1. William E. Boden, MD, FACC, FAHA
Medical Therapy Should Work Well for Patients with Documented Ischemia Why Guideline-Directed Medical Therapy Has Altered the Therapeutic Landscape
William E. Boden, MD, FACC, FAHA
Professor of Medicine, Albany Medical College
Chief of Medicine, Stratton VA Medical Center
Vice-Chairman, Department of Medicine
Albany Medical Center, Albany, NY
Cardiovascular Research Technology 2013 Washington, D.C. February 25, 2013 1

2. An SIHD Patient with CCS 2 Angina & 1. 5 mm ST ↓ at 9
An SIHD Patient with CCS 2 Angina & 1.5 mm ST ↓ at 9.5 min ETT Exercise
Is this a benign lesion
in a benign condition?

3. Dual Goals for Management of Stable Ischemic Heart Disease (SIHD)
Prevent MI and Death (Disease Modification)
Improve “Quantity of Life”
Reduce Ischemia & Relieve Anginal Symptoms
Improve “Quality of Life”
Boden WE. Medical management of chronic coronary disease. Am J Cardiol. 2008;101:69D-74D.
Gibbons RJ et al. Circulation. 2003;107: 3

4. Pharmacologic Therapy in SIHD: 2000
Disease-Modifying
Therapy
Aspirin
Statins
ACE inhibitors and/or ARBs
Beta-blockers Post-MI
Symptomatic Treatment for Angina/Ischemia Control
Beta-blockers w/o MI
Calcium antagonists
Nitrates
Boden WE et al. N Engl J Med. 2007; 356: 4

5. Pharmacologic Rx in SIHD: 2013… A Moving Target—and Improving!
Disease-Modifying
Therapy
Aspirin
Thienopyridines
Statins
ACE inhibitors and/or ARBs
Beta-blocker Post-MI
Aldosterone Inhibitors
? Fibrates and Niacin
Symptomatic Treatment for Angina/Ischemia Control
Beta-blockers w/o MI
Calcium antagonists
Nitrates
Ranolazine
Ivabradine (in Europe)
Boden WE et al. N Engl J Med. 2007; 356: 5

6. What Can Be Achieved with OMT in SIHD: COURAGE Primary Endpoint Survival Free of Death or MI
Randomization to PCI + OMT vs OMT
Intensive, Guideline- driven Medical Therapy & Lifestyle Intervention In Both Groups
Years 1 2 3 4 5 6
0.0
0.5
0.6
0.7
0.8
0.9
1.0
PCI + OMT
Optimal Medical Therapy (OMT)
Hazard ratio: 1.05
95% CI ( )
P = 0.62 7
Boden WE et al. N Engl J Med. 2007; 356: 6

7. Freedom from Angina: CASS vs. COURAGE
Percent
From 1975 to 1979, CASS randomized 780 patients with stable CAD to CABG or medicine. BOTH groups received medical therapy: modify risk factors, and nitrates and beta blockers were given for angina. At 5 years, average annual mortality for CABG was 1.1% and for medicine was 1.6%.
Assuming that CABG is the benchmark for complete revascularization, note that at 1 year PCI and CABG had the same 66% angina free. At 5 years only 63% of CABG patients were angina-free, compared with 74% in COURAGE. This should silence any who believe that PCI done properly should have produced more freedom from angina than we achieved (although it is fair to acknowledge that DES might have improved our statistics). 
Notice how much better the medical group fared in COURAGE compared with CASS. This speaks to the extraordinary advances made in medical therapy and the comprehensiveness of our medical intervention, and suggests why the PCI arm in COURAGE outperformed the CABG arm in CASS.
Rogers et al. Circulation 1990;82:
Boden et al. N Engl J Med 2007; 356:

8. COURAGE Nuclear Substudy: Pre-Rx & 6-18 Mo Post-PCI + OMT vs. OMT
PCI + OMT (n=159)
OMT (n=155)
8.1%
(6.9%-9.4%)
8.6%
8.2%
5.5%
(4.7%-6.3%)
p<0.0001
Mean=-2.7% (95% CI=-1.7% to -3.8%)
Mean=-0.5% (95% CI=-1.6% to 0.6%) 8

9. COURAGE Nuclear Substudy: Unadjusted and Risk-Adjusted Outcomes for Reduction in Ischemic Myocardium

10. Does PCI Reduce Clinical Events?
COURAGE: Death/MI rates PCI vs. OMT in Pts with Moderate-to-Severe Ischemia at Baseline, with or without a 2nd scan during Follow-Up
HR: 1.39 ( )
PCI vs. OMT
24% vs. 21%
HR 1.19
95% CI
(N=407)
Shaw LJ, Berman DS, Boden WE et al: Am Heart J 2012; 164:
Site read Moderate-to-Severe
Ischemia
Core Lab read Moderate-to-Severe Ischemia
(N=189)
Death or MI
COURAGE patients who had nuclear myocardial perfusion imaging (MPI) at baseline were included in this analysis. There are important differences between this analysis and the COURAGE nuclear substudy published in Circulation in 2008:
The analysis is on baseline MPI only, not paired scans obtained at baseline and 6-18 months later.
The association between baseline ischemia and outcomes is reported by treatment group.
There were far more patients included in this analysis with moderate-to-severe ischemia (N=407 vs. N=105).
The scans were interpreted by local sites, not the core lab (although the right hand side of the slide shows a subset that also had core lab interpretations).
There is no signal from this analysis that patients randomized to PCI with moderate-to-severe ischemia at baseline have lower rates of death or MI compared with OMT patients. 10 10

11. After optimal anti-ischemic
COURAGE Nuclear Substudy
2000
2003
Stress
Rest
Stress
Rest
Patient randomized
to medical treatment only
Apex
Mid
Base
Before treatment
After optimal anti-ischemic
medical therapy
Circulation 2008; 117: 11

12. BARI 2D Study: Medical Therapy Versus Revascularization
Primary Outcome (All-Cause Death)
PCI
CABG
89.9%
86.4%
89.2%
83.6%
P=0.48
P=0.33
Survival (%)
Survival (%)
Slide: BARI 2D Study: Medical Therapy Versus Revascularization
The rate of death did not differ significantly between the revascularization group and the medical-therapy group in either the CABG or the PCI stratum.1
Reference
BARI 2D Study Group, Frye RL, August P, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360:
Medical therapy
Revascularization
Medical therapy
Revascularization
Follow-Up (Years)
Follow-Up (Years)
BARI 2D Study Group. N Engl J Med. 2009;360: 12 12

13. BARI 2D Study: Medical Therapy Versus Revascularization
Principal Secondary Endpoint (Death, MI, or Stroke)
PCI
CABG
78.9%
77.6%
77.0%
69.5%
Survival (%)
P=0.15
Survival (%)
P=0.01
Slide: BARI 2D Study: Medical Therapy Versus Revascularization
The rate of death, MI, or stroke did not differ significantly between the revascularization group and the medical-therapy group in either the PCI stratum, but was significantly better in the revascularization group in the CABG stratum.1
Reference
BARI 2D Study Group, Frye RL, August P, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360:
Medical therapy
Revascularization
Medical therapy
Revascularization
Follow-Up (Years)
Follow-Up (Years)
BARI 2D Study Group. N Engl J Med. 2009;360: 13 13

14. De Bruyne BD et al. N Engl J Med. 2012 (published online Aug. 28)
2. Boden WE et al. N Engl J Med (published online Aug. 28)

15. No Difference in All-Cause Death or MI
FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD
On recommendation of the DMC, recruitment was halted on after inclusion of 1220 patients (± 54% of planned Pts)
Primary Outcomes
All-Cause Death, MI, Unplanned Hosp w/ Urgent Revasc 5 10 15 20 25 30
Cumulative incidence (%) 1 2 3 4 6 7 8 9 11 12
Months after randomization
PCI+MT vs. MT: HR 0.32 ( ); p<0.001
No Difference in All-Cause Death or MI
De Bruyne, B, et al. NEJM 15

16. FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD
Patients with Angina Class II to IV 20 40 60 80
Percentage of patients with CCS II to IV, %
Baseline
30 days
6 months
12 months
PCI+MT MT
Registry
P<0.001
P=0.002
P=0.002
P=0.073
De Bruyne, B, et al. NEJM 16

17. Limitations of FAME 2 Trial1
Only 888 of a planned 1,600 stable CAD patients were randomized to FFR-guided PCI vs. OMT (55% of projected initial sample size)
Trial was stopped early by DSMB due to benefit in FFR-guided stenting group for the composite primary endpoint, but this was driven solely by a lower rate of urgent revasc. rate (1.6%) in the PCI pts compared to pts on OMT alone with no difference in death or MI
Mean follow-up was only 7 months (projected mean follow-up=24 months), which was too short a time for even restenosis to emerge in PCI pts
In an unblinded trial, an endpoint such as “urgent revasc” (which did not mandate either ECG ischemia or (+) cTnT) could have introduced MD bias
Only 98 patients were followed longer than 12 months, after which there were 0 deaths in either group, and only 2 MIs (both in the PCI group)
OMT was not rigorously used to achieve treatment targets for BP, LDL, HbA1c, etc., as in COURAGE
1. Boden WE: Which Is More Enduring: FAME or COURAGE? N Engl J Med (published online Aug. 28) 17

18. How Superior is PCI to OMT for Angina Relief In the Modern Era of Contemporary Medical Therapy?

19. Summary Odds Ratio of Freedom from Angina
Study, Year (Reference)
PCI, n/n
Medical Therapy, n/n
OR (95% CI)
ACME, 1997 (27), 1998 (28)
78/124
55/127
2.22 ( )
MASS, 1995 (19), 1999 (20)
44/68
17/66
5.28 ( )
TOPS, 1992 (13)
34/42
23/45
4.07 ( )
RITA-2, 2003 (4), 1997 (9)
130/188
105/206
2.16 ( )
AVERT, 1999 (31)
95/177
67/164
1.68 ( )
Dakik et al, 1998 (12)
18/19
21/22
0.86 ( )
SWISSI II, 2007 (11)
85/96
73/105
3.39 ( )
ALKK, 2003 (14)
115/149
92/151
2.17 ( )
Bech et al, 2001 (5); Pijls et al, 2007 (38)
51/90
61/91
0.64 ( )
MASS II, 2004 (29), 2007 (30)
119/205
92/103
1.67 ( )
Hambrecht et al, 2004 (6)
43/50
50/51
0.12 ( )
DECOPI, 2004 (15)
101/109
1.51 ( )
COURAGE, 2007 (8)
316/423
296/406
1.10 ( )
OAT, 2006 (7)
234/263
233/257
0.83 ( )
Summary
1463/2003 (73.0%)
1277/1997 (63.9%)
1.69 ( )
OR (95% CI)
P = 0.001
Heterogeneity Q = 47.7 (P < 0.001)
I 2 = 72.7
0.01
0.1 1 10
100
Favors Medical Therapy
Favors PCI
Wijeysundera HC et al. Ann Intern Med. 2010;152: 19

20. Summary Odds Ratios Stratified by Duration of Follow-up and Recruitment Period
Studies, n
PCI, n/n (%)
Medical, n/n (%)
Summary OR (95% CI)
P value
<1 y 8
1993/2792 (71.4)
1801/2800 (64.3)
1.44 ( )
<0.001
1-5 y 10
1567/2197 (71.3)
1361/2198 (61.9)
1.70 ( )
0.002
>5 y 5
615/882 (69.7)
539/871 (61.9)
1.75 ( )
0.07
Recruitment Period
Studies, n
PCI, n/n (%)
Medical, n/n (%)
Summary OR (95% CI)
P value
≤1994 3
156/234 (66.6)
95/238 (39.9)
3.38 ( )
<0.001 6
494/719 (68.7)
419/739 (56.7)
1.72 ( )
0.01
≥2000 5
813/1050 (77.4)
763/1020 (74.8)
1.13 ( )
0.54
Wijeysundera HC et al. Ann Intern Med. 2010;152: 20

21. Why PCI Does Not Reduce Long-Term Events in Stable CAD
“Revascularization fixes the lesion and the segment, but not the artery or the patient; OMT reduces clinical events” -Peter Libby, MD; HMS, 2008

22. Why Scientific Evidence Supports OMT as an Appropriate Initial Approach to SIHD Patient Management
16 RCTs in 8,820 patients (including COURAGE, BARI-2D, & FAME-2) show no difference in death, MI, stroke, or other “hard” CV events between PCI and OMT
Aggressive medical therapy & lifestyle intervention without initial PCI can be implemented safely in the majority of SIHD patients—1/3 of whom may require a symptom-driven procedure over 7 years of F/U, but 2/3 of whom may not require even a first revascularization. This approach incurs no penalty with respect to death, MI, ACS, or need for CABG
Although routine PCI + OMT provides some advantages in angina/physical limitation/QOL, these differences are numerically small, not durable, and achieved only at an unattractive cost for chronic disease management