1. Ischemia Guided Strategy in NSTE-ACS – When to go Invasive?
Vinod Sharma
MD, DM, MBA, FACC
National Heart Institute
New Delhi

4. GUSTO 2B: ST Depression A High-Risk Patient Population
T-wave
inversion
Data from GUSTO 2B demonstrates that ST depression is not a low risk syndrome. Patients with ST depression are older and have more comorbidities, and their mortality is actually higher at 6 months when compared with ST elevation.
CM Gibson 2002

8. Non ST Elevation MI Ruptured Plaque
90% of acute MIs are caused by thrombus formation from rupture of unstable plaques

9. Generally caused by partially occlusive, platelet-rich thrombus
Non-ST Elevation ACS
Generally caused by partially occlusive,
platelet-rich thrombus
Unobstructed lumen
thrombus
Results from cross-linking of fibrinogen by platelet GP IIb-IIIa receptors at sites of plaque rupture
platelet
fibrinogen
Ruptured plaque
GP IIb-IIIa
Artery wall

10. Red Vs White Thrombus ……

11. NSTEMI
Platelet rich Thrombus
Anti-platelet drugs
STEMI
Fibrin rich Thrombus
Thrombolysis / PCI

12. Evidence of multiple “vulnerable” plaques in acute coronary syndrome

13. Plaque Rupture – Clinical Manifestation
People who died due to ACS, harbour both thrombosed & non thrombosed ruptured plaques in their coronary arteries.
Goldstein JA et al: NEJM 2000
Additional plaques are frequently found adjacent to the culprit lesions in patients undergoing PTCA.
Schoenhager Petal: 2003

14. Additional Unstable Plaques Beyond the Culprit Lesion
27 patients with ACS. Angio + 3 vessel IVUS
Plaque instability beyond the culprit lesion
Content points:
Rioufol et al used intravascular ultrasound (IVUS) to measure plaque ruptures in the three coronary arteries of 24 patients with first acute coronary syndrome (ACS).1
There were 50 distinct plaque ruptures detected, with a range of 0 to 6 per patient and a mean of 2.08.
In all, 79% of patients showed at least one plaque rupture somewhere other than the culprit lesion, and 12.5% of patients had at least one rupture in all three arteries.
These results support the idea that unstable atherosclerotic plaques occur throughout the coronary tree.
1 Rioufol G, Finet G, Ginon I, André-Fouët X, Rossi R, Vialle E, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: A three-vessel intravascular ultrasound study. Circulation. 2002;106:

15. Acute Coronary Syndrome a “PANCORONITIS”
Acute Coronary Syndrome a “PANCORONITIS” ? Local manifestation of systemic disease

16. Culprit is vulnerability ……

17. Link between CV risk factors, endothelial dysfunction, inflammation & ACS
Smoking Diabetes Hypertension
Shear stress Oxidative stress
Infection ?
INFLAMMATION
ENDOTHELIAL DYSFUNCTION
NFkB
↓ Nitric Oxide, PGI2, TGF ↑ Adhesion molecules (ICAM, VCAM)
↓ Andrenomedullin, CNP ↑ Chemotactic proteins (MCP – 1)
↑ Endothelin – 1, PDGF, ACE ↑ Interleukins, C-reactive protein
↑ Apoptosis, tissue factor
PLATELET AGGREGATION, FIBRIN PRODUCTION, PLAQUE GROWTH
ACUTE CORONARY SYNDROMES

21. Non STEMI – Management Strategy
Red Vs White Thrombus
- Thrombolysis doesn’t work
Diffuse Pancoronitis?
- Local manifestation of systemic process
- Plaque passivation & stabilization is a must

23. Ischaemia Guided Management of NSTEMI
Rapid Initiation of intensive medical management
Non invasive risk stratification
Cardiac catheterization
Medical Rx Revascularization –
PCI / CABG

24. Management of NSTEMI – Early Invasive Strategy
Non invasive testing is deferred &
All patients with suspected ACS are referred for Coronary angiography & possible revascularization early in their hospital course.

25. Management of NSTEMI – Early Invasive Approach
Helps in determining coronary anatomy early in the hospital course.
Avoid lengthy delays & possible ambiguities associated with noninvasive testing.
Specific anatomical subgroups can be expeditiously identified & treated.
Early hospital discharge for low risk cases.

26. Management of NSTEMI – Limitation of Coronary Angiography
Most patients with ACS have diffuse systemic atherosclerosis involving entire coronary vascular system.
CAG is only capable of measuring cross sectional anatomy from a simple planar two dimensional silhouette of contrast filled lumen.
It grossly underestimate plaque burden and true extent of atherosclerosis.

27. Management of NSTEMI – Limitation of Coronary Angiography (contd)
CONTINUED NEED FOR AGGRESSIVE MEDICAL THERAPY
Individual lesion assessment may be difficult, if the adjacent “normal” coronary segment is diffusely diseased or if there is coronary remodeling with development of “extra luminal plaque”.
CAG is incapable of assessing plaque vulnerability & sub-segment risk for plaque rupture.

28. Ischaemia Guided Approach
Intensive medical therapy with antithrombotic, antiplatelet, anti-ischemic & lipid lowering drug may result in rapid clinical stabilization.
Exercise test may reliably identify those patients for risk of future events who need CAG & revascularization.
This approach “Tailoring the Therapy to Risk”, optimizes clinical efficacy & cost effectiveness, because high risk cases are identified & low risk patients avoid costly invasive procedure that are unlikely to confer clinical benefit & may actually harm them.

29. Non ST  ACS 30 Day Death/MI Risk
Low Risk
Intermediate Risk
High Risk
Very High Risk
Non ST  ACS 30 Day Death/MI Risk
< 3 %
3-8 %
8-15 %
>15%
No higher risk features
Single short duration (<10 min.) rest pain
Crescendo angina/New onset angina (Mod severity)
6 Hour Observation
ECG X 2 normal, unchanged or non-specific ST ’s
Negative biomarkers X 2
Rest pain < 20 min.
New onset/ Crescendo angina (Low threshold severity)
ECG non-specific abnormalities or normal
Biomarkers normal or borderline 
Increased baseline risk DM
Previous CABG/MI
Recent PCI
Rest pain > 20 min.
Prolonged recurrent pains
ECG ST depression < 2mm
Deep T inversion (e.g. > 5 mm)
T inversion > 2 mm
Especially in > 5 leads
Isolated biomarker clearly +ve
ST depression < 2mm
With  CK-MB or Tn
ST depression > 2mm
Multiple leads
With pain
Transient ST  > 1 mm
Hemodynamic instability
 BP/CHF
Refractory ischaemia with ST shift
D Fitchett, SG Goodman M Gupta, A Langer. Can J Card 2002; 18 (11):

33. GRACE Risk Score Variable Odds ratio Older age 1.7 per 10 y
Killip class
2.0 per class
Systolic BP
1.4 per 20 mm Hg ↑
ST-segment deviation
2.4
Cardiac arrest during presentation
4.3
Serum creatinine level
1.2 per 1-mg/dL ↑
Positive initial cardiac biomarkers
1.6
Heart rate
1.3 per 30-beat/min ↑
The sum of scores is applied to a reference monogram to determine the corresponding all-cause mortality from hospital discharge to 6 months. Eagle KA, et al. JAMA 2004;291:2727–33. The GRACE clinical application tool can be found at Also see Figure 4 in Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157.
GRACE = Global Registry of Acute Coronary Events.

42. Invasive versus conservative treatment in unstable coronary syndromes
ICTUS Trial
Invasive versus conservative treatment in unstable coronary syndromes
Presented at
European Society of Cardiology
Congress 2004
Presented by Dr. R.J. De Winter

43. Selective Invasive Strategy Early Invasive Strategy
ICTUS Trial
1,201 patients with non-ST elevation MI acute coronary syndromes who were troponin-positive
Selective Invasive Strategy
Medical stabilization with angiography and revascularization only in case of refractory angina or ischemia exercise testing
n=597
Early Invasive Strategy
Coronary angiography within hours and PCI within 48 hours or CABG as soon as possible
n=604
Primary Endpoint:
Death, MI or rehospitalization for acute coronary syndrome (ACS) at 6 months
Presented at ESC 2004

44. Death, MI or rehospitalization for ACS at 6 months
ICTUS Trial
Death, MI or rehospitalization for ACS at 6 months
p = 0.59
Revascularization was performed by hospital discharge in 73% of patients in the early invasive group and 47% of patients in the selective invasive group
No difference by treatment group in the primary composite endpoint of death, MI, or rehospitalization for ACS at 6 months
Presented at ESC 2004

45. Rehospitalization for ACS
ICTUS Trial
MI by 6 months
p = 0.006
Rehospitalization for ACS
by 6 months
p = 0.017 % %
Presented at ESC 2004

49. TACTICS-TIMI 18
Treat Angina with Aggrastat + Determine Cost of Therapy with an Invasive or Conservative Strategy TIMI 18
As presented by Dr. Cannon at AHA 2000.

51. TACTICS TIMI 18 20% 19.4% Initial Medical Rx 16% 15.9% 12%
Patients (%)
20%
19.4%
Initial Medical Rx
16%
15.9%
12%
Early Cath + PTCA 8% 4%
The primary results from the TACTICS-TIMI 18 study demonstrated that the strategy of early cardiac catheterization and revascularization resulted in a statistically significantly lower incidence of adverse ischemic events at 6 months than a strategy of initial medical therapy. 5 6 1 2 3 4
Months
Cumulative Incidence of the Primary Endpoint of Death, Nonfatal MI, rehospitalization for an ACS within 6 months
Cannon CP, et al. N Engl J Med. 2001;344:

52. TACTICS Trial Results Based on Troponin
Initial Medical Rx
Early Cath + PTCA
P<0.001
25%
20%
P=NS
15%
10%
In TACTICS TIMI-18, patients with positive troponins experienced dramatically lower major ischemic events when treated with a strategy of early cardiac catheterization and revascularization 5%
Negative
Troponin
Positive
Troponin
Cannon CP, et al. N Engl J Med. 2001;344:

53. TACTICS-TIMI 18: Conclusions
Pts with UA/NSTEMI (+ ECG/+ markers/CAD), “upstream” Rx with GP IIb/IIIa inhibitor tirofiban
Early invasive strategy results in significant reduction in major cardiac events (Death/MI/ Rehosp for ACS)
“Troponin hypothesis” confirmed: Tn useful in choosing strategy,  benefit of INV if Tn +
TIMI Risk Score:
Intermediate- and high-risk Pts: INV superior
Low risk Pts: INV and CONS equal

54. TACTICS-TIMI 18: Conclusions
Possible mechanisms:
Benefit of early INV - prevents events compared with “wait and see” approach
Upstream tirofiban improved INV strategy
Results of TACTICS-TIMI 18 suggest need to
Update ACC/AHA UA/NSTEMI Guidelines
Change clinical management of UA/NSTEMI: broader use of an early invasive strategy with GP IIb/IIIa inhibition
EQOL being analyzed: W. Weintraub – ACC 2001

56. The Primary Composite Ischemic End Point in RITA-3
The RITA-3 trial also randomized patients with NSTE-ACS to either a strategy of early cardiac catheterization and revascularization, or to initial medical therapy. Those randomized to early intervention experienced a lower incidence of death, myocardial infarction, or recurrent unstable angina.
Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Lancet. 2002;360:

59. Clinical Trial Links: Invasive vs Conservative Strategy for UAP/NSTEMI
Favors
Conservative
No Difference
Invasive
VANQUISH
TIMI III B
TACTICS-
TIMI 18
INSPIRE
MATE
FRISC II
ICTUS
RITA 3
TRUCS
VINO

60. Comparison to Prior Trials
TIMI 3 VANQWISH FRISC II TACTICS TIMI 18
INV
Stents No No Yes Yes
GP IIb/IIIa No No No Yes
Cath Timing 24 hrs days days hrs
CONS
ETT Nuclear Nuc./Echo ECG Nuc/Echo
ST  criteria 1mm mm 3mm mm
In-hosp Cath 57% % 10% %
Result Early INV INV < Del. INV Early INV
=Select. CONS > Very ? Select.
INV CONS INV

61. Invasive vs. Conservative Strategy for UA/NSTEMI – All Studies
ISAR-COOL
RITA-3
VINO
VANQWISH
TRUCS
MATE
TACTICS- TIMI 18
ICTUS
TIMI IIIB
FRISC II
Invasive
Conservative
# Pts:

64. TACTICS-TIMI18: Rates of Death, Nonfatal MI, or Rehospitalization for an ACS at Six Months, According to Base-Line Characteristics
Figure 2. Rates of the Primary End Point of Death, Nonfatal Myocardial Infarction, or Rehospitalization for an Acute Coronary Syndrome at Six Months, According to Base-Line Characteristics. Odds ratios and 95 percent confidence intervals were determined by logistic-regression analysis. P values for the interaction were significant only for prior aspirin use (P=0.02) and ST-segment changes (P=0.006). For the analysis of the TIMI risk score, which assesses the risk of death and ischemic events in patients with unstable angina and myocardial infarction without ST-segment elevation, the upper bound of the confidence interval for a score of 3 to 4 was (P=0.048; P for the interaction among the three risk groups=0.15). Troponin T was measured at base line in a total of 1826 patients. MI denotes myocardial infarction.
Cannon C et al. N Engl J Med 2001;344:

66. Benefit of Invasive Strategy by Troponin and ST Changes
Death, MI, or Rehospitalization for ACS at 6 Months
Conservative
P<.001
P<.001
Invasive 30 30
P=NS
25.0*
P=NS
24.5* 25 25 20 20
16.0
16.6
16.4*
15.3*
15.1
CV Events (%) 15 15
12.4 10 10
Subgroup analysis from the TACTICS-TIMI 18 Study demonstrated that a strategy of early cardiac catheterization and revascularization reduced ischemic complications in patients with positive troponin T levels and in those with ischemic ST segment abnormalities. There was no significant difference in outcome in patients who lacked these risk markers. 5 5
TnT –
TnT +
No ST change
ST change
Morrow DA, et al. JAMA. 2001;286: and Cannon CP, et al. N Engl J Med. 2001;344:

67. Timing of Intervention in Patients with Acute Coronary Syndromes (TIMACS)
AHA, 2008

68. Background
For UA/NSTEMI pts that are treated with an invasive strategy, the timing of catheterization has not been rigorously investigated.

69. TIMACS: Methods
Pts with UA/NSTEMI randomized to early invasive strategy (angiography within 24 hrs) or delayed invasive strategy (angiography any time after 36 hrs).
Primary endpoint:
- composite of death, new MI, or CVA at months.
Secondary endpoints:
- death, new MI, or refractory ischemia
- death, new MI, CVA, refractory ischemia, repeat revascularization
- CVA

70. 3,031 pts enrolled (1,593 pts in early invasive strategy – median time to cath 14 hrs; 1,438 pts in delayed invasive strategy – median time to cath 50 hrs).
Mean age 65.4 yrs; 35% females.
77% pts with NSTEMI
27% pts with DM; 20% pts with h/o MI
ASA (98%), Thienopyridine (87%), BBlockers (86.9%), Statins (85%), LMWH (64.3%), UFH (24.6%), Fondaparinux (41.5%, part of the pts were enrolled in OASIS), gp2b/3a (23%), bivalirudin (0.5%).
25% pts crossed from delayed to early strategy (refractory ischemia, new MI or instability). 12% crossed from early to delayed strategy.

71. Primary and secondary outcomes in TIMACS hazard ratio (95% CI), early vs delayed strategies
End point
HR (95% CI) p
Death, MI, stroke*
0.85 (0.68–1.06)
0.15
Death, MI, refractory ischemia
0.72 (0.58–0.89)
0.002
Death, MI, stroke, refractory ischemia, repeat intervention
0.84 (0.71–0.99)
0.039
Refractory ischemia
0.30 (0.17–0.53)
<
*Primary end point
Mehta SR et al. American Heart Association 2008 Scientific Sessions; November 10, 2008; New Orleans, LA.

72. Rates of death, MI, or stroke within six months according to GRACE risk level and HR (95% CI), early vs delayed
Risk level by GRACE score*
Early (%)
Delayed (%)
HR (95% CI) p
Low/
intermediate (n=2070)
7.7
6.7
1.14 (0.82–1.58)
0.43
High (n=961)
14.1
21.6
0.65 (0.48–0.88)
0.005
*Low/intermediate risk=GRACE score <140
High risk=GRACE score >140
Mehta SR et al. American Heart Association 2008 Scientific Sessions; November 10, 2008; New Orleans, LA.

73. TIMACS: Conclusions
Early invasive strategy in pts with UA/NSTEMI is not superior to delayed invasive strategy with regard to the composite of death, new MI and CVA at 6 months, unless pt is high risk (as assessed by the GRACE risk model).
Early invasive strategy is superior in reducing the incidence of refractory angina without increasing the risk of bleeding.
Early invasive strategy can be implemented very early after pt’s admission – no benefit in “cooling pt off”.

78. Management Strategy for ACS/NSTEMI
Aggressive Therapy
(early cath/intervention)
Non-cardiac exacerbation of known CAD
Anemia
Infection
Hyperthyroidism
Other medical causes
Patient preference
Stability
Normal LV Function
Good exercise tolerance
Relative C/I to CABG/PCI
Brief duration of ischaemia
No ST changes
Negative biomarkers
Dynamic ST changes
Positive Enzymes or Biomarkers
Recurrent ischaemia on medical Rx
Prolonged ischaemic pain
PTCA < 6 months
Known severe CAD
LV dysfunction
Pre-existing
new MR
new CHF
Intolerance to medical Rx
Recurrent ventricular arrythmia’s/SCD
Early positive non-invasive test
Poor exercise tolerance
ACS/NSTEMI
Conservative Therapy (medical Rx/non-invasive evaluation)

79. Management of NSTEMI – When to go Invasive?
CONCLUSION
Early identification & risk stratification is a key factor.
Medical management, passivation of plaque is essential initial step in managing patients with NSTEMI .
Invasive strategy is proven to be of benefit in majority except in low risk groups.

81. THANK YOU