Overcoming Challenges in Treating Diabetic Patients

1
Overcoming Challenges in Treating Diabetic
Patients

• Dean J. Kereiakes, MD, FACC
• Medical Director - The Lindner Center
• Director of Research and Chief Executive Officer
• Ohio Heart Health Center
• Professor of Clinical Medicine
• Ohio State University
• Cincinnati, Ohio

2
Endothelial Dysfunction in Diabetes
Diabetes Mellitus
Insulin Resistance
Hyperglycaemia
Hyperlipidemia Hypertension
Endothelial Dysfunction
Inhibited by SIROLIMUS
SMCMigration
SMC Proliferation
Inflammation
Vasoconstriction
Thrombosis

• NO
• ? NF-kB
• ? AP-1
• ? Cytokines
• ? Chemokines

? NO ? Endothelin-1

• Protein Kinase C
• ? NO

? NO ? Endothelin-1

• NO
• ? Tissue Factor
• Prostacyclin

Restenosis
Atherogenesis
Illustration based on Beckman JA et al. JAMA.
20022872572.
3
Macrophage Infiltrationin Diabetic Plaque
Diabetes
No Diabetes
Moreno PR et al. Circulation. 20001022180.
4
Macrophage InfiltrationPredicts Restenosis
20 2
Macrophage Percent Area ()
9 2
P0.0007
Restenosis
No Restenosis
Moreno PR et al. Circulation. 1996943098.
5
Maladaptive Arterial Remodelingin Diabetes
Mellitus

Lumen compromised when40 lesion plaque-filled
Kornowski R, Mintz GS, et al. Am J Cardiol.
1998811298.
6
Diabetes Is a Predictor of Late LossFollowing
Stenting
Late Loss vs. of Diabetics inBare (non-DES)
Stent Study
30
1.00
0.98
25
0.97
0.83
1.19
0.93
0.8
20
0.9
15
of Diabetics in the study
0.6
0.54
0.7
10
5
0
0
0.5
1
1.5
Late Loss in mm.
7
Coronary Stenting in Diabetic Patients Results
of Quantitative Angiography
100 80 60 40 20 0
Non-DM
Lesions ()
Non-ITDM (P0.0006 vs Non-DM)
ITDM (P0.0007 vs Non-DM)
-20
-40
0
20
60
40
80
100
Diameter Stenosis () at Follow-Up
Schofer J, Mathey DG, et al. J Amer Coll
Cardiol. 2000351554.
8
MACE Following Coronary Stenting
Elezi S et al. J Amer Coll Cardiol. 1998321866.
Death, MI, TVR
9
MACE Following Coronary Stenting
100
90
Non-Diabetics (76) NonIDDM (70) IDDM (60)
80
MACE-Free Survival ()
70
60
P0.0004
0
2
4
6
8
10
12
Months after stent placement
Abizaid AS et al. J Amer Coll Cardiol.
199832584.
Death, MI, Any revascularization
10
Multivessel Stenting in Diabetic Patients
100
90
80
70
60
50
Event-free survival ()
40
30
No DM DM treated with oral agent DM treated
with insulin
20
Plt0.001
10
0
0
100
200
300
400
Days after stent placement
Mehran R et al. J Amer Coll Cardiol.
2004431348-1354.
Death, myocardial infarction, TLR
11
Covariate Adjusted Predictors of Mortality
Following MultivesselCoronary Revascularization
0 1.0 2.0 3.0 4.0 5.0
872 PCI vs 5161 CABG
Brener SJ et al. Circulation. 20041092290.
12
Predictors of Late (4 Year) Mortality in
Patientswith Systematic 6-Month
AngiographyFollowing Stent Deployment
Older age Restenosis
0.5
1
5
P0.02
Schuhlen H, Schomig A, et al. Am Heart J.
2004147317-322.
13
Late Survival by Vessel Patency at Follow-Up
Angiography after PCI
100
90
80
70
60
50
Survival ()
40
No restenosis, n162 Nonocclusive restenosis,
n257 Occlusive restenosis, n94
30
20
10
Plt0.0001
0
0
2
3
4
1
7
5
6
8
9
10
Years
Mean 6.5 2.4 yrs (SD) 15 Late Vessel
Occlusion
Van Belle E et al. Circulation. 20011031218.
14
SIRIUS Trial Late Outcomes in Diabetics and
Non-Diabetics by Treatment
60
50.5
1.2 1.0 0.8 0.6 0.4 0.2 0
Bx
Cypher
50
1.0
40
Plt0.001
30.7
30
0.73
Percent
22.3
mm


17.6
20
0.4
14.1



0.18
6.9
10

6.0
3.0
0
DM NDM DM NDM
DM NDM
Late Loss (In-Lesion)
Binary Restenosis (In-Lesion)
Target Lesion Revascularization
Moussa I et al. Circulation. 20041092273-2278.
15
Freedom from MACE to 9 Months by Diabetic Status
and Treatment SIRIUS Trial
Cypher
Bx Velocity
100
100
90
90
80
80
Freedom from MACE ()
70
70
60
60
Non-diabetics Diabetics
P0.018
P0.30
50
50
0
30
120
60
90
150
180
210
240
270
0
30
120
60
90
150
180
210
240
270
Time after initial procedure (days)
Moussa I et al. Circulation. 20041092273-2278.
16
Percent Reduction in 12-Month TLR with Cypher vs
Bx Velocity by Lesion Length, Vessel Size, and
Diabetic Status
Lesion Length lt12 mm gt12 - lt15 mm gt15
mm Non-Diabetics RVD gt3.0
mm 78.5 78.1 77.5 2.5 mm RVD lt3.0
mm 77.6 77.1 76.2 RVD lt2.5 mm 76.6 76.0 74.7 Di
abetics RVD gt3.0 mm 77.2 76.7 75.6 2.5
mm RVD lt3.0 mm 75.8 75.0 73.4 RVD lt2.5
mm 74.1 73.1 71.0
RVD indicates reference-vessel diameter.
Holmes D et al. Circulation. 2004109634.
17
DIRECT Trial Evaluate Direct Stenting Technique
vs SIRIUS Pre-Dilatation Strategy8-Month Binary
Restenosis
Prox
In-stent
Distal
In-lesion
Combined edge restenosis 3.1 vs 7.4, P0.049
Moses JW for DIRECT PIs. Presented at the
American College of Cardiology Annual Scientific
Session March 7-10, 2004 New Orleans, Louisiana.
SIRIUS Cypher QCA Cohort
18
DIRECT Diabetic AnalysisIn-Lesion Binary
Restenosis
Moses JW for DIRECT PIs. Presented at the
American College of Cardiology Annual Scientific
Session March 7-10, 2004 New Orleans, Louisiana.
19
DIRECT 8-mo QCA Binary Restenosis All Diabetics
P0.22
P0.22
20
DIRECT Diabetic Analysis TLR

12
10.3
DIRECT
10
SCAC
8.0
8
P1.00
P0.51
Percent
6
3.7
4
P1.00
2
1.0
0.6
0.0
0
Non DM
Non-insulin-dependentdiabetics
Insulin-dependentdiabetics
N 155 307 54 80 16 25
Moses JW for DIRECT PIs. Presented at the
American College of Cardiology Annual Scientific
Session March 7-10, 2004 New Orleans, Louisiana.
21
Cypher Stent Consistent Benefitfor Clinical
Restenosis in Diabetics
Cypher Stent Clinical Data in Diabetic Patients
30
100
69
73
N/A
20
TLR ()
10
0
RAVEL12 mos
SIRIUS9 mos
New SIRIUS9 mos
e-Cyphersm6 mos
0
6.9
7.0
1.4
of Patients
19
131
45
2716
C-SIRIUSE-SIRIUS Combined
22
E-Cyphersm Diabetics (n3438) Selected Baseline
Characteristics
Diabetics Non-Diabetics P value Age 62.2
? 10.4 60.6 ? 11.7 P lt0.0001 Female
gender 28.9 19.4 P lt0.0001 History of
hypertension 70.9 58.1 P lt0.0001 Body mass
index gt30 17.7 11.1 P lt0.0001 Prior CVA/TIA
3.7 2.7 P lt0.005 Multivessel
disease 59.7 54.8 P lt0.001 of
stents/patient 1.4 ? 0.7 1.3 ? 0.7 P
lt0.0001 Multi-lesion procedure 18.8 16 P
0.0002 LMS lesion 1.6 2.4 P lt0.005 Estimated
RVD (mm) 2.8 ? 0.4 2.9 ? 0.4 P lt0.0001 Estimated
LL (mm) 17.8 ? 9.3 17.0 ? 8.7 P lt0.0001
n 8670 Urban P et al. Presented at EuroPCR
Symposia May 20-23, 2004 Paris, France.
23
6-Months Follow-UpE-Cyphersm Diabetics
CEC-Adjudicated Events
5
Diabetics (n2716)
4.2
4
Non-Diabetics (n6757)
3
2.5
Percent
2

1.6
1.3
0.8
0.8
0.7
1
0.5

0.4
0.4
0.4
0.2
0.1
0.1
0
Cardiacdeath
Otherdeath
Q AMI
NQ AMI
TLR PCI
TLRCABG
MACE
Plt0.001 Plt0.0001
Total TLR1.4 in diabetics vs 0.9
non-diabetics (P NS)
24
BRIDGE RegistryCYPHER and DM Real World
Experience Lesion Characteristics
Commeau P, TCT 2004
25
BRIDGE RegistryCYPHER and DM Real World
Experience 180-day Adverse Events
n547 patients (90 FU compliance)
5.9
3.3
Percent
1.6
Commeau P, TCT 2004
26
Small Vessels In-Stent Late Loss
1.2
1.01
0.99
1.0
0.93
0.91
0.85
0.8
0.69
mm
0.6
0.35
0.4
0.22
0.21
0.20
0.16
0.2
0.01
0.0
RAVEL
SIRIUS
New SIRIUS
SES- SMART
SVELTE
Taxus IV
Reference Vessel Diameter (RVD)
27
Taxus IV Late Loss Reduction(vs Express)by
Reference Vessel Diameter
1.25 1.0 0.75 0.5 0.25 0
Express
Late Loss in-stent (mm)
Taxus
0.38 0.49
0.44 0.55
0.35 0.63
lt2.5 mm 2.5-3.0 mm gt3.0
mm
28
Relationship Between Late Loss andVessel
Diameter Determines Restenosis Rate
Its all about late loss
100
90
80
70
60
Constant Late Loss
Restenosis rate ()
50
40
30
20
10
0
1.5
2
2.5
3
3.5
4
Post-procedure MLD (mm)
Kuntz R. Presented at American College of
Cardiology 52nd Annual Scientific Session March
30April 2, 2003 Chicago, IL.
29
Binary Restenosis (6-9 Months)in Randomized
Trials of DES vs BMS
Study or DES Stents OR (fixed) 95 Weight OR
(fixed) 95 Subcategory n/N n/N CI CI ASPECT 8/10
0 15/55 9.59 0.23 (0.90,0.59) DELIVER (9
mos) 34/228 44/214 20.80 0.68 (0.41,1.11) ELUTES
17/139 7/34 5.32 0.54 (0.20,1.42) PATENCY (9
mos) 8/21 6/17 2.21 1.13 (0.30,4.26) Taxus
I 0/30 3/29 1.88 0.12 (0.01,2.51) Taxus II
1/SR 3/128 24/134 12.33 0.11 (0.03,0.38) Taxus
II 2/MR 6/128 26/129 13.29 0.19
(0.08,0.49) Taxus IV (9 mos) 16/292 65/267
34.57 0.18 (0.10,0.32) Subtotal (95
CI) 1066 879 100.00 0.32 (0.24,0.42) RAVEL 0/10
5 28/107 13.39 0.01 (0.00,0.22) SIRIUS (8
mos) 11/348 125/353 57.26 0.06
(0.02,0.11) E-SIRIUS (8 mos) 6/152 65/156 29.36 0
.06 (0.02,0.14) Subtotal (95 CI) 605 616 100.00
0.05 (0.03,0.09)
0.01 0.1 1 10 100
Hill RA et al. Eur Heart J. 200425902-919.
Favors DES Favors BMS
30
Events to 1 Year in Randomized Trials of DES vs
BMS
0.1 0.2 0.5 1 2 5 10
Death, MI, TVR, TLR, SAT
Favors DES Favors BMS
Hill RA et al. Eur Heart J. 200425902-919.
31
GP IIb/IIIa Blockade and Diabetes
Placebo
GP IIb/IIIa
5
5
4.1
4
4
3.5
3
3
Mortality to one year ()
1.9
2
2
1.5
1.4
1.3
1.2
1.0
1
1
0
0
Diabetes No Diabetes EPISTENT
Trial abciximab
Diabetes No Diabetes ESPRIT
TRIAL eptifibatide
Lincoff AM. Circulation. 20031071556-1559.
stent arms
32
Mortality to One Year for Insulin-Treated
Diabeticsin Abciximab TreatmentEPIC, EPILOG,
EPISTENT Pooled Analysis
9 8 7 6 5 4 3 2 1 0
8.1
IDDM/placebo (n197)
Mortality ()
4.2
IDDM/abciximab (n265)
0
50
100
250
300
350
200
150
Days from Randomization
Bhatt DL et al. Cardiovasc Rev Rep.
200121161-164.
33
Statins and SurvivalFollowing Coronary Stenting
8
No statins (n3,585)
6
4
Mortality ()
Statins (n935)
2
Plt0.001
0
0
2
3
4
5
6
7
8
9
10
11
12
1
Months after discharge
Schomig A, Kastrati A et al. J Amer Coll Cardiol.
200240854-861.
34
Fasting Blood Glucose Affects Mortality Following
Percutaneous Coronary Intervention
1.00
FBG 110 mg/dL
.75
.50
Sensitivity
Area under the curve 0.68 Plt0.001
.25
0
0
.25
.50
.75
1.00
1 - Specificity
Muhlestein JB et al. Am Heart J. 2003146351-358.
Mortality Risk Increased by FBG 110
35
Glycemic Control and Target Vessel
Revascularization
P0.03
40
P0.02
30
Target Vessel Revascularization ()
20
10
N60
N52
N127
0
No diabetes
Diabetes, Hg A1c 7
Diabetes, Hg A1c gt7
Corpus RA et al. J Am Coll Cardiol. 2004438-14.
36
Clinical Outcomes by Treatment in Diabetic
Patients with Acute Coronary Syndromes SYMPHONY
/ 2nd SYMPHONY
14
12.0
12
Insulin-providing
10
8
Cumulative frequency ()
6
5.0
Insulin-sensitizing
4
2
P0.03
0
20
0
60
40
80
Days
McGuire DK, Calif et al. Am Heart J.
2004147246-252.
Death, MI, Severe Recurrent Ischemia
37
Clinical Event-Free Survival by Diabetic
Treatment Following PCI PRESTO Trial
1.0
0.9
Non-sensitizer therapy
(n1110)
0.8
Proportion event-free
Metformin therapy
0.7
(n887)
0.6
0.5
0
50
100
150
200
250
Follow-up time (days)
Kao J et al. Am J Cardiol. 2004931347-1350.
38
Troglitazone (Thiazolidinedione) Treatment of
Diabetic Inflammation sCD40L
Baseline Post-Treatment 12 weeks
Placebo
Troglitazone
3.0
3.0
2.5
2.5




2.0
2.0
sCD40L (ng/mL)
sCD40L (ng/mL)
1.5
1.5
1.0
1.0
0.5
0.5
0.0
0.0
Recentonset
Withcomplic
Recentonset
Withcomplic
Withoutcomplic
Withoutcomplic
All pts
All pts
n
30
13
10
8
38
15
11
11
Varo et al. Circulation. 20031072664.
39
Anti-Inflammatory Effects of Rosiglitazone in
Non-Diabetics
E-selectin
vWF
CRP
.1 0.0 -.1 -.2 -.3 -.4 -.5 -.6
180 170 160 150 140 130 120 110
60 50 40 30


E-selectin ng/mL
Von Willebrand Factor IU/dL
Log (CRP)

Placebo
Rosiglitazone
Placebo
Rosiglitazone
Placebo
Rosiglitazone
Plt0.05 Plt0.005
Sidhu JS et al. J Am Coll Cardiol. 2003
421757-1763.
40
Rosiglitazone Antiplatelet Effects
-.5 -1.0 -1,5 -2.0

Log ( P-selectin positive platelets)
Placebo
Rosiglitazone
Sidhu JS et al. Am Heart J. 2004147e25.
P0.04 (12 weeks therapy)
41
Rosiglitazone Antiplatelet Effects Correlation
with Insulin Resistance
Change in log () P-selectin positive platelets
Sidhu JS et al. Am Heart J. 2004147e25.
R0.11
42
Adjunctive Therapies Are Importantfor Improving
Outcomes Following DESin Diabetics

• HMG Co-A Reductase Inhibitors (Statins)
• ACE Inhibitors
• Angiotensin-Receptor Blockers
• Beta-Receptor Blockers
• Extended Thienopyridine Therapy
• Diabetes Control

43
Percutaneous Revascularization of Diabetic
Patients in the DES Era Conclusions

• DES have demonstrated improved angiographic and
  clinical outcomes compared with BMS in diabetics
• Late loss / restenosis are markedly reduced by
  Sirolimus, but careful deployment technique is
  required (direct stenting limiting injury zone
  to stented zone)
• Durable benefit of Cypher stenting with low MACE
  has been demonstrated in a large cohort of
  diabetic patients
• Best outcomes following DES in diabetic patients
  will require optimal adjunctive pharmacotherapies
  including close control of diabetes