ESC: 2016 Guidelines on CVD Prevention inClinical Practice

Δ. ΡΙΧΤΕΡ, MD, FESC, FAHA Διευθυντής Β Καρδιολογικής Κλινικής Κλινικής

• Τα τελευταία τέσσερα έτη έχω λάβει αµοιβή για συµµετοχή σε µελέτες, ab, ή δορυφορικά συµπόσια από

• AstraZeneca, Bayer, Sanofi, Pfizer, Vianex, MSD, Unilever, Boehringer, Novartis, Abbott, Galenica, Amgen, Specifar, Menarini, Merck, Pharmaswiss, Winmedica

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2016 European Guidelines on cardiovascular disease preventionin clinical practiceThe Sixth Joint Task Force of the European Society of Cardiology and Other Societies onCardiovascular Disease Prevention in Clinical Practice (constituted by representatives of10 societies and by invited experts).Developed with the special contribution of the European Association for CardiovascularPrevention & Rehabilitation (EACPR).

ESC Chairperson Co- ChairpersonMassimo F. Piepoli Arno W. Hoes

Task Force Members: Stefan Agewall (Norway), Christian Albus (Germany), Carlos Brotons (Spain),Alberico L. Catapano (Italy), Marie-Therese Cooney (Ireland), Ugo Corrà (Italy), Bernard Cosyns (Belgium),Christi Deaton (UK), Ian Graham (Ireland), Michael Stephen Hall (UK), F. D. Richard Hobbs (UK), Maja-Lisa Løchen (Norway), Herbert Löllgen (Germany), Pedro Marques-Vidal (Switzerland), Joep Perk (Sweden), Eva Prescott (Denmark), Josep Redon (Spain), Dimitrios J. Richter (Greece), Naveed Sattar (UK), Yvo Smulders (The Netherlands), Monica Tiberi (Italy), H. Bart van der Worp (The Netherlands), Ineke van Dis (The Netherlands), W. M. Monique Verschuren (The Netherlands)

Additional Contributor : Simone Binno (Italy)

ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.ESC entities having participated in the development of this document:Associations: European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association of Cardiovascular Imaging (EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), Heart Failure Association (HFA).Councils: Council on Cardiovascular Nursing and Allied Professions, Council for Cardiology Practice, Council on Cardiovascular Primary Care.Working Groups: Cardiovascular Pharmacotherapy

www.escardio.org/guidelines European Heart Journal 2016 - doi:10.1093/eurheartj/ehw 106

On behalf of the6th Joint TaskForce on the

CardiovascularDisease

Prevention inClinical Practice

Massimo F Piepoli3

International Federation of Sports Medicine

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Guidelines based upon the principles of teaching

Plato, 424-347 b.C.

1. What is CVD prevention2. Who needs CVD prevention3. How is CVD prevention applied4. Where should CVD prevention be offered

www.escardio.org/guidelines

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Population-approachto prevent CVD

• PreventionParadox : “ A large number ofpeople exposed to a small risk may generatemanymore cases of CVD than a smallnumber exposed to a high risk”

• Population approach is cost saving andefficient:A 10% population-widereduction in bloodcholesterol, blood pressure and smokingwould save approximately three timesmore lives than treating 40% of high-riskindividualswith a statin, three half-doseanti-hypertensivesand aspirin.

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Recommendationfor cost-effectiveprevention ofcardiovasculardisease NEWNEW

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Population-approachto prevent CVD NEWNEW

• Topics: • Levels:• Governmental restrictions• Diet and mandate

• Physical activity • Media and education• Tobacco use • Labelling and information• Alcohol abuse • Economic incentives

• Schools• Workplaces• Community Setting

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Recommendationsfor population-basedapproaches tosmoking and other tobacco use (1) NEWNEW

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Objectives

1. Outline the rationale for and methods oftotal CVD risk estimation

2. Presentdevelopments with regardto riskestimation

3. Make this accessible to the busy clinician

6th Joint task Force on the prevention of CVDin clinical practice

Why stressassessmentof totalCVD risk ?

• Multiple risk factors usually contributeto the atherosclerosis thatcauses CVD

• These risk factors interact, sometimesmultiplicatively

• Thus the aim should be to reduce totalrisk; if a target cannot be reached withone risk factor, total risk can still bereduced by trying harder with others.

• There is no reason to suppose that thisprinciple doesnotapply to allcountries

Table 1Impactof combinationsof risk

factorson 10 year risk of CVD death-Who gets the statin?

SEX AGE CHOL BP SMOK RISK%

F 60 8 120 NO ?

F 60 7 140 YES ?

M 60 6 160 NO ?

M 60 5 180 YES ?

Table 1Impactof combinationsof risk

factorson 10 year risk of CVD death-Who gets the statin?

SEX AGE CHOL BP SMOK RISK%

F 60 8 120 NO 2

F 60 7 140 YES 5

M 60 6 160 NO 8

M 60 5 180 YES 21

TheSCOREdatabase12 European cohort studies– Somewith multiple componentcohorts–Mainly population studies

In round figures:• 205,000 persons• 3 million person-yearsof observation• Over 7,000 fatal cardiovascularevents

Low, High, Very High Risk CountriesHigh risk countries : Bosnia and Herzegovina,Croatia, Czech Republic, Estonia,

Hungary, Lithuania, Montenegro, Morocco, Poland, Romania, Serbia, Slovakia andTurkey

Very high risk countries: Albania, Algeria, Armenia, Azerbaijan, Belarus,Bulgaria, Egypt, Georgia, Kazakhstan, Kyrgyzstan, Latvia, Macedonia FYR,

Moldova, Russian Federation, Syrian Arab Republic, Tajikistan, Turkmenistan,Ukraine, Uzbekistan.

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SCORESCORE chartchart: 10-year riskof fatal CVD based on thefollowing risk factors: age,sex, smoking, systolicblood pressure, totalcholesterol

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Risk categories

Very high-risk Subjects with any of the following:

• Documented CVD, clinical or unequivocal on imaging. Documented clinical CVD includes previous AMI, ACS, coronary revascularization and other arterial revascularization procedures, stroke and TIA, aortic aneurysm and PAD.Unequivocally documented CVD on imaging includes significant plaque on coronary angiography or carotid ultrasound. It does NOT include some increase in continuous imaging parameters such as intima–media thickness of the carotid artery.

• DM with target organ damage such as proteinuria or with a major risk factor suchas smoking or marked hypercholesterolaemia or marked hypertension.

• Severe CKD (GFR <30 mL/min/1.73 m 2).

• A calculated SCORE ≥10%.

High-risk Subjects with:

• Markedly elevated single risk factors, in particular cholesterol >8 mmol/L (>310 mg/dL) (e.g. in familial hypercholesterolaemia) or BP ≥180/110 mmHg.

• Most other people with DM (with the exception of young people with type 1 DM and without major risk factors that may be at low or moderate risk).

• Moderate CKD (GFR 30–59 mL/min/1.73 m 2).

• A calculated SCORE ≥5% and <10%.

SCORE is ≥1% and <5% at 10 years. Many middleaged subjects belong to this Moderate-risk

category.

Low-risk SCORE <1%.

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And what about the other 100+ CV risk factors?

• hs-CRP ?• Lp(a) ?• stress ?• body mass index? waist-hip ratio ?• intima-media thickness?• coronary calcium score?• …• etcetera

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Examples of risk modifiers that(1) have risk reclassificationpotential and (2) are feasible

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Risk Factor Targets

* Smoking: No exposure to tobacco in any form.* Diet : Low in saturated fat with a focus on wholegrain

products, vegetables, fruit and fish.• Physical activity: At least 150 minutes a week of

moderate aerobic PA (30 minutes for 5 days/week) or 75minutes a week of vigorous aerobic PA (15 minutes for 5days/week) or a combination thereof.

• Body weight: BMI 20–25 kg/m2.• Waist circumference:

<94 cm (men)or <80 cm (women).* HbA1c in patients with DM : < 7.0% (< 53 mmol/mol)

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Επιπρόσθετα στοιχεία στην αξιολόγηση του καρδιαγγειακού κινδύνου

Piepoli MF, Hoes AW, Agewall S, et al. Eur Heart J. 2016. pii: ehw106. [Epub ahead of print]

• Οι γυναίκες έχουν γενικά χαµηλότερο κίνδυνο από τους άνδρες, αλλά ο κίνδυνός τους διαφέρει κατά µια δεκαετία – δεν εξαλείφεται.

• Η προσέγγιση του συνολικού καρδιαγγειακού κινδύνου επιτρέπει ελαστικότητα στους χειρισµούς: αν δεν είναι εφικτή η βέλτιστη ρύθµιση ενός παράγοντα κινδύνου µπορεί να γίνει εντατικότερη προσπάθεια στους άλλους παράγοντες ώστε να περιορισθεί ο κίνδυνος.

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Υπολογισµός της «ηλικίας κινδύνου» (“risk age”)

Piepoli MF, Hoes AW, Agewall S, et al. Eur Heart J. 2016. pii: ehw106. [Epub ahead of print]

Σε νεαρής ηλικίας άτοµα ο χαµηλός απόλυτος κίνδυνος µπορεί να συγκαλύψει έναν αυξηµένο σχετικό κίνδυνο και ο υπολογισµός της «ηλικίας κινδύνου» (“risk age”) µπορεί να βοηθήσει για την υιοθέτηση επιθετικών µέτρων πρόληψης.

BPgoals:Aneverendingstory

• BPgoalsisoneof thekeyissuestoreducemorbidityandmortalityassociatedtoHTN

• FewstudieshavefixedBPgoalsat differentlevelstoaddressthequestion

• Meta-analysishavetriedtoanswertheissuepoolingstudieswithdifferentselectioncriteriaandmethodologicalapproach

• In theabsenceofgroundedinformation,guidelines(NICE,CEP,ESH-ESC,JNC8,ISH-ASH)recommendationsaremainlybasedinexpertopinions

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WhatisnewinHypertension:Bloodpressuregoals(I)

• SBPshouldbeloweredto< 140 mmHg(andDBPto< 90mmHg)inall treatedhypertensivepatients< 60 yearsold.(I,B)

• Inpatients> 60 yearsoldwithSBP≥ 160 mmHg,thetreatmentgoalisto reduceSBPtobetween150 and140mmHg.(I,B)

• In fit patients<80 yearsold, a targetSBP< 140 mmHgmaybeconsideredif treatmentiswelltolerated.Insomeofthesepatientsa targetSBP<120 mmHgmaybeconsideredwhentheyareat (very)highriskandcantoleratemultipleantihypertensivedrugs(IIb,B)

Eur Heart J 2016www.escardio.org/guidelines doi:10.1093/eurheartj/ehw106

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WhatisnewinHypertension:Bloodpressuregoals(II)

• In individuals>80 yearsandwithinitialSBP≥160 mmHg,itisrecommendedto reduceSBPtobetween150 and140mmHgprovidedtheyareingoodphysicalandmentalconditions(I,B)

• In frailelderlypatients,it shouldbeconsideredtobecarefulintermsoftreatmentintensity(e.g.numberofantihypertensivedrugs)andBPtargets,andclinicaleffectsof treatmentshouldbecarefullymonitored(IIa,B)

Eur Heart J 2016www.escardio.org/guidelines doi:10.1093/eurheartj/ehw106

Benefitsandriskoneventsofmorevs.lessBPreduction

BPmmHg Primary All-cause CV CHD Stroke Heartoutcome mortality mortality disease Failure

ACCORD1 120 vs -12% +7% +6% -13% -41% -16%(diabetes) 140

(119-133)

SPRINT2 120 vs -25% -27% -43% -17% -11% -38%(highrisk) 140 (121-

136)

SPS33 130 vs -5% +12% -14% -12% -19%(post-stroke) 140 (127-

138 )

META- AroundANALYSIS 1304,5

• Independentof the levelof CVrisk1. ACCORDStudyGroup.N EnglJMed 2010;362:1575-158622. TheSprintResearchGroup.NEJM2015;373:2106-2116 • ByloweringSBPa fewmmHg belowvs.above3. TheSPS3StudyGroup.Lancet2013;382:507-515 130 mmHg absoluteriskreductionbecome4. Thomopoulos,Parati, Zanchetti.JHypertens2016;34:613-622 smaller5. Thomopoulos,Parati, Zanchetti.JHypertens2014;32;2285-2295

Today:Recommendationscomefromabove

“…onesizefitsall…”

BPgoals,theneverendingstory:Episodeon2016

FutureACCORD SPRINT SPS3 Meta- approach

analysis?

Tomorrow:Recommendationswillcomefrombottom-up

“…movingtopersonalfit…”

BPgoals:Whatshouldbenext?

• BPgoalsisoneof thekeyissuestoreducemorbidityandmortalityassociatedtoHTN

• ThebenefitofmorereducedBPlevelspaya tollderivedfromexcessivehypotension

• SearchingformarkersofCVfragilitycanhelptodecidetailoredgoals

• Startingapproachcouldbetheindividualanalysisof thealreadyexistingdatafromclinicaltrials

• BigdatafromEHRcanalsocontributeto thisrelevantissue

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Επαναξιολόγηση του στόχου για την LDL-C σε

ασθενείς υψηλού και πολύ υψηλού

καρδιαγγειακού κινδύνου

Piepoli MF, Hoes AW, Agewall S, et al. Eur Heart J. 2016. pii: ehw106. [Epub ahead of print]

Δυσλιπιδαιµία

LDL-C is a major causal factor foratheroscleroticCVD

LDL-C: primary risk factor in CHD and causative for development of coronaryatherosclerosis6

Lipid disorders 1

Hypertension 1 (LDL↑, HDL↓, TG↑)

Metabolic syndrome 2

Smoking, physicalinactivity 1

Type 2 diabetes 1

Prior CVevent/manifest Increased High CRP, 4 chronic

atherosclerosis 3 CV risk kidney disease 5

Age, ethnicity, gender, Obesity 1

family history/geneticvariations 1

Genetic evidence supports LDL-C as a riskfactor for CV events

54.5% reduction in CHD riskper 1mmol/L lower LDL-C

30%

Genetically lower LDL-CPCSK9 46L rs11591147

reduction

20%NPC1L1 LDL-C score

ABCG5/8 HMGCR LDL-C scorers4299376 LDLR rs2228671

CHD

PCSK9 LDLR rs6511720

Proportional

10% rs11206510 CombinedNPC1L1 & HMGCR LDL-C score

HMGCR rs12916PCSK9 rs2479409 HMGCR LDL-C score

NPC1L1 LDL-C scoreNPC1L1 rs217386

0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0

Absolute magnitude of lower LDL-C (mg/dL)

Ference et al. J Am Coll Cardiol 2012;60:2631–2639. Ference et al. J Am Coll Cardiol 2015;65:1552–1561.

Pharmacologicalevidence shows lower LDL-Clevels are associated with lower CV event rates

Treatment group

Control group Primary prevention

%Secondaryprevention

Events

LDL-C (mg/dL)Besseling et al. Drugs 2013;73:293–301.

Clinical benefit of lower LDL is determined byabsolute exposure to lower LDL

54.5% reduction in CHDrisk for each 1mmol/L

30% (38mg/dL) lower LDL-C

Genetically lower LDL-Cscale) PCSK9 46L

reduction rs11591147(log

20%risk NPC1L1 LDL-C score 17.2% reduction in

HMGCR LDL-C score A to Z GISSI-P CHD risk for eachCHD LDLR

rs2228671 Pharmacologically 1mmol/L (38mg/dL)Proportionalin LDLR lower LDL-C

rs6511720 lower LDL-C10% ABCG5/8 PCSK9

rs4299376 Combined NPC1L1 &rs11206510HMGCR LDL-C score

ALLHAT-LLTHMGCR rs12916HMGCR LDL-C scorePCSK9 rs2479409 IMPROVE-ITNPC1L1 LDL-C score

NPC1L1 rs217386 SEARCH

0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0

Lower LDL-C (mg/dL)

Ference et al. J Am Coll Cardiol 2015;65:1552–1561.

Very potent LDL lowering is associatedwith atherosclerosisregression

2%

1%

PAV0%Δ

Mean % atheroma-1% volume (PAV)

95% CI

-2%

On-treatmentLDL-C(mg/dL)

Nicholls et al. JAMA 2007;297:499–508.

Greater reductions in LDL-C levels are associatedwith greater reductions in CV event rates

50%

(SE)40%

Rate

30%Eventin CTT-meta-analysis

20%

Reduction10%

IMPROVE-IT0%

Proportional 19 39 58 77

Reduction in LDL-C (mg/dL)

CTTC. Lancet 2005;366:1267–1278. CTTC. Lancet 2010;376:1670–1681.Cannon et al. N Engl J Med 2015;372:2387– 2397.

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Υπολιπιδαιµικά Φάρµακα▪ Στατίνες: Ελαττώνουν LDL-C µε παράλληλο τεκµηριωµένο καρδιαγγειακό όφελος

– Φάρµακα πρώτης εκλογής.

▪ Εζετιµίµπη: µονοθεραπεία µόνο επί δυσανεξίας σε στατίνες.

▪ Ιοντοαναταλλακτικές ρητίνες: πτωχή ανοχή ασθενών, αύξηση τριγλυκεριδίων – δεν προτείνονται ως χρήση ρουτίνας.

▪ Φιµπράτες: κυρίως για ελάττωση των τριγλυκεριδίων - δεν προτείνονται ως χρήση ρουτίνας.

▪ Νικοτινικό Οξύ: κυρίως για ελάττωση των τριγλυκεριδίων, αύξηση της HDL-C - δεν προτείνεται ως χρήση ρουτίνας.

▪ Αναστολείς της PCSK-9 : ελάττωση της LDL-C κατά ~ 60% - εκκρεµούν αποτελέσµατα µελετών κλινικών συµβαµάτων .

Piepoli MF, Hoes AW, Agewall S, et al. Eur Heart J. 2016. pii: ehw106. [Epub ahead of print]

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Συνδυασµοί Φαρµάκων▪ Στατίνη + Εζετιµίµπη: ο µόνος συνδυασµός που έχει αποδείξει

καρδιαγγειακό όφελος σε διπλά-τυφλή τυχαιοποιηµένη µελέτη (σε ασθενείς υψηλού - πολύ υψηλού κινδύνου).

▪ Στατίνη + Νικοτινικό οξύ: συχνά επεισόδια εξάψεων, δεν έχει αποδείξει καρδιαγγειακό όφελος.

▪ Στατίνη + Φαινοφιµπράτη: περιορισµένο κλινικό όφελος σε υποκατηγορίες ασθενών µε αυξηµένα τριγλυκερίδια και/ή χαµηλή HDL-C.

Piepoli MF, Hoes AW, Agewall S, et al. Eur Heart J. 2016. pii: ehw106. [Epub ahead of print]

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Η θέση της Εζετιµίµπης στις κατευθυντήριες οδηγίες καρδιαγγειακής πρόληψης 2016

1. Piepoli MF, Hoes AW, Agewall S, et al. Eur Heart J. 2016. pii: ehw106. [Epub ahead of print] 2. Cannon CP, Blazing MA, Giugliano RP, et al. Ν Engl J Med. 2015;372:2387–2397. 3. Sharp Collaborative Group. Am Heart J. 2010;160:p785– 794.e10

▪ Η προσθήκη εζετιµίµπης σε θεραπεία µε στατίνη επιφέρει καρδιαγγειακό όφελος συµβατό µε τα δεδοµένα της CTT µετα-ανάλυσης.1

▪ Συνδυαστική θεραπεία στατίνης και εζετιµίµπης προτείνεται σε ασθενείς υψηλού και πολύ υψηλού κινδύνου που δεν πετυχαίνουν το στόχο µε µονοθεραπεία µε µέγιστη ανεκτή δοσολογία στατίνης.2

▪ Ασθενείς µε ΧΝΝ: Η θεραπεία µε συνδυασµό στατίνης µε εζετιµίµπη έχει επιδείξει όφελος στα καρδιαγγειακά συµβάµατα.3

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Αλγόριθµος Αντιµετώπισης

Στατίνη στη µέγιστη ανεκτή δόση

Ezetimibe

PCSK9-i

Δυσανεξία στη στατίνη Ezetimibe

& απεκκριτικά χολικών οξέων (κατ’ επιλόγη)

Piepoli MF, Hoes AW, Agewall S, et al. Eur Heart J. 2016. pii: ehw106. [Epub ahead of print]

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European Heart Journal doi:10.1093/eurheartj/ehw272

Prediction is very difficult,especially if it’sabout the

future

Attributed to Nils Bohr