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Myocardial Ischemia Redefined: Optimal Care in CAD. Learning objectives. To improve patient management through a better understanding of:. Pathophysiology of myocardial ischemia Efficacy and safety of behavioral and pharmacologic approaches to minimize recurring ischemic episodes

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learning objectives
Learning objectives

To improve patient management through a better understanding of:

  • Pathophysiology of myocardial ischemia
  • Efficacy and safety of behavioral and pharmacologic approaches to minimize recurring ischemic episodes
  • Clinical trials investigating multiple treatment targets
  • Current clinical guidelines
curriculum overview
Curriculum overview
  • Epidemiology and prevalence of myocardial ischemia
    • Magnitude of the problem
    • Challenges in selected populations
  • Issues in contemporary clinical practice
  • Scientific review
  • Clinical trial update
  • New guidelines in myocardial ischemia management
  • Risk stratification
chronic ischemic heart disease overview
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
Repeat revascularization is common post-PCI/CABG

N = 18,240 who underwent elective PCI or CABG

50

46

40

30

30

Patients(%)

20

10

0

Recurrentangina

2nd revascularization

Kempf J et al. Presented at ESC. 2007.

angina increases cost of care
Angina increases cost of care

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)

ED visits

ED visits

Hospitalizations

Prior to diagnosis

Following diagnosis

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

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

slide7
Challenges in selected populations: Pathophysiology and implications of ischemic heart disease in women

Women

Ischemic heart disease

Diabetes

Elderly

wise landmark study in women
WISE: Landmark study in women

Prospective cohort study conducted at 4 US sites

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

Women’s Ischemia Syndrome Evaluation

Bairey Merz CN et al. J Am Coll Cardiol. 1999;33:1453-61.

wise persistent chest pain in women predicts future cv events
WISE: Persistent chest pain in women predicts future CV events

n = 673 WISE participants with chest pain at baseline

1

0.9

Without CAD

HR 1.89 (1.06–3.39)P = 0.03

Event-freesurvival (%)

0.8

0.7

With CAD

HR 1.17 (0.76–1.80)P = 0.49

0.6

0

1

2

3

4

5

6

Years from PChP diagnosis (at one year)

Neither

PChPNo CAD

No PChPCAD

Both

PChP = persistent chest pain

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

wise persistent chest pain associated with diminished qol
WISE: Persistent chest pain associated with diminished QOL

*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
WISE: CAD imposes an economic burden

N = 883 women with angiographic CAD

80

70

*

*

*

60

*

50

Cumulative observed direct costs ($, thousands)

40

*

30

20

10

0

1

2

3

4

5

Follow-up (years)

Nonobstructive CAD

1 vessel CAD

2 vessel CAD

3 vessel CAD

*P < 0.0001 nonobstructive vs 1-3 vessel CAD

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

contemporary clinical practice of ischemic heart disease
Contemporary clinical practice of ischemic heart disease

Opportunity for early detection, risk stratification, and medical therapy

Healthy population

Revas = revascularization

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

severe obstruction angina no rupture vs mild obstruction no angina likely to rupture
Severe obstruction (angina, no rupture) vs mild obstruction (no angina, likely to rupture)
  • Vulnerable plaque
  • Minor obstruction
  • Eccentric plaque
  • Lipid pool
  • Thin cap
  • Severe fibrotic plaque
  • Severe obstruction
  • No lipid
  • Fibrosis, Ca2+
  • Plaque rupture
  • Acute MI
  • Unstable angina
  • Sudden death
  • Exertional angina
  • (+) ETT

Revascularization

Anti-anginal Rx

Pharmacologic stabilization

Early identification of high-risk?

Courtesy of PH Stone, MD.

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

20

15

Hazardrate (%)

10

Non-target lesion event

5

Target lesion event

0

1

2

3

Year

4

5

Substantial number of cardiac events could be prevented

if non-obstructive, high-risk lesions were identified

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

local determinants of the natural history of individual coronary lesions
Local determinants of the natural history of individual coronary lesions

Opportunities for identification and intervention

Local factors

Shear stress

Quiescent,

stable plaque

No symptoms

  • Proliferation
  • Inflammation
  • Remodeling

Quiescence

Inflammation

Thin cap

Fibroatheroma

MI, sudden death

Proliferation

Calcification

Fibrotic/

scarred plaque

Angina

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

proposed classification scheme for atherosclerotic plaque
Proposed classification scheme for atherosclerotic plaque

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

the spectrum of cad
The spectrum of CAD

ESS = endothelial shear stress

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

ventricular arrhythmogenesis in ischemic myocardium
Ventricular arrhythmogenesis in ischemic myocardium
  • 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
  • Substrate
  • Vulnerable ischemic zone
  • Intracoronary thrombus
  • Autonomic influence
  • Hemodynamic compromise

Ventricular fibrillation

+

VPC = ventricular premature contraction

VT = ventricular tachycardia

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

causes and consequences of myocardial ischemia new understanding
Causes and consequences of myocardial ischemia: New understanding

Development of ischemia

Consequences of ischemia

Ischemia

O2 demand

Na+ and Ca2+ overload

Heart rate

Blood pressure

Preload

Contractility

Electrical instability

Myocardial dysfunction

O2 supply

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

overview of the sodium channel
Overview of the sodium channel

Na+

Na+

Na+

Resting

closed

Inactivated

Activated

out

Na+

Na+

in

[Na+]

Na+

Na+

[Na+]

= 140 mM

Na+

Na+

~10mM

Ca2+

Ca2+

in

Ca2+

Ca2+

Na+

Ca2+

Ca2+

out

Na+/Ca2+

Exchanger

Na+

Ca2+

Courtesy of L Belardinelli, MD.

origin of late i na
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

Origin of late INa

0

Sodiumcurrent

Late

Peak

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

myocardial ischemia causes enhanced late i na
Myocardial ischemia causes enhanced late INa

0

Sodiumcurrent

Late

Peak

0

Ischemia

Sodiumcurrent

Late

Peak

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

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

role of altered ion currents in adverse consequences of myocardial ischemia
Role of altered ion currents in adverse consequences of myocardial ischemia

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

Late INa

Na+ entry ([Na+]i)

NCX

Cytosolic Ca2+

  • Electrical instability
  • Afterpotentials
  • Beat-to-beat APD
  • Arrhythmias (VT)
  • Mechanical dysfunction
  • Abnormal contraction and relaxation
  • Diastolic tension

[Na+]i = intracellular [Na+]NCX = Na+/Ca2+ exchanger APD = action potential duration

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

diastolic relaxation failure adversely affects myocardial o 2 supply and demand
Sustained contraction of ischemic tissue during diastole:

Increases MVO2

Compresses intramural small vessels

Reduces myocardial blood flow

Diastolic relaxation failure adversely affects myocardial O2 supply and demand

Exacerbates ischemia

MVO2 = myocardial oxygen consumption

Courtesy of PH Stone, MD.

late i na inhibition blunts ca 2 accumulation
Late INa inhibition blunts Ca2+ accumulation

0.30

12

ATX-II

RAN

0.25

Indo fluorescence(F405/F485 ratio)

8

*

LV work(L/min per mm Hg)

*

0.20

*

4

*

0.15

ATX-II

RAN

0.10

0

0

10

20

30

40

50

0

10

20

30

40

50

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)

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

ranolazine blunts sotalol induced action potential prolongation in dogs
Ranolazine blunts sotalol-induced action potential prolongation in dogs

d-Sotalol

+ Ranolazine 5 uM

+ Ranolazine 10 uM

Transmembrane action potentials (superimposed)

Control

50 mV

1 sec

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

issues in chronic myocardial ischemia treatment
Issues in chronic myocardial ischemia treatment

Implications for clinical trials

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

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

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

stable cad multiple treatment options
Stable CAD: Multiple treatment options

Lifestyle intervention

Medicaltherapy

Reduce symptomsTreat underlying disease

CABG

PCI

safe life evaluation of intensive lifestyle intervention
SAFE-LIFE: Evaluation of intensive lifestyle intervention

N = 101 with CAD

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

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

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

P = 0.015

P = 0.01

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

chronic ischemic heart disease treatment gaps
Chronic ischemic heart disease: Treatment gaps
  • Most patients have relative intolerances to maximum doses of traditional antianginal agents (-blockers, CCBs, and nitrates)
  • Patients continue to experience myocardial ischemia
  • -blockers and many CCBs have similar depressive hemodynamic and electrophysiologic effects
  • Antianginal drugs without these limitations are needed

Pepine CJ et al. Am J Cardiol. 1994;74:226-31.Gibbons RJ et al. www.acc.org.

novel anti ischemic strategy
Novel anti-ischemic strategy

Development of ischemia

Consequences of ischemia

Ischemia

O2 demand

Ca2+ overload

Heart rate

Blood pressure

Preload

Contractility

Electrical instability

Myocardial dysfunction

O2 supply

Nitrates, β-blockers, CCBs

Ranolazine (late Na+ current inhibition)

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

ranolazine clinical trial program
Ranolazine clinical trial program

MARISA

CARISA

ERICA

Silent

CAD

Stable

angina

Unstable

angina

Myocardial infarction

Heart failure

Death

NSTEMI

STEMI

MERLIN-TIMI 36

Courtesy of BR Chaitman, MD.

ranolazine clinical trial program in chronic stable angina
Ranolazine clinical trial program in chronic stable angina

Monotherapy Assessment of Ranolazine In Stable Angina

Combination Assessment of Ranolazine In Stable Angina

Efficacy of Ranolazine In Chronic Angina

Chaitman BR et al. J Am Coll Cardiol. 2004.Chaitman BR et al. JAMA. 2004.Stone PH et al. J Am Coll Cardiol. 2006.

marisa carisa erica main findings
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.

challenges in selected populations experience with ranolazine
Challenges in selected populations: Experience with ranolazine

Women

Ischemic heart disease

Diabetes

Elderly

antianginal efficacy by gender
Antianginal efficacy by gender

Improved exercise duration

MARISA

CARISA

60

150

NS

NS

NS

NS

NS

40

100

Exercise duration, sec(Δ from placebo)

Exercise duration, sec(Δ from baseline)

*

20

50

0

0

500 mg

1000 mg

1500 mg

Placebo

750 mg

1000 mg

Ranolazine

Ranolazine

Women

Men

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

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

antianginal efficacy by gender40
Antianginal efficacy by gender

Improved angina score

NS

30

P = 0.016

20

SAQ angina frequency score (Δ from baseline)

10

0

Placebo + amlodipine

Ranolazine + amlodipine

Women

Men

ERICA studySAQ = Seattle Angina Questionnaire

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

antianginal efficacy by age
Antianginal efficacy by age

P = 0.074

P = 0.15

Age <65 years

Age ≥65 years

Placebo + amlodipine

Ranolazine + amlodipine

ERICA study

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

antianginal efficacy by diabetes status
Antianginal efficacy by diabetes status

Placebo

Ranolazine 750 mg bid

Ranolazine 1000 mg bid

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

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

carisa reductions in a1c diabetes substudy
Possible mechanisms: Insulin sensitivity

Physical activity

CARISA: Reductions in A1C (diabetes substudy)

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

AIC change from baseline

Least squares mean(%)

*

*

Placebo

Ranolazine 750 mg bid

Ranolazine 1000 mg bid

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

summary ranolazine in challenging populations
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
ROLE: Long-term safety and tolerability in stable CAD patients

N = 746 ranolazine patients who completed MARISA or CARISA

  • 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

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

Ranolazine Open-Label Experience

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

merlin timi 36 study design
MERLIN-TIMI 36: Study design

Patients with non-ST-elevation ACStreated with standard medical/interventional therapiesN = 6560

RandomizedDouble-blind

IV/oral ranolazine

Placebo

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

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

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

merlin timi 36 effect on primary endpoint
MERLIN-TIMI 36: Effect on primary endpoint

Ranolazine vs placebo within 48 hrs of ischemic symptom onset

30

CV death, MI, or recurrent ischemia (%)

20

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

10

0

0

180

360

540

Days

Placebo

Ranolazine

No. at risk

Placebo

Ranolazine

3281

3279

2454

2450

1223

1223

268

269

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

merlin timi 36 components of primary endpoint
MERLIN-TIMI 36: Components of primary endpoint

n = 3279 ranolazine group, n = 3281 placebo group

CV death or MI

Recurrent ischemia

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 16.1%*

20

20

Placebo 10.5%*

15

15

Cumulativepercentage

10

10

Ranolazine 13.9%*

Ranolazine 10.4%*

5

5

0

0

0

180

360

540

0

180

360

540

Days

*Event rates at 12 months

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

merlin timi 36 efficacy results in major subgroups
MERLIN-TIMI 36: Efficacy results in major subgroups

Primary endpoint

Subgroup

Pinteraction

n

Favors ranolazine

Favors placebo

0.12

Gender

Men

Women

4269

2291

0.80

Age

<75 years

≥75 years

5406

1154

Diabetes

No DM

DM

4340

2220

0.39

TIMI Risk

0-3

4-7

3601

2959

0.16

Index event

UA

NSTEMI

3067

3342

0.85

0.23

STD ≥1 mm

No

Yes

4255

2304

Overall

6560

0.6

0.8

1.2

1.4

1.6

HR (95% CI)

STD = ST-segment depression

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

merlin timi 36 primary arrhythmia endpoints
MERLIN-TIMI 36: Primary arrhythmia endpoints

SVT = supraventricular tachycardia

Scirica BM et al. Circulation. 2007;116.

merlin timi 36 reduction in vt lasting 8 beats
MERLIN-TIMI 36: Reduction in VT lasting ≥8 beats

10

8.3%

RR 0.65

P < 0.001

8

Placebo

5.3%

RR 0.67

P = 0.008

Incidence(%)

6

4

Ranolazine

2

RR 0.63 (0.52-0.76)

P < 0.001

0

0

24

48

72

96

120

144

168

Hours from randomization

Scirica BM et al. Circulation. 2007;116.

merlin timi 36 incidence of vt 8 beats in high risk subgroups
MERLIN-TIMI 36: Incidence of VT ≥8 beats in high-risk subgroups

Ranolazine

(%)

Placebo

(%)

P

EF ≥40%

5.3

7.3

0.011

EF <40%

8.8

16.6

0.005

QTc ≤450 msec

7.8

<0.001

5.2

QTc >450 msec

10.5

0.002

5.6

TRS 0-4

8.2

<0.001

5.5

TRS 5-7

8.9

0.001

4.4

No prior HF

8.1

<0.001

5.2

Prior HF

9.3

0.013

5.4

No ischemia on cECG

8.3

<0.001

5.0

Ischemia on cECG

8.3

0.12

6.3

1

10

0.1

RR (95% CI)

TRS = TIMI risk scorecECG = continuous ECG

Scirica BM et al. Circulation. 2007;116.

slide53

MERLIN-TIMI 36: Ventricular tachycardia events

Scirica BM et al. Circulation. 2007;116.

merlin timi 36 major safety outcomes
MERLIN-TIMI 36: Major safety outcomes

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

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

slide55

MERLIN-TIMI 36: Sudden cardiac death by subgroup

Scirica BM et al. Circulation. 2007;116.

merlin timi 36 summary and implications
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

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

stable cad multiple treatment options57
Stable CAD: Multiple treatment options

Lifestyle intervention

Medicaltherapy

Reduce symptomsTreat underlying disease

CABG

PCI

acip study design
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
ACIP: Baseline characteristics

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

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

8

6.6%

Angina guided

6

P = 0.34

4.4%

Ischemia guided

P < 0.005

Percent

4

P < 0.05

2

1.1%

Revascularization

0

0

4

8

12

15

20

24

Follow-up (months)

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

swissi ii study design
SWISSI II: Study design

Recent first MI with asymptomatic myocardial ischemia on exercise testing and 1- or 2-vessel coronary disease suitable for PCI

Randomized, unblinded

PCI (n = 96)

Anti-ischemic therapy*(n = 105)

Primary outcomes: Cardiac death, nonfatal MI, symptom-driven revascularization

Follow-up: 10.2 years (mean)

*Nitrates, β-blockers, CCBs

All patients also received aspirin and statin

Swiss Interventional Study on Silent Ischemia Type II

Erne P et al. JAMA. 2007;297:1985-91.

swissi ii baseline characteristics
SWISSI II: Baseline characteristics

Erne P et al. JAMA. 2007;297:1985-91.

swissi ii treatment effect on primary outcome
SWISSI II: Treatment effect on primary outcome

Cardiac death, nonfatal MI, symptom-driven revascularization

1.00

PCI

0.75

Event-free survival

0.50

Drug therapy

0.25

P < 0.001*

0

0

5

10

15

Time from randomization (years)

No. at risk

PCI

96

7

7

54

Anti-ischemic drug therapy

105

6

4

37

*Log-rank

Erne P et al. JAMA. 2007;297:1985-91.

acip swissi ii summary and implications
ACIP, SWISSI II: Summary and implications
  • ACIP: In patients with documented CAD + symptomatic and asymptomatic ischemia, PCI compared with anti-ischemic or antianginal therapy reduced 2-year risk of major CV events
  • SWISSI II extended these finding to post-MI patients with asymptomatic ischemia and a longer 10-year follow-up
  • Data reported after ACIP and SWISSI II began suggest that risk factor management in these trials was not optimal

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

Erne P et al. JAMA. 2007;297:1985-91.

courage defining optimal care
COURAGE: Defining optimal care

Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation

Intensive lifestyle intervention

Intensive medicaltherapy

Reduce symptomsTreat underlying disease

Revascularization?

what is the definitive role of pci in chronic angina and stable cad
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
Patient expectations about elective PCI for stable CAD

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

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

courage study design
COURAGE: Study design

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)

Optimal medical therapy* + PCI (n = 1149)

Optimal medical therapy*(n = 1138)

Randomized

Primary outcomes: All-cause mortality, nonfatal MI

Secondary outcomes: Death, MI, stroke; ACS hospitalization

Follow-up: Median 4.6 years

*Intensive pharmacologic therapy + lifestyle interventionCCS = Canadian Cardiovascular Society

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

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

COURAGE: Lifestyle intervention and risk factor goals

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

COURAGE: Pharmacologic therapy

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
COURAGE: Baseline angiographic data

*Patients who underwent previous CABG†P = 0.01

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

courage baseline angina
COURAGE: Baseline angina

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

courage inducible ischemia at baseline
COURAGE: Inducible ischemia at baseline

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

courage treatment effect on primary outcome
COURAGE: Treatment effect on primary outcome

All-cause death, MI

1.0

0.9

0.8

Survival

free of

primary

outcome

HR 1.05

(0.87-1.27)

P = 0.62*

0.7

0.6

0.5

0

0

1

2

3

4

5

6

7

Years

Medical therapy PCI + medical therapy

No. at risk

Medical therapy 1138 1017 959 834 638 408 192 30

PCI 1149 1013 952 833 637 417 200 35

*Unadjusted, log-rank

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

courage treatment effect on angina
COURAGE: Treatment effect on angina

NS

P = 0.02

P < 0.001

Angina-free(%)

NS

Years

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

courage treatment effect in cv and diabetes subgroups
COURAGE: Treatment effect in CV and diabetes subgroups

Baseline characteristics

PCI better

Medical therapy better

Myocardial infarction

Yes

No

Extent of CAD

Multivessel disease

Single-vessel disease

Diabetes

Yes

No

Angina

CCS 0-I

CCS II-III

Ejection fraction

≤50%

>50%

Previous CABG

No

Yes

0.25

0.50

1.00

1.50

1.75

2.00

Hazard ratio (95% CI)

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

courage change in quality of life scores
COURAGE:Change in quality-of-life scores

After 1 year, both strategies associated with comparable improvement

90

85

80

75

SAQ QOL score

70

65

60

55

50

Baseline

6

24

48

Time (months)

PCI + medical therapy

Medical therapy

WS Weintraub, MD. Presented at ACC. 2007.

courage summary and implications
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

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

aha scientific statement pharmacologic treatment of hypertension in stable angina
AHA Scientific Statement: Pharmacologic treatment of hypertension in stable angina

I

IIa

IIb

III

A

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

B

B

B

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

cvd prevention in high risk women class i recommendations
BP <120/80 mm Hg

LDL-C <100 mg/dL

Antiplatelet therapy

β-Blocker

ACEI or ARB

A1C <7%

Aldosterone blocker (select women)

Smoking cessation

Heart-healthy eating pattern

Regular physical activity

Weight management

CVD prevention in high-risk women: Class I recommendations

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

cvd prevention in high risk women class ii recommendations
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
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
available methods for risk stratification in cad patients
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

Gibbons RJ et al. www.acc.org.

high risk criteria
High-risk criteria

>3% annual mortality rate

  • 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

Gibbons RJ et al. www.acc.org.

intermediate risk criteria
Intermediate-risk criteria

1%-3% annual mortality rate

  • 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

Gibbons RJ et al. www.acc.org.

low risk criteria
Low-risk criteria

<1% annual mortality rate

  • 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

Gibbons RJ et al. www.acc.org.

comparison of 3 different risk scores
Comparison of 3 different risk scores

N = 460 consecutive patients with NSTE-ACS

TIMI risk score

PURSUIT risk score

GRACE risk score

30

30

30

25

25

25

20

20

20

Deathor MI(%)

15

15

15

10

10

10

5

5

5

0

0

0

<96

96-112

113-133

>133

0-2

3-4

5-7

<10

10-12

13-14

>14

Death/MI:

30 days 1 year

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

summary
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
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