The importance of lipid

management in ACS patients

BACPR October 2016

Shahid JunejoConsultant Cardiologist & Lead for PCI

City Hospitals Sunderland NHS Foundation trust

Associate Lecturer

Newcastle University Medical School

Sessional Tutor

University of Sunderland

Founder Chairperson

Integrated Vascular Centre, IVasC South of Tyne

This session has been sponsored by MSD

Prescribing and Adverse Event Reporting information can be found on the final slide

The views of the speaker are their own and do not represent the opinions of MSD

CARD-1197520-0000 Date of Preparation October 2016,

Declarations

Sponsorship for Scientific meetings, Research and Data

registry work

Advisory board participation

Sponsorship for Speaker meetings

Aims

Review CHD prevalence & presentations

Review recurrence risk after index event

Review treatment strategies

Review Guidelines / recommendations

Background..

CVD causes 4 million deaths in Europe (almost 50% of all

cause mortality)

CHD contributes to 1.8 million deaths (almost 20% of all

cause mortality)

In UK CVD costs £14.7bn (1.4% of GDP) - expected to

rise to £17.9bn in 2020

1. Centre for Economics and business research: http://www.cebr.com/reports/the-rising-cost-of-cvd/assuming £:Euro = 1.29 Date accessed 05/09/2016,

Kotseva K. E-Journal of Cardiology Practice.

Vol.14N24-27 Sep 2016

Global burden of disease and impact on mortality

Lopez AD et al.Lancet 2006; 367: 1747–57

Projections of global mortality and

burden of disease from 2002 to 2030

Mathers CD et al. PLoS Med. 2006 Nov;3:e442

Disease presentation

New Angina - OP setting

UA / ACS (NSTeMI) or STeMI - de novo (Type 1)

UA / ACS (NSTeMI) or STeMI - secondary (Type 2)

CHD in the context of other cardiac presentation -Valve

disease, CCF, Arrhythmias etc

Other Vascular or Metabolic presentations - PVD, Stroke,

AAA, Diabetes, CKD

The UK Human Cost

170000deaths per

year

CVDA quarter of all

deaths 7 millionliving with CVD

175000 heart attacks p.a

One death every

3 minutes

Heart AttackKills most CHD

patients

23000 deaths in under 75s per

year

2.3millionLiving with

CHDA death every

7 minutes

CHDNo1 Killer

BHF Headline Statistics 2015. https://www.bhf.org.uk/research/heart-statistics,

170000deaths per

year

CVDA quarter of all

deaths 7 millionliving with CVD

175000 heart attacks p.a

One death every

3 minutes

Heart AttackKills most CHD

patients

23000 deaths in under 75s per

year

2.3millionLiving with

CHDA death every

7 minutes

CHDNo1 Killer

MINAP report 2013-14

80724 Heart attacks

31653 (39%) STeMI vs 49071 (61%) NSTeMI

PPCI & early PCI recommended respectively

MINAP report 2013-14

In STeMI presentation 27% (8010) did not get reperfusion

In NSTeMI presentation 34% (16802) did not get

diagnostic angiography (various reasons)

Risk profile at first presentation

33% patients on BP medications

30% on Lipid lowering treatments

20% women were Diabetic vs 18% of men

At discharge nearly 88% of eligible patients were on

secondary preventive medications [Antiplatelets, BB, Statins, ACE inhibitors]

against the NSF for CHD standard of 80% for 3

medications [Asp, BB, Statins])

MINAP 2013-14 Annual report

Residual risk …

Untreated disease (irrespective of reason not to treat)

Persistent or resistant risk factors (Smoking, BP, BMI, DM,

Lipids)

New or emergent risk (Stroke, CCF, Diabetes, CKD, age)

Novel risk factors - Heart Rate & cellular mechanism of

disease

EUROASPIRE IVCross-sectional survey 78 centres, 24 countries, patients 18-80 years

who have had CABG, PCI or ACS

16,426 medical records reviewed and 7998 patients interviewed

50% continue to smoke - younger patients more persistent smokers

60% do not perform moderate or vigorous activity

<33% reached 130/80 (only 40% met 140/90)

<66% had LDL-C <2.5 (20% had LDL-C <1.8)

33% had HbA1C 6.5%

BMI - unchanged or rising

EUROASPIRE IV : Kotseva K et al.

@ ESC 2015

European Journal of Preventive Cardiology

Residual risk

Figure 1. EUROASPIRE IV: prevalence of smoking, persistent smoking, obesity, central obesity, elevated blood pressure and LDL-cholesterol, and

self-reported diabetes.

Smoking: self-reported smoking or >10 ppm carbon monoxide in breath; Persistent smoking: self-reported smoking or >10 ppm carbon monoxide in

breath in patients reporting to have been smoking in the month prior to the index event; Obesity: BMI ≥30 kg/m2; Central obesity: waist circumference

≥88 cm for women and ≥102 cm for men BP: ≥140/90 mmHg (≥140/80 mmHg in patients with diabetes mellitus); LDL-C: ≥1.8 mmol/L

Impact of residual risk

High disease and symptom burden

High resource utilisation and costs

Poor quality of life

Patients most at risk..

ACS patients :13% readmission within 1 month after

initial presentation (*1) A UK audit of 158 UA/NSTeMI patients from an Acute Cardiac Unit.

After MI : 18% probability of nonfatal MI, nonfatal CVA,

or CV death in first 12 months after MI (2)

1. Alfakih et al. British J Cardiology 2009;16:132-134 2. Jernberg et al. Eur Heart J 2015;36(19):1163-1170

Patients with stable CAD are still at risk of cardiovascular events

Adapted from Steg PG et al. JAMA. 2007;297: 1197-1206.

1.9

3.8

4.6

0 5 10 15 20

CV death

PCI

6.44UA

1.4

1.4

Non-fatal MI

CABG

CHF

15.2Death/MI/

Stroke/Hosp*

Annual event rates adjusted for sex and age in stable CAD outpatients, REACH registry: CAD outpatients (n=38602), 1-year follow-up

3 of 20 patients with established CAD had a major event or had been hospitalized

within a year

1 year mortality of approx. 38%Heart Disease and Stroke Statistics—2008 Update. Circulation. 2008;117.

COURAGE1

Angina symptoms persist in many patients despite

receiving PCI and/or optimal medical therapy

194496/RAN/MAR/2013/DAP. Date of preparation: March 2013.

Prescribing Information can be found on the last slide.31

PCI + Optimal medical therapy (21.1%

Revascularisation)

Optimal medical therapy

(32.6% Revascularisation)

Baseline 1 yr 3 yr 5 yr Baseline 1 yr 3 yr 5 yr

Continuing

angina (%)88 34* 28† 26 87 42 33 28

Beta-blockers

(%)85 85 84 85 89 89 86 86

Calcium channel

blockers (%)40 40 43 42 43 49 50 52

Long-acting

nitrates (%)62 53 47 40 72 67 61 57

*p<0.001 for PCI + OMT vs OMT alone. †p=0.02 for PCI + OMT vs OMT alone

Clinical Outcome Utilizing Revascularization and Aggressive drug Evaluation

1. Adapted from Boden WE et al. N Engl J Med 2007;356:1503–1516.

Analysis from MERLIN-TIMI 36 trial; 5460 stable outpatients after ACS; meadian follow up of 12 months

Cumulative costs of cardiovascular hospitalization by angina frequency group

Arnold SV et al. Circ Cardiovasc Qual outcomes. 2009;2:344-353

Economic impact of stable CAD

Reducing risk..

Assess residual risk and treat with evidence based

interventions - established as well as new

Educate Health professionals, Patients and carers about

the threat from untreated or under-treated risk factors

New evidence……

Heart rate reduction

PCSK9 Inhibitors

Ezetimibe - Improve-IT

New evidence……

Heart rate reduction

PCSK9 Inhibitors

Ezetimibe - Improve-IT

Heart Rate

Well recognised as a risk marker

Good evidence for Risk ‘factor’ status from observational

data as well as secondary prevention studies (Beautiful,

Shift & others)

Baseline heart rate is a predictor of endpoints for HF patients on placebo

Primary composite endpoint: risk increases by 2.9% per 1-bpm increase, and by 15.6% per 5-bpm increase

50

40

30

20

10

00 6 12 18 24 30

Months

≥87 bpm

80 to <87 bpm

75 to <80 bpm

72 to <75 bpm

70 to <72 bpm

P<0.001

Patients with primary composite end point (%)

50

40

30

20

10

00 6 12 18 24 30

Months

≥87 bpm

80 to <87 bpm

75 to <80 bpm

72 to <75 bpm

70 to <72 bpm

P<0.001

First hospital admission for heart failure (%)

≥87 bpm

80 to <87 bpm

75 to <80 bpm72 to <75 bpm70 to <72 bpm

50

40

30

20

10

00 6 12 18 24 30

Months

Patients with cardiovascular death (%)

P<0.001

Böhm M, et al. Lancet. 2010;376:886-894.

New evidence……

Heart rate reduction

PCSK9 Inhibitors

Ezetimibe - Improve-IT

PCSK9 Inhibitors

PCSK9 is a protein which binds to LDL Receptor and

helps to degrade it

LDL Receptor degradation allows higher levels of LDL in

circulation

Monoclonal antibodies blocking PCSK9 help preserve

LDL Receptors thus increasing removal of LDL from

circulation

PCSK9 Inhibitors

Evidence from RCTs

Recommended by NICE - The National Institute for Health and

Care Excellence (NICE) has recommended the PCSK9 inhibitors alirocumab

and evolocumab for patients with primary hypercholesterolaemia, or mixed

dyslipidaemia that is not controlled with statins, or who cannot tolerate

statins because of their side effects or have another condition which means

they cannot take them

in final draft guidance based on manufacturers providing the drugs at

discounted prices.

BMJ 2016; 353 doi: http://dx.doi.org/10.1136/bmj.i2609 (Published 09 May 2016)

Cite this as: BMJ 2016;353:i2609

https://www.nice.org.uk/news/press-and-media/nice-draft-guidance-recommends-new-drugs-for-cholesterol-disorder. date accessed 03.10.16

New evidence……

Heart rate reduction

PCSK9 Inhibitors

Ezetimibe - Improve-IT

please refer to relevant SPC for full prescribing information

rs2228671

rs646776

rs4420638

rs4299376

rs11206510rs12916

rs6511720

0%

30%

10%

20%

Coronary Events Prevention by

Genetic LDL-C Reduction vs LDL-C

Reduction

Earlier LDL-C lowering results in a 3-fold greater reduction than that observed during treatment with a statin started later in life for the same quantity of LDL-C reduction.

Adapted from Ference et al J Am Coll Cardiol 2012;60:2431-2439 Adapted from Cannon et al. NEJM 2015; 372: 2387-2397

Early LDL-C Reduction (genetic) Late LDL-C Reduction (pharmacologically)

50%

40%

30%

20%

10%

0%

-10%

0.5 1.0 1.5 2.0

Pro

po

rtio

nal

Ris

k R

edu

ctio

n (

SE)

7%

10.5 mg/dL0.3 mmol/L

0 0.05 0.1 0.16 0.21 0.26 0.31 0.36 0.41 0.47

rs599839

rs11591147

Lower LDL-C (mmol/L)

Each 1 mmol/l of lower LDL-C was associated with54.5% reduction of risk of CHD

Each 1 mmol/l of lower LDL-C was associated with22% reduction of risk of CHD

Ezetimibe

Interacts with NPC1L1 receptor in the gut

Reduces Cholesterol absorption

Complements the action of Statins in the Liver

Complementary Mode of Action

Statins inhibit the biosynthesis of cholesterol in the liver, however, the body compensates by increasing cholesterol absorption from the small intestine

Peripheral tissue

Ezetimibe lowers Total Cholesterol and LDL-C by selectively inhibiting the absorption of cholesterol from the small intestine by interacting with a key intestinal sterol transporter protein called Niemann-Pick C1-Like protein, or NPC1L1

Adapted from Santosa S et al. Physiological and therapeutic factors affecting cholesterol metabolism:Does a reciprocal relationship between cholesterol absorption and synthesis really exist? Life Sciences. 2007:80:505-514.

The Relation Between LDL-C and CHD Events in Statin

Trials

The Greater the LDL-C Reduction the Greater the Benefit

LDL-C achieved mmol/L

WOSCOPS - Pl

AFCAPS - Pl

ASCOT - Pl

AFCAPS - RxWOSCOPS - Rx

ASCOT - Rx

4S - Rx

HPS - Pl

LIPID - Rx

4S - Pl

CARE - Rx

LIPID - Pl

CARE - Pl

HPS - Rx

0

5

10

15

20

25

30

1.0 1.6 2.1 2.6 3.1 3.6 4.1 4.7

6

Secondary Prevention

Primary Prevention

Rx - Statin therapy Pra – pravastatinPl – Placebo Atv - atorvastatin

5.2

PROVE-IT - Pra

PROVE-IT - Atv

TNT - Atv10

TNT - Atv80

Adapted from: Rosenson RS. Expert Opin Emerg Drugs 2004;9(2):269-279, Faergeman O. Eur Heart J Suppl 2004;6(suppl A):A3-A7. LaRosa JC et al. N Engl J Med 2005;352:1425-1435

5.2

Diminishing Risk Reduction for the same relative LDL-C

Lowering with Lower baseline LDL-C

Adapted from Laufs U et al. Eur Heart J 2014;35:1996-2000

Improve-It

IMProved Reduction of Outcomes: Vytorin

Efficacy International Trial

A multicenter, double-blind, randomized study to establish the clinical benefit and safety of Vytorin (ezetimibe/simvastatin tablet) vs simvastatin monotherapy in high-risk subjects presenting with acute coronary syndrome

Aim: This study was designed to evaluate whether addition of ezetimibe to statin therapy translates into increased clinical benefit on CV outcomes relative to simvastatin alone in patients with ACS Does lowering LDL-C with the non-statin agent ezetimibe reduce cardiac events?

“Is (Even) Lower (Even) Better?” (estimated mean LDL-C ~1.4 vs. ~ 1.8 (mmol/L)

Safety of ezetimibe

Canon CP et al. NEJM (2015); 372: 2387-2397

Improve-It Baseline Characteristics

Simvastatin(N=9077)%

EZ/Simva(N=9067)%

Age (years) 64 64

Female 24 25

Diabetes 27 27

MI prior to index ACS 21 21

STEMI / NSTEMI / UA 29 / 47 / 24 29 / 47 / 24

Days post ACS to rand (IQR) 5 (3, 8) 5 (3, 8)

Cath / PCI for ACS event 88 / 70 88 / 70

Prior lipid Rx 35 36

LDL-C at ACS event (mg/dL, IQR) 95 (79, 110) 95 (79,110)

Adapted from Canon CP et al. NEJM (2015); 372: 2387-2397

Results: LDL-C and Lipid Changes

1 Yr Mean LDL-C TC TG HDL hsCRP

Simva 1.81 3.75 1.55 1.24 3.8

EZ/Simva 1.38 3.25 1.36 1.26 3.3

Δ in mmol/L -0.43 -0.50 -0.19 +0.02 -0.5

Median Time avg1.8 vs 1.4 mmol/L

Adapted from Canon CP et al. NEJM (2015); 372: 2387-2397

The Greater the LDL-C Reduction the greater the benefit,

even at very low LDL-C levels

Major Vascular Events defined as a composite of:

Death from coronary heart disease; Myocardial infarction; Stroke and Revascularisation > 30 days after randomisation

The IMPROVE-IT trial1 demonstrated that in patients who have had an ACS event reducing LDL-C from 1.8mmol/L to 1.4mmol/L significantly reduced further major vascular events (Absolute Risk Reduction 2.9%, Relative Risk Reduction 6.4% (HR 0.936 95% CI (0.89-0.99) P=0.016)

Confirms consistency in CTT correlation between lipid lowering and improved outcomes even at very low LDL-C levels

1.Adapted from Cannon et al. NEJM 2015; 372: 2387-2397

Improve-It

IMPROVE-IT Total Event Analysis

39

More than double

the number of

events reduced

if total events

counted

•www.acc.org/~/media/Clinical/PDF-Files/Approved-

PDFs/2015/03/15/10/35/1230PM%20PT%20316%20ACC15%20Presentation%20Slides%20IMPROVE%”0IT.ppt

What do guidelines say? NICE CG181

ESC Hyperlipidemia, August 2016

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

•European Heart Journal. doi:10.1093/eurheartj/ehw106, online May 2016

Coronary patients

Risk categories remain similar to 2011

NICE CG 181

Lipid Modification : Secondary prevention

Initiate atorvastatin 80 mg* for patients with established CVD unless:

Potential drug interactions exist

There is a high risk of adverse events

Patient preference

Aim for a greater than 40% reduction in non-HDL cholesterol after 3 months of treatment with high intensity statin

Consider ezetimibe if cholesterol is not appropriately controlled on initial statin or as monotherapy in statin intolerant patients

Acute coronary syndrome – do not delay treatmentTake a lipid sample on admission and 3months after treatment

*At the time of publication (July 2014), atorvastatin did not have UK marketing authorisation for CVD

NICE Clinical Guideline 181. July 2014. Reproduced with permission. NICE Technology Appraisal Guidance 132. November 2007. Reproduced with permission

please refer to atorvastatin SPC for full prescribing information

NICE CG 181 & TA 385

Lipid Modification :Other treatments

Bile acid sequestrantsWeak monotherapy evidence on CVDNo combination evidence with statinsDo not use either alone or as combination therapy

FibratesMeta-analysis: moderate monotherapy benefitMeta-analysis: No combination therapy benefitNo routine use either alone or as combination therapy

NiacinWeak monotherapy evidenceMeta-analysis: no combination therapy benefitDo not use either alone or as combination therapy

Omega-3 Fatty acidsMixed diet and supplement trials. Multiple supplement trials usedMeta-analysis: no combination therapy benefitDo not use either alone or as combination therapy

NICE Clinical Guideline 181. July 2014. Reproduced with permission. NICE Technology Appraisal Guidance 132. November 2007. Reproduced with permission

ESC & ACC Guidelines

Post Improve IT

2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation1

“Based on the results of the trial, further LDL cholesterol lowering with a non-statin agent should be considered in patients with LDL cholesterol ≥70 mg/dL (≥1.8 mmol/L) after NSTE-ACS despite a maximally tolerated dose of statin. At the time of finalizing the guidelines, this recommendation applies only to ezetimibe.”

2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents2

“Although there is a gap in RCT evidence demonstrating outcomes benefits of using combination therapy in stable clinical ASCVD patients, the Expert Consensus Writing Committee supports consideration of adding ezetimibe 10 mg daily as the first non-statin agent, given the benefits on ASCVD outcomes and demonstrated safety of ezetimibe in patients with ACS treated with ezetimibe-simvastatin versus simvastatin monotherapy.”

1. European Heart Journal (2015) doi:10.1093/eurheartj/ehv320. 2. Lloyd-Jones et al. J Am Coll Cardiol. 2016:. doi:10.1016/j.jacc.2016.03.519

Intervention strategies as a function of total cardiovascular risk and LDL cholesterol level

SCORE : (Systematic Coronary Risk Evaluation) only accounts for Gender, Age, TC, Sys BP, Smoking

Risk may be underestimated in : Low HDL, High Lp(a), DM,

Fam Hx of CHD, CKD (eGFR<60) & Social deprivation

Treatment pathway

Statin in highest tolerated dose

Ezetimibe

PCSK9-i

Statin intolerance

Ezetimibe& BAS (optional)

•European Heart Journal. doi:10.1093/eurheartj/ehw106, online May 2016

Conclusions….1

Identify “all” risk factors : modifiable and non modifiable

Address and direct management of each to target level

Crucial to recognise residual risk despite excellent first

line management

Poor risk control is common and increases with time but

can be multifactorial

Conclusions….2

Prevention & Rehabilitation is “everyone’s” business and

starts from first contact with patient

Encourage and educate patient and carers to continue

“prevention & rehabilitation”

The Human Cost: Coronary Heart Disease

(CHD)3

CHD is the UK's single biggest killer

Nearly one in six men and one in ten women die from coronary heart disease

CHD is responsible for around 73,000 deaths in the UK each year, an average of 200 people each day, or one every seven minutes

Around 23,000 people under the age of 75 in the UK die from CHD each year

2.3 million people are living with CHD in the UK

Most deaths from coronary heart disease are caused by a heart attack

There are up to 175,000 heart attacks in the UK each year; that’s one every three minutes

3. BHF Cardiovascular Disease Statistics 2014 p.54