medical management of coronary artery disease focus on...

Harvard Medical School

Duane Pinto, M.D., M.P.H.

Medical Management of Coronary Artery Disease

Focus on Residual Risk

Interventional Cardiologist

Chief, Interventional Section, Beth Israel Deaconess CV Division

Associate Professor of Medicine Harvard Medical School


Aspirin Evidence: Dose and Efficacy

0.5 1.0 1.5 2.0

500-1500 mg 34 19

160-325 mg 19 26

75-150 mg 12 32

<75 mg 3 13

Any aspirin 65 23

Antiplatelet Better Antiplatelet Worse

Aspirin Dose No. of Trials (%)

Odds Ratio for

Vascular Events

0

P<.0001

Indirect Comparisons of Aspirin Doses on Vascular Events

in High-Risk Patients

Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86


Study Drug

HF

Severity

Patients

(n)

Follow-up

(years)

Mean

Dosage

Effects on Outcomes

CIBIS Bisoprolol* Moderate-

Severe

641 1.9 3.8

mg/day

All cause mortality

22% (p=NS)

CIBIS-II Bisoprolol* Moderate-

Severe

2,647 1.3 7.5

mg/day

All cause mortality

34% (P<0.0001)

BEST Bucindolol* Moderate-

Severe

2,708 2.0 152

mg/day

All cause mortality

10% (p=NS)

MERIT-HF Metoprolol

succinate#

Mild-

Moderate

3,991 1.0 159

mg/day

All cause mortality

34% (P=0.0062)

MDC Metprolol

tartrate*

Mild-

Moderate

383 1.0 108

mg/day

Death or Need for Tx

30% (P=NS)

CAPRICORN Carvedilol Mild 1,989 1.3 40

mg/day

All cause mortality

23% (P =0.03)

US Carvedilol Carvedilol Mild-

Moderate

1,094 0.5 45

mg/day

All-cause mortality†

65% (P=.0001)

COPERNICUS Carvedilol Severe 2,289 0.9 37

mg/day

All-cause mortality

35% (P =0.0014)

b-blocker Evidence: Benefit in HF and LVSD

*Not an approved indication†Not a planned end point. #Not approved for severe HF or mortality reduction alone


Yes >100 >160 Stage 2

Hypertension

Yes 90–99 140–159 Stage 1

Hypertension

Yes 80–89 120–139Pre-

hypertension

Encourage <80<120 Normal

With compelling

indications

Initial drug therapy Lifestyle

modification

DBP*

mmHg

SBP*

mmHg BP classification

JNC VII Guidelines for Management and Treatment

ACEI=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker, BB=b-blocker, BP=Blood pressure,

CCB=Calcium channel blocker, DBP=Diastolic blood pressure, SBP=Systolic blood pressure

Chobanian AV et al. JAMA. 2003;289:2560-2572

*Treatment determined by highest blood pressure category. †Initial combined therapy should be used cautiously in those at

risk for orthostatic hypotension.

‡Treat patients with chronic kidney disease or diabetes mellitus to blood pressure goal of <130/80 mmHg.

Drug(s) for the

compelling indications.‡

Other antihypertensive

drugs (diuretics, ACEI,

ARB, BB, CCB) as

needed.

Drug(s) for compelling

indications. ‡


Goal: Complete Cessation and No Exposure

to Environmental Tobacco Smoke

IIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIII

Cigarette Smoking Recommendations

•Ask about tobacco use status at every visit.

•Advise every tobacco user to quit.

•Assess the tobacco user’s willingness to quit.

•Assist by counseling and developing a plan for

quitting.

•Arrange follow-up, referral to special programs,

or pharmacotherapy (including nicotine

replacement and bupropion.

•Urge avoidance of exposure to environmental

tobacco smoke at work and home.


Lipid Management Goal

LDL-C should be less than 100 mg/dL

Further reduction to LDL-C to < 70 mg/dL is

reasonable

III I I aI I aI I a I I bI I bI I b I I II I II I IIII I I aI I aI I a I I bI I bI I b I I II I II I IIII I I aI I aI I a I I bI I bI I b I I II I II I II I aI I aI I a I I bI I bI I b I I II I II I I

*Non-HDL-C = total cholesterol minus HDL-C

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL*


LaRosa JC et al. NEJM. 2005;352:1425-1435

LDL-C=Low density lipoprotein cholesterol; TNT=Treating to New Targets; HPS=Heart Protection Study; CARE=Cholesterol and Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in IschaemicDisease; 4S=Scandinavian Simvastatin Survival Study.

StatinPlacebo

Relationship between LDL Levels and Event Rates in Secondary Prevention Trials

of Patients with Stable CHD

HMG-CoA Reductase Inhibitor: Secondary Prevention

30

25

20

15

10

5

00 70 90 110 130 150 170 190 210

LDL-C (mg/dL)

TNT (atorvastatin 80 mg/d)

TNT (atorvastatin 10 mg/d)HPS

CARE

LIPIDLIPID

CARE

HPSEve

nt (%

) 4S

4S


Components of Secondary

Prevention

• Cigarette smoking cessation

• Physical activity

• Weight management to goal

• Diabetes management to goal

• Influenza vaccination


5 Major Trials Addressing Residual Risk

• PEGASUS-TIMI 54

• FOURIER

• ODYSSEY

• CANTOS

• COMPASS


Sever P & Mackay J. Br J Cardiol 2014;21:91-

3

Giugliano RP, et al. Lancet 2012;380:2007-17

Sabatine MS, et al. NEJM 2015;372:1500-9

Proprotein convertase subtilisin/kexin type 9 (PCSK9)– Chaperones LDL-R to destruction circulating LDL-C

– Loss-of-fxn genetic variants LDL-R LDL-C & risk of MI

Evolocumab

– Fully human anti-

PCSK9 mAb

– ~60% LDL-C

– Safe & well-tolerated

in Ph 2 & 3 studies

– Exploratory data

suggested CV

events

Background

evolocumab


Trial Design

Evolocumab SC 140 mg Q2W or 420 mg QM

Placebo SCQ2W or QM

LDL-C ≥70 mg/dL or

non-HDL-C ≥100 mg/dL

Follow-up Q 12 weeks

Screening, Lipid Stabilization, and Placebo Run-in

High or moderate intensity statin therapy (± ezetimibe)

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

(prior MI, prior stroke, or symptomatic PAD)

RANDOMIZED

DOUBLE BLIND

Sabatine MS et al. Am Heart J 2016;173:94-101


An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72 84 96 108 120

LD

L C

ho

leste

rol

(mg

/dl)

Weeks

LDL Cholesterol

Cohort of 11,077 patients who

• had all measurements through 120 weeks

• did not discontinue study drug

• did not D concomitant background lipid-lowering Rx

Evolocumab

Placebo

Similar data out to 4 years

in OSLER-1

(JAMA Cardiology online)


Types of CV Outcomes

Endpoint

Evolocumab(N=13,784)

Placebo(N=13,780) HR (95% CI)

3-yr Kaplan-Meier rate

CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88)

Cardiovascular death 2.5 2.4 1.05 (0.88-1.25)

Death due to acute MI 0.26 0.32 0.84 (0.49-1.42)

Death due to stroke 0.29 0.30 0.94 (0.58-1.54)

Other CV death 1.9 1.8 1.10 (0.90-1.35)

MI 4.4 6.3 0.73 (0.65-0.82)

Stroke 2.2 2.6 0.79 (0.66-0.95)


ACC.18

11

ALIROCUMAB- ODYSSEY

Post-ACS patients (1 to 12months)

Run-in period of 2−16 weeks on high-intensity

or maximum-tolerated dose of atorvastatin or

rosuvastatin

At least one lipid entry criterion

met

Placebo SCQ2WAlirocumab SCQ2W

Randomization

Schwartz GG, et al. Am Heart J2014;168:682-689.e1.

Patient and investigators remained blinded to treatment and lipid levels for the entire duration of

the study


ACC.18

32

Primary Efficacy and Components

Endpoint, n (%)Alirocumab

(N=9462)

Placebo

(N=9462)HR (95%CI)

Log-rank

P-value

MACE 903 (9.5) 1052 (11.1) 0.85 (0.78, 0.93) 0.0003

CHDdeath 205 (2.2) 222 (2.3) 0.92 (0.76, 1.11) 0.38

Non-fatal MI 626 (6.6) 722 (7.6) 0.86 (0.77, 0.96) 0.006

Ischemic stroke 111 (1.2) 152 (1.6) 0.73 (0.57, 0.93) 0.01

Unstable angina 37 (0.4) 60 (0.6) 0.61 (0.41, 0.92) 0.02


Stable CAD (post MI)

Residual Inflammatory Risk

(hsCRP > 2 mg/L)

Randomized

Canakinumab 150 mg

SC q 3 months

Randomized

Placebo

SC q 3 months

Primary Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE)

Randomized

Canakinumab 300 mg

SC q 3 months

Secondary Endpoint: MACE plus Unstable Angina Requiring Urgent Revascularization (MACE+)

Randomized

Canakinumab 50 mg

SC q 3 months

Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)

N = 10,061

39 Countries

April 2011 - June 2017

1490 Primary Events

Ridker PM et al. N Engl J Med. 2017;377:1119-31


Placebo SC q 3 months

Canakinumab 150/300 mg SC q 3 months

HR 0.85

95%CI 0.76-0.96

P = 0.007

Ridker PM et al. N Engl J Med. 2017;377:1119-31

Cu

mu

lati

ve In

cid

en

ce (

%)

Follow-up Years

CANTOS: Primary Cardiovascular Endpoints

HR 0.83

95%CI 0.74-0.92

P = 0.0006

MACE MACE - Plus

Follow-up Years

35 - 40% reductions in hsCRP and IL-6

No change in LDLC

0 1 2 3 4 5

Cu

mu

lati

ve In

cid

en

ce (

%)


Thrombus: Made of Both Platelets & Fibrin

Slide by C. Michael Gibson, M.S., M.D.


Months from Randomization

Ticagrelor 60 mg

HR 0.84 (95% CI 0.74 – 0.95)

P=0.004

CV

Death

, M

I, o

r S

tro

ke (

%)

3 6 9 120 15 18 21 24 27 30 33 36

Ticagrelor 90 mg

HR 0.85 (95% CI 0.75 – 0.96)

P=0.008

Placebo (9.0%)

Ticagrelor 90 (7.8%)Ticagrelor 60 (7.8%)

PEGASUS TIMI 54 Primary Endpoint

6

5

4

3

10

9

8

7

2

1

0

21,162 patients with MI 1-3

years prior and treated with

low-dose aspirin

Bonaca MP et al. and Sabatine MS. NEJM 2015;372:1791-800


Platelet AmplificationTwo Positive Feedback Loops

Slide by C. Michael Gibson, M.S., M.D.

Thrombin Made

on Platelet

Surface

Thrombin Most

Potent Activator

of Platelet

ADP Secreted

by Platelet

ADP Activates

Platelet

Antithrombins Thienopyridines

“Amplification”“Burst”

“Activation”“Growth of Thrombus”


Why Add An Antithrombin To A Thienopyridine?

• Platelet activation diminishes over time after an ACS event

• Thrombin generation in contrast is persistently elevated following ACS

• Thienopyridines do not block activation of the platelet by thrombin

• Factor Xa inhibition with Rivaroxaban has been shown to improve outcomes following ACS

• Dual pathway therapy with Rivaroxaban + clopidogrel is as effective in animal models as triple therapy and is associated with less bleeding


ACS Is Associated With Long Term Abnormalities in Coagulation

Christina Yip1*, Aruni Seneviratna2*, Sock Hwee Tan2, Sock Cheng Poh2, Zhen Long Teo3, Joshua

Loh2, Eng Soo Yap1,4 , E. Magnus Ohman5, C. Michael Gibson6,

Mark Richards2,3 and Mark Chan2,3


Placebo

0 24

Rivaroxaban

2.5 mg BID

All Cause Death

0 24

Cardiovascular Death

Months

CV Death / MI / StrokeE

sti

mate

d C

um

ula

tive i

ncid

en

ce (

%)

0 24Months Months

HR 0.85

mITT

p=0.039

ITT

p=0.011

HR 0.62

mITT

p<0.001

ITT

p<0.001

2.7%

4.5%

4.2%

2.5%

10.4%

9.0%

Rivaroxaban

2.5 mg BID

Rivaroxaban

2.5 mg BID

PlaceboPlacebo HR 0.64

mITT

p<0.001

ITT

p<0.001

NNT = 56NNT = 71 NNT = 5912 12 12

12%

5% 5%

TIMI 51: EFFICACY ENDPOINTS:Very Low Dose 2.5 mg BID

Patients Treated with ASA + Thienopyridine

N Engl J Med 2012; 366:9-19. Gibson CM, TIMI 51 AHA 2011


30-day run-

in,

ASA 100 mg

Rivaroxaban 5.0 mg bid

± pantoprazole 40 mg od

ASA 100 mg od


Rivaroxaban 2.5 mg bid + ASA 100 mg od


Final

follow-up

visit#

R

30-day

washout

period*

Final

washout

period visit

1:1:1

N~27,000

Population:Documented CAD or PAD

Objective: efficacy and safety of rivaroxaban, low-dose rivaroxaban plus ASA or ASA alone for reducing risk of MI, stroke or CV death in CAD or PAD

*Patients treated according to local standard of care#≤30 days of the required pre-specified number of events having

occurred

www.clinicaltrials.gov/show/NCT01776424

Start: Q1-13End: ~Q1-18

COMPASS: Rivaroxaban in CAD or PAD


COMPASS Trial: Riva + ASA vs ASAPrimary Endpoint: CV Death, MI, Stroke

Eikelboom et al. August 27, 2017DOI: 10.1056/NEJMoa1709118

Xaretlo 2.5mg is indicated for the prevention of stroke, myocardial infarction and cardiovascular death, and for the prevention of

acute limb ischemia and mortality in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) in

combination with ASA 100M. Use of Rivaroxaban is approved as well as for AF, DVT and PE at present.


COMPASS: Components of Primary Endpoint

Outcome

R + A N=9,152

AN=9,126

Rivaroxaban + Aspirinvs. Aspirin

N(%)

N(%)

HR(95% CI)

p

CV death160

(1.7%)203

(2.2%)0.78

(0.64-0.96)0.02

Stroke83

(0.9%)142

(1.6%)0.58

(0.44-0.76)<0.0001

MI178

(1.9%)205

(2.2%)0.86

(0.70-1.05)0.14

Eikelboom et al. August 27, 2017DOI: 10.1056/NEJMoa1709118

Rivaroxaban is not FDA approved in the ACS setting or in patients with atrial fibrillation undergoing stent placement. It is in

many other countries. Check your local label. The use of Rivaroxaban in chronic CAD is under regulatory review and is off label

at present.


CAD and PADSubgroups for primary outcome

Outcome

R + A N=9,152

AN=9,126

Rivaroxaban +Aspirin

vs. Aspirin

N(%)

N(%)

HR(95% CI)

CAD347

(4.2%)

460

(5.6%)

0.74

(0.65-0.86)

PAD126

(5.1%)174

(6.9%)0.72

(0.57-0.90)


Rivaroxaban 2.5 mg: EfficacyPooled Analysis of ATLAS ACS 2–TIMI 51 and COMPASS

All-Cause Death

CV Death

N Engl J Med 2012; 366:9-19. Eikelboom et al. August 27, 2017DOI: 10.1056/NEJMoa1709118

Data on file PERFUSE Study Group


Rat

e D

iffe

ren

ce /

1

0,0

00

Pat

ien

t-ye

ars

Benefit = Non-hemorrhage CV death, MI + ischemic strokeHarm = Fatal Bleeding + ICH

30 days 180 days 360 days 540 days 720 days

NCO = 62 63 142

NCO = Net Clinical Outcome (# fatal/irreversible harm events prevented/10,000 patient-years)

BenefitHarm

70 123

Net Clinical Outcome Over Time

-55 -6

-200

-150

-100

-50

0

50

-70

0

-76

14

-146

23

-165

23

Gibson CM et al, JACC 2018 in press


Summary

• Residual risk for atherothrombosis is actionable in 2019

• Targets include thrombin, platelets, inflammation and lipid deposition

• With regard to thrombus, low dose anticoagulants (rivaroxaban 2.5 mg BID) addresses an unmet pathophysiology mechanism for adverse events

• Patients risk for the competing risk for bleeding should be assessed when determining candidates for longtermantiocoagulation/antithrombotic therapy

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