Myocardial Ischemia Update

MyocardialIschemia Update

Chronic Ischemic Heart Disease: Overview

• Highly prevalent– 6.5-16.5 million in the US

• Multifactorial etiology– CAD, hypertension, hypertrophic cardiomyopathy, valvular heart

disease

• High socioeconomic burden– Depression– Quality of life– High costs of care

Gibbons RJ et al. www.acc.org.

Repeat revascularization is common post-PCI/CABG

Kempf J et al. Presented at ESC. 2007.

N = 18,240 who underwent elective PCI or CABG

46

30

0

10

20

Patients(%)

Recurrentangina

2nd revascularization

30

40

50

Angina increases cost of care

0

10

20

30

40

50

Patients (%)

Asymptomatic CAD Angina

Prior to diagnosis Following diagnosis

ED visits HospitalizationsED visits

Kempf J et al. Presented at Scientific Forum on Quality of Care and Outcomes Res in CV Disease. 2006.

US managed care enrollees, n = 140,001 with asymptomatic CAD, n = 23,535 with angina Dx*

Average yearly cost/patient

$11,530 (asymptomatic CAD)

vs $22,004 (angina)

*And Rx nitrates and/or β-blockers and/or CCBs

WISE: Landmark study in women

Goals:

• Improve diagnostic testing for ischemic heart disease in women

• Study pathophysiologic mechanisms for ischemia in the absence of epicardial coronary artery stenoses

• Evaluate the influence of menopausal status and reproductive hormone levels on diagnostic testing results

Bairey Merz CN et al. J Am Coll Cardiol. 1999;33:1453-61.Women’s Ischemia Syndrome Evaluation

Prospective cohort study conducted at 4 US sites

WISE: Persistent chest pain in women predicts future CV events

Johnson BD et al. Eur Heart J. 2006;27:1408-15.

With CADHR 1.17 (0.76–1.80)P = 0.49

Without CADHR 1.89 (1.06–3.39)P = 0.03

Event-freesurvival

(%)

Years from PChP diagnosis (at one year)

0.7

0.6

1

0.9

0.8

0 1 2 3 4 5 6

Neither PChPNo CAD

No PChPCAD

Both

n = 673 WISE participants with chest pain at baseline

PChP = persistent chest pain

WISE: Persistent chest pain associated with diminished QOL

No obstructive CAD Obstructive CAD

No PChP PChPNo

PChP PChP

Angina symptoms

Typical presentation (%) 30 33 32 40

Intensity (range 1-5) 2.3 2.6* 2.6 2.6

Daily frequency (%) 30 49* 34 39*

Psychological symptoms

Perceived QOL† 7.3 6.6* 7.1 6.6

Depression‡ 8.8 12.2* 9.3 12.9*

Anxiety‡ 18.0 20.1* 17.7 20.1

*Adjusted P ≤ 0.04†Range: 1 - 10 (best); ‡score = trait

Johnson BD et al. Eur Heart J. 2006;27:1408-15. Bairey Merz CN et al. J Am Coll Cardiol. 1999;33:1453-61.

*

** * *

WISE: CAD imposes an economic burden

Shaw LJ et al. Circulation. 2006;114:894-904.

N = 883 women with angiographic CAD

80

70

60

50

40

30

20

10

0

Cumulative observed

direct costs ($, thousands)

Nonobstructive CAD

2 3 4 5

1 vessel CAD 2 vessel CAD 3 vessel CAD

Follow-up (years)

1

*P < 0.0001 nonobstructive vs 1-3 vessel CAD

Contemporary clinical practice of ischemic heart disease

Adapted from Timmis AD et al. Heart. 2007;93:786-91.

Angiogram

Cardiologist referral

Treatment(Angina, risk factors)

Risk stratification(Stress test, CT angio)

Presentation to PCP

Incident angina

Visible

Submerged

Revas

Healthy population

Opportunity for early detection, risk stratification, and medical therapy

Revas = revascularization

Examining the Science Underlying Myocardial Ischemia

Severe obstruction (angina, no rupture) vs mild obstruction (no angina, likely to rupture)

RevascularizationAnti-anginal Rx

Exertional angina• (+) ETT

Severe fibrotic plaque• Severe obstruction• No lipid• Fibrosis, Ca2+

Pharmacologic stabilizationEarly identification of high-risk?

Plaque rupture• Acute MI• Unstable angina• Sudden death

Vulnerable plaque• Minor obstruction• Eccentric plaque• Lipid pool• Thin cap

Courtesy of PH Stone, MD.

Major cardiac events occur in non-target areas following successful PCI

Hazardrate (%)

Cutlip DE et al. Circulation. 2004;110:1226-30.

Substantial number of cardiac events could be preventedif non-obstructive, high-risk lesions were identified

Target lesion event

Non-target lesion event

0

5

10

15

20

1 2 3Year

4 5

Local determinants of the natural history of individual coronary lesionsOpportunities for identification and intervention

Courtesy of PH Stone, MD and R Gerrity, PhD.

Quiescent,stable plaque No symptoms

Fibrotic/scarred plaque Angina

Thin capFibroatheroma MI, sudden death

Quiescence

Inflammation

Proliferation

Calcification

Local factorsLocal factorsShear stress

•Proliferation•Inflammation•Remodeling

Proposed classification scheme for atherosclerotic plaque

Plaque trajectory Histopathology

Progression rate

Vascular remodeling

Proclivity to rupture

Clinical manifestation

Quiescent plaque

Small lipid core

Thick fibrous cap

Minimal Compensatory expansive remodeling

Low Asymptomatic

Stenotic plaque

Small lipid core

Very thick fibrous cap

Gradual Constrictive remodeling

Low Stable angina

High-risk plaque

Large lipid core

Thin and inflamed fibrous cap

Increased Excessive expansive remodeling

High ACS

Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.

The spectrum of CAD

Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.ESS = endothelial shear stress

Physiologiccoronary artery

Asymptomatic Stable angina ACS

Early fibroatheroma

Inner curvature:Low ESS region

(atherosclerosis-prone)

20%

Fibroproliferation

Quiescent plaque Stenotic plaque Thin cap fibroatheroma

Ru

ptu

re

Microruptures

Low ESS

High ESS

Lower ESSVulnerability

Intense inflammation

Physiologic ESS

Limited inflammation

Erosion

20%60%

Substrate• Vulnerable ischemic zone• Intracoronary thrombus• Autonomic influence• Hemodynamic compromise

Ventricular arrhythmogenesis in ischemic myocardium

Adapted from Luqman N et al. Int J Cardiol. 2007;119:283-90.

VPC = ventricular premature contractionVT = ventricular tachycardia

Risk factors• Age• Heredity• Gender• Smoking• Lipids• Hypertension• Diabetes• Obesity

•Clinical or subclinical susceptibility •Structural substrate present

High risk of transient acute ischemia reperfusion

Triggers• VPC• VT• Reentry

+ Ventricular fibrillation

O2 demand

Causes and consequences of myocardial ischemia: New understanding

Consequences of ischemia

Electrical instabilityMyocardial dysfunctionIschemia

Heart rateBlood pressurePreloadContractility

Development of ischemia

O2 supply

Na+ and Ca2+ overload

Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

Na+

Na+

Overview of the sodium channel

out

in

out

in

Na+/Ca2+

Exchanger

Ca2+

Ca2+

Ca2+

Ca2+

Na+

Na+

Na+

Na+Na+

Restingclosed

Na+

ActivatedActivatedInactivated

Na+

Na+

Na+ Ca2+

Ca2+

[Na+]= 140 mM ~10mM

Courtesy of L Belardinelli, MD.

Ca2+

[Na+]

Origin of late INa

• During the plateau phase of the action potential, a small proportion of sodium channels either do not close, or close and then reopen

• These late channel openings permit a sustained Na+ current to enter myocytes during systole


Sodiumcurrent

0

Late

Peak

Sodiumcurrent

0

Late

Peak

0

Late

Peak

Sodiumcurrent

Ischemia

Myocardial ischemia causes enhanced late INa

Enhanced late INa appears to be a major contributor to increased intracellular Na+ during ischemia


Role of altered ion currents in adverse consequences of myocardial ischemia

[Na+]i = intracellular [Na+]NCX = Na+/Ca2+ exchanger APD = action potential duration Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

Disease(s) and pathological states linked to imbalance of O2 supply/demand

Cytosolic Ca2+

NCX

Late INa

Na+ entry ([Na+]i)

Mechanical dysfunction• Abnormal contraction and relaxation• Diastolic tension

Electrical instability• Afterpotentials• Beat-to-beat APD• Arrhythmias (VT)

Diastolic relaxation failure adversely affects myocardial O2 supply and demand

• Sustained contraction of ischemic tissue during diastole:– Increases MVO2

– Compresses intramural small vessels• Reduces myocardial blood flow

Courtesy of PH Stone, MD.

Exacerbates ischemia

MVO2 = myocardial oxygen consumption

Fraser H et al. J Mol Cell Cardiol. 2006;41:1031-8.

Late INa inhibition blunts Ca2+ accumulation

Time of perfusion (min)

ATX-II alone (n = 11)

ATX-II + ranolazine 4 μM (n = 9) or 9 μM (n = 9)

*P < 0.05 vs ATX-II aloneATX-II = sea anemone toxin (selectively late INa)

Indo fluorescence(F405/F485

ratio)

0.30

0.25

0.20

0.15

0.100 10 20 30 40 50

LV work(L/min per

mm Hg)

12

8

4

0

ATX-II

RAN

0 10 20 30 40 50

RAN

ATX-II

**

*

*

Ranolazine blunts sotalol-induced action potential prolongation in dogs

Antzelevich C et al. Circulation 2004;110:904-10.

Control

d-Sotalol

+ Ranolazine 5 uM

+ Ranolazine 10 uM

50 mV

1 sec

Transmembrane action potentials (superimposed)

Issues in chronic myocardial ischemia treatment

Bhatt AB, Stone PH. Curr Opin Cardiol. 2006;21:492-502.Boden WE et al. Am Heart J. 2006;151:1173-9.

Despite existing treatments, ischemic episodes frequently occur

PCI is one approach to reduce angina frequency

Trials of all proven noninterventional therapies alone and in combination are needed

Pathophysiology of angina is complex; relationship of angina to ACS is unclear

Implications for clinical trials

Stable CAD: Multiple treatment options

Reduce symptoms

Treat underlying

diseasePCI

Lifestyle intervention

CABG

Medicaltherapy

SAFE-LIFE: Evaluation of intensive lifestyle intervention

Michalsen A et al. Am Heart J. 2006;151:870-7.

Advice on Mediterranean

diet

Stress management≥30 min daily

Encouraged to physical

activity

3-day nonresidential retreat

Weekly 3-hr meetings x 10 weeks

Biweekly 2-hr meetings x 9 months

Control group received printed lifestyle advice only

N = 101 with CAD

SAFE-LIFE: Reduction in angina at 1 year with intensive lifestyle intervention

Angina score

-35

-30

-25

-20

-15

-10

-5

0

Percent change

Control Lifestyle

Angina frequency

-60

-50

-40

-30

-20

-10

0

10

20

Michalsen A et al. Am Heart J. 2006;151:870-7.

P = 0.015 P = 0.01

Chronic ischemic heart disease: Treatment gaps

• Most patients have relative intolerances to maximum doses of traditional antianginal agents (-blockers, CCBs, and nitrates)

Pepine CJ et al. Am J Cardiol. 1994;74:226-31.


• Antianginal drugs without these limitations are needed

• Patients continue to experience myocardial ischemia -blockers and many CCBs have similar depressive hemodynamic and

electrophysiologic effects

Novel anti-ischemic strategy

Consequences of ischemia

Electrical instabilityMyocardial dysfunctionIschemia

Heart rateBlood pressurePreloadContractility

Development of ischemia

Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.

Ranolazine (late Na+ current inhibition)Nitrates, β-blockers, CCBs

O2 demand

O2 supply

Ca2+ overload

StableStableanginaangina

UnstableUnstableanginaangina

Myocardial Myocardial infarctioninfarction

Heart Heart failurefailure

Silent Silent CADCAD DeathDeath

NSTEMINSTEMI STEMISTEMI

MARISACARISAERICA

MERLIN-TIMI 36

Courtesy of BR Chaitman, MD.

Ranolazine clinical trial program

Ranolazine clinical trial program in chronic stable angina

Study NRanolazine dosing

(mg bid)Background antianginal therapy

MARISA 191 50010001500

No

CARISA 823 7501000

Amlodipine 5 mgAtenolol 50 mgDiltiazem 180 mg

ERICA 565 1000 Amlodipine 10 mg

Chaitman BR et al. J Am Coll Cardiol. 2004.Chaitman BR et al. JAMA. 2004.

Stone PH et al. J Am Coll Cardiol. 2006.

Monotherapy Assessment of Ranolazine In Stable AnginaCombination Assessment of Ranolazine In Stable AnginaEfficacy of Ranolazine In Chronic Angina

MARISA, CARISA, ERICA main findings

• As monotherapy, ranolazine improves exercise performance in the absence of clinically meaningful pathophysiologic effects

• These studies provide evidence of additional antianginal and anti-ischemic efficacy in patients who remain symptomatic on standard therapies or maximal amlodipine therapy

Chaitman BR et al. J Am Coll Cardiol. 2004.Chaitman BR et al. JAMA. 2004.

Stone PH et al. J Am Coll Cardiol. 2006.

Antianginal efficacy by gender

Wenger NK et al. Am J Cardiol. 2007;99:11-8.

MARISA CARISA

Ranolazine

*P = 0.014, †P < 0.001, ‡P ≤ 0.037 vs placebo

Exercise duration, sec

(Δ from placebo)

60

40

20

0500 mg 1000 mg 1500 mg

Exercise duration, sec

(Δ from baseline)

150

100

50

0Placebo 750 mg 1000 mg

Women Men

NS

*

NS†

NS

†

NS

‡

NS

‡

Ranolazine

Improved exercise duration

SAQ angina frequency score

(Δ from baseline)

0

10

20

30

Placebo + amlodipine Ranolazine + amlodipine

Antianginal efficacy by gender

Wenger NK et al. Am J Cardiol. 2007;99:11-8.

ERICA studySAQ = Seattle Angina Questionnaire

Women Men

NS

P = 0.016

Improved angina score

Antianginal efficacy by diabetes status

3.03.4

2.1

2.6

1.0

2.5

0

1

2

3

4

Diabetes (n = 189) No diabetes (n = 634)

Anginaepisodes per week (mean)

Timmis AD et al. Eur Heart J. 2006;27:42-8.

Placebo Ranolazine 750 mg bid

Ranolazine 1000 mg bid

CARISA studyP = 0.81 (interaction between diabetes status and treatment effect)

CARISA: Reductions in A1C (diabetes substudy)

Possible mechanisms: Insulin sensitivityPhysical activity

-0.02

-0.5

-0.72-0.8

-0.6

-0.4

-0.2

0

Cooper-DeHoff R, Pepine CJ. Eur Heart J. 2006;27:5-6.Timmis AD et al. Eur Heart J. 2006;27:42-8.*P ≤ 0.008 vs placebo

n = 131 with diabetes (n = 31 on insulin)

Least squares

mean(%)

*

*

AIC change from baseline

Placebo Ranolazine 750 mg bid

Ranolazine 1000 mg bid

Summary: Ranolazine in challenging populations

• Antianginal efficacy independent of:– Gender– Age– Diabetes status

• Also associated with ↓A1C in patients with diabetes

Wenger NK et al. Am J Cardiol. 2007.Stone PH et al. J Am Coll Cardiol. 2006.

Timmis AD et al. Eur Heart J. 2006.

ROLE: Long-term safety and tolerability in stable CAD patients

• Adverse events:– Most common: dizziness (11.8%) and constipation (10.9%)– Discontinuation: dizziness (0.9%), constipation (0.6%)– Total of 72 patients (9.7%) discontinued due to adverse events

• ECG findings:– Mean QTc prolongation 2.4 ms (P < 0.001 vs baseline)– QTc >500 ms in 10 patients (1.2%)– No cases of Torsades de Pointes

Ranolazine Open-Label Experience Koren MJ et al. J Am Coll Cardiol. 2007;49:1027-34.

2.8-year mean follow-up; >80% entered open-label extension

N = 746 ranolazine patients who completed MARISA or CARISA

MERLIN-TIMI 36: Study design

IV/oral ranolazine Placebo

Patients with non-ST-elevation ACStreated with standard medical/interventional therapies

N = 6560

Primary efficacy endpoint:CV death, MI, recurrent ischemia

Safety endpoints:All-cause death, CV hospitalization, symptomatic documented arrhythmia,

clinically significant arrhythmia on Holter during first 7 days

RandomizedDouble-blind

Morrow DA et al. JAMA. 2007;297:1775-83.

Metabolic Efficiency with Ranolazine for Less Ischemia in Non-St-Elevation Acute Coronary Syndromes

MERLIN-TIMI 36: Effect on primary endpoint


Ranolazine vs placebo within 48 hrs of ischemic symptom onset

No. at riskPlaceboRanolazine

32813279

24542450

12231223

268269

HR 0.92(95% CI 0.83-1.02)Log-rank P = 0.11

30

20

10

00 180 360 540

Days

Placebo Ranolazine

CV death, MI, or

recurrent ischemia

(%)

MERLIN-TIMI 36: Components of primary endpointMERLIN-TIMI 36: Components of primary endpoint

Morrow DA et al. JAMA. 2007;297:1775-83.*Event rates at 12 months

n = 3279 ranolazine group, n = 3281 placebo group

CV death or MI Recurrent ischemia

Ranolazine 13.9%*

Placebo 16.1%*

0 180 360 5400

5

10

15

20

0

5

10

15

0 180 360 540

Ranolazine 10.4%*

20

Days

Cumulativepercentage

HR 0.99(95% CI 0.85-1.15)Log-rank P = 0.87

HR 0.87(95% CI 0.76-0.99)Log-rank P = 0.03

Placebo 10.5%*

MERLIN-TIMI 36: Efficacy results in major subgroups


0.6 0.8 1.41.2 1.6

Favors ranolazine Favors placebo

Gender MenWomen

Age <75 years≥75 years

Diabetes No DMDM

SubgroupPrimary endpoint

n

TIMI Risk 0-34-7

STD ≥1 mm NoYes

Overall 6560

42692291

54061154

43402220

36012959

42552304

Pinteraction

0.12

0.80

0.39

0.16

0.23

Index event UANSTEMI

30673342

0.85

HR (95% CI)

STD = ST-segment depression

MERLIN-TIMI 36: Primary arrhythmia endpoints

Rate (%)

Ranolazine Placebo P

Ventricular events

VT ≥3 beats 52.1 60.6 <0.001

Supraventricular events

SVT ≥4 beats 44.7 55.0 <0.001

New-onset AF 1.7 2.4 0.08

Bradycardiac events

Bradycardia, heart block, pause ≥2.5 sec 39.8 46.6 <0.001

Bradycardia 35.6 43.0 <0.001

Pause ≥3 sec 3.1 4.3 0.01

Scirica BM et al. Circulation. 2007;116.

SVT = supraventricular tachycardia

MERLIN-TIMI 36: Reduction in VT lasting ≥8 beats


0

2

4

6

8

10

0 24 48 72 96 120 144 168

Hours from randomization

Incidence

(%) Ranolazine

Placebo

RR 0.63 (0.52-0.76)P < 0.001

RR 0.67P = 0.008

RR 0.65P < 0.001

8.3%

5.3%

Ranolazine(%)

Placebo(%) P

RR (95% CI)

Ischemia on cECG 6.3 8.3 0.12

No ischemia on cECG 5.0 8.3 <0.001

Prior HF 5.4 9.3 0.013

No prior HF 5.2 8.1 <0.001

TRS 5-7 4.4 8.9 0.001

TRS 0-4 5.5 8.2 <0.001

0.1 1 10

QTc >450 msec 5.6 10.5 0.002

QTc ≤450 msec 5.2 7.8 <0.001

EF <40% 8.8 16.6 0.005

EF ≥40% 5.3 7.3 0.011

MERLIN-TIMI 36: Incidence of VT MERLIN-TIMI 36: Incidence of VT ≥≥8 beats 8 beats in high-risk subgroupsin high-risk subgroups

TRS = TIMI risk scorecECG = continuous ECG Scirica BM et al. Circulation. 2007;116.

Ranolazine (%)

Placebo (%) P

Polymorphic VT ≥8 beats 1.2 1.4 0.40

Sustained VT (≥30 sec) 0.44 0.44 0.98

Monomorphic VT 0.13 0.22 0.37

Polymorphic VT 0.32 0.22 0.46


MERLIN-TIMI 36: Ventricular tachycardia eventsMERLIN-TIMI 36: Ventricular tachycardia events

MERLIN-TIMI 36: Major safety outcomes

Event rate (%)

Ranolazine(n = 3268)

Placebo(n = 3273) P

All-cause death 5.3 5.4 0.91

Sudden cardiac death 1.7 1.8 0.43

All-cause death or CV hospitalization 33.2 33.4 0.53

Symptomatic documented arrhythmia 3.0 3.1 0.84

Clinically significant arrhythmia on Holter* 73.7 83.1 <0.001


*VT ≥3 beats, SVT ≥120 bpm, new AF, bradycardia <45 bpm, CHB, or pulse >2.5 sec

Ranolazine (%) Placebo (%) P

Overall 1.7 1.8 NS

EF ≥40% 1.5 1.5 0.48

EF <40% 2.7 4.9 0.07

QTc ≤450 msec 1.4 1.6 0.86

QTc >450 msec 3.0 3.0 0.27

TRS 0-4 1.2 1.3 0.47

TRS 5-7 3.5 3.9 0.73

No prior HF 1.2 1.3 0.63

Prior HF 4.1 4.3 0.58


MERLIN-TIMI 36: Sudden cardiac death MERLIN-TIMI 36: Sudden cardiac death by subgroupby subgroup

MERLIN-TIMI 36: Summary and implications

• In patients with ACS, ranolazine added to standard therapy was associated with– No difference in:

• Composite efficacy endpoint of CV death, MI, recurrent ischemia• Safety endpoints of all-cause death, all-cause death or CV

hospitalization, symptomatic documented arrhythmia– Significant reduction in arrhythmias detected by Holter

monitoring during first 7 days


Findings do not support use of ranolazine in ACS but add to previous safety data and provide additional support for ranolazine as antianginal therapy in stable CAD

Stable CAD: Multiple treatment options

Reduce symptoms

Treat underlying

diseasePCI

Lifestyle intervention

CABG

Medicaltherapy

ACIP: Study design

Angiographic CAD (≥50% stenosis in ≥1 major vessel or branch) suitable for revascularization + ischemia during exercise or pharmacologic stress

testing and ≥1 asymptomatic episode during 48-hr AECG

Angina-guided strategy(n = 183)

Ischemia-guided strategy(n = 183)

Revascularization strategy(n = 192)

Primary outcome: Absence of ischemia at 12 weeksSecondary outcomes: Death, MI, recurrent hospitalization for cardiac

disease, nonprotocol revascularization at 1 and 2 years

Pepine CJ et al. J Am Coll Cardiol. 1994:24:1-10.Davies RF et al. Circulation. 1997;95:2037-43. Asymptomatic Cardiac Ischemia Pilot

ACIP: Baseline characteristics

Angina-guided Ischemia-guided Revascularization

Age (years) 61 62 61

Women (%) 10 15 17

Diabetes (%) 11 19 18

Heart failure (%) 3 2 4

Hypertension (%) 32 41 39

Family history (%) 45 36 43

Smoking (%) 19 17 13

Prior MI (%) 38 40 43

Davies RF et al. Circulation. 1997;95:2037-43.

ACIP: Two-year cumulative all-cause mortality rates for the treatment strategies

P < 0.05

P = 0.34

P < 0.005

0

2

4

6

8

Percent

24201512840

Follow-up (months)

1.1% Revascularization

4.4% Ischemia guided

6.6% Angina guided

Davies RF et al. Circulation. 1997;95:2037-43.

COURAGE: Defining optimal care

Reduce symptoms

Treat underlying

disease

Revascularization?

Intensive lifestyle

intervention

Intensive medicaltherapy

Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation

What is the definitive role of PCI in chronic angina and stable CAD?

• PCI improves angina and short-term exercise capacity

• However, compared to optimal medical therapy, does PCI– Prolong survival?– Reduce risk of subsequent MI?– Reduce hospitalization for unstable angina?– Decrease need for subsequent CABG?– Improve quality of life?

Courtesy of WE Boden, MD.

Patient expectations about elective PCI for stable CAD

Holmboe ES et al. J Gen Intern Med. 2000;15:632-7.

Do you think the angioplasty will prevent a heart attack?

Yes 75%

Do you think the angioplasty will help you live longer?

Yes 71%

N = 52 consecutive patients scheduled for first elective PCI; semi-structured questionnaire completed prospectively

COURAGE: Study design

Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16.

Optimal medical therapy* + PCI (n = 1149)

Optimal medical therapy*(n = 1138)

AHA/ACC Class I/II indications for PCI, suitable coronary artery anatomy + ≥70% stenosis in ≥1 proximal epicardial vessel + objective evidence of ischemia

(or ≥80% stenosis + CCS class III angina without provocation testing)

Primary outcomes: All-cause mortality, nonfatal MI

Follow-up: Median 4.6 years

Randomized

*Intensive pharmacologic therapy + lifestyle interventionCCS = Canadian Cardiovascular Society

Secondary outcomes: Death, MI, stroke; ACS hospitalization

COURAGE: Lifestyle intervention and risk factor goals

• Smoking cessation

• Exercise program– ≥30 min moderately intensive exercise

5x/week

• Nutrition counseling– Total dietary fat <30% of calories– Saturated fat <7% of calories– Dietary cholesterol <200 mg/day

• Weight control– BMI <25 kg/m2 (if baseline BMI 25.0-27.5)– 10% relative weight loss

(if baseline BMI >27.5)

• LDL-C (mg/dL)60-85

• HDL-C (mg/dL)≥40

• Triglycerides (mg/dL) <150

• BP (mm Hg)<130/85<130/80 if diabetes or

renal disease present

• A1C (%)<7.0

Boden WE et al. Am Heart J. 2006;151:1173-9.

COURAGE: Pharmacologic therapy

• Antiplatelet – Aspirin– Clopidogrel in accordance with

established practice standards

• Dyslipidemia– Simvastatin ± ezetimibe,

ER niacin, or fibrates

• ACEI, ARB, or diuretic– Lisinopril or losartan

-blocker– ER metoprolol

• Calcium channel blocker– Amlodipine

• Nitrate– Isosorbide 5-mononitrate

Boden WE et al. Am Heart J. 2006;151:1173-9.Boden WE et al. N Engl J Med. 2007;356:1503-16.

COURAGE: Baseline angiographic data

PCI + medical therapy(n = 1149)

Medical therapy(n = 1138)

Vessels with disease (%) 1 2 3

313930

303931

Disease in graft vessel* (%) 62 69

Proximal LAD disease (%) 31 37†

Ejection fraction (%) 60.8 60.9

Boden WE et al. N Engl J Med. 2007;356:1503-16.

*Patients who underwent previous CABG†P = 0.01

COURAGE: Baseline angina



CCS class (%) 0 I II III

12303623

13303719

Median duration (mo) Interquartile range

51-15

51-15

Median episodes/week Interquartile range

31-6

31-6


COURAGE: Inducible ischemia at baseline



Nuclear imaging, % (n) 70 (685) 72 (708)

Single reversible defect, % (n) 22 (154) 23 (161)

Multiple reversible defects, % (n) 65 (444) 68 (483)


COURAGE: Treatment effect on primary outcome

HR 1.05(0.87-1.27)P = 0.62*


All-cause death, MI

*Unadjusted, log-rank

No. at riskMedical therapy 1138 1017 959 834 638 408 192 30PCI 1149 1013 952 833 637 417 200 35

Medical therapy PCI + medical therapy

Survival free of primaryoutcome

0 2 4 70

0.5

0.6

0.7

0.8

1.0

0.9

Years6531

COURAGE: Treatment effect on angina

0

10

20

30

40

50

60

70

80

Baseline 1 3 5

PCI + medical therapy Medical therapy


P < 0.001P = 0.02 NS

Angina-free(%)

NS

Years


COURAGE: Treatment effect in CV and diabetes subgroups

0.25 0.50 1.00 2.001.751.50

Medical therapy betterPCI betterMyocardial infarctionYesNo

Extent of CADMultivessel diseaseSingle-vessel disease

DiabetesYesNo

AnginaCCS 0-ICCS II-III

Ejection fraction

>50%Previous CABG

NoYes

≤50%

Baseline characteristics

Hazard ratio (95% CI)

COURAGE: Change in quality-of-life scores

WS Weintraub, MD. Presented at ACC. 2007.

50

55

60

65

70

75

80

85

90

Baseline 6 24 48

PCI + medical therapy Medical therapy

Time (months)

SAQ QOL score

After 1 year, both strategies associated with comparable improvement

COURAGE: Summary and implications

• PCI added to optimal medical therapy did not reduce risk of death, MI, or other major CV events compared with optimal medical therapy alone

• Findings reinforce existing clinical practice guidelines– Optimal medical therapy and aggressive management of

multiple treatment targets without initial PCI can be implemented safely in the majority of patients with chronic stable angina, even those with objective evidence of ischemia and significant multivessel CAD


New Guidelines for Myocardial Ischemia Management

β-blocker (prior MI), ACEI/ARB (diabetes and/or LV dysfunction), and diuretic

If β-blocker contraindicated or side effects occur, substitute a nonDHP CCB

Add long-acting DHP CCB to β-blocker, ACEI/ARB, diuretic regimen if angina or BP remains uncontrolled

Target BP is <130/80 mm Hg or <120/80 mm Hg if LV dysfunction is present

AHA Scientific Statement: Pharmacologic treatment of hypertension in stable angina

II IIaIIa IIbIIb IIIIII

A

B

B

B

Rosendorff C et al. Circulation. 2007;115:2761-88.

• BP <120/80 mm Hg

• LDL-C <100 mg/dL

• Antiplatelet therapy

• β-Blocker

• ACEI or ARB

• A1C <7%

• Aldosterone blocker (select women)

CVD prevention in high-risk women: Class I recommendations

• Smoking cessation

• Heart-healthy eating pattern

• Regular physical activity

• Weight management

Mosca L et al. Circulation. 2007;115:1481-1501.

CVD prevention in high-risk women: Class II recommendations

Consider

• LDL-C <70 mg/dL (very-high-risk women)

• HDL/non-HDL therapy

• Omega-3 fatty acid supplementation

• Depression referral and treatment

Mosca L et al. Circulation. 2007;115:1481-1501.

Optimal patient care in stable CAD: Summary

• Establish aggressive treatment goals

• Utilize intensive, multifaceted therapy to achieve and maintain treatment goals – Lifestyle modification– Risk factor reduction– Antianginal therapy

Risk Stratification In Patients With Chronic Myocardial Ischemia

Available methods for risk stratification in CAD patients

• Clinical parameters

• ECG

• Chest x-ray

• Noninvasive testing– Resting LV function– Exercise test– Stress imaging

• Coronary angiography


High-risk criteria

• Severe resting LV dysfunction (LVEF <35%)

• High-risk treadmill score (≤-11)

• Severe exercise LV dysfunction (LVEF <35%)

• Stress-induced large perfusion defect (esp anterior)

• Multiple, moderate-sized perfusion defects

• Large, fixed perfusion defect with LV dilation or increased lung uptake (thallium-201)

• Stress-induced moderate perfusion defect with LV dilation or increased lung uptake (thallium-201)

• Echocardiographic wall motion abnormality (>2 segments) at low dobutamine dose (≤10 mg/kg per min) or low HR (<102 bpm)

• Stress echocardiographic evidence of extensive ischemia


>3% annual mortality rate

Intermediate-risk criteria

• Mild/moderate resting LV dysfunction (LVEF 35%-49%)

• Intermediate-risk treadmill score (-11 < score < 5)

• Stress-induced moderate perfusion defect without LV dilation or increased lung intake (thallium-201)

• Limited stress echocardiographic ischemia with a wall motion abnormality only at higher doses of dobutamine involving ≤2 segments

1%-3% annual mortality rate


Low-risk criteria

• Low-risk treadmill score (≥5)

• Normal or small myocardial perfusion defect at rest or with stress

• Normal stress echocardiographic wall motion or no change of limited resting wall motion abnormalities during stress


<1% annual mortality rate

Comparison of 3 different risk scores

de Araújo Gonçalves P et al. Eur Heart J. 2005;26:865-72.

N = 460 consecutive patients with NSTE-ACS

30 days 1 year

Deathor MI(%)

PURSUIT risk score GRACE risk scoreTIMI risk score

0

5

10

15

20

25

30

<96 96-112 113-133 >1330

5

10

15

20

25

30

<10 10-12 13-14 >140

5

10

15

20

25

30

0-2 3-4 5-7

Death/MI:

Summary

• Chronic IHD continues to impose a high socioeconomic burden

• Mechanistic understanding has undergone a paradigm shift– Traditional focus: Determinants of myocardial O2 supply/demand– Contemporary focus: Changes in Na+ and Ca2+ currents during

ischemia

• Contemporary management:– Aggressive treatment of multiple risk factors – Multifactorial treatment of symptoms

• Renewed interest in the role of optimal medical therapy vs PCI

Myocardial Ischemia Update

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