

Conditions in which masked hypertension is more common, for example:

• High-normal office BP

• Normal office BP in individuals with HMOD or at high total CV risk

Postural and post-prandial hypotension in untreated and treated patients

Evaluation of resistant hypertension

Evaluation of BP control, especially in treated higher-risk patients

Exaggerated BP response to exercise

When there is considerable variability in the office BP

Evaluating symptoms consistent with hypotension during treatment

Specific indications for ABPM rather than HBPM:

• Assessment of nocturnal BP values and dipping status (e.g. suspicion of nocturnal hypertension, such as in sleep apnoea, CKD, diabetes, endocrine hypertension, or autonomic dysfunction)

ABP/Home BP, Documented advantages over Office BP

• Greater reproducibility (Trazzi, JH 1991, 9, 115)

• Little/No placebo effect (Mancia, AJH 1995, 8, 311)

• Little/No white coat effect (Parati, Hypertension 1985, 7, 597)

• Better prediction of CV outcomes

➢ Steeper 24h BP/outcome relationship

➢ Outcome prediction survives adjustment for office BP

Scientific quality of office vs ABP/Home BP prognostic studies

• In office BP-based long term prognostic studies serial office BP values (“usual” BP) are

available while in ABP/Home BP long term prognostic studies only one initial value is

available

• This is true in studies on both untreated and treated patient cohorts

• Are the single ABP/Home BP values reproducible and representative of the prevailing

values during the FU, particularly in treated patients?

▪ What is the incremental benefit for CV risk prediction of the addition of out-of-office BP (HBPM or

ABPM) to office BP measurements?

▪ What are the optimal treatment targets according to HBPM and ABPM?

Routine use of out-of-office BP or

improvement of the quality of office BP measurements?

Johnson KC et al. Hypertension. 2017;71:848-857.

Average post-randomization Systolic BPs and medications, controlling for subject, visit and clinical site

Always Alone Never Alone Alone for Rest Alone for BP Measurement

Mean (95%CI) Mean (95%CI) Mean (95%CI) Mean (95%CI)

Systolic BP, mm HG

Intensive Participants 121.4 (120.7, 122.0) * 121.0(120.2,121.8)* 122.2 (121.3, 123.1)* 120.6 (119.1, 122.2)*

Standard Participants 134.4 (133.8, 135.1)* 134.4 (133.6, 135.1)* 134.7 (133.8, 135.6) 135.4 (133.8, 136.9)*

Difference 13.1 (12.6, 13.5)* 13.3 (12.7, 13.9) * 12.5 (11.9, 13.2)* 14.7 (13.5, 15.9)

Number of Medications

Intensive Participants 2.7 (2.7, 2.8)* 2.8 (2.7, 2.9)* 2.7 (2.6, 2.8)* 2.5 (2.4, 2.7)*

Standard Participants 1.8 (1.8, 1.9)* 1.9 (1.8, 2.0)* 1.8 (1.7, 1.9)* 1.8 (1.6, 1.9)*

Difference 0.9 (0.8, 1.0)* 0.9(0.9, 1.0)* 0.9 (0.8, 1.0)* 0.8 (0.6, 0.9)*

*P>0.05 for pairs of BP measurement techniques

SPRINT Attended vs. Unattended BP Measurement Survey

To fully realize benefits and minimize risks associated with SPRINT intensive treatment

algorithm

Use of validated automated BP device,

Staff training to allow for a quiet rest period,

Proper positioning, use of proper cuff size, and

Averaging readings

seemed more important than whether BP measurement was attended or unattended.

Johnson KC et al. Hypertension. 2017;71:848-857

Identification and reversal of Lifestyle factors contributing to uncontrolled HTN

◼ Salt consumption

◼ Obesity

There is very limited evidence for long-term effects of lifestyle interventionson BP and health outcomes but yet, there is no evidence for harmful effects

Patnode, JAMA 2017

The benefit is greatest whenmultiple lifestyle interventions are incorporated simultaneously

History and physical examination

Quantification of Daytime sleepiness

Objective methods MULTIPLE SLEEP LATENCY TEST (MSLT)

Subjective methods EPWORTH SLEEPINESS SCALE

Diagnosis of Sleep apnea syndrome

Quantification of sleep related breathing disorders (Polysomnography)

Sleep disorders are

common, serious, treatable and

underdiagnosed

CPAP in OSA-related HTN

◼Most interventional trials in OSA and subsequent meta-analyses have indicated that CPAP has only a modest

effect on BP levels

◼ Tsioufis et al, J Hypertension 2010

Randomized controlled study

In patients with RHTN and OSA, CPAP treatment for 3 months achieved significant reductions in 24-h BP.

This effect was seen in patients with ABPM-confirmed RHTN who use CPAP more than 5.8 h/night.

◼ Lozano L, et al, J Hypertens. 2010 ;28:2161-8

Drug therapy in OSAS-related HTN

There is no clear evidence for preference for a specific type of antihypertensive drug and selection should be

guided by the patient’s cardiometabolic profile and associated clinical conditions

◼ Tsioufis et al, J Hypertension 2010

Drug-induced RHTN

Nonsteroidal anti-inflammatory drugs (including cyclo-oxygenase-2 inhibitors)

Sympathomimetics (decongestants, anorectics)

Cocaine, amphetamines, other illicit drugs

Oral contraceptive hormones

Adrenal steroid hormones

Erythropoietin

Cyclosporine and tacrolimus

Licorice (included in some chewing tobacco)

Over-the-counter dietary and herbal supplements (e.g. ginseng, yohimbine,

bitter orange)

Antiangiogenic drugs induced hypertension

De novo HTN or worsening HTN in

association with anti angiogenic drugs varies

between 17-90%

Preferable choice: NO donors

Low interaction potential: RAS blockers, diuretics ,

b-blockers

Use cautiously : CCBs

Contrainticated: verapamil, diltiazem

Prevalence of PA in Patients with RHTN

Calhoun DA, Annu Rev Med 2013; 64: 233-247

(%)

20

17

22

19

7

11

0

5

10

15

20

25

30

BirminghamUSA

SeattleUSA

OsloNorway

PragueCzech Rep.

ShanghaiChina

ThessalonikiGreece

Primary aldosteronism is an underdiagnosed cause of RHTN

Variable Presentation of Primary aldosteronism

• Hypertension

• Unexplained hypokalemia

• Metabolic alkalosis

The presence of PA should be suspected in any patient with the triad of:

Mulatero P et al. J Clin Endocrinol Metab 2004

Normokalemia is more common than hypokalemia

<50% of diagnosed cases were hypokalemic at presentation

Drug therapy and Aldo/PRA ratio

β- blockers

ΑCE-inh

ΑΤ1

α- blockers

ALD

PRAARR

False positive

ALD

PRA

ARR

False negative

PRA, ALDDiuretics

What is his cardiovascular risk?

2018 ESH/ESC Hypertension Guidelines

Classification of hypertension stages according to BP levels, presence of CV risk factors, HMOD, or comorbidities

SCORE CV risk assessment is recommended.

Stratification of total CV risk in categories of low, moderate, high and very high risk

To:

• Achieve BP control over 24 hours

• Protect against Target Organ Damage

• Reduce Mortality

What is the aim of treatment?

To:

• Reduce weight

• Limit salt intake

• Start drug treatment

What is the treatment Strategy?

Effects of BP Lowering (10/5 mmHg SBP/DBP) in Trials with Average Baseline BP in Grade 1 and Average Low-to-Moderate CV Risk

Thomopoulos et al., J Hypertens 2014; 32: 2296

Outcome

Stroke

CHD

Stroke + CHD

CV Death

All-cause Death

Trials

(n)

4

5

4

4

4

Baseline

SBP/DBP

(mmHg)

146/91

145/91

146/91

146/91

146/91

Difference

SBP/DBP

(mmHg)

-7.1/-4.5

-6.5/-4.2

-7.1/-4.5

-7.1/-4.5

-7.1/-4.5

Absolute

Risk Reduction

1000 pts/5 years

(95%CI)

-21 (-26, -1)

-12 (-18, -2)

-34 (-43, -19)

-9 (-14, +1)

-19 (-25, -8)

NNT

5 years

(95% CI)

47 (39, 1301)

86 (55, 531)

29 (23, 54)

110 (72, -2223)

54 (40, 119)

Standardized RR

(95% CI)

0.1 0.2 0.5 1 2 5

Active better Control better

Standardized RR

(95% CI)

0.33 (0.11-0.98)

0.68 (0.48-0.95)

0.51 (0.36-0.75)

0.57 (0.32-1.02)

0.53 (0.35-0.80)

Treatment of grade I HTN low-moderate CV risk◼ No direct evidence from RCT

2018 ESH/ESC Hypertension Guidelines

Thresholds for initiation of BP-lowering treatment less conservative

2018 ESH/ESC Hypertension Guidelines, Summary of Office BP thresholds for treatment

Office BP Thresholds for treatment

Uncontrolled on 2 drugs

Hypertension drug-treatment strategy:Which is the most effective evidence-based treatment strategy to improve BP control?

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)

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

Incr

emen

tal

SB

P r

edu

ctio

n r

ati

o

of

ob

serv

ed t

o e

xp

ecte

d a

dd

itiv

e ef

fect

s

* 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

1.5

1.0

0.5

0.0

Adding a drug from

another class (on average

standard doses)

Doubling dose of same

drug (from standard

dose to twice standard)

1.04

(0.88-1.20)

1.00

(0.76-1.24)

1.16

(0.93-1.39)

0.89

(0.69-1.09)

1.01

(0.90-1.12)

0.19

(0.08-0.30)

0.23

(0.12-0.34)0.20

(0.14-0.26)

0.37

(0.29-0.45)

0.22

(0.19-0.25)

Thiazide Beta-

blocker

ACE-

inhibitor

Calcium channel

blocker

All

classes

Core drug-treatment strategy for uncomplicated hypertension

The core algorithm is also appropriate for most patients with HMOD, cerebrovascular disease, diabetes, or PAD

Treatment

Started on RAS blocker/Amlodipine

41

42

ΑΝΤΑΓΩΝΙΣΤΕΣ ΑΣΒΕΣΤΙΟΥ στην ΑΥΠλεονεκτήματα

1. Υψηλή αποτελεσματικότητα

Ιδίως σε ISH

Υπέρταση εκ κυκλοσπορίνης

Αλατοευαίσθητους-σύνδρομο Raynaud’s-ΧΑΠ-Διαστολική

καρδιακή ανεπάρκεια

2. Επιτυχής συνδυασμός με όλα τα υπόλοιπα αντιυπερτασικά

3. Ίσως υπερτερεί σε άτομα υψηλού κινδύνου για ΑΕΕ

Each class vs all other

D BB CA ACEI ARB RASB

Stroke

CHD

HF

St + CHD

St + CHD + HF

CV Death

All-cause Death

Summary results of the direct comparisons of each class vs all other classes of BP-lowering drugs on seven major outcomes

Thomopoulos, Parati, Zanchetti, J Hypertens 2015; 33: 1321-1341

Chlorthalidone and indapamide have been used in a number of RCTs showing CV benefits,

and these agents are more potent per milligram than hydrochlorothiazide in lowering BP,

with a longer duration of action compared with hydrochlorothiazide and no evidence of a

greater incidence of side effects.

A recent meta-analysis of placebo-controlled : similar effects on CV outcomes of the three

types of diuretics.

……..thiazides, chlorthalidone, and indapamide can all be considered suitable

antihypertensive agents.

Treatment of HTN: Which diuretic

ESC/ESH guidelines 2018

Treatment

Started on RAS blocker/Amlodipine

Follow up after 4 weeks months:

• office BP 130/85 mmHg

Does the patient receive regularly the antihypertensive

medications? (medication adherence)

Can we optimize the antihypertensive therapy?

For every 100

prescriptions written:

30%–50% never makeit to the pharmacy

34%–52% are filledbut never picked up

70%–75% are nottaken as prescribed

15-20% are refiled as prescribed

The importance of a collaborative approach

PhysicianNurse

( building a personal connection to identify a

patient’s treatment concerns)

Pharmacist(Establishing themselves as a

primary educator for the patient)

Specialist(simplifying

optimal therapy)

Each profession should value the unique role that others can play in

enhancing patient adherence

Agenda

◼ Office BP or out of office BP

◼ How to measure BP correctly

◼ How to manage Hypertension in the very elderly

◼ Do beta blockers have any role in the HTN management

◼ How to manage Resistant hypertension

◼ Do antihypertensive drugs increase the risk of cancer

◼ Should we use RDN for the routine treatment of HTN

Limited Available data

◼ How to manage Hypertension in the very elderly

How old would you be if you didn’t know how old you are?Satchel Paige

Management of Hypertension in the very elderly

80+ years

The most « hypertensive » population (prevalence of HTN over 80 yrs >75%)

The most growing population (5% in 2015, 10% in 2040 will be over 80 yrs)

The most heterogeneous population

Young hyperadrenergichypertensive patient

Obese metabolichypertensive patient

Elderly hypertensivevascular patient

Different hypertensive phenotypes

Many comorbidities- CKD,CAD, StrokeToo many drugs, inappropriate useIncreased number of side effects Increased hospitalizationsIncreased fraility

80+: 5.7% (3.8 M)

35% (1.3 M) significant

loss of autonomy

50% (650,000)

Living in NHs

50% (650,000)

At home with

daily assistance

Population in France: 66 M

>4 chronic diseases

>8 different medications/day

0% have the inclusion criteria of HYVET and

SPRINT

65% (2.5 M): preserved

autonomy for activities

of daily living (ADL)

and often good

functional status

Approx. 30-50% have the

inclusion criteria for HYVET and

SPRINT

Presenting in Athens Meeting by A.Benetos

Who is frail?

2018 ESC/ESH Hypertension Guidelines

Williams, Mancia et al., J Hypertens 2018;36:1953-2041 and Eur Heart J 2018;39:3021-3104

Office BP treatment target range

Age18-65 years

Age>65-79 years*

Age≥ 80 years*

IA IA IA

• First SBP <140 mmHg• Aim for SBP 130 mmHg or

lower if tolerated• DBP <80-70 mmHg• Do not go <120/70 mmHg

• First SBP <140 mmHg• Aim for SBP 130 mmHg

• DBP <80-70 mmHg• Do not go <130/70 mmHg

• First SBP <140 mmHg• Aim for SBP 130 mmHg

• DBP <80-70 mmHg• Do not go <130/70 mmHg

* Consider frailty/independence/tolerability of treatment

77

‘PRESERVED

FUNCTION’

‘LOSS OF

FUNCTION/PRESERVE

D AUTONOMY’

(FOR THE ADL)

-Therapeutic approach

similar to younger

adults with treatment

goal: SBP 130-140

mmHg

-Start with

monotherapy and

titrate antihypertensive

medication cautiously

-Always check for

orthostatic

hypotension

Tailor

antihypertensive

strategy after a

detailed geriatric

assessment.

‘LOSS OF AUTONOMY’

(FOR THE ADL)

-Revision of the

prescription

-If BP lowering it is

considered, SBP goal

140-150 mmHg ;

-Under treatment: SBP <

130 mmHg or orthostatic

hypotension: Consider

reducing antihypertensive

treatment.

-Correct other factors

and medications

decreasing BP

Moderately

altered

functional

status

Significantly

altered

functional

status

ADAPTING ANTIHYPERTENSIVE STRATEGIES ACCORDING TO

THE PROFILE OF THE ‘FRAILTY/FUNCTION/AUTONOMY’ STATUS

Benetos A, Petrovic M, Strandberg T, Circ. Res. 2019, 124: 1045-1060

Magkas, Tsioufis et al, J Clin Hypertens (Greenwich). 2019

Jordan J et al. J Hypertens 2019; Epub

↓ Supine blood pressure

↓ Nocturnal sodium excretion

↓ Orthostatic hypotension in morning

◼ How to manage Resistant hypertension

Different but arbitrary Terminology for the same clinical problem

◼ Resistant Hypertension (Treatment Resistant Hypertension) (5-30% in the overall hypertensive population)

◼ Apparent Treatment Resistant Hypertension (2-5%)

◼ Resistant Controlled Hypertension (21%)

◼ Refractory Hypertension (5% of the Resistant Hypertension)

…but consensus about the adverse prognosis

Patterns of RHTN and CV events1911 treated hypertensive patients for a mean period of 3.9 years follow up

6.4 events

9.1events

13.2 events

18.1 events

Tsioufis C, et al. J Hypertens. 2013

Resistant hypertensionRecommendations Class Level

It is recommended that hypertension be defined as resistant to treatment (i.e.

resistant hypertension) when:

• Optimal doses (or best-tolerated doses) of an appropriate therapeutic strategy,

which should include a diuretic (typically an ACE inhibitor or an ARB with a CCB

and a thiazide/thiazide-type diuretic), fails to lower clinic SBP and DBP values to <

140 mmHg and/or 90 mmHg, respectively; and

• The inadequate control of BP has been confirmed by ABPM or HBPM; and

• After exclusion of various causes of pseudo-resistant hypertension (especially

poor medication adherence) and secondary hypertension.

I C

2018 ESC/ESH Hypertension Guidelines

Core drug-treatment strategy for uncomplicated hypertension

The core algorithm is also appropriate for most patients with HMOD, cerebrovascular disease, diabetes, or PAD

Subgroup analysis comparing the effects of mineralocorticoid receptorantagonists on achieved blood pressure difference between resistanthypertension and nonresistant hypertension trials

Bazoukis, Thomopoulos, Tsioufis. J Hypertens. 2018 May;36(5):987-994

Although the rate of BP control was similarbetween the 2 tested drugs, spironolactone is preferable as a fourth drug considering the dosage facilities and higher impact in some ABPM secondary end points.

◼ hould we use RDN for the routine treatment of HTN

Device-based therapies for hypertension

Recommendation Class Level

Use of device-based therapies is not recommended for the routine

treatment of hypertension, unless in the context of clinical studies and

RCTs, until further evidence regarding their safety and efficacy

becomes available.

III B

RDN for HTN management: Back on track

RDN: Efficacy to lower BP

-9

-1,6

-14

-12

-10

-8

-6

-4

-2

0

Systolic

RDN Sham

152

RDN(N=36)

Sham(N=36)

ON Med6 months24-h systolic BP

-12.7 to -5.3p<0.0001

-5.2 to 2.0p=0.365

(-12.5 to -2.3)p=0.0051

-5,5

-0,5

-14

-12

-10

-8

-6

-4

-2

0

Systolic

RDN Sham

-9.1 to -2.0p=0.003

-3.9 to 2.9p=0.76

RDN(N=35)

Sham(N=36)

OFF Med3 months24-h systolic BP

(-9.9 to -0.2)p=0.04

-8,5

-2,2

-14

-12

-10

-8

-6

-4

-2

0

Systolic

RDN Sham

RDN(N=74)

Sham(N=72)

SOLO2 monthsDaytime systolic BP

-10.6 to -6.3

-4.5 to 0.2

(-9.4 to -3.1)p<0.001

151150 150 153152

-6.3 -5.0-7.4

Schmieder RE ESH 2018

Change in Ambulatory BP in RADIANCE SOLO, SPYRAL HTN OFF MED and SPYRAL HTN ON MED

SPYRAL HTN – OFF MED

24-hr Systolic Blood Pressure from Baseline to 3 Months

RDN

130

140

150

160

170

1am

2am

3am

4am

5am

6am

7am

8am

9am

10a

m

11a

m

12p

m

1p

m

2p

m

3p

m

4p

m

5p

m

6p

m

7p

m

8p

m

9p

m

10p

m

11p

m

12a

m

Systo

lic

Blo

od

Pre

ssu

re (

mm

Hg

)

Sham Control

130

140

150

160

170

1am

2am

3am

4am

5am

6am

7am

8am

9am

10a

m

11a

m

12p

m

1p

m

2p

m

3p

m

4p

m

5p

m

6p

m

7p

m

8p

m

9p

m

10p

m

11p

m

12a

m

3 Months

Baseline

3 Months

Baseline

Graphs based on actual clock times. Similar results were observed when 24-hour BP patterns were normalized to patient reported time of waking.

Kario K, et al. Circulation 2018ss

▪ RDN: ‘’always on” effect

Renal Denervation (N=74)

Sham Procedure (N=72)

% Patients with

≥ 5 mm Hg Decrease

Renal Denervation: 66%

Sham Procedure: 33%

P<0.001

66%

33%

Unmet Needs –I. Identification of Responders

Azizi M, Lancet 2018

Unmet Needs –II. Real time feedback

Mapping Ablation Verification

Four pivotal trials in HTN are underway◼ SPYRAL OFF-MED PIVOTAL

◼ RADIANCE SOLO II

◼ SPYRAL ON-MED PIVOTAL

◼ REQUIRE PIVOTAL

No drugs

On drugs

Larger trials beyond HTN is under development