1. REVASCULARIZATION Vs MEDICAL THERAPY IN STABLE CAD
Dr Binjo J Vazhappilly
SR Cardiology
MCH , Calicut

2. Introduction
Coronary artery disease remains the leading cause of mortality in industrialized countries.
Majority of percutaneous coronary interventions are performed in pts with chronic stable coronary artery disease.
Benefit of revascularization among patients with chronic stable CAD is debatable

3. Introduction
There are 30 randomized trials comparing medical treatment with revascularization (PCI or CABG ) in pts with chronic stable CAD.
CABG was applied as revascularization therapy in 13 trials, of which 6 were performed more than 2 decades ago.
Balloon angioplasty alone was used in 8 studies
Subsequent trials used stents , but DES implantation was negligible except for BARI-2D.

6. COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Guideline-Driven Drug Evaluation
Hypothesis : PCI + Optimal Medical Therapy will be Superior to Optimal Medical Therapy Alone . Study period : 1999 to 2004 Follow-up : 2.5 to 7.0 yrs (median, 4.6). Primary Outcome : Death or non fatal MI

7. COURAGE
Inclusion Criteria : 1, 2 or 3 vessel disease ( >70% visual stenosis of proximal coronary segment) , Anatomy suitable for PCI , CCS Class I-III angina , Objective evidence of ischemia at baseline. Exclusion criteria : Persistent CCS class IV angina Markedly positive stress test ( Stage 1 Bruce protocol +ve ) LMCA disease > 50% Refractory heart failure or cardiogenic shock EF less than 30% Revascularization within previous 6 months Coronary anatomy not suitable for PCI.

8. Enrollment

9. Enrollment and Outcomes

10. Baseline Clinical & Angiographic Characteristics
PCI + OMT (N=1149)
OMT (N=1138)
P Value
CLINICAL
Stress test
0.84
Total patients - %
85 %
86 %
Treadmill test
57 %
Pharmacologic stress
43 %
Nuclear imaging - %
70 %
72 %
0.59
Single reversible defect
22 %
23 %
0.09
Multiple reversible defects
65 %
68 %
ANGIOGRAPHIC
Vessels with disease – %
0.72
1, 2, 3
31, 39, 30 %
30, 39, 31 %
Disease in graft
62 %
69 %
0.36
Proximal LAD disease
31 %
37 %
0.01
Ejection fraction
60.8 ± 11.2
60.9 ± 10.3
0.86

11. Baseline Clinical and Angiographic Characteristics
PCI + OMT (N=1149)
OMT (N=1138)
P Value
CLINICAL
History – %
Diabetes
32 %
35 %
0.12
Hypertension
66 %
67 %
0.53
CHF
5 %
4 %
0.59
Cerebrovascular disease
9 %
0.83
Myocardial infarction
38 %
39 %
0.80
Previous PCI
15 %
16 %
0.49
CABG
11 %
0.94

12. OUTCOMES

13. Need for Subsequent Revascularization
At a median 4.6 yr follow-up, 21.1% of the PCI patients required an additional revascularization, compared to 32.6% of OMT group who required a 1st revascularization.
77 pts in the PCI group and 81 pts in OMT group required subsequent CABG surgery
Median time to subsequent revascularization was 10.0 mo in the PCI group and 10.8 mo in the OMT group

14. Freedom from Angina During Long-Term Follow-up
Characteristic
PCI + OMT
OMT
CLINICAL
Angina free – no.
Baseline
12%
13%
1 Yr
66%
58%
3 Yr
72%
67%
5 Yr
74%
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.

15. Conclusions
As an initial management strategy in pts with stable CAD , PCI did not reduce the risk of death, MI or other major CV events when added to OMT
PCI resulted in better angina relief during most of the follow-up period, but medical therapy was also remarkably effective, with no difference in angina-free status at 5 yrs.

16. Limitations of COURAGE trial
Only 6.3 % of screened pts were randomized.
Among 70% of pts assigned to PCI who had 2-vessel disease, only 36% received > 1 stent.
Only 2.7% were treated with a DES.
32% of OMT patients crossed over to PCI.
Excluded high risk patients.
Post angiography selection bias.

17. BARI 2D Trial: Study Design
2368 pts with mild to moderate CAD and Type 2 diabetes prior to randomization.
CABG Stratum (N= 763)
PCI Stratum (N= 1605) R R
OMT alone (N= 385)
CABG +OMT (N= 378)
OMT alone (N= 807)
PCI +OMT (N= 798)
Study period : January 2001, to March 2005
Mean follow up : 5.3 yrs
Primary Endpoint: Death (from any cause)
Secondary Endpoint: Composite of Death, MI, or Stroke
BARI 2D Study Group, NEJM 2009 24 17

18. BARI 2D Inclusion criteria: Diagnosis of both type 2 diabetes & CAD.
CAD diagnosis by documented on angiography ( ≥50% stenosis of a major epicardial coronary artery associated with a positive stress test or ≥70% stenosis of a major epicardial coronary artery and classic angina).
Exclusion criteria :
Pts requiring immediate revascularization or had left main coronary disease
Creatinine level > 2.0 mg per deciliter
Glycated Hb > 13.0%
Class III or IV heart failure or hepatic dysfunction
Undergone PCI or CABG within the previous 12 months.

19. BARI 2D Trial: Primary Endpoint
The 5-year death rate for the group receiving revascularization plus optimal medical therapy was 13.2% vs. 13.5% in the group receiving optimal medical therapy alone.
The difference between the two treatment groups did not reach statistical significance.
Death (%)
n =155
n =161
Copyleft Clinical Trial Results. You Must Redistribute Slides
BARI 2D Study Group, NEJM 2009

20. BARI 2D Trial: Secondary Endpoint
The rates of MI, stroke and the combined secondary endpoint of death, MI and stroke were similar in 2 groups.
The difference between the two treatment groups for the combined secondary endpoint of death, MI and stroke did not reach statistical significance (p=0.70)
Cardiovascular Event (%)
n=138
n=283
n=118
n=33
n=266
n=30
BARI 2D Study Group, NEJM 2009

21. BARI 2D Trial
Summary : Prompt coronary revascularization in pts who had been treated with intensive medical therapy for diabetes and stable ischemic disease did not significantly reduce rate of death from any cause or major cardiovascular events.
Limitations
Patients who are at high risk for MI revascularization were excluded from the trial.
BARI 2D Study Group, NEJM 2009

22. MASS II Trial
Randomized Controlled Clinical Trial of therapeutic strategies for multivessel CAD, stable angina and preserved ventricular function.
Study period : May 1995 and May 2000
Inclusion criteria: Pts with angiographically documented proximal multivessel coronary stenosis of more than 70% by visual assessment and documented ischemia.
Exclusion criteria: Unstable angina or acute MI , ventricular aneurysm requiring surgical repair, LVEF < 40% , history of PCI or CABG and single-vessel disease.
Primary end point : cardiac mortality, Q-wave myocardial infarction (MI) or refractory angina requiring revascularization.

23. Database: 20.769 coronary angiographies (suitable to PCI-CABG)
MASS 2 TRIAL
Database: coronary angiographies
coronary <70% lesion
single coronary disease
previous CABG/PCI
valvar disease 2701
other
excluded patients:
Eligible: patients
(suitable to PCI-CABG)
refused to participate in this trial
or refused the surgical procedure
1465 patients non-randomized:
MASS II
Randomized: 611 patients
Angioplasty
(n=205)
Surgery
(n=203)
Medical Treatment
(n=203)
Hueb W, et al. J Am Coll CardioI 2004; 43:

24. Baseline Characteristics of MASS IIMT
(n = 203)
PCI
(n=205)
CABG
(n = 203) P
Characteristic
Demographic Profile
Male, (%)
Age (years) mean ± SD
Medical History
Previous MI (%)
Smoker (%)
Hypertension (%)
Diabetes mellitus (%)
CCS class 2 or 3 (%) 67
60±4 52 27 60 26 76 72
61±8 41 32 63 29 85
0.412
0.959
0.024
0.013
0.215
0.062
0.006 69
60±9 39 33 55 36 78

25. Overall Mortality-Free Survival

26. Ten-Year Follow-up Event-free Survival

27. CONCLUSION All three groups had similar rates of overall mortality.
Compared with CABG, angioplasty was associated with elevated rate of myocardial infarction and need for revascularization.
Medical therapy showed significant incidence of myocardial infarction and high rate of additional revascularization.

28. Limitations of MASS-II Trial
Single center study
Small number of subjects
No DES usage
Post-angiography selection bias

29. STICH TRIAL Randomized controlled trial, non-blinded
Study period : July 2002 and May 2007
A total of 1212 pts were randomly assigned to medical therapy alone (602 patients) or medical therapy plus CABG (610 pts).
Primary Endpoint
All-cause mortality
Major Secondary Endpoints
Cardiovascular mortality
Death (all-cause) + cardiovascular hospitalization

30. STICH TRIAL Inclusion criteria
Pts with coronary artery disease that was amenable to CABG and EF of 35% or less
Medical therapy eligible
Absence of left main CAD as defined by an intraluminal stenosis of ≥ 50%
Absence of CCS III angina or greater (angina markedly limiting ordinary activity)
Exclusion criteria
Recent acute MI (within 30 dys) ,Cardiogenic shock (within 72 hrs of randomization) , Plan for percutaneous intervention , Aortic valve disease requiring repair or replacement , Life expectancy of < 3 yrs .
OUR RPIMARY ENDPOINT WAS
ALLL CAUSE MORTALITY
IMPORTANT SECONDARY ENDPOINTS
INCLUDED
CARDIOVASCULAR MORTALITY
AND
ALL CAUSE DEATH OR CARDIOVASCULAR HOSITALIZATION

31. STICH Revascularization Hypothesis Treatment Per Protocol
1212
Received
MED only
CABG
555
537
Randomized
MED only
610
602
Randomized
CABG
17% 9% 55 65
WE ALSO PERFORMED
A PER PROTOCOL ANALYSIS
COMPARING ONLY THE 537 PATIENTS RANDOMIZED TO MEDICAL THERAPY
WHO REMAINED ON MEDICAL THERAPY
AND
THE
555 PATIENTS RANDOMIZED TO CABG WHO RECEIVED CABG BY PROTOCOL ONLY
Per protocol: MED (537) vs CABG (555)

32. All-Cause Mortality — As Randomized
HR 0.86 (0.72, 1.04)
P = 0.123
Adjusted HR 0.82 (0.68, 0.99)
Adjusted P = 0.039
0.46
0.41
AFTER ADJUSTING FOR PRE-SPECIFIED BASELINE VARIABLES
THE HAZARD RATIO FOR CABG WAS 0.82
WHICH CORRESPONDED TO A
P VALUE OF 0.039
Model 3 Covariate adjusted – all variables prospectively specified in STICH protocol or with significant prognostic effect.
Stratum, age, gender, race, HF class at baseline, MI history, previous revascularization, best available EF, number of diseased vessels, chronic renal insufficiency, MR, stroke hx, AF hx

33. Cardiovascular Mortality — As Randomized
HR 0.81 (0.66, 1.00)
P = 0.050
Adjusted HR 0.77 (0.62, 0.94)
Adjusted P = 0.012
0.39
0.32
AMONG THE 602 PATIENTS
RANDOMIZED TO MEDICAL THERAPY ALONE
THE OVERALL CARDIOVASCULAR MORTALITY RATE WAS 39%
AMONG THE 610 PATIENTS RANDOMIZED TO MEDICAL THERAPY WITH CABG
THE OVERALL MORTALITY RATE WAS 32%
THIS ABSOLUTE RISK REDUCTION OF 7%
CORRESPONDED TO A HAZARD RATIO WITH CABG OF 0.8 1
AND A P VALUE OF 0.050

34. Death or Cardiovascular Hospitalization — As Randomized
0.68
0.58
HR 0.74 (0.64, 0.85)
P < 0.001
Adjusted HR 0.70 (0.61, 0.81) P < 0.001
FOR THE ENDPOINT OF ALL CAUSE DEATH OR CARDIOVASCULAR HOSPITALIZATION
THE OVERALL EVENT RATE WAS
68% WITH MEDICAL THERAPY ALONE
AND
58% WITH CABG
THIS ABSOLUTE EVENT REDUCTION OF 10% IN FAVOR OF CABG
WAS STATISTICALLY SIGNIFICANT WITH AND WITHOUT ADJUSTMENT

35. Stich trial : summary
No significant difference between the two study groups with respect to the primary end point of the rate of death from any cause.
The rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiac causes were lower among patients assigned to CABG than among those assigned to medical therapy.

36. Urgent revascularization
FAME 2
Trial design: Patients with stable angina who were appropriate candidates for PCI and had a fractional flow reserve (FFR) value ≤0.80 were randomized to either PCI + optimal medical therapy (OMT) or OMT alone. Patients were followed for a mean of 7 months.
Results
(p < 0.001)
(p < 0.001)
Trial was terminated early. Primary endpoint (death/ MI/ urgent revascularization) for PCI + OMT vs. OMT: 4.3% vs. 12.7%, HR 0.32, 95% CI , p < 0.001
Mortality: 0.2% vs. 0.7%, p = 0.31; MI: 3.4% vs. 3.2%, p = 0.89; urgent revascularization: 1.6% vs. 11.1%, p < 0.001
Highest benefit if lesion FFR <0.65
100
100 % 50 % 50
12.7
11.1
Conclusions
4.3
1.6
FFR-guided PCI + OMT was superior to OMT in patients with stable angina, mainly due to a reduction in need for urgent revascularization
These results suggest that a positive FFR may be a good method to risk stratify these patients
Primary endpoint
Urgent revascularization
PCI + OMT
(n = 447)
OMT
(n = 441)
De Bruyne B, et al. N Engl J Med 2012;367:

37. Meta-Analysis of Randomized clinical trials

38. Risk of all-cause mortality
Circ Cardiovasc Interv. 2012;5:

39. Risk of cardiac death
Circ Cardiovasc Interv. 2012;5:

40. Risk of revascularization
Circ Cardiovasc Interv. 2012;5:

41. Freedom from angina
Circ Cardiovasc Interv. 2012;5:

42. Conclusions
Pts with stable CAD there is no definitive evidence of an added benefit of PCI to reduce risk of mortality , cardiac death , nonfatal MI and need for revascularization when compared with medical therapy alone.
PCI provides a benefit over medical therapy in symptom relief of angina in patients with stable CAD.

43. Meta-Analyses Assessing Impact of PCI Versus OMT
J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 6 , N O ,

44. ISCHEMIA :International Study of Comparative Health Effectiveness with Medical and Invasive Approaches
Study Group : Stable CAD with atleast moderate ischemia.
Primary Aim: to determine whether an initial PCI or CABG + OMT is superior to a conservative strategy of OMT alone, with cath reserved for OMT failure
Primary Endpoint: CV death or MI
Secondary Endpoint: angina-related QOL
Sample size : 8000
Follow up : Average 4 years.

46. 2013 ESC Guidelines Revascularization of stable CAD pts on OMT

47. ACCF/AHA/SCAI PCI Guidelines: Revascularization to Improve Survival

48. Revascularization to Improve Symptoms

49. THANK YOU