Κων/νος Τσιούφης

Καθηγητής Καρδιολογίας ΕΚΠΑ

President of European Society of Hypertension (ESH)

Πρόεδρος ΕΚΕ (2017-18)

AMEA ή Σαρτάνες ως πρώτη επιλογή

1. The importance of RAAS blockade for CV protection

2. The contraindication for ACEI and ARBS combination

3. ACEI are first line treatment for the complications of Hypertension (heart failure, post MI etc) but not ARBS

Three points of Consensus

James Black-1960’2 (Nobel Prize)

β-blockers

David Cushman-1970’s

ACE-i

Akira Endo-1976

Statins

Drugs that changed the prognosis and lives of millions of cardiovascular patients worldwide

Πώς ταξινομούνται οι ενδείξειςRCTs: 3 διαφορετικά επίπεδα ενδείξεων

◼ RCTs ενεργή ουσία vs placebo ACEi vs placebo

ARBs vs placebo

◼ Head to HeadΕνεργή ουσία vs όλες οι άλλες ενεργείς

◼ ACEi vs all others

◼ ARBs vs all others

Ενεργή ουσία vs άλλη ενεργή ουσία◼ ACEi vs ARBs

RCTs υπέρτασηςACEi or ARBs vs placebo

ACEi vs placebo

◼ LEWIS (captopril)◼ AIPRI (benazapril)◼ UKPDS (captopril)◼ HOPE (ramipril)◼ Fogari (fosinopril)◼ HYVET-pilot (lisinopril)◼ HYVET (perindopril ± indapamide)◼ CAMELOT (enalapril)◼ BENEDICT (trandolapril)◼ DIABHYCAR (ramipril)◼ PEACE (trandolapril)◼ DREAM (ramipril)◼ EUROPA (perindopril)◼ PROGRESS (perindopril ± indapamide)◼ ADVANCE (perindopril + indapamide)◼ DEMAND (delapril+ manidipine)

ARBs vs placebo

◼ RENAAL (losartan)

◼ IDNT (irbesartan)

◼ IRMA-2 (irbesartan)

◼ SCOPE (candesartan)

◼ PROFESS (telmisartan)

◼ TRANSCEND (telmisartan)

◼ DIRECT-2 (candesartan)

◼ I-PRESERVE (irbesartan)

◼ GISSI-AF (valsartan)

◼ NAVIGATOR (valsartan)

◼ ACTIVE-I (irbesartan)

◼ ROADMAP (olmesartan)

◼ ORIENT (olmesartan)

◼ HOPE-3 (valsartan + HCTZ)

C. Thomopoulos et al No4 J Hypertens 2015

Σχετική και απόλυτη μείωση κινδύνου σε μελέτες υπέρτασηςACEi vs placebo (35,707 pts for 4.2 years)

Πρωτογενής

Thomopoulos, Parati, Zanchetti. J Hypertens 2014;32:2285

0.4 0.7 1 1.3

Stroke

CHD

HF

Stroke+CHD

Stroke+CHD+HF

CV Death

All-cause Death

Outcome NTrials

10

10

6

12

6

11

10

Δ-BP

-4.2/-2.1

-4.2/-2.1

-3.5/-1.6

-4.1/-2.1

-3.5/-1.6

-4.1/-2.0

-4.1/-2.0

RR(95% CI)

0.80 (0.69-0.93)

0.87 (0.79-0.97)

0.79 (0.66-0.93)

0.85 (0.79-0.92)

0.83 (0.75-0.92)

0.89 (0.75-1.07)

0.92 (0.83-1.03)

RR(95% CI)

Mean Absolute Risk ReductionPer 1000 pts treated for 5 years

0-10-20-30-40

Active Better Control Better Active Better Control Better

-9

-12

-16

-9

-29

-5

-7

10

NS

NS

Σχετική και απόλυτη μείωση κινδύνου σε μελέτες υπέρτασηςACEi vs placebo (50,944 pts for 4.2 years)

Δευτερογενής

Thomopoulos, Parati, Zanchetti. J Hypertens 2014;32:2285

0.4 0.7 1 1.3

Stroke

CHD

HF

Stroke+CHD

Stroke+CHD+HF

CV Death

All-cause Death

Outcome NTrials

11

11

7

15

7

15

13

Δ-BP

-5.1/-2.3

-5.1/-2.3

-4.1/-1.8

-5.0/-2.3

-4.1/-1.8

-5.0/-2.3

-5.0/-2.3

RR(95% CI)

0.79 (0.69-0.90)

0.86 (0.79-0.94)

0.83 (0.71-0.96)

0.83 (0.77-0.91)

0.86 (0.78-0.94)

0.87 (0.78-0.98)

0.91 (0.85-0.98)

RR(95% CI)

Mean Absolute Risk ReductionPer 1000 pts treated for 5 years

0-10-20-30-40

Active Better Control Better Active Better Control Better

-11

-9

-20

-10

-23

-7

-9

10

Σχετική και απόλυτη μείωση κινδύνου σε μελέτες υπέρτασηςARBs vs placebo (65,256 pts for 3.8 years)

Thomopoulos, Parati, Zanchetti. J Hypertens 2014;32:2285

0.4 0.7 1 1.3

Stroke

CHD

HF

Stroke+CHD

Stroke+CHD+HF

CV Death

All-cause Death

Outcome NTrials

11

11

9

10

8

10

13

Δ-BP

-3.7/-2.0

-3.5/-1.6

-3.8/-2.1

-3.7/-2.0

-3.8/-2.1

-3.7/-2.0

-3.7/-2.0

RR(95% CI)

0.91 (0.86-0.97)

0.94 (0.86-1.04)

0.90 (0.83-0.97)

0.92 (0.87-0.97)

0.91 (0.86-0.95)

1.03 (0.94-1.13)

1.01 (0.97-1.06)

RR(95% CI)

Mean Absolute Risk ReductionPer 1000 pts treated for 5 years

0-10-20-30-40

Active Better Control Better Active Better Control Better

-9

-7

-11

-2

-20

+2

+1

10

NS

NS

NS

Τι σημαίνουν τα αποτελέσματα vs. placebo;Ποιες οι ενδείξεις προστασίας;

Καταληκτικό Σημείο ACEi vs placebo ARBs vs placebo

Stroke Ναι Ναι

CHD Ναι Όχι*

HF Ναι Ναι

CardiovascularDeath

Ενδείξεις προστασίας

Όχι*

All-Cause Death Ενδείξεις προστασίας

Όχι*

Η απουσία ενδείξεων ότι οι ARBs δεν προστατεύουν απόθανατηφόρα επεισόδια

δεν σημαίνει “evidence against”

C. Thomopoulos et al No4 J Hypertens 2015

Each class vs all other

D BB CA ACEI ARB RASB

Stroke

CHD

HF

St + CHD

St + CHD + HF

CV Death

All-cause Death

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

Άμεση σύγκρισηACEi vs ARBs

Thomopoulos, Parati, Zanchetti. No5. J Hypertens 2015

0.4 0.7 1 1.3

Stroke

CHD

HF

Stroke+CHD

Stroke+CHD+HF

CV Death

All-cause Death

Outcome NTrials

3

3

3

3

3

2

2

Δ-BP

1.01/0.61

1.01/0.61

1.01/0.61

1.01/0.61

1.01/0.61

1.03/0.63

1.03/0.63

RR*(95% CI)

1.09 (0.95-1.25)

0.93 (0.82-1.06)

0.89 (0.78-1.02)

1.00 (0.91-1.10)

0.97 (0.90-1.04)

1.00 (0.90-1.12)

1.02 (0.94-1.11)

RR(95% CI)

ACEi Better ARBs Better

Ισοδυναμία *

n=3

FU D-systolic

D-

diastol

ic

Treated Controls Total

DETAIL, 2004 5 3,2 3 130 120 250

ONTARGET, 2008 4,7 1 0,6 8576 8542 17118

ROAD, 2007 3,7 0 -0,5 180 180 360

4,68 1,01 0,61 17728

*

ONTARGETKey results

Telmisartan was non-inferior to ramipril for reducing CV-risk profile…

CI: confidential interval.1- ONTARGET investigators. New Engl J Med. 2008;358:1547-1559.

…with 12% increase risk of hospitalization for heart failure

DBP: diastolic blood pressure; SBP: systolic blood pressure.1- ONTARGET investigators. New Engl J Med. 2008;358:1547-1559. 2- Mancia G et al. Hypertension. 2012;60:1400-1406.

ONTARGETKey results

Telmisartan had a greater 24h blood pressure reduction than ramipril…

Telmisartan

Ramipril

…which did not translate into greater benefits

Υπάρχει διαφορά ACEi vs ARBs σε διαβητικούς και μη διαβητικούς;

0.4 0.7 1 1.3

Stroke+CHD

All Death

Stroke+CHD+HF

All-cause Death

ACEi

DMNon-DM

DMnonDM

DMnonDM

DMnonDM

DMnonDM

Trials

73

64

64

61

RR*(95% CI)

0.40 (0.29-0.59)0.58 (0.47-0.73)

0.61 (0.40-0.95)0.77 (0.60-0.97)

0.80 (0.63-1.03)0.82 (0.68-1.02)

1.09 (070-1.65)-

RR(95% CI)

Active Better Placebo Better

ACEi vs placebo and ARBs vs placebo

ARBs

Pinteraction

0.009

0.015

0.75

NA

Όφελος τόσο σε διαβητικούς και μη διαβητικούςΜεγαλύτερο όφελος στους διαβητικούς

Δεν καταδεικνύεται διαφορικό όφελοςμεταξύ διαβητικών και μη διαβητικών

C. Thomopoulos et al No10 J Hypertens 2017

Ποια η επιλογή μεταξύ των φαρμάκων του άξονα;

CHD, HF(2ndary prevention) ACEi as first choice

CHDprevention

ACEi

Stroke and HF prevention

ACEi or ARB

Mortalityprevention

1. No evidence as monotherapy for both2. ACEi combo with indapamide or CCBs

Diabetes vs non-Diabetes

ACEi

Will future antihypertensive drugs contribute in the better management of HTN?

R.Kreitz, in: Tsioufis, Schmieder, Mancia: Interventional therapies for essential and secondary hypertension, Springer 2016

Revisiting mode of action of RAAS isDifferences do exist between ACE inhibitors and ARBs

Bradykinin

Angiotensinogen

B1 B2

Renin

AT1 AT2

ChymasesCathepsin G

CAGE

ACE inhibitor

ARB

➢ Vasodilation

➢ Antifibrosis

➢ Anti-inflammation

➢ Anti-ROS

➢ Antithrombosis

➢ Vasoconstriction

➢ Pro-fibrosis

➢ Pro-inflammation

➢ ROS production

➢ PAI-1 increase

ACE: angiotensin converting enzyme; ARB: angiotensin receptor blocker.

ACE

Inactive fragments Ang I

Ang II

The bradykinin benefits are missing with ARBs

2016 ESC guidelines for heart failure

Drug treatment strategy for hypertension

Recommendations Class Level

Among all antihypertensive drugs, ACE inhibitors, ARBs, beta-blockers,

CCBs, and diuretics (thiazides and thiazide-like such as chlorthalidone

and indapamide) have demonstrated effective reduction of BP and CV

events in RCTs, and thus are indicated as the basis of antihypertensive

treatment strategies.

I A

Combination treatment is recommended for most hypertensive patients,

as initial therapy. Preferred combinations should comprise a RAS

blocker (either an ACE inhibitor or an ARB) with a CCB or diuretic.

Other combinations of the five major classes can be used.

I A

Hypertension drug treatment strategies

Monotherapy at increasing doses

Sequential monotherapy

Stepped-care approach, i.e.monotherapy with sequential addition of other drugs

Two-drug combination as first step

Core drug-treatment strategy for uncomplicated hypertension

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

The realistic approach to improve

the unacceptable high rate of uncontrolled HTN

1 pill/two-drug combination as first step

2017 ACC/AHA Clinical Practice Guidelines

Choice of Initial Monotherapy Versus Initial Combination Drug Therapy

*Fixed-dose combination antihypertensive medications are listed in Online Data Supplement D.

Widely available as SPC, facilitating simplification of treatment

Available with ranges of doses, facilitating flexible prescribing/uptitration from lower to

higher doses

Complementary mechanisms of action because CCB/D activate RAS, which is counteracted

by RAS blockers

Limitation of adverse effects, e.g. D-induced hypokalaemia is reduced by CCB and CCB-

dependent ankle oedema is reduced by RAS blockers

RAS inhibition important for many patient groups (LVH, Diabetes, Proteinuria etc)

Rationale for RAS blocker and CCB or D combination

First step combination treatment in some specific conditions

Diabetes: RAS blocker+CCB or D (IA)

CAD: BB or CCB+RAS blocker (IA)

CKD: RAS blocker+ CCB or D (loop D)

Cerebrovascular Disease:RAS Blocker+CCB or D(IA)

AF: BB and/or nondihCCB (IIaB)

Hf(r/p*EF):RAS blocker+BB,D+Antialdo(IA)(*IIaB)

COPD: RAS blocker+CCB

LEAD: RAS blocker+CCB or D (*BB may be considered)

Blacks: D+CCB (IB)

Smartphones and wearable sensors could bring personalized healthcare to billions of people

“Whole population worldwide registry”

We work togetherESH and the 35 National Hypertension EU societies and the 5Associated Hypertension societies

We work togetherESH and the 191 Excellence Centres

Blood Pressure Control in ESH Excellence Centers BP-CON study

To determine1. Average BP values in different ESH Excellent Centers, countries and European regions (attended

and unattended BP)

2. Prevalence of uncontrolled hypertensive patients and analyze the most important factors/predictors for treatment failure in ESH Excellence Centers.

3. Preparation of strategies aiming to increase hypertension control globally but with specificities for particular countries/regions

Timeframe: December 2018-December 2019

GREEK EXCELLENCE CENTERSCardiology Dept. of Heraklion University Hospital, Heraklion Dr. Marketou, MariaHypertension and Cardiovascular Prevention Clinic, 3rd Department of Internal Medicine, Evangelismos Hospital,

Athens

Dr. Andreadis,

EmmanuelHypertension Center of Sotiria Hospital, Athens Prof. Stergiou, George

S.

Hypertension Center, Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki,

Thessaloniki

Prof. Sarafidis, Pantelis

Hypertension Center, Department of Nephrology, University Hospital of Ioannina, Ioannina Dr. Kalaitzidis, RigasHypertension Centre, Department of Clinical Therapeutics, Medical School of Athens, Alexandra Hospital, Athens Prof E.ManiosHypertension Clinic, Cardiology Department, Asklepeion Hospital, Athens Prof. Manolis, AthansiosHypertension Clinic, Department of Cardiology, KAT General Hospital, Athens Dr Grassos,

CharalamposHypertension Clinic, University Hospital Laiko, Athens Dr. Papadopoulos,

Dimitris P.Hypertension Division of the Third Department of Internal Medicine, Aristotle University of Thessaloniki,

Papageorgiou General Hospital, Thessaloniki

Prof. Douma, Stella

Hypertension Outpatient Clinic,1st Propedeutic Dept. of Internal Medicine, AHEPA Hospital, Thessaloniki Prof Hatzitolios,

ApostolosHypertension Unit of the First Department of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital,

Thessaloniki

Prof. Zebekakis, Pantelis

Hypertension Unit, “Elena Venizelou” General & Maternity Hospital, Athens Dr. Makris, ThomasHypertension Unit, 1st Department of Cardiology, University of Athens, Hippokration Hospital, Athens Prof. Tsioufis, CostasHypertension Unit, 2nd Department of Cardiology, Medical School, Univeristy of Athens, ATTIKON Hospital,

Athens

Dr. Triantafyllidi, Helen

Hypertension Unit, Department of Internal Medicine, University Hospital of Heraklion, Heraklion Dr. Papadakis, IoannisHypertension-24h ABPM Center, Papageorgiou Hospital, Nea Efkarpia Prof. Kotsis, VasiliosPartner BP Clinic(s):Hypertension Clinic, Department of Internal Medicine, Grevena Hospital Dr. Zervos, NikolaosPediatric Outpatient Hypertension Clinic, 1st Pediatric Department Aristotle University Thessaloniki Prof. Stambouli, Styliani

ESH Summer Schools

Les Diablerets, Switzerland/9/2018

Course Director: M. Burnier

Athens, Greece14-20/9/2019

Course Director: C. Tsioufis

mschyperandkidney@gmail.com

213 2088386

hypertasi.med.uoa.gr

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