The Fourth IAS-OSLA Course on “Lipid Metabolism and ...

New Guidelines in Dyslipidemia Management Dr. Khalid Al-Waili, MD, FRCPC, DABCL

Senior Consultant Medical Biochemist & LipidologistSultan Qaboos University Hospital

The Fourth IAS-OSLA Course on “Lipid Metabolism and Cardiovascular Risk”Muscat, Oman, February 2018

Outline

• HistoryofU.S.DyslipidaemiaGuidelineDevelopment

• NewACC/AHAcholesteroltreatmentguidelinepublishedNov2013

• NewNICEGuidelines2014

• GuidelinesforPatientswithCKD

• NewESC/EASGuidelines2016

• NewMiddleEastGuidelines2016

• 2017UpdateofESC:EASonPCSK9Inhibitors

History of U.S. Dyslipidemia Guideline Development

ATPI1

• ExclusivefocusonLDL-C

ATPII2

• Riskassessmentguidestherapy

ATPIII3

• LowerLDL-Cthresholdfortherapyinitiationinhighriskpatients

ATPIIIUpdate4

• LowerLDL-Cthresholdfortherapyinitiationinveryhighriskpatients

ACC/AHAGuidelines5

• Useofmoderate- orhigh-intensitystatintherapyforpatientsacross4majorgroupsatriskforASCVD*

1988 1993 2001 2004 2013

*ASCVD,AtheroscleroticCardiovascularDisease

1.NCEP.ArchInternMed.1988;148:36-69.2.NCEPATPII.Circulation .1994;89:1333-445.3.NCEPATPIII.Circulation.2002;106:3143.

4.GrundySM,etal.Circulation.2004;110:227-239..5.StoneNJ,etal.JAmColl Cardiol.2013:doi:10.1016/j.jacc.2013.11.002.Availableat:http://content.onlinejacc.org/article.aspx?articleid=1770217.AccessedNovember13,2013.

NCEP ATP III Updated Report: LDL-C Goals Based on Risk Category

LowerRisk ModerateRisk ModeratelyHigh-Risk High-Risk VeryHigh-Risk

Grundyetal.Circulation.2004;110:227-239.

LDL-CGoal<160mg/dL

LDL-CGoal<130mg/dL

LDL-CGoal<130mg/dL

LDL-CGoal<100mg/dL

LDL-CGoal<100mg/dL

IncreasingRisk

OptionalGoal<100mg/dL

OptionalGoal<70mg/dL

New ACC/AHA cholesterol treatment guideline published Nov 2013

AHA,AmericanHeartAssociationACC,AmericanCollegeofCardiology

What is new in the 2013 Guideline?

• Identificationof4majorstatinbenefitgroups

• Shiftawayfromtreattotargetapproach

• Definitionsofstatinintensityprovided

• Newglobalriskassessmenttoolforprimaryprevention

• Additionofnon-statindrugtherapytostatinstofurtherdecreaseASCVDriskaddressed

StoneNJ,etal.JAmCollCardiol.2013:doi:10.1016/j.jacc.2013.11.002.Availableat:http://content.onlinejacc.org/article.aspx?articleid=1770217.AccessedNovember13,2013.

Major Statin Benefit Groups

ASCVD LDL(mg/dL) DM(40 – 75years) 10yearriskASCVD≥7.5%

1 Yes - - -

2 - >190 - -

3 No 70– 189 Yes -

4 No 70– 189 No Yes

ASCVD,AtheroscleroticCardiovascularDisease

Group 1: Patients with clinical ASCVD

Guideline Direction “High-intensity statin therapy should be initiated or continued as first-line

therapy in women and men ≤75 years of age who have clinical ASCVD, unless contraindicated.”*

*ACC/AHA Guideline 2013/p 22/secondary prevention #1

GuidelineDirection“Adults≥21yearsofagewithprimaryLDL–C≥190mg/dL (≥4.9mmol/L)shouldbetreatedwithstatintherapy(10-yearASCVDriskestimationisnotrequired):Usehigh-intensitystatintherapyunlesscontraindicated.”*

*ACC/AHAGuideline2013/p22/primaryprevention≥21/#2

Group 2: Patients with primary elevations of LDL–C ≥190 mg/dL (≥4.9 mmol/L)

GuidelineDirection“Moderate-intensitystatintherapyshouldbeinitiatedorcontinuedforadults40to75yearsofagewithdiabetesmellitus.High-intensitystatintherapyisreasonableforadults40to75yearsofagewithdiabetesmellituswitha≥7.5%estimated10-yearASCVDriskunlesscontraindicated.”*

*ACC/AHAGuideline2013/p23/primarypreventionwithdiabetes/#1,2

Group 3: Patients with diabetes aged 40-75 years with LDL 70-189 mg/dL (1.8-4.9 mmol/L) and without clinical ASCVD

Group 3: Patients with diabetes aged 40-75 years with LDL 70-189 mg/dL (1.8-4.9 mmol/L) and without clinical ASCVD

*ExpectedtoreduceLDL-Cby≥50%†ExpectedtoreduceLDL-Cby30to<50% StoneNJ,etal.JAmCollCardiol2013Nov7.Epubaheadofprint

Age40–75years

ASCVDrisk≥7.5%

High-intensitystatin*

ASCVDrisk<7.5%

Moderate-intensitystatin†

Considerstatinindividually

No

Yes

Estimate10-yearASCVDriskwithPooledCohortEquations

Type1or2diabetes

GuidelineDirection“Adults40to75yearsofagewithLDL–C70to189mg/dL (1.8to4.9mmol/L),withoutclinicalASCVDordiabetesandanestimated10-yearASCVDrisk≥7.5%shouldbetreatedwithmoderate- tohigh-intensitystatintherapy.”*

*ACC/AHAGuideline2013/p23/PrimaryPreventionw/oDiabetes/#2

Group 4: Patients without clinical ASCVD or diabetes with LDL–C 70 to 189 mg/dL (1.8 to 4.9 mmol/L) and estimated 10-year ASCVD risk

≥7.5%

Guidelines use new ASCVD risk calculator

Risk factorSex (male or female)Age (years)Race(African-American or White/other)Total cholesterol (mg/dL)HDL-C (mg/dL)SBP (mmHg)Treatment for high BP (yes or no)Diabetes (yes or no)Smoker (yes or no)

10-yearrisk(%)ofASCVD(non-fatalMI,CHDdeath,orfatal/non-fatalstroke)iscalculatedfromsimpleparameters:

GoffDCJr,etal.JAmCollCardiol2013Nov7.Epubaheadofprint

BP,bloodpressureHDL-C,highdensitylipoprotein-cholesterolSBP,Systolicbloodpressure

10yearriskandLifetimeRisk

Guidelines specify statin doses

High-intensity ↓ LDL-C by ≥50%

Moderate-intensity ↓ LDL-C by 30–50%

Low-intensity ↓ LDL-C by <30%*

Atorvastatin (40)–80 mg 10–20 mg –Rosuvastatin 20–40 mg 5–10 mg –

Simvastatin – 20–40 mg 10 mg

Pravastatin – 40–80 mg 10–20 mg

Lovastatin – 40 mg 20 mg

Fluvastatin XL – 80 mg –

Fluvastatin – 40 mg bid 20–40 mg

Pitvastatin – 2–4 mg 1 mg

Bold: Statins and doses evaluated in RCTsItalics: Statins and doses approved by US FDA but not tested in RCTs reviewed*Should be used in patients unable to tolerate moderate-to high-intensity therapyAsian ancestry may modify the statin dose prescribed

Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead of printReproduced with kind permission from American College of Cardiology Jan 2014

Patients outside the four benefit groups:Consider statin therapy individually

1.StoneNJ,etal.JAmCollCardiol2013Nov7.Epubaheadofprint2.GoffDCJr,etal.JAmCollCardiol2013Nov7.Epubaheadofprint

Exceptions:1

NYHA class II–IV HF or maintenance hemodialysis –

insufficient evidence

LDL-C >160 mg/dL(~4.0mmol/L)

Other genetic hyperlipidemias1

Elevated lifetime ASCVD

risk1

Family history of ASCVD1

C-reactive protein >2 mg/L(~19nmol/L)

Ankle-brachial index <0.9High coronary artery calcium (CAC)

score1

Carotid intimal-medial thickness not recommended2

HF,heartfailure

Statinscanbeconsideredforpatientswith10-yearASCVDrisk<7.5%basedonadditionalfactors1

Individualdiscussionofbenefitsandrisks1

A New Perspective on LDL–C and/or Non-HDL–C Treatment Goals

StoneNJ,etal.JAmCollCardiol.2013:doi:10.1016/j.jacc.2013.11.002.Availableat:

http://content.onlinejacc.org/article.aspx?articleid=1770217.AccessedNovember13,2013.

NorecommendationsfororagainstspecificLDL-Candnon-HDL-Cgoalsforprimaryorsecondaryprevention

Lack of RCT evidence to support continued use of specific LDL–C and/or non-HDL–C treatment targets

Summary: 2013 Guideline Recommendations for Statin Therapy

ClinicalASCVD

•High-Intensitystatin(age≤75years)

•Moderate-intensitystatinif>75yearsornotacandidateforhigh-intensitystatin

LDL-C≥190mg/dL

•High-intensitystatin

•Moderate-intensitystatinifnotacandidateforhigh-intensitystatin

Diabetes;age40-75years*

•Moderate-intensitystatin

•High-intensitystatinifestimated10yearASCVDrisk≥7.5%

Estimated10-yrASCVDrisk≥7.5%†;age40-75years*

•Moderate- tohigh-intensitystatin

ASCVDStatinBenefitGroupsHearthealthylifestylehabitsarethefoundationofASCVDprevention

ASCVDpreventionbenefitofstatintherapymaybelessclearinothergroups.ConsideradditionalfactorsinfluencingASCVDrisk,potentialASCVDriskbenefitsandadverseeffects,drug-druginteractions,andpatientpreferencesforstatintreatment.*WithLDL-Cof70-189mg/dL† EstimatedusingthePooledCohortRiskAssessmentEquations

StoneNJ,etal.JAmColl Cardiol.2013:doi:10.1016/j.jacc.2013.11.002.Availableat:


Safety Considerations

StoneNJ,etal.JAmCollCardiol.JAmCollCardiol.2013:doi:10.1016/j.jacc.2013.11.002.Availableat:


• RoutinemonitoringofCKnotrecommended•Measurementmaybeusefulatbaselineinthoseatincreasedriskofmuscleeventsandinpatientswithmusclesymptoms

•Guidelineprovidesrecommendationsformanagementofmusclesymptoms

CreatinineKinase (CK)

•Baselinemeasurementrecommended•Routinehepaticmonitoringnotrecommendedunlesssymptomssuggestinghepatotoxicity arepresent

Alanine Transaminase (ALT)

• Statinsmodestlyincreaseriskoftype-IIdiabetesinpatientswithriskfactorsfordiabetes•PotentialforASCVDriskreductionbenefitoutweighsriskofdiabetesinallbutlowestriskindividuals• Evaluatefornewonsetdiabetesaccordingtocurrentdiabetesscreeningguidelines

Type-2Diabetes

NICE July 2014

Key priorities for implementation – NICE 2014

Identifying and assessing cardiovascular disease (CVD) risk

* For the primary prevention of CVD in primary care, use a systematic strategy to identify people who are likely to be at high risk. [2008, amended 2014]

* Prioritize people for a full formal risk assessment if their estimated 10-year risk of CVD is 10% or more. [2008, amended 2014]

* Use the QRISK2 risk assessment tool to assess CVD risk for the primary prevention of CVD in people up to and including age 84 years. [new 2014]

* Do not use a risk assessment tool to assess CVD risk in people with an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 and/or albuminuria. These people are at increased risk of CVD. [new 2014]

Key priorities for implementation

Lipid modification therapy for the primary and secondary prevention of CVD

* Before starting lipid modification therapy for the primary prevention of CVD, take at least 1 lipid sample to measure a full lipid profile. This should include measurement of TC, HDL, non-HDL and triglyceride concentrations. A fasting sample is not needed. [new 2014]

* Offer atorvastatin 20 mg for the primary prevention of CVD to people who have a 10% or greater 10-year risk of developing CVD. Estimate the level of risk using the QRISK2 assessment tool. [new 2014]

* Start statin treatment in people with CVD with atorvastatin 80 mg. Use a lower dose of atorvastatin if any of the following apply:* potential drug interactions* high risk of adverse effects* patient preference [new 2014]

Key priorities for implementationLipid modification therapy for the primary and secondary prevention of CVD

* Measure TC, HDL and non-HDL in all people who have been started on high-intensity statin treatment at 3 months of treatment and aim for > 40% reduction in non-HDL cholesterol. If a greater than 40% reduction in non-HDL cholesterol is not achieved:* discuss adherence and timing of dose* optimize adherence to diet and lifestyle measures* consider increasing dose if started on less than atorvastatin 80 mg and the person is judged to be at higher

risk because of comorbidities, risk score or using clinical judgment. [new 2014]

Grouping of Statins as per NICE

1 20%–30%: low intensity.2 31%–40%: medium intensity.3 Above 40%: high intensity.4 Advice from the MHRA: there is an increased risk of myopathy associated with high-dose (80 mg) simvastatin. The 80 mg dose should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.

Reduction in LDL-C

Dose (mg/day) 5 10 20 40 80

Fluvastatin – – 21%1 27%1 33%2

Pravastatin – 20%1 24%1 29%1 –

Simvastatin – 27%1 32%2 37%2 42%3,4

Atorvastatin – 37%2 43%3 49%3 55%3

Rosuvastatin 38%2 43%3 48%3 53%3 –

Be Aware

NICE 2014 - Do not delay in 2ndary prevention

NICE 2014 - NODM

NICE 2014 - T1DM

NICE 2014 - T2DM

Guidelines for Patients with CKD

* ACC/AHA did not address specific recommendations for patients with CKD * Appendix of Evidence Statements includes the following statement regarding use of atorvastatin

for secondary prevention in patients with CKD, based on results of TNT:‒ In adults with CHD/CVD and chronic kidney disease (CKD) (excluding hemodialysis), fixed high-intensity

statin treatment (atorvastatin 80 mg) that achieved a mean LDL–C of 79 mg/dL reduced CHD/CVD events more than fixed lower-dose statin treatment that achieved a mean LDL–C of 99 mg/dL (2.6 mmol/L). In this trial, the mean LDL–C levels achieved differed by 20 mg/dL (0.52 mmol/L), or 20% between the 2 groups.

* However, KDIGO (Kidney Disease Improving Global Outcomes) 2013 guidelines recommend statin therapy for CKD patients ≥50 years of age and patients 18-49 years of age with known coronary disease, diabetes, prior ischemic stroke, or 10-year CHD risk >10%* Once appropriate therapy has been selected, measuring LDL-C is not recommended unless

results would change management* Escalation to reach specific LDL-C goals is no longer recommended

NICE 2014 - CKD

Adaptedfromreference:NationalKidneyFoundation.KDOQIclinicalpracticeguidelinesandclinicalpracticerecommendations fordiabetesandchronickidneydisease.AmJKidneyDis.2007;49(suppl2);S1-S179.

35

JOINT ESC GUIDELINES

2016 European Guidelines on cardiovasculardisease prevention in clinical practiceThe Sixth Joint Task Force of the European Society of Cardiologyand Other Societies on Cardiovascular Disease Prevention inClinical Practice (constituted by representatives of 10 societiesand by invited experts)

Developed with the special contribution of the European Associationfor Cardiovascular Prevention & Rehabilitation (EACPR)

Authors/Task Force Members: Massimo F. Piepoli* (Chairperson) (Italy),Arno W. Hoes* (Co-Chairperson) (The Netherlands), Stefan Agewall (Norway)1,Christian Albus (Germany)9, Carlos Brotons (Spain)10, Alberico L. Catapano (Italy)3,Marie-Therese Cooney (Ireland)1, Ugo Corra (Italy)1, Bernard Cosyns (Belgium)1,Christi Deaton (UK)1, Ian Graham (Ireland)1, Michael Stephen Hall (UK)7,F. D. Richard Hobbs (UK)10, Maja-Lisa Løchen (Norway)1, Herbert Lollgen(Germany)8, Pedro Marques-Vidal (Switzerland)1, Joep Perk (Sweden)1, Eva Prescott(Denmark)1, Josep Redon (Spain)5, Dimitrios J. Richter (Greece)1, Naveed Sattar(UK)2, Yvo Smulders (The Netherlands)1, Monica Tiberi (Italy)1,H. Bart van der Worp (The Netherlands)6, Ineke van Dis (The Netherlands)4,W. M. Monique Verschuren (The Netherlands)1

Additional Contributor: Simone Binno (Italy)

* Corresponding authors: Massimo F. Piepoli, Heart Failure Unit, Cardiology Department, Polichirurgico Hospital G. Da Saliceto, Cantone Del Cristo, 29121 Piacenza, Emilia Romagna,Italy, Tel: +39 0523 30 32 17, Fax: +39 0523 30 32 20, E-mail: [email protected], [email protected].

Arno W. Hoes, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85500 (HP Str. 6.131), 3508 GA Utrecht, The Netherlands,Tel: +31 88 756 8193, Fax: +31 88 756 8099, E-mail: [email protected].

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 ofPercutaneous 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

The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of theESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to OxfordUniversity Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.

Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available atthe time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic ortherapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate andaccurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nordo the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competentpublic health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also thehealth professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

& The European Society of Cardiology 2016. All rights reserved. For permissions please email: [email protected].

European Heart Journaldoi:10.1093/eurheartj/ehw106

European Heart Journal Advance Access published May 23, 2016

by guest on July 21, 2016http://eurheartj.oxfordjournals.org/

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3a.7 Lipid controlKey messages† Elevated levels of plasma LDL-C are causal to atherosclerosis.† Reduction of LDL-C decreases CV events.† Low HDL-C is associated with increased CV risk, but man-

oeuvres to increase HDL-C have not been associated with a de-creased CV risk.

† Lifestyle and dietary changes are recommended for all.† Total CV risk should guide the intensity of the intervention.† Total cholesterol and HDL-C are adequately measured on non-

fasting samples, thus allowing non-HDL-C to be derived.

Recommendations for lipid control

Recommendations d e Classa Levelb Ref c

In patients at VERY HIGH CV risk, an LDL-C goal <1.8 mmol/L (<70 mg/dL), or a reduction of at least 50% if the baseline is between 1.8 and 3.5 mmol/L (70 and 135 mg/dL) is recommended.f

I B 350–353

In patients at HIGH CV risk, an LDL-C goal <2.6 mmol/L (<100 mg/dL), or a reduction of at least 50% if the baseline is between 2.6 and 5.1 mmol/L (100 and200 mg/dL) is recommended.

I B 350–353

In the remaining patients on LDL-C lowering treatment, an LDL-C goal <3.0 mmol/L (<115 mg/dL) should be considered.

IIa C 350–353

CV ¼ cardiovascular; HDL-C ¼ high-density lipoprotein cholesterol;LDL-C ¼ low-density lipoprotein cholesterol.aClass of recommendation.bLevel of evidence.cReference(s) supporting recommendations.dNon-HDL-C is a reasonable and practical alternative target because it does notrequire fasting. Non HDL-C secondary targets of ,2.6, ,3.3 and ,3.8 mmol/L(,100, ,130 and ,145 mg/dL) are recommended for very high, high and low tomoderate risk subjects, respectively See section 3a.7.10 for more details.eA view was expressed that primary care physicians might prefer a single LDL-Cgoal of 2.6 mmol/L (100 mg/dL). While accepting the simplicity of this approachand that it could be useful in some settings, there is better scientific support for thethree targets matched to level of risk.fThis is the general recommendation for those at very high-risk. It should be notedthat the evidence for patients with CKD is less strong.

3a.7.1 IntroductionThe crucial role of dyslipidaemia, especially hypercholesterolaemia,in the development of CVD is documented beyond any doubt bygenetic, pathology, observational and intervention studies.

In blood plasma, lipids such as cholesterol and triglycerides circu-late as lipoproteins in association with various proteins (apolipopro-teins). The main carrier of cholesterol in plasma (LDL-C) isatherogenic. The role of triglyceride-rich lipoproteins is currentlyunder active investigation: chylomicrons and large very-low-densitylipoproteins (VLDLs) appear not to be atherogenic, but very highconcentrations of these triglyceride-rich lipoproteins can cause pan-creatitis. Remnant lipoproteins [total cholesterol 2 (LDL-C +

HDL-C)] have recently been identified in Mendelian randomizationstudies as pro-atherogenic lipoproteins.

3a.7.2 Total and low-density lipoprotein cholesterolMost cholesterol is normally carried in LDL-C. Over a wide range ofplasma cholesterol concentrations, there is a strong and gradedpositive association between total as well as LDL-C and risk ofCVD.354 This association applies to men and women, and to thosewithout CVD as well as with established CVD.

The evidence that reducing plasma LDL-C reduces CVD risk isunequivocal; the results of epidemiological studies and trials withand without statins using angiographic or clinical endpoints confirmthat the reduction of LDL-C is of prime concern in the prevention ofCVD.38

Meta-analyses of many statin trials show a dose-dependent rela-tive reduction in CVD with LDL-C lowering. Every 1.0 mmol/L re-duction in LDL-C is associated with a corresponding 20–25%reduction in CVD mortality and non-fatal MI.350

3a.7.3 Apolipoprotein BApolipoprotein B (apoB; the main apoprotein of atherogeniclipoproteins) levels have also been measured in outcome studiesin parallel with LDL-C.355 Based on the available evidence, it appearsthat apoB is a similar risk marker to LDL-C.356 Also, there appearsto be less laboratory error in the determination of apoB thanLDL-C, particularly in patients with marked hypertriglyceridaemia[.3.4 mmol/L (.300 mg/dL)], but there is no evidence that apoBis a better predictor of CVD than LDL-C.357

3a.7.4 TriglyceridesHypertriglyceridaemia is a significant independent CVD risk factor,but the association is far weaker than for hypercholesterolaemia.358

The risk is associated more strongly with moderate than with verysevere hypertriglyceridaemia [.10 mmol/L (.!900 mg/dL)],which is a risk factor for pancreatitis. There are, however, no rando-mized trials to provide sufficient evidence to derive target levels fortriglycerides. Meta-analyses suggest that targeting triglycerides mayreduce CVD in specific subgroups with high triglycerides and lowHDL-C. At present, fasting triglycerides .1.7 mmol/L (.

!150 mg/dL) continue to be considered a marker of increasedrisk, but concentrations ≤1.7 mmol/L are not evidence-based tar-get levels for therapy.

3a.7.5 High-density lipoprotein cholesterolLow HDL-C is independently associated with higher CVD risk.359

Low HDL-C may even rival hypercholesterolaemia (due to highconcentrations of LDL-C) as a risk factor for CAD.360 The combin-ation of moderately elevated triglycerides and low concentrationsof HDL-C is very common in patients with type 2 DM, abdominalobesity and insulin resistance and in those who are physicallyinactive. This lipid pattern is also characterized by the presenceof small, dense, atherogenic LDL particles. An HDL-C level,1.0 mmol/L (,40 mg/dL) in men and ,1.2 mmol/L (,45 mg/dL) in women may be regarded as a marker of increased risk. RecentMendelian randomization studies, however, cast doubt on the causalrole of HDL-C in CVD.361 Physical activity and other lifestyle fac-tors, rather than drug treatment, remain important means of in-creasing HDL-C levels.

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– High-risk persons (calculated SCORE ≥5% and <10%):qualify for intensive lifestyle advice and may be candidates fordrug treatment.

– Very-high-risk persons (calculated SCORE ≥10%):drug treatment is more frequently required. In persons .60years of age, these thresholds should be interpreted more le-niently, because their age-specific risk is normally aroundthese levels, even when other CV risk factor levels are ‘nor-mal’. In particular, uncritical initiation of drug treatments ofall elderly with risks greater than the 10% threshold shouldbe discouraged.

Use of the risk charts should be qualified by knowledge of the fol-lowing aspects:

† The charts assist in risk estimation but must be interpreted in lightof the clinician’s knowledge and experience and in view of the fac-tors that may modify the calculated risk (see below).

† Relative risks may be high in young persons, even if 10 year abso-lute risks are low, because events usually occur later in life. Therelative risk chart or estimating risk age may be helpful in identi-fying and counselling such persons.

† The lower risk in women is explained by the fact that risk is de-ferred by 10 years—the risk of a 60-year-old woman is similar tothat of a 50-year-old man. Ultimately, more women than men dieof CVD.

† The charts may be used to give some indication of the effects ofreducing risk factors, given that there will be a time lag before riskreduces and that the results of RCTs in general give better esti-mates of the benefits of interventions. Those who stop smokinggenerally halve their risk.

2.3.6 Modifiers of calculated total cardiovascular riskApart from the conventional major CV risk factors included in therisk charts, there are other risk factors that could be relevant for as-sessing total CVD risk. The Task Force recommends additional riskfactor assessment if such a risk factor improves risk classification[e.g. by calculation of a net reclassification index (NRI)] and if the as-sessment is feasible in daily practice. In general, reclassification is ofmost value when the individual’s risk lies close to a decisionalthreshold, such as a SCORE risk of 5%. In very-high-risk orvery-low-risk situations, the impact of additional risk factors is un-likely to alter management decisions. While the presence of riskmodifiers may move an individual’s estimated risk upward, absenceof these modifiers should lead to lowering an individual’s estimatedrisk.

Table 4 lists examples of factors that fulfil the aforementioned cri-teria. Several other factors that are frequently discussed in the litera-ture, but may not have the ability to reclassify subjects, are discussedin subsequent paragraphs. Also discussed further in this section arethe roles of ethnicity and of specific conditions or diseases that maybe associated with a higher than calculated risk, such as CKD, auto-immune diseases, etc. The way modifiers are related to CV risk maybe very different. Social deprivation and being overweight, for ex-ample, are important as ‘causes of the causes’ of CVD, in thatthey may be associated with higher levels of conventional risk fac-tors. Family history may reflect a shared environment, genetic fac-tors or both. Markers such as computed tomography (CT)calcium scoring are indicators of disease rather than risk factorsfor future disease.

2.3.7 Risk categories: prioritiesIndividuals at highest risk gain most from preventive efforts, and thisguides the priorities, which are detailed in Table 5.

2.3.8 Risk factor targetsRisk factor goals and target levels for important CV risk factors arepresented in Table 6.

2.3.9 ConclusionsEstimation of total CV risk remains a crucial part of the presentguidelines. The priorities (risk categories) defined in this sectionare for clinical use and reflect the fact that those at highest risk ofa CVD event gain most from preventive measures. This approachshould complement public actions to reduce community risk factorlevels and promote a healthy lifestyle. The principles of risk estima-tion and the definition of priorities reflect an attempt to make com-plex issues simple and accessible. Their very simplicity makes themvulnerable to criticism. Above all, they must be interpreted in light of

Table 5 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 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 such as smoking or marked hypercholesterolaemia or marked hypertension.• Severe CKD (GFR <30 mL/min/1.73 m2).• 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 m2).• A calculated SCORE ≥5% and <10%.

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

Low-risk SCORE <1%.

ACS ¼ acute coronary syndrome; AMI ¼ acute myocardial infarction; BP ¼ bloodpressure; CKD ¼ chronic kidney disease; DM ¼ diabetes mellitus; GFR ¼glomerular filtration rate; PAD ¼ peripheral artery disease; SCORE ¼ systematiccoronary risk estimation; TIA ¼ transient ischaemic attack.

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Piepoli et al. European Heart Journal doi:10.1093/eurheartj/ehw106

Priority Patient Groups for PCSK9 Inhibition

• Patients with clinical ASCVD and substantially elevated LDL-C levels.

Patients should be on maximally tolerated statin therapy (ideally with concomitant ezetimibe), or unable to tolerate three or more statins.

• Familial hypercholesterolaemia (FH) patients without clinical ASCVD but with substantially elevated LDL-C levels

Patients should be on maximally tolerated statin therapy plus ezetimibe

LandmesserUetal.EurHeartJ2017;https://doi.org/10.1093/eurheartj/ehx549

Patients with Clinical ASCVD : When to Consider a PCSK9 Inhibitor

Two LDL-C thresholds:

>3.6 mmol/L (>140 mg/dL)

>2.6 mmol/L (>100 mg/dL) with additional indices of risk severity


Patients with Clinical ASCVD : When to Consider a PCSK9 Inhibitor


Two LDL-C thresholds:

>4.5 mmol/L (>180 mg/dL)

>3.6 mmol/L (>140 mg/dL) with additional indices of risk severity

LDL-C Thresholds for Considering a PCSK9 Inhibitor

Patients with clinical ASCVD •On maximally tolerated statin (with or without ezetimibe) or with statin intolerance •With additional indices of risk severity

LDL-C threshold>3.6 mmol/L (140 mg/dL) >2.6 mmol/L or 100 mg/dL

Indices of risk severity: FH, diabetes mellitus with target organ damage or with a major risk factor such as marked hypertension; severe or extensive ASCVD; or rapid progression of ASCVD (repeated acute coronary syndrome, unplanned coronary revascularizations or ischaemic stroke within 5 years of the event).

Familial hypercholesterolaemia patients without clinical ASCVD •On maximally tolerated statin plus ezetimibe •With additional indices of risk severity (see below)

LDL-C threshold>4.5 mmol/L (180 mg/dL) >3.6 mmol/L (140 mg/dL)

Indices of risk severity: Diabetes mellitus with target organ damage or with a major risk factor such as marked hypertension; lipoprotein(a) >50 mg/dl; major risk factors such as smoking, marked hypertension; >40 years without treatment; premature ASCVD (<55 years in males and <60 years in females) in first degree relatives; and imaging indicators of increased risk.

• IthasbeenproveninmanylargeclinicaltrialsthatreducinglevelofLDLcholesterolreducestheriskofhavingacardiovascularevent.ThebenefitisproportionaltotheCVDrisk.

• Moreintensivetreatmentsaremoreeffectiveinpreventingclinicalevents

• LowLDL-Cissafe

• StatinsarethecornerstoneofLDL-Clowering

• AdditionofezetimibetoastatinreducesASCVDevents(IMPROVE-ITtrial)

• LargeclinicalASCVDoutcomestrialsofPCSK9inhibitorsshowedthattheseagentsreduceASCVDrisk(FOURIERandSPIRE-2)

Conclusions

Thank you

*Questions ????

The Fourth IAS-OSLA Course on “Lipid Metabolism and ...

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