1. Coronary Revascularization
in Diabetic Patients: Optimizing Outcomes in 2007
David J. Cohen, M.D., M.Sc. Director of Cardiovascular Research Saint-Luke’s Mid America Heart Institute Professor of Medicine University of Missouri-Kansas City

2. Atherosclerosis in Diabetes Mellitus: Pathophysiologic Considerations
Abnormal platelet function
 activation and adhesion in response to shear stress
 expression of GpIIb/IIIa receptors  aggregation
More diffuse atherosclerosis pattern
Impaired coronary flow reserve reduced tolerance of embolization
 plaque burden and more lipid-rich plaques predisposed to rupture
Impaired ability to develop collaterals larger MIs
Increased response to vascular injury
 rates of restenosis and reocclusion following both balloon angioplasty and bare stent implantation

3. Impact of Diabetes on Short- and Long-Term Outcomes of PCI
Predictors of TLR (n=6186)
1-year mortality (n=6534)
Ref. Diam ( per mm)
Lesion length (per 5 mm)
Diabetes
Current Smoker
Prior MI 1 2
RR=1.5
Diabetes
No Diabetes
3.3%
2.1%
P=0.012
Cutlip DE et al. JACC 2002;40:2082-9
Bhatt et al. JACC 2000;35:922-8

4. Relationship Between Restenosis and Mortality In Diabetic Patients
Freedom from Cardiac Death (%)
Non-Occlusive Restenosis
Occlusive Restenosis
Adjusted RR = 2.38 (95% CI )
Years
No Restenosis
513 diabetic pts underwent 6 month f/u angio and long-term clincal f/u
10-yr survival
No restenosis: 24%
Non-occlusive: 35%
Occlusive: 59%
Occlusive (but not non-occlusive) restenosis associated with strong, independent risk of 10-year mortality (RR 2.4)
Van Belle E et al. Circulation 001;103:

5. Optimizing Outcomes in Diabetic PCI
Drug-eluting stents– which stent for which patient?
What is the optimal antithrombotic regimen?
Discharge care and secondary prevention
Patient selection: PCI vs. CABG

6. Optimizing Outcomes in Diabetic PCI
Do they work in diabetic patients?
Differential effects in IDDM vs. NIDDM?
Is diabetes still a risk factor for restenosis in DES era?
Device selection
Is there a preferred DES for diabetic patients?
Insights from registries and comparative clinical trials
Drug-Eluting Stents

7. CYPHER Pooled: Diabetic Subgroup
Angiographic Restenosis
P<0.001
P<0.001
 79%
 80%

8. Pooled TAXUS Trials (II, IV, VI) Overall Diabetic Subset: Angiographic Restenosis
Pooled TAXUS data
Suggests TAXUS stent also somewhat compromised by “edge restenosis” in smaller vessels
Pooled TAXUS II data suggests TAXUS stent also somewhat compromised by “edge restenosis” in smaller vessels
 87% P<0.001
(n=263)
(n=264)

9. SIRIUS – Reduced Efficacy in IDDM
In-Segment Restenosis
P=NS
P<0.001
P<0.001
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10. CYPHER Trials-- Excluding SIRIUS
In-Segment Restenosis
P=0.06
P<0.001
P<0.001
This is the Sample Column Chart slide.
To create this particular slide, copy and paste the sample in the Slide Sorter view as follows:
Select View / Slide Sorter
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Place the courser where you want the new slide to be and select Edit / Paste
Double-click on the pasted-in slide to return to Slide view
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When you are finished making your changes, select File / Exit and return to… from the menu bar.
THIS METHOD IS PREFERRED TO DOUBLE-CLICKING THE GRAPH AND OPENING IT IN POWERPOINT. Double-clicking the graph can sometimes reformat the sizes, colors, animations and fonts in your graph.

11. Optimizing Outcomes in Diabetic PCI
Do they work in diabetic patients?
Differential effects in IDDM vs. NIDDM?
Is diabetes still a risk factor for restenosis in DES era?
Device selection
Is there a preferred DES for diabetic patients?
Insights from registries and comparative clinical trials
Drug-Eluting Stents

12. Independent Predictors of TVR after DES: RESEARCH and T-SEARCH Results
Angio. Restenosis (n=238)
1-year MACE (n=1084)
ISR rx
Ostial lesion
Diabetes
Stent length (per 10 mm)
Ref. diam (per mm)
0.1 1 10
LAD
Cardiogenic Shock
Female
Multivessel Dz
Diabetes
Left main stenting
0.1 1 10
Bifurcation stenting
RR = 2.6
RR = 1.6
Lemos PA et al. Circulation 2004;109:
Ong ATL, et al. JACC 2005;45:

13. Optimizing Outcomes in Diabetic PCI
Do they work in diabetic patients?
Differential effects in IDDM vs. NIDDM?
Is diabetes still a risk factor for restenosis in DES era?
Device selection
Is there a preferred DES for diabetic patients?
Insights from registries and comparative clinical trials
Drug-Eluting Stents

14. Patients with Diabetes Mellitus
Study Protocol
Patients with Diabetes Mellitus
(n = 250)
CYPHER®
(n = 125)
TAXUS™
(n = 125)
1° EP: Late lumen loss at 6 months (in-segment analysis)
2 EP: Angiographic restenosis at 6 months  50% diameter stenosis (in-segment analysis)
Target lesion revascularization at 6 months

15. Angiographic Outcomes
Late Loss (mm)
In-Segment Restenosis
P<0.001
P=0.03
P<0.001
Pooled TAXUS data
Suggests TAXUS stent also somewhat compromised by “edge restenosis” in smaller vessels
Pooled TAXUS II data suggests TAXUS stent also somewhat compromised by “edge restenosis” in smaller vessels
In-Stent
In-Segment

16. 9-Month Clinical Outcomes
P=0.16
P=NS
Pooled TAXUS data
Suggests TAXUS stent also somewhat compromised by “edge restenosis” in smaller vessels
Pooled TAXUS II data suggests TAXUS stent also somewhat compromised by “edge restenosis” in smaller vessels
P=NS

17. Are the ISAR-Diabetes Findings Real? Comparison with SIRIUS and TAXUS
Placebo-Control Trials
ISAR-Diabetes
CYPHER
TAXUS
In-stent LL (mm)
0.26
0.36
0.19
0.46
In-segment LL (mm)
0.32
0.22
0.43
0.67
In-stent restenosis
5.7%
5.2%
N/A
In-segment restenosis
8.3%*
7.4%
6.9%
16.5%
TLR
5.8%
6.0%
6.4%
12.0%
* Results excluding SIRIUS Trial

18. Nearly 500 diabetic lesions
Are the ISAR-Diabetes Findings Real? Comparison with REALITY
Nearly 500 diabetic lesions

19. Summary: DES in Diabetes
Both sirolimus- and paclitaxel-eluting stents substantially reduce angiographic and clinical restenosis compared with BMS
Nonetheless, DES have not eliminated the excess risk of restenosis in diabetics c/w non-diabetics
Edge effects appear to be more severe in diabetic patients greater emphasis on stenting “normal to normal”
Head to head trials not entirely consistent 2 of 3 trials suggest a restenosis advantage with Cypher, but true magnitude of clinical benefit probably overestimated

20. Optimizing Outcomes in Diabetic PCI
Drug-eluting stents– which stent for which patient?
What is the optimal antithrombotic regimen?
Discharge care and secondary prevention
Patient selection: PCI vs. CABG

21. Hemostatic Derangements in Diabetes
Increased platelet adhesion and activation in response to shear stress (P-selectin, Fibrinogen binding capacity)
Up-regulation of GpIIb/IIIa receptors associated with hyperglycemia, leading to enhanced platelet aggregation
Reduced capacity for endogenous thrombolysis
Intrinsic endothelial dysfunction less tolerant of in-situ thrombosis and distal embolization

22. Mortality Benefit of Abciximab in Diabetic Pts
Diabetic/Placebo
Diabetic/Abcix
Non-diabetic/placebo
Non-diabetic/ABcix
4.5%
2.5%
P=0.03
Death (%)
Days from randomization
Pooled analysis of 1-year mortality from EPIC, EPILOG, and EPISTENT databases
Among patients with diabetes (n=1420), abciximab reduced 1-year mortality by 45% (20 lives saved per 1000 pts; p=0.03)
Mortality benefits particularly striking among diabetic patients with:
IDDM (4.2% vs. 8.1%, p=0.07)
Multivessel PCI (0.9% vs. 7.7%; p=0.02)
Bhatt DL et al. JaCC 2000;35:922-8

23. Are Gp2b/3a Inhibitors Still Beneficial in the High-Dose Clopidogrel Era?
1-Year Outcomes
ISAR-SWEET Trial
701 diabetic patients (28% IDDM, 20% diet alone) undergoing elective PCI
Excluded any recent MI or ACS, angiographic thrombus, EF<30%
All pretreated with clopidogrel 600 mg at least 2 hrs prior to PCI
Randomized to abciximab vs. placebo
Primary Endpoint: 1-year D/MI
Issues with ISAR-SWEET
Enrolled only low-risk diabetic patients
Observed 1-yr D/MI 8% vs. 14% expected
Trial dramatically underpowered to detect clinically meaningful differences in ischemic complications
Does not exclude a 40% reduction in 1-yr death or MI
P=NS for all comparisons
Death MI
Death or MI
Mehilli J et al. Circulation 2004;110:

24. 1-year mortality – subgroups
Results consistent across subgroups
Bivalirudin better
Heparin + GPI better
H+GPI Bival
All patients
2.5% 1.9%
Eptifibatide
Abciximab
2.2% 1.7%
2.7% 2.1%
Age ≤75
Age >75
1.7% 1.6%
6.9% 3.6%
N=1606
Male gender
Female gender
2.1% 1.7%
3.5% 2.5%
Diabetes
No diabetes
3.9% 2.3%
1.9% 1.7%
Treatment with bivalirudin resulted in an approximately 62% reduction in the risk of major hemorrhagic complications and a 70% reduction in TIMI major hemorrhage (5 g/dL or more fall in Hgb, 15% decrease in hematocrit or intracranial hemorrhage) .
Prior MI, PCI or CABG
No prior MI, PCI or CABG
2.9% 2.1%
1.8% 1.6%
Unstable angina <48h
Unstable angina >48h
2.1% 1.2%
3.6% 1.5%
Odds ratio ±95% CI for death at 12 months

25. Optimizing Outcomes in Diabetic PCI
Drug-eluting stents– which stent for which patient?
What is the optimal antithrombotic regimen?
Discharge care and secondary prevention
Patient selection: PCI vs. CABG

26. Secondary Coronary Prevention in Diabetes
Intervention
Evidence
High-intensity statin
HPS: 27%  in CHD death or MI among DM subgroup (20%  in CHD death, p=0.02)

27. Secondary Coronary Prevention in Diabetes
Intervention
Evidence
High-intensity statin
HPS: 27%  in CHD death or MI among DM subgroup (20%  in CHD death, p=0.02)
ACE-Inhibitor
HOPE diabetic substudy: 25%  in CV-death/MI/stroke (p<0.001); 37%  in CV-death over 5 yr follow-up (p=0.001)

28. Secondary Coronary Prevention in Diabetes
Intervention
Evidence
High-intensity statin
HPS: 27%  in CHD death or MI among DM subgroup (20%  in CHD death, p=0.02)
ACE-Inhibitor
HOPE diabetic substudy: 25%  in CV-death/MI/stroke (p<0.001); 37%  in CV-death over 5 yr follow-up (p=0.001)
Intensive glycemic control
Clearcut benefits on microvascular complications (UKPDS trial)
Observational studies suggest improved CV outcomes and less restenosis associated with lower HbA1c
? Specific benefit of glitazones

29. Optimizing Outcomes in Diabetic PCI
Drug-eluting stents– which stent for which patient?
What is the optimal antithrombotic regimen?
Discharge care and secondary prevention
Patient selection: PCI vs. CABG

30. BARI: Impact of Diabetes on Survival
BARI Subgroups
Treated diabetic pts only subgroup to show significant survival advantage with CABG
5 year survival
CABG 81%
PTCA 65%
Diabetic subgroup (p=0.006)
CABG
PTCA
Treated diabetic patients only subgroup to show significant survival advantage to CABG
5-yr survival
CABG 81%
PTCA 65%
? benefit of LIMA
NEJM 1996;335:217-25

31. Do Diabetics Have Increased Mortality After Multivessel Stenting?
Summary: Stents do not appear to have significantly attenuated the mortality advantage of CABG in multivessel CAD
Yellow = Stent vs. CABG
* P<0.05

32. Recommendations for 2007: Which diabetic patients should undergo PCI?
Single-vessel disease
No evidence of involvement of proximal or mid- LAD (i.e., no LIMA)
Patients with 2 or 3 highly discrete lesions without evidence of diffuse atherosclerosis (I.e., “low risk”)
Patients with important contraindications to CABG
Previous CABG with patent LIMA
Advanced age

33. If you are going to perform PCI…
Think twice (esp. in multivessel dz)
Use drug-eluting stents
Use a Gp 2b/3a inhibitor (or possibly bivalirudin + high dose clopidogrel)
Maximize secondary coronary prevention, even in the short-term
Optimal glycemic control
Aggressive lipid lowering (? LDL<80)
ACE-inhibition

34. Question
&
Answer