Transcript Syed Zahid Jamal - Karachi Institute of Heart Diseases

Controversies in Cardiology:
Stable CAD & COURAGE
Pro: Optimal Medical Therapy vs. PCI
SYED ZAHID JAMAL MD
ASSOC PROF NICVD
Ha ha ha ha !
Varying Degrees of CAD Lesion Severity in
a Single Coronary Artery
Highly variable degrees of:
• plaque formation
• luminal obstruction
• inflammation
• likelihood of rupture
Stable Angina
Is this a benign lesion
in a benign condition?
What are you lookin at?
Nature of the Problem:
Severe Obstruction (Angina, No Rupture) vs Mild
Obstruction (No Angina, Likely to Rupture)
Vulnerable Plaque
Severe Fibrotic
Plaque
Minor obstruction,
Eccentric plaque,
Lipid pool, Thin cap
Severe obstruction, No lipid,
Fibrosis, Ca++
Plaque Rupture
Exertional Angina,
(+) ETT
Acute MI,
Unstable Angina,
Sudden death
Revascularization;
Anti-anginal Rx
Pharmacologic Stabilization;
? Early Identification of High-risk
Courtesy of
P. Stone, 2007
The Differing Fates of Coronary Stenoses of
Varying Severity
• Clinical manifestations of coronary lesions behave differently
based on the degree of luminal obstruction and morphology:
– Lesions > 50-75% obstruction
Angina;
positive stress test;
positive calcium score
– Lesions < 50% obstruction
Rupture,
superimposed
thrombus
ACS/Death
Both types of lesions are inevitably present within
the same stable CAD patient at any point in time
Goals of Therapy in CAD Management
1.
2.
Improve anginal symptoms by optimizing myocardial O2
supply:demand balance
Medication:
Reduce HR, BP, contractility, preload
• β-blockers
• Ca++ blockers
• Nitrates
Enhance myocardial O2 supply
• Ca++ blockers & ? Ranolazine
Revascularization (PCI or CABG)
Reduce/stabilize atherosclerotic plaque, reducing likelihood of rupture
ACS/Cardiac death
–
Aggressive statin therapy
–
ACE inhibitors
–
Aspirin ± Clopidogrel
–
β-blockers
–
Lifestyle modifications
(Courtesy of P. Stone, 2007)
Increased Mortality with Medical
Management for UA/NSTEMI Patients:
Patients with Significant CAD on Cath in the SYNERGY Trial
* Med Management (MM), Percutaneous Coronary Intervention (PCI), Coronary Artery Bypass Grafting
(CABG)
Chan M, JACC Cardiovasc Int 2008
A Different Story in Stable CAD:
Contrasting 1 Year Death/MI Rates: ACS,
Stable Angina, “Primary Prevention”
Death/ MI (%)
16
12
Unstable angina/non Q wave MI (FRISC II)
8
Stable angina (SAPAT)
Primary Prevention (WOSCOPS)
COURAGE 3.8%
ACTION trial (stable CAD)
4
0
0
2
4
6
8
Months of follow up
Wallentin L et al. Lancet 2000;356:9–16
Juul-Moller S et al. Lancet 1992;340:1421–1425
Shepherd J et al. N Engl J Med 1995;333:1301–1307
Poole-Wilson et al ACTION Lancet 2004;364:849-57.
10
12
Approx 1.5%
Stable CAD
THE PROBLEM:
Major Cardiac Events Occur in Non-Target
Lesions Following Successful PCI
5 year Followup of 1228 Patients Treated with Bare Metal Stents
Hazard
Rate (%)
20
18
16
14
12
10
8
6
4
2
0
Non-Target Lesion
Event Rates:
• 12.4% Year 1
• 37.4% Year 1-5
18.3
12.4
Target Lesion Event
5.6
2.3
7.0
6.7
5.7
1.3
1.5
Non-target Lesion
Event
1.4
(Cutlip, et al. Circulation
2004;110:1226)
Year 1
Year 2
Year 3
Year 4
Year 5
Substantial number of cardiac events
could be prevented if we knew how to identify them
Classification of Natural History of
Early Atherosclerotic Plaques
Plaque
Trajectory
Histopathology
Progression
Rate
Vascular
Remodeling
Proclivity to
Rupture
Clinical
Manifestations
Quiescent
Plaque
Small lipid
core/thick cap
Minimal
Compensatory
Low
Asymptomatic
High-risk
vulnerable
plaque
Large lipid
core/
thin,inflamed
cap
Increased
Excessive
expansive
High
Acute Coronary
Syndrome
Stenotic
Plaque
Small lipid
core/very
thick cap
Gradual
Constrictive
Low
Stable Angina
(Chatzizisis, et al.
JACC 2007;49:2379)
Relative Risk of Recurrent Cardiac Events
with PTCA vs Medical Therapy
Meta-analysis of 6 randomized trials (n=1904)
(Bucher, et al. BMJ 2000;321:73)
Stable CAD: PCI vs Conservative
Medical Management
Meta-analysis of 11 randomized trials; N = 2950
Favors PCI
Favors Medical Management
P
Death
Cardiac death or MI
Nonfatal MI
CABG
PCI
0
Katritsis DG et al. Circulation. 2005;111:2906-12.
0.68
0.28
0.12
0.82
0.34
1
Risk ratio
(95% Cl)
2
Long-Term Clinical Outcome:
PTCA vs Medical Management in RITA-2
RITA-2, 1018 patients (504 PTCA, 514 medical management)
Death or MI
Death
P=NS
P=NS
No difference in outcome over median of 7 years
(Henderson, et al. JACC 2003;42:1161)
What Is The Concern Of Leaving
Coronary Stenoses Alone?
In Patients with Chronic Angina and Stable CAD:
• We know that PCI improves angina and short-term
exercise capacity, so if we don’t “fix what we see”:
1.
2.
3.
4.
5.
Will we expose patients to increased risk of death/MI?
Will angina and quality of life be worse?
Will residual ischemia be less well treated?
Will patients feel they did not receive “best care”?
What about high-risk patients—3V CAD; ↓ EF?
Evidence Prior to COURAGE of Leaving
Coronary Stenoses Alone
RITA-2, 1018 patients (504 PTCA, 514 medical management)
Death or MI
Death
P=NS
P=NS
No difference in outcome over median of 7 years
(Henderson, et al. JACC 2003;42:1161)
Stable CAD: PCI vs. Medical
Management Pre-COURAGE
Meta-analysis of 11 randomized trials; N = 2950
Favors PCI
Favors Medical Management
P
Death
Cardiac death or MI
Nonfatal MI
CABG
PCI
0
Katritsis DG et al. Circulation. 2005;111:2906-12.
0.68
0.28
0.12
0.82
0.34
1
Risk ratio
(95% Cl)
2
COURAGE Primary EP:
Survival Free of Death or MI
• 2,287 Pts. Randomized to
Optimal Medical Therapy (OMT)
1.0
PCI + OMT vs. OMT
0.9
0.8
• Intensive, Guideline-Driven
Medical Therapy & Lifestyle
Intervention In Both Groups
PCI + OMT
0.7
Hazard ratio: 1.05
95% CI (0.87-1.27)
P = 0.62
0.6
0.5
0.0
0
Source: Boden et al. N Engl J Med. 2007; 356:1503-16.
1
2
3
Years
4
5
6
7
Optimal Medical Therapy
Pharmacologic
• Anti-platelet: aspirin; clopidogrel (c/w with established practice standards)
• Statin: simvastatin ± ezetimibe or extended-release niacin
• ACE Inhibitor or ARB: lisinopril or losartan
• Beta-blocker: long-acting metoprolol (Toprol XL®)
• Calcium channel blocker: amlodipine
• Nitrate: isosorbide 5-mononitrate
Lifestyle
•
Smoking cessation
•
Exercise program
•
Nutrition counseling
•
Weight control
Applied to Both Arms by Protocol and Case-Managed
Value of Optimal Medical Therapy:
The COURAGE Trial
Compared with Optimal Medical Therapy Alone,
PCI provided no incremental benefit on Death, MI, New ACS
Death/MI
New ACS
(Boden, et al. NEJM 2007;356:1503)
Death
New MI
Value of Optimal Medical Therapy:
The COURAGE Trial
Compared with Optimal Medical Therapy alone,
PCI is associated with a reduction in angina, but not after 5 yrs
100
pNS
88
Percent
With
Angina
PCI + Optimal Rx
Optimal Rx alone
87
75
P<0.001
50
34
P=0.02
pNS
42
33
26
28
28
25
Baseline
1 Year
3 Year
(Boden, et al. NEJM 2007;356:1503)
5 Year
Tertiary Outcomes:
Cardiac Death/MI/ACS
30%
23.5%
PCI + OMT
22.6%
20%
Hazard ratio: 1.07
CI 95% (0.91, 1.27)
P = 0.60
OMT
10%
0
1
2
3
Years
4
5
6
“COURAGE Enrolled
Low-Risk Patients”… Huh???
•Diabetes: 34%
•Angina at BL: 88%
•Dyslipidemia: 71 %
•Angina Duration: 26 mo
•HTN: 67%
•Angina Freq.: 6 episodes/wk
•Smokers: 29%
•Multivessel CAD: 70%
•Prior MI: 39%
•LAD disease: 68%
•Prior Revasc: 26%
•Inducible Ischemia: 85%
•Stress MPI: Multiple defects 67%
•Death/MI Event Rate: 4.3%/year
COURAGE Patient
Randomized to OMT Alone
COURAGE Patient
Randomized to OMT Alone
Need for Subsequent
Revascularization: 7 Years of F/U*
PCI + OMT
OMT
Overall Need for
Revascularization
Subsequent CABG
21%
33%
N=77
N=81
Median Time to
Revascularization†
10 months;
10.5%
10.8 months;
16.5%
*Median 4.6 years of follow-up
†Median time to Repeat or 1st Revascularization
After ~ 11 mo, the avg. X-over from OMT to PCI was 2.8%/year over years 1-7
Freedom from CCS Angina During
Follow-up & NNT to Improve Sx
Characteristic:
CCS Class 0
CLINICAL
Angina free – no.
Baseline
1 Yr
3 Yr
5 Yr
PCI + OMT
OMT
NNT to
improve angina
in 1 pt with PCI
12%
*66%
*72%
74%
13%
58%
67%
72%
--12.5
20
50
* The comparison between the PCI group and the medical-therapy group
was significant at 1 year ( P<0.001) and 3 years (P=0.02) but not at
baseline or 5 years.
SAQ Mean QOL Scores During
Follow-up & NNT to Improve Sx
Characteristic
Mean SAQ QOL
Score: 0-100 Scale
Baseline
1 Mo
6 Mo
1 Yr
2 Yr
PCI + OMT
OMT
NNT to improve
SAQ QOL in 1
pt with PCI
51
51
---
*68
*75
*76
77
62
70
73
76
16.7
20
33.3
100
*P < 0.001 between groups
COURAGE QOL
Editorial Commentary
Nuclear Substudy (n=314)
Hypothesis: Reduction in Ischemia will be greater for Pts.
Randomized to PCI+OMT than for those Randomized to OMT as
Measured By Changes in Ischemic Burden by MPS at Baseline & 618m after Randomization
Documented Pre-Rx Ischemia
Rest/Stress Myocardial Perfusion
SPECT (MPS)
• Pre-Rx
• Following 6-18m Randomized
Rx (mean 374 ± 50 days)
Source: Shaw et al. J Nucl Cardiol 2006 Sep;13(5):685-98.
Pre-RxTc-99m
sestamibi MPS
PCI + OMT
(n=159)
OMT
(n=155)
Repeat MPS
at 6-18m
Repeat MPS
at 6-18m
Patient Expectations About
Elective PCI for Stable CAD
• 52 consecutive patients scheduled for first
elective PCI completed semi-structured
questionnaire prospectively
Do you think the angioplasty will prevent a heart
attack?
Yes
75%
Do you think the angioplasty will help you live
longer?
Yes
71%
Holmboe et al. J Gen Intern Med 2000;15:632.
Recent Mid-America Heart Institute
Patient PCI Survey
• One million PCI procedures
per year
• Majority elective
• Prospective survey of 350
elective PCI patients with
stable CAD @ MAHI between
1/06-10/07
• Focus: are pt. perspectives
of PCI benefit aligned with
current evidence?
•
John H. Lee, MD et al: 2008 AHA Scientific
Sessions, November 12, 2008
Patient Perceived Benefits
of Elective PCI
100
90
80
71
Percent
70
66
60
50
40
42
42
33
31
30
20
10
0
Emergent?
Prevent Heart
Attack?
Extend Life
Span?
Saved Life?
Normalize
Stress test?
Decreases
Angina?
Alternate Therapies Offered
100
90
80
68
Percent
70
60
50
40
30
20
18
13
10
0
Medical Therapy
CABG
None
Why The Evidence Supports OMT
as the Initial Approach to
Stable CAD Management
For Patients Undergoing Elective Coronary
Angiography for Chronic Angina:
• 13 RCTs in 7,605 patients (including BARI-2D) show no
difference in death, MI, stroke or other “hard” endpoints
between PCI and OMT
• An initial course of OMT preserves the option for PCI if
medical therapy fails (only 16.5% of COURAGE OMT
patients “crossed over” to PCI within 1 year)
• Over a full 7-year follow-up period, 2/3 of all OMT
patients never required even a 1st PCI procedure
Where Does COURAGE Give Us
Clarity of Management?
In Patients with Chronic Angina and Stable CAD:
• There is better angina relief with PCI over 1-3 years
• There is better QOL with PCI over 1-2 years
• The subsequent need for revascularization in the 1st year
is lower in PCI than OMT patients
• OMT is a safe & viable option for most patients, and for
those who may not be good candidates for PCI (frailty;
CKD; multiple co-morbidities; treacherous anatomy, etc.)
• OMT as an initial approach preserves PCI as a
subsequent option for symptom/QOL relief, if needed
Where Do the Results of
COURAGE Still Leave Uncertainty?
In Patients with Chronic Angina and Stable CAD:
• Is OMT as good as PCI + OMT in patients with impaired LV
systolic function (EF < 40%)?
• Do patients with high-grade 3-vessel CAD fare as well with
OMT vs. PCI + OMT, esp. with EF < 40%?
• Does stenosis severity (≥ 90% vs. 70%-80%) alter PCI vs.
OMT outcomes, and does defining coronary anatomy in all
patients aid clinical decision-making?
• Is it important to delineate the presence or absence of highrisk inducible ischemia in all patients?
Selective Management Strategies Focusing on
Obstructive and Non-Obstructive CAD
Summary and Conclusions
• CAD manifestations in an individual patient are due both
to:
– Flow-limiting obstructions (angina, + stress test, + Ca++
score)
– Minor obstructions with high-risk vulnerable plaque
(ACS, death)
– Catheter-based treatment directed only at flow-limiting
obstructions will do little to reduce the burden of CAD
events precipitated by olaque rupture of non-flowlimiting stenoses
Selective Management Strategies Focusing on
Obstructive and Non-Obstructive CAD
Summary and Conclusions
• Non-obstructive high-risk plaque:
– Difficult to identify/predict natural history at this time
– Aggressive systemic pharmacologic therapy stabilizes
vulnerable plaque and thereby reduces mortality and
morbidity
• Statins, ACE-inhibitors, ? Niacin
– Ultimately, risk stratification (and local intervention) of
individual lesions may be possible
Selective Management Strategies Focusing on
Obstructive and Non-Obstructive CAD
Summary and Conclusions
• Flow-limiting Obstructive CAD:
– Optimal Medical Therapy is a viable & defendable initial
management strategy and is supported by existing ACC/AHA
Clinical Practice Guidelines
– Revascularization is appropriate in patients with severe angina
symptoms (or who have failed medical Rx), or in those who
have substantial ischemic jeopardy
– Revascularization may be more effective than medications to:
•
•
•
•
reduce angina
increase exercise capacity
decrease subsequent revascularization procedures
but not to improve mortality, reduce MI, or other CV events.
OAT Trial
Occluded Artery Trial (OAT)
Presented at
The American Heart Association
Scientific Session 2006
OAT Trial: Background
• The goal of the trial was to evaluate percutaneous
coronary intervention (PCI) compared with
medical therapy among stable, high-risk patients
with persistent total occlusion of the infarct-related
artery post-myocardial infarction (MI).
Presented at AHA 2006
OAT Trial: Hypothesis
• A strategy of routine PCI for total occlusion of the
infarct-related artery 3-28 days after acute MI
would reduce the occurrence of the composite of
death, reinfarction, or New York Heart Association
(NYHA) class IV heart failure.
Presented at AHA 2006
OAT Trial: Study Design
2166 patients with angiography on day 3-28 post-MI with evidence of total occlusion of the infarctrelated artery with poor or absent antegrade flow (TIMI flow grade 0 or 1); and met a criterion for
increased risk, defined as ejection fraction <50%, proximal occlusion of a major epicardial vessel
with a large risk region, or both
Exclusions: NYHA class III or IV heart failure, shock , serum creatinine concentration >2.5 mg/dl, angiographically
significant left main or three-vessel coronary artery disease, angina at rest, or severe ischemia on stress testing.
Randomized.
22% female, mean age 59 years, mean follow-up 3 years, mean EF 48% at baseline
Concomitant medications: Aspirin, anticoagulation if indicated, ACE inhibitors, beta-blockers,
and lipid-lowering therapy, unless contraindicated
Medical Therapy
n=1084
PCI with stenting
n=1082

Primary Endpoints: Death, MI, or NYHA class IV heart failure
Presented at AHA 2006
OAT Trial: Primary Endpoint
Primary Endpoint of death, reinfarction, NYHA
class IV heart failure (% patients)
Hazard Ratio 1.16, p=0.20
20%
17.2%
15.6%
15%
10%
5%
• The primary
endpoint of death,
reinfarction, or
NYHA class IV
heart failure
occurred in 17.2%
of the PCI group
and 15.6% of the
medical therapy
group ([HR] 1.16,
p=0.20).
0%
PCI
Medical Therapy
Presented at AHA 2006
OAT Trial: Primary Component Endpoints
Primary Component Endpoints (% patients)
PCI
Medical Therapy
15
p<0.001
p=0.83
% patients
12
10.0
p=0.13
9
6
7.0
9.1
p=0.08
9.4
6.9
5.3
p=0.92
5.0
4.4
3.3
3
0
Total
Nonfatal
Repeated ↑
Reinfarction Reinfarction of Cardiac
Biomarkers
Death
• Total reinfarction trended
higher in the PCI group (7.0%
vs. 5.3%, HR 1.36, p=0.13), as
did nonfatal reinfarction (6.9%
vs. 5.0%, HR 1.44, p=0.08).
• Repeated elevation of cardiac
biomarkers within 48 hours of
randomization occurred
significantly more frequently
in the PCI group (10.0% vs.
3.3%, p<0.001).
4.5
• There was no difference in the
individual endpoints of death
(9.1% for PCI vs. 9.4% for
medical therapy, p=0.83) or
NYHA class IV heart failure
NYHA Class
(4.4% vs. 4.5%, p=0.92)
IV Heart
between the treatment groups.
Failure
Presented at AHA 2006
OAT Trial: Summary
• Among stable, high-risk patients with persistent
total occlusion of the infarct-related artery post-MI,
performance of PCI 3-28 days post-MI was not
associated with a difference in the composite of
death, reinfarction, or NYHA class IV heart failure
through a mean follow-up of 3 years compared with
medical therapy.
• Despite no reduction in the composite endpoint,
PCI was associated with a trend toward higher
rates of reinfarction compared with medication
Presented at AHA 2006
OAT Trial: Summary (cont.)
• The reinfarctions were not only procedural-related
infarcts (i.e., early procedural enzymatic leaks), but
true ST elevation reinfarctions that accumulated
throughout follow-up.
• One explanation for the trend toward an increase in
reinfarctions with PCI may be embolization resulting
in myocardial damage and impaired collateral flow.
• Presence of persistent total occlusion remains a
problem for a sizeable cohort of patients for whom
Presented at AHA 2006
suitable treatment is lacking.
OAT Trial: Summary (cont.)
• Early reperfusion therapy, the goal of ST elevation MI
treatment, with either primary PCI or thrombolysis, is
not indicated for patients who present late, often with
persistent total occlusion.
• The present study, the largest randomized trial to
date in this population, does not support the use of
late PCI for stable but persistent total occlusion.
Presented at AHA 2006
Dang, HE IS DRUNK