Myocardial Ischemia Update
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Transcript of 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
Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.
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
Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.
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.
Gibbons RJ et al. www.acc.org.
• 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
Morrow DA et al. JAMA. 2007;297:1775-83.
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
Morrow DA et al. JAMA. 2007;297:1775-83.
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
Scirica BM et al. Circulation. 2007;116.
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
Scirica BM et al. Circulation. 2007;116.
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
Morrow DA et al. JAMA. 2007;297:1775-83.
*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
Scirica BM et al. Circulation. 2007;116.
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
Morrow DA et al. JAMA. 2007;297:1775-83.
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
PCI + medical therapy(n = 1149)
Medical therapy(n = 1138)
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
Boden WE et al. N Engl J Med. 2007;356:1503-16.
COURAGE: Inducible ischemia at baseline
PCI + medical therapy(n = 1149)
Medical therapy(n = 1138)
Nuclear imaging, % (n) 70 (685) 72 (708)
Single reversible defect, % (n) 22 (154) 23 (161)
Multiple reversible defects, % (n) 65 (444) 68 (483)
Boden WE et al. N Engl J Med. 2007;356:1503-16.
COURAGE: Treatment effect on primary outcome
HR 1.05(0.87-1.27)P = 0.62*
Boden WE et al. N Engl J Med. 2007;356:1503-16.
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
Boden WE et al. N Engl J Med. 2007;356:1503-16.
P < 0.001P = 0.02 NS
Angina-free(%)
NS
Years
Boden WE et al. N Engl J Med. 2007;356:1503-16.
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
Boden WE et al. N Engl J Med. 2007;356:1503-16.
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
Gibbons RJ et al. www.acc.org.
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
Gibbons RJ et al. www.acc.org.
>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
Gibbons RJ et al. www.acc.org.
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
Gibbons RJ et al. www.acc.org.
<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