Management of Ischemic Heart Disease and Lipids 2020

Benjamin M. Scirica, MD MPHSenior Investigator, TIMI Study Group

Cardiovascular Division, Brigham and Women’s HospitalAssociate Professor of Medicine, Harvard Medical School

Disclosures

• Financial Relationships over past 24 months

• Institutional research grant to Brigham and Women’s Hospital from AstraZeneca, Eisai, Merck, Novartis, NovoNordisk, and Pfizer. Consulting fees from AbbVie, Allergan, AstraZeneca, Boehringer Ingelheim, Eisai, Elsevier Practice Update Cardiology, Esperion, Lexicon, Medtronic, Merck, NovoNordisk, and equity in Health [at] Scale.

• I am amember of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from: Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences

What is Ischemic Heart Disease

SIHD by Any Other Name…• Chronic stable angina• Stable angina pectoris• Stable ischemic heart disease• Stable coronary artery disease • Non-acute coronary syndrome

“… angina secondary to stable ischemic heart disease (SIHD) is the most common clinical presentation of cardiovascular disease encountered by general practitioners and cardiologists.”

Harrington R, et al. http://theheart.medscape.org/viewarticle/739504. Accessed: Feb 16, 2012.

Stable Ischemic Heart Disease (Old School)

But it’s just not that simple

Small Vessel Atherosclerosis and Microvascular Disease

Della Rocca and Pepine. EHJ. 2012 (Oct)

Pathobiological Contributors to IHD

Marzilli M et al. J Am Coll Cardiol. 2012;60:951-956.

INFLAMMATION

PLATELETS AND COAGULATION

VASOSPASM

MICROVASCULAR DYSFUNCTION

ENDOTHELIAL DYSFUNCTION

CRITICAL CORONARYSTENOSIS

MYOCARDIAL ISCHEMIA

Reduce Ischemia & Relieve Anginal Symptoms

Improve “Quality of Life”

Dual Goals for Management of Stable Ischemic Heart Disease (SIHD)

Prevent MI and Death (Disease Modification)

Improve “Quantity of Life”

Secondary Prevention Goals of Therapy in SIHD

• Antiplatelet Therapy– ASA 81 mg; ADP antagonist if recent ACS or stent

• ACEI / ARB (especially if DM, HF, EF <40%, HTN)

• Lipid Lowering

• Diabetes Rx with proven CV benefit (GLP1RA and SGLT2i)

• Smoking cessation

• Other Secondary Prevention Measures– BP control

– Weight management

– Physical exercise

– Influenza Vaccine

Reduce/stabilize atherosclerotic plaque → ACS/MI/SCD

Consider

initiating

low-dose

aspirin

and adding a

proton-pump

inhibitor

Consider

initiating

low-dose

aspirin

Initiate

low-

dose

aspirin

ASCVD DIABETESINCREASED BLEED RISK

AGE > 70 years

High

ASCVD

riskLow

ASCVD

risk

Do not

initiate

low-dose

aspirin

High

ASCVD

risk

High

ASCVD

risk

Do not

initiate

low-

dose

aspirin

Do not

initiate

low-dose

aspirin

PRIMARY PREVENTION

Low

ASCVD

risk

SECONDARY

PREVENTION

IMAGED VASCULAR DISEASE*

High

ASCVD

risk

Consider

initiating

low-dose

aspirin

*Evidence of atherosclerosis on CT scan or vascular ultrasound tests, or an elevated

coronary calcium score; ASCVD = atherosclerotic cardiovascular disease.

IMPROVE-IT vs CTT: CV Benefit Proportional to LDL-C for Both Ezetimibe and Statins

*Using CTT methods: LDL difference between groups using baseline LDL for Pts without blood samples. Endpoint of CV Death, MI,

stroke or revascularization >30days post Rand. Cox HR reported.

Cannon CP, et al. N Engl J Med. 2015;372(25):2387-97.

IMPROVE-IT

Reduction in LDL Cholesterol (mmol/L)

Red

uc

tio

n in

Rate

of

Ma

jor

Va

sc

ula

r E

ve

nts

(%

)

-10

0

10

20

30

40

50

0 0.5 1.0 1.5 2.0

ALLHAT-LLT

GISSIALERT

LIPS

AFCAPS/TexCAPSASCOT-LLA

WOSCOPS

PosT CABGCAREHPS

4SCARDS

PROSPER

LIPID

Yasuyoshi Ouchi, et al. Circulation. 2019;140:992–

1003

EWTOPIA 75: Ezetimibe vs. Placebo in Primary Prevention Patients > 75 years old

Sudden cardiac death, MI, coronary

revascularization, or strokeLDL

PCSK9 Regulates LDL-R Expression

Shimada YJ, Cannon CP. Eur Heart J. 2015;36:2415–2424.

PCSK9

SecretionEndocytosis

LDL, LDL-R, and PCSK9

degradation

PCSK9/LDL-R

complex

LDL-C Reduction via PCSK9 Inhibition

Shimada YJ, Cannon CP. Eur Heart J. 2015;36:2415–2424.

LDL-R

recycling

X

Secretion

PCSK9PCSK9 inhibitor

Endocytosis

FOURIER: Effects of PCSK9i Evolocumab

27,564 high-risk, stable patients with established CV disease

Evolocumab

(median 30 mg/dl, IQR 19-46 mg/dl)

Placebo

59% reduction

P<0.00001

Absolute 56 mg/dl

HR 0.85 (0.79-0.92)

P<0.0001

HR 0.80 (0.73-0.88)

P<0.0001

CVD, MI, stroke

UA, cor revasc

CVD, MI, stroke

Sabatine MS et al. NEJM. 2017; 376: 1713-22.

14.6

9.9

12.6

7.9

0

5

10

15

KM

Ra

te (

%)

at

3 Y

ea

rs

ACC.18

19

Primary Efficacy Endpoint: MACE

ARR* 1.6%

*Based on cumulative incidence

MACE: CHD death,

non-fatal MI,

ischemic stroke, or

unstable angina requiring

hospitalization

HR 0.85(95% CI 0.78, 0.93)

P=0.0003

FOURIER – Lower CV Event Rates with Lower

LDL-C Levels*, Even Down to 20 mg/dL

*Relationship between the achieved LDL-cholesterol concentration at 4 weeks and the risk of CVD, MI, or stroke.

Giugliano RP, et al. Lancet. 2017 Aug 25. [Epub ahead of print]

0.06

0.08

0.1

0.12

0.14

0.16

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5

Ad

juste

d e

ven

t ra

te (

pro

bab

ilit

y)

LDL cholesterol 4 weeks after randomization mmol/L)

p=0.0001 for the β coefficient

Inclisiran

Ray KK, et al. N Engl J Med. N Engl J Med 2020; 382:1507-1519

Inclisiran

• small interfering

RNA(siRNA)

targeting PCSK9 messenge

r RNA

• Dosed q 6 or 12 months

• Possible approval in 2020

• ?s about cost (less than

mAb)

Bempedoic Acid

• Inhibitor of ATP

citrate lyase in

cholesterol synthesis

pathway

• “upstream to HMG-

CoA reductase

• FDA Approved as

Nexletol

• Do not use with statin

Ray KK et al. N Engl J Med 2019;380;11

hs-CRPLDL Chol

REDUCE IT Targeting Triglycerides with Omega-3 FFACV Death, MI, Stroke, Coronary Revasc, Unstable Angina

Icosapent Ethyl

23.0%Placebo

28.3%

Years since Randomization

Pati

en

ts w

ith

an

Even

t (%

)

0 1 2 3 4 5

0

10

20

30

P=0.00000001

RRR = 24.8%

ARR = 4.8%

NNT = 21 (95% CI, 15–33)

Hazard Ratio, 0.75(95% CI, 0.68–0.83)

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018. Bhatt DL. AHA 2018, Chicago.

REDUCE IT Outcomes by baseline Trig level

https://doi.org/10.1016/j.jacc.2019.06.043

ACC/AHA Cholesterol

Guidelines 2018

Secondary Prevention

Very High-Risk* for ASCVD

Major ASCVD Events

Recent ACS (within the past 12 mo)

History of MI (other than recent ACS

event listed above)

History of ischemic stroke

Symptomatic peripheral arterial

disease (history of claudication with

ABI <0.85, or previous

revascularization or amputation)

High-Risk Conditions

Age ≥65 y

Heterozygous familial hypercholesterolemia

History of prior coronary artery bypass surgery or

percutaneous coronary intervention outside of the

major ASCVD event(s)

Diabetes mellitus

Hypertension

CKD (eGFR 15-59 mL/min/1.73 m2)

Current smoking

Persistently elevated LDL-C (LDL-C ≥100 mg/dL

despite maximally tolerated statin and ezetimibe

History of congestive HF

ACC/AHA Cholesterol

Guidelines 2018

Secondary Prevention

* Multiple ASCVD events or 1 major

event and multiple high risk conditions

Statin Safety and Statin-Associated Side Effects

Recommendations for Statin Safety and Statin-Associated Side Effects

COR LOE Recommendations

III: No

BenefitB-R

Coenzyme Q10 is not recommended for routine use in

patients treated with statins or for the treatment of

SAMS.

III: No

BenefitC-LD

In patients treated with statins, routine measurements

of creatine kinase and transaminase levels are not

useful.

What if we did full lipid therapy intensification for goal < 70 mg/dl?

A theoretical approach

ALI 75 = alirocumab 75 mg; ALI 150 = alirocumab 150 mg; EZE = ezetimibe; HIS = high-intensity statin; MIS = moderate- to low-intensity statin.

Cannon CP, Khan I, et al. JAMA Cardiol. 2017 Aug 2. [Epub ahead of print]

0%

1%

1%

2%

2%

3%

3%

4%

4%

5%

5%

0 20 40 60 80 100 120 140 160

Before Treatment Intensification

HIS + EZE (1%)

MIS + EZE (1%)

HIS Only (14%)

MIS Only (37%)

EZE Only (1%)

No Statin or EZE (46%)

% P

ati

en

ts in

1 m

g/d

L r

an

ges

LDL-C (mg/dL)

0 20 40 60 80 100

After Treatment Intensification

HIS + EZE + ALI 150 (2%)

HIS + EZE + ALI 75 (12%)

HIS + EZE (17%)

MIS + EZE (1%)

HIS Only (25%)

MIS Only (43%)

LDL-C (mg/dL)

LDL-C Levels for Optimal CV Risk Reduction: What We Know Now

High is bad

Average is not good

Lower is better

Even lower is even

better

Lowest is best

Conclusions on Lipids• 2018 ACC/AHA guidelines – still several years behind data

• Recommend statins for 4 groups

• Then add non-statins if LDL > 70 mg/dl for secondary prevention

• Ezetimibe, alirocumab, evolocumab, and icosapent ethyl have shown:

• Non-statin agents are effective in lowering LDL AND at reducing cardiovascular events

• Achieving lower LDL levels (< 55 mg/dL) is safe and can significantly reduce the risk of CV events in very high risk ASCVD

The Eternal Question in SIHD

“To cath, or not to cath, that is the question:Whether 'tis nobler in the mind to suffer

The slings and arrows of outrageous fortune,

Or to take Arms against a Sea of troubles,

And by opposing end them: to die, to sleep;

No more; and by a sleep, to say we end

The heart-ache, and the thousand natural shocks

That Flesh is heir to?”

Primary Endpoint:CV death, MI, hosp for UA, heart failure or resuscitated cardiac arrest

Qualifying Stress Test: Core Lab Interpretation

Baseline Coronary Anatomy by Cardiac CTA

Risk Factor ManagementBaseline vs last visit

No between group differences Inv v. Con

Clinical Outcomes

Effect on Quality of Life

• Invasive strategy had larger improvements in disease-specific health status (including angina symptoms, physical function, and disease-specific quality of life) than conservative strategy.

• modest differences favoring the invasive strategy in the overall trial population reflected differences that were confined to par participants who had had angina within the 4 weeks before randomization, with minimal, if any, benefit among those who had been asymptomatic at randomization.

• The magnitude of the difference was largest among participants who had entered the trial with daily or weekly angina.

Thus, provided there is strict adherence to guideline-based medical therapy, patients with stable ischemic heart disease who fit the profile of those in ISCHEMIA and do not have unacceptable levels of angina can be treated with an initial conservative strategy. However, an invasive strategy, which more effectively relieves symptoms of angina (especially in patients with frequent episodes), is a reasonable approach at any point in time for symptom relief.

Summary of “Disease Altering” Interventions in SIHD

• Greatest evidence for life prolonging or MI-reducing therapy is with optimal medical therapy

• Revascularization is very good for reducing angina and minimizing need for recurrent coronary interventions

• But, except in small, high risk populations immediate revascularization does not prolong life or reduce risk of future MI