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Coronary Artery Disease in 2015:Acute Coronary Syndrome and beyond…(Primary and Secondary Prevention of CAD)

Andrew R. Waxler, MD, FACCBerks Cardiologists, Ltd.

President Elect, Berks County Medical SocietyCardiology Rep. to PAMED (Specialty Leadership Cabinet)

Director, Cardiac Rehab., St. Joseph Medical Center (Reading, PA)

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Disclosure

• Dr. Waxler has a financial relationship or interest with a commercial entity that may have a direct interest in the subject matter of this session. Dr. Waxler is a consult and part of a speaker’s bureau for Sanofi Pasteur.

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For a cigarette-smoking patient who has an MI, what is the approximate risk reduction of future MI (over the next several years) that he/she will get from smoking cessation?

A. There is no significant change in risk of second MI from smoking cessation at time of first MI

B. Only about 10%

C. About 25%

D. About 50%

E. Between 75-100%

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4

Based on the most recent (2013) lipid guidelines, which of the following patients do NOT automatically qualify for statin therapy:

A. Healthy 37 y.o. woman with LDL 227, no other medical probs

B. 54 y.o. man with recent MI and PCI of LAD; his LDL is 65

C. 44 y.o. man with Diabetes and LDL 90; asymptomatic

D. Options A and C

E. All of the above qualify

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Which of the following types of patients should receive dual-antiplatelet therapy for 9-12 months following ACS? (ASA/clopid.)

A. Patient with ACS treated with Percutaneous Coronary Intervention(PCI)?

B. Patient with ACS treated Coronary Artery Bypass Graft (CABG)?

C. Patient with ACS treated medically (no PCI or CABG)?

D. What about a High-risk patient who has NOT had ACS (ie, DM)?

E. A, B, and C

F. All of the above

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We All Know About the Problem

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Vascular Disease: A GeneralizedVascular Disease: A Generalizedand Progressive Processand Progressive Process

UnstableanginaMI

Ischemicstroke/TIA

Critical legischemiaCardiovasculardeath

ACS

AtherosclerosisAtherosclerosis

Adapted from Adapted from StaryStary HC et a l. HC et a l. Circu lationCircu lation. 1995;92:1355-1374 and . 1995;92:1355-1374 and FusterFuster V. V. VascVasc Med Med . 1998;3:231-239.. 1998;3:231-239.

Stable anginaIntermittent claudication

Thrombosis

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One Method of Diagnosing CAD

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Cardiac CT – 64 Slice

• Coronary Artery Disease

• Congenital abnormalities

• 45 minutes• Correlation needed

with other studies (stress test or cardiac cath)

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Sadly, a Common Method of Diagnosing CAD

ACS

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1.67 Million Hospital DischargesACS

1.352 MillionDischarges per Year

652,000Discharges per Year

* UA=unstable angina.† NSTEMI=nonST-segment elevation myocardial infarction (also known as non–Q-wave MI). **STEMI=ST-segment elevation MI (also known as Q-wave MI).American Heart Association. Heart Disease and Stroke Statistics—2005 Update. 2004.

ACS

USA/NSTEMI

MI

Hospital Discharges for ACS: UA/NSTEMI vs STEMI

USA*

STEMI**NSTEMI†

700,000 973,000

321,000‡

Discharges per Year

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A Dangerous Transition

Coronary artery with “stable” atherosclerosis

Coronary artery with ruptured “unstable” atherosclerotic plaque

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When “there’s an elephant on my chest”:

Don’t Do/Watch This Instead, Do This

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One Often Leads to Another…

Coronary Atherosclerosis Cardiac catheterization and PCI

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CAD Starts EARLY

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Vascular Disease: A GeneralizedVascular Disease: A Generalizedand Progressive Processand Progressive Process

UnstableanginaMI

Ischemicstroke/TIA

Critical legischemiaCardiovasculardeath

ACS

AtherosclerosisAtherosclerosis

Adapted from Adapted from StaryStary HC et a l. HC et a l. Circu lationCircu lation. 1995;92:1355-1374 and . 1995;92:1355-1374 and FusterFuster V. V. VascVasc Med Med . 1998;3:231-239.. 1998;3:231-239.

Stable anginaIntermittent claudication

Thrombosis

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Superior doctors prevent the disease.Mediocre doctors treat the disease before evident.

Inferior doctors treat the full-blown disease.--Huang Dee: Nai Ching

(2600 BC First Chinese Medical Text)

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Framingham, Mass.

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National ACC speaker for my upcoming conference 5/2/2015

Circulation. 1999; 100: 988-998

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Circulation.1998; 97: 1837-1847

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Framingham Score (CAD event risk)

Circulation. 1999; 100: 988-998

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1.20

1.101.06

1.02

1.006

0.95

5 10 20 40 60 80 1000

ChylomicronRemnants

VLDL

IDL

LDL

HDL2

HDL3

Diameter (nm)

De

ns

ity

(g

/ml)

Chylo-microns

Lipoprotein (Sub)Classes

Lp(a)

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LDL-C Levels and CAD Risk

Adapted from Am J Cardiol, Vol 82, CM Ballantyne, Low-density lipoproteins and risk for coronary artery disease, pp. 3Q-12Q, Copyright 1998, with permission from Excerpta Medica Inc. Heart Protection Study Collaborative Group.

Lancet. 2002;360:7–22.

0

5

10

15

20

25

30

40 60 80 100 120 140 160 180 200

Mean On-Treatment LDL-C Level at Follow-Up, mg/dL

▼4S

CARE

LIPID

HPS

AFCAPS

WOSCOPS

2° Prevention

1° Prevention

CAD + Revasc + Stroke (HPS = CAD Only)Solid Shapes = Drug Rx

Outline Shapes = Placebo

CA

D E

ven

ts,

%

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Landmark Statin Trials: LDL-C Levels vs Events (primary prevention)

Per

cen

tag

e w

ith

CH

D e

ven

t

Primary preventionPravastatinLovastatin

Modified from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1):S17-S21

Atorvastatin

10

5.4 (210)2.3 (90) 2.8 (110)

3.4 (130) 3.9 (150) 4.4 (170) 4.9 (190)

WOSCOPS-S WOSCOPS-P

0

5 AFCAPS-S AFCAPS-P

9876

4321

ASCOT-P

ASCOT-S

LDL-C, mmol/L (mg/dL)

S = statin treated; P = placebo treated

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Baseline

LDL-C (mg/dL)Statin

(n = 10,269)Placebo

(n = 10,267)

<100 282 (16.4%) 358 (21.0%)

100–129 668 (18.9%) 871 (24.7%)

130 1083 (21.6%) 1356 (26.9%)

All patients 2033 (19.8%) 2585 (25.2%)

Event Rate Ratio (95% CI)

Statin Better Statin Worse

0.4 0.6 0.8 1.0 1.2 1.4

0.76 (0.72–0.81)

P<0.0001

Heart Protection Study (HPS)

20,536 patients with CAD, other occlusive arterial disease, or DM randomized to simvastatin (40 mg) or placebo for 5.5 years

CAD=Coronary artery disease, CI=Confidence interval, DM=Diabetes mellitus,

HPS Collaborative Group. Lancet 2002;360:7-22

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Heart Protection Study(5-Year Trial)

0

1

LogCHDRisk

100 LDL-C (mg/dL)

Simvastatin40 mg

60

26% Reduction in CVD

22% Reduction in CVD

Simvastatin40 mg

Heart Protection Study Collaborative Group. Lancet 2002;360:7–22.

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What Is Desirable Cholesterol?

50 70 90 110 130 150 170 190 210

Adult American

San

Pygmy

!Kung

Inuit

Hazda

Hunter-gatherer humans

Mean total cholesterol, mg/dL

Cholesterol Levels Among Different Human Populations

Adapted from O’Keefe JH Jr et al. J Am Coll Cardiol. 2004;43:2142–2146.

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Coronary IVUS Progression Trials

-1.2

-0.6

0

0.6

1.2

1.8

50 60 70 80 90 100 110 120

)

REVERSAL

pravastatin

REVERSAL

atorvastatin

CAMELOT

placebo

A-Plus

placebo

ACTIVATE

placebo

Relationship between LDL-C and Progression Rate

ASTEROIDrosuvastatin

r2= 0.95p<0.001

Nissen S. JAMA 2006

MedianChange

In PercentAtheromaVolume

(%)

Mean Low-Density Lipoprotein Cholesterol (mg/dL)

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Intensive LDL-C Goals for High-Risk Patients

*And other forms of atherosclerotic disease.2†Factors that place a patient at very high risk: established cardiovascular disesase (CVD) plus:

multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (eg, cigarette smoking); metabolic syndrome (triglycerides [TG] ≥200 mg/dL + non–HDL-C ≥130 mg/dL with HDL-C

<40 mg/dL); and acute coronary syndromes.1

1. Grundy SM et al. Circulation. 2004;110:227–239.2. Smith SC Jr et al. Circulation, 2006; 113:2363–2372.

AHA/ACC guidelinesfor patients with CHD*,2

<100 mg/dL:Goal for all

patients with CHD†,2

<70 mg/dL:A reasonable

goal for all patientswith CHD†,2

ATP IIIUpdate 20041

<100 mg/dL:Patients with

CHD or CHD riskequivalents

(10-year risk >20%)1

<70 mg/dL:Therapeutic

option for veryhigh-risk patients1

<100 mg/dL

<70 mg/dL

2006Update

Recommended LDL-C treatment goals

• If it is not possible to attain LDL-C <70 mg/dLbecause of a high baseline LDL-C, it generally

is possible to achieve LDL-C reductions of >50% with more intensive LDL-C─lowering

therapy, including drug combinations.

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We’ve Come a Long Way Since Back Then…

But Sadly, Some People Still Haven’t Gotten the

Message…

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“Stopping smoking is easy………….I’ve done it many times!”

“I don’t smoke; the cigarette does!”

- Said by a patient to Andrew R. Waxler, Internal Medicine intern at UPMC 1992

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56Circulation. 1999; 100: 988-998

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60

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61Clinical Diabetes January 2006 vol. 24 no. 1 27-32

62BMJ 316:823 -828, 1998

63BMJ 316:823 -828, 1998

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What about meds for Secondary Prevention?

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ACC/AHA Treatment Recommendationsfor the Long-term Management of ACS*

* UA/NSTEMI=unstable angina/non–ST-segment elevation myocardial infarction (also known as non–Q-wave MI).† If possible, withhold clopidogrel 5 to 7 days prior to the procedure.Braunwald E, et al. Available at: www.acc.org. Accessed February 10, 2005.

Cath lab

CABG†

ACS(UA/NSTEMI* patients)

Long-term management1. ASA2. Clopid.(?Prasug./Ticag.)3. ß-blocker4. ACE Inhibitor5. Statin

PCI (with or

without stent)

Medical Management

Medical Management

(no intervention required)

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67ADP=adenosine diphosphate, TXA2=thromboxane A2, COX=cyclooxygenase.Schafer AI. Am J Med. 1996;101:199-209.

collagenthrombin

TXA2

ADP

TXA2

ADP phosphodiesterase

ADP

(fibrinogenreceptor)

GP IIb/IIIaActivation

COX

clopidogrel bisulfate

ticlopidine HCl

aspirin

dipyridamole

cAMP

Mechanisms of Action of Oral Antiplatelet Therapies

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Efficacy of Aspirin Doses on Vascular Events in High-Risk Patients

* Odds reduction. Treatment effect P<0.0001.Adapted with permission from the BMJ Publishing Group. Antithrombotic Trialists’

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

0 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 # Trials OR* (%) Odds Ratio

Antithrombotic Trialists’ Collaboration

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Primary End Point: MI/Stroke/CV Death

* Other standard therapies were used as appropriate.† PLAVIX Prescribing Information.

Adapted with permission (2002) from the Massachusetts Medical Society. The CURE Trial Investigators. N Engl J Med.2001;345:494-502.

CURE

Months of Follow-Up

Clopidogrel + ASA*

3 6 9

Placebo + ASA*

P=0.00009†

N=12,562

0 12

20%Relative Risk

Reduction

The primary outcome occurred in 9.3% of patients in the clopidogrel + ASA group and 11.4% in the placebo + ASA group.C

um

ula

tiv

e H

azar

d R

ate

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

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Patients Treated with PCI* and/or CABG

* PCI was also referred to as PTCA.† Other standard therapies were used as appropriate.‡ In the combined end point of MI, stroke, or CV death. Only first events after randomization were counted in the composite end

point.Data on file, Sanofi-Synthelabo Inc.

CURE

Clopidogrel + ASA†

(11.4%)

100 200

Placebo + ASA†

(13.8%)

0 300

18%Relative Risk

Reduction

(P=0.015‡)

0.00

0.05

0.10

0.15

0.20

Days of Follow-Up

Cu

mu

lati

ve

Haz

ard

Rat

e

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Patients Treated with Medical Therapy

* PCI was also referred to as PTCA. † Other standard therapies were used as appropriate.‡ In the combined end point of MI, stroke, or CV death. Only first events after randomization were counted in the composite end

point.Data on file, Sanofi-Synthelabo Inc.

CURE

100 200 3000

Placebo + ASA†

(10.0%)

Clopidogrel + ASA†

(8.1%)

20%Relative Risk

Reduction

(P=0.0025‡)

0.00

0.05

0.10

0.15

0.20 Without PCI* and/or CABG

Days of Follow-Up

Cu

mu

lati

ve

Haz

ard

Rat

e

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CHARISMA: Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death)*

* First occurrence of MI, stroke (of any cause), or cardiovascular death.† All patients received ASA 75-162mg/day.‡ The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary efficacy events that occurred

beyond this time (13 clopidogrel and 8 placebo)1. Adapted from Bhatt DL et al. 2006, in press.2. Bhatt DL. Presented at ACC 2006.

Cu

mu

lati

ve

even

t ra

te (

%)

0

2

4

6

8

Months since randomization‡

0 6 12 18 24 30

Placebo + ASA†

7.3%

Clopidogrel + ASA†

6.8%1

RRR: 7.1% [95% CI: -4.5%, 17.5%]p=0.222

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Population N RR (95% CI) p value

Documented AT 12,153 0.88 (0.77, 0.998) 0.046

Coronary 5,835 0.86 (0.71, 1.05) 0.13

Cerebrovascular 4,320 0.84 (0.69, 1.03) 0.09

PAD 2,838 0.87 (0.67, 1.13) 0.29

Multiple RF 3,284 1.20 (0.91, 1.59) 0.20

Overall Population 15,603 0.93 (0.83, 1.05) 0.22

CHARISMA: Primary Efficacy Results (MI/Stroke/CV Death)* by Category of Inclusion Criteria

RF=Risk Factors, AT=Atherothrombosis.* First occurrence of MI, stroke (of any cause), or CV Death.

Bhatt DL. Presented at ACC 2006.

0.6 0.8 1.41.2Clopidogrel Better Placebo Better

1.60.4

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2002 ACC/AHA UA/NSTEMI* Guideline Update: Recommendations for Long-Term Medical Therapy

Class I

Aspirin 75 to 325 mg/day (level of evidence: A)

Clopidogrel 75 mg daily (in the absence of contraindications) when ASA is not tolerated because of hypersensitivity or gastrointestinal intolerance(level of evidence: A)

The combination of ASA and clopidogrel for 9 months after UA/NSTEMI (level of evidence: B)

Beta-blockers in the absence of contraindications (level of evidence: B)

Lipid-lowering agents and diet in post-ACS and post-revascularization patients with LDL cholesterol >130 mg/dL (level of evidence: A)

Lipid-lowering agents if LDL cholesterol level after diet is >100 mg/dL (level of evidence: C)

ACE inhibitors for patients with CHF, LV dysfunction (EF <0.40), hypertension, or diabetes (level of evidence: A)

* Also known as non–Q-wave MI. Braunwald E, et al. Available at: www.acc.org. Accessed February 18, 2004.

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Discharge Medication Use – Last 12 Months(In patients without contraindications)

* LVEF <40%, CHF, DM, HTN.† Known hyperlipidemia, TC, LDL.

CRUSADE data October 1, 2003-September 30, 2004 (n=40,386) Adapted with permission from CRUSADE Web site. Available at: http://www.crusadeqi.com. Accessed March 11, 2005.

CRUSADE

93% 89%

0%

20%

40%

60%

80%

100%

ASA Beta Blockers

ACE-Inhibitors*

64%

Any Lipid-Lowering

Agent†

86%

69%

Clopidogrel

Util

izat

ion

of T

hera

pies

(%

)

84

0

1

2

3

4

5

6

7

≤25% ≥75%

Hospital Composite Adherence Quartiles

In-H

ospi

tal M

orta

lity

(%)*

Relationship Between Guidelines Adherence and In-Hospital Mortality

Improved Hospital Adherence

* Adjusted figure.Cumulative CRUSADE data (adjusted) through September 2004. Adapted with permission from CRUSADE Web site. Available at: http://www.crusadeqi.com. Accessed February 10, 2005.

4.2%

5.0%5.2%

6.0%

25–50% 50–75%

CRUSADE

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Clinical Outcomes Utilizing Revascularization and Aggressive Guideline-Driven Drug Evaluation

- Presented at the ACC meeting, March, 2008, New Orleans, LA

- Published NEJM 2007; 356

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COURAGE: Risk Factor GoalsVariable Goal

Smoking Cessation

Total Dietary Fat / Saturated Fat <30% calories / <7% calories

Dietary Cholesterol <200 mg/day

LDL cholesterol (primary goal) 60-85 mg/dL

HDL cholesterol (secondary goal) >40 mg/dL

Triglyceride (secondary goal) <150 mg/dL

Physical Activity 30-45 min. moderate intensity 5X/week

Body Weight by Body Mass index Initial BMI Weight Loss Goal25-27.5 BMI <25>27.5 10% relative weight loss

Blood Pressure <130/85 mmHg

Diabetes HbAlc <7.0%

- Presented at the ACC meeting, March, 2008, New Orleans, LA Published NEJM 2007; 356

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COURAGE: Overall Survival

Number at Risk

Medical Therapy 1138 1073 1029 917 717 468 302 38PCI 1149 1094 1051 929 733 488 312 44

Years0 1 2 3 4 5 6

0.0

0.5

0.6

0.7

0.8

0.9

1.0

PCI + OMT

OMT

7

Hazard ratio: 0.8795% CI (0.65-1.16)P = 0.38

- Presented at the ACC meeting, March, 2008, New Orleans, LA Published NEJM 2007; 356

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COURAGE: Long-Term Improvement in Treatment Targets (Group Median ± SE Data)

Treatment Targets Baseline 60 Months

PCI +OMT OMT PCI +OMT OMT

SBP 131 ± 0.77 130 ± 0.66 124 ± 0.81 122 ± 0.92

DBP 74 ± 0.33 74 ± 0.33 70 ± 0.81 70 ± 0.65

Total Cholesterol mg/dL 172 ± 1.37 177 ± 1.41 143 ± 1.74 140 ± 1.64

LDL mg/dL 100 ± 1.17 102 ± 1.22 71 ± 1.33 72 ± 1.21

HDL mg/dL 39 ± 0.39 39 ± 0.37 41 ± 0.67 41 ± 0.75

TG mg/dL 143 ± 2.96 149 ± 3.03 123 ± 4.13 131 ± 4.70

BMI Kg/M² 28.7 ± 0.18 28.9 ± 0.17 29.2 ± 0.34 29.5 ± 0.31

Moderate Activity (5x/week) 25% 25% 42% 36%

- Presented at the ACC meeting, March, 2008, New Orleans, LA Published NEJM 2007; 356

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Keep it Simple; Don’t Overthink it

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Summary

• CAD remains the number one cause of morbidity and mortality among adults in the USA. There are approximately 1.5-2.0 million episodes of ACS annually.

• For essentially half a century, we have had data regarding “CAD risk factors”. We also some very reasonable data demonstrating that interventions do work.

• Primary and secondary prevention of CAD events can be accomplished but is challenging and may require an astute/aggressive doctor and a motivated patient

• Keep it simple….remember the basics……

99

For a cigarette-smoking patient who has an MI, what is the approximate risk reduction of future MI (over the next several years) that he/she will get from smoking cessation?

A. There is no significant change in risk of second MI from smoking cessation at time of first MI

B. Only about 10%

C. About 25%

D. About 50%

E. Between 75-100%

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100

Based on the most recent (2013) lipid guidelines, which of the following patients do NOT automatically qualify for statin therapy:

A. Healthy 37 y.o. woman with LDL 227, no other medical probs

B. 54 y.o. man with recent MI and PCI of LAD; his LDL is 65

C. 44 y.o. man with Diabetes and LDL 90; asymptomatic

D. Options A and C

E. All of the above qualify

101

Which of the following types of patients should receive dual-antiplatelet therapy for 9-12 months following ACS? (ASA/clopid.)

A. Patient with ACS treated with Percutaneous Coronary Intervention(PCI)?

B. Patient with ACS treated Coronary Artery Bypass Graft (CABG)?

C. Patient with ACS treated medically (no PCI or CABG)?

D. What about a High-risk patient who has NOT had ACS (ie, DM)?

E. A, B, and C

F. All of the above