1. Konstantinos Dean Boudoulas, MD
Optimal Revascularization of the Diabetic Patient with Coronary Artery Disease
Konstantinos Dean Boudoulas, MD
Associate Professor of Medicine/Cardiovascular Medicine
Section Head, Interventional Cardiology
Director, Cardiac Catheterization Laboratory
The Ohio State University

2. Diabetes Mellitus Background
Estimated > 170 million people worldwide have diabetes mellitus.
Diabetics have a 2- to 4-fold increase risk of coronary artery disease (CAD) compared to non-diabetics.
75% of diabetics die from cardiovascular disease.
Diabetes often is associated with chronic kidney disease; interventions (PCI or CABG) are associated with higher risk in diabetics, especially if chronic kidney disease is present.
Revascularization (PCI or CABG) outcomes in diabetics are inferior to non-diabetics.
Baber U, et al. Eur Heart J. 2016;37:3440–47.
Armstrong EJ, et al. Circulation. 2013;128:

3. Diabetes Mellitus Background
Hyperglycemia, insulin resistance, and altered free fatty acid metabolism found in diabetics alters inflammatory pathways causing:
endothelial dysfunction
thrombogenesis
monocyte activation
foam cell transformation
altered smooth muscle cell migration
others
These changes result in increased coronary artery plaque burden and plaque instability.
Armstrong EJ, et al. Circulation. 2013;128:

4. Ascending Aorta Distensibility
Aortic Dysfunction In Non-Diabetics with Insulin Resistance
n=181
Ascending Aorta Distensibility
(cm-2 x dynes-1 x 10-6)
insulin sensitivity index (ISI)
Modified from Stakos DA, Boudoulas KD, et al. J Clin Endocrinol Metab. 2013;98:

5. Coronary Artery Disease Progression and Clinical Manifestations
Lipid
Pool
Plaque Rupture and Thrombosis
Years
Plaque
rupture
Thrombosis/
Progression/
Angina
Thrombosis
Occlusion
Death/SCD
Asymptomatic
Stable Disease
(± Angina)
Myopathy,
CHF/MR
AMI
Normal
(Unstable)
Boudoulas KD, et al. Prog Cardiovasc Dis. 2016;58:

6. Coronary Artery Disease Medical Management
Therapy for the plaque
statin, PCSK9 inhibitors, smoking cessation, others
Therapy to preserve/improve left ventricular function
b-blockers, ACE inhibitors, angiotensin receptor blockers, others
Therapy for angina/ischemia
b-blockers, calcium channel blockers, nitrates, others
Therapy to prevent sudden cardiac death
These measures should be applied to all patients with coronary artery disease regardless of symptoms and/or underlying pathology.

7. Optimal Coronary Artery Revascularization in the Diabetic Patient

8. Angioplasty (PTCA) vs. CABG in Multi-vessel Disease BARI Trial (Bypass Angioplasty Revascularization Investigation)
Non-DM CABG 77%
Non-DM PTCA 77% NS
N=1829
Survival (%)
DM CABG 57%
DM PTCA 45%
p=0.025
CABG
PTCA
N=1829
Follow-up Time in Years
BARI Investigaors. J Am Coll Cardiol. 2007;49:

9. Angioplasty (PTCA) vs. CABG in Multi-vessel Disease BARI Trial (Bypass Angioplasty Revascularization Investigation)
10 Year Follow-up
n=1829
Survival (%)
- underwent CABG had increased rates of 10-year survival and decreased rates of MI
BARI Investigators. J Am Coll Cardiol. 2007;49:

10. PCI vs. CABG in Diabetics with Multi-vessel Disease FREEDOM Trial
1st Generation Drug Eluting Stents (sirolimus or paclitaxel)
n=1900
- LIMA was used in 94 patients
- primarily first-generation PES or SES
- (P = 0.005), 5-year rates of 26.6% in PCI and 18.7% in CABG
- benefit of CABG driven by MI (P<0.001) and death from any cause (P = 0.049). Stroke more in CABG, 5-year rates 2.4% in PCI and 5.2% in CABG (P = 0.03).
FREEDOM Trial Investigators. NEJM. 2012;367:

11. PCI vs. CABG in Diabetics with Multi-vessel Disease FREEDOM Trial
1st Generation Drug Eluting Stents (sirolimus or paclitaxel)
Death, Myocardial Infarction or Stroke
LIMA was used in 94% patients
FREEDOM Trial Investigators. NEJM. 2012;367:

12. PCI vs. CABG for Insulin and Non–Insulin Diabetes FREEDOM Trial
Approximately 1/3 of subjects had insulin dependent diabetes.
Insulin treated diabetics had increase major adverse cardiovascular events compared to non-insulin treated diabetics.
CABG was superior to PCI regardless of diabetic type.
- Insulin treated diabetics had increase major adverse cardiovascular events is greater (death, MI, or stroke) was significantly higher in patients treated with insulin (28.7%) than in those not treated with insulin (19.5%; p<0.001).
FREEDOM Trial Investigators. J Am Coll Cardiol. 2014;64:1189–97.

13. Nyström T, et al. J Am Coll Cardiol. 2017.
PCI vs. CABG in Type 1 Diabetics with Multi-vessel Disease SWEDEHEART & Swedish National Diabetes Registers
n=2546
Mean follow-up of 10.6 years
CABG superior to PCI in:
Death from coronary heart disease (2.1 vs. 2.9/100 person-years; HR: 1.45)
Myocardial infarction (2.7 vs. 4.6/100 person-years; HR: 1.47)
Repeat revascularization (1.9 vs. 20.1/100 person-years; HR: 5.64)
- From
- adjusted risk of hospitalization for stroke and heart failure was similar in PCI and CABG
Nyström T, et al. J Am Coll Cardiol

14. PCI vs. CABG in Multi-vessel Disease
BEST Trial
2nd Generation Drug Eluting Stent (everolimus)
Overall (DM and non-DM) PCI greater than CABG for primary end point (spontaneous MI and repeat revasc).
Left internal thoracic artery graft — no. (%) 398 (99.3)
* primary composite end point of death, myocardial
infarction, or target-vessel revascularization at 2 years
Modified from BEST Trial Investigators. N Engl J Med. 2015;372:

15. PCI vs. CABG for Left Main Coronary Artery Disease
EXCEL Trial
2nd Generation Drug Eluting Stent (everolimus)
p=0.77
- SYNTAX score of ≤32 to compare the Xience Prime everolimus-eluting stents (EES) with CABG
* primary composite end point of death, stroke, or
myocardial infarction at 3 years
Modified from EXCEL Trial Investigators. N Engl J Med. 2016;375:

16. Major Cardiovascular Events in Diabetics Based on SYNTAX Score
Low (≤ 22) SYNTAX score there is no difference between medical therapy and revascularization (PCI or CABG) in diabetics at 5 year follow-up.
Mid (23-32) and high (≥ 33) SYNTAX scores there is a decrease in major cardiovascular events with CABG compared to PCI in diabetics at 3 year follow-up.
In non-diabetics, CABG resulted in a decrease in major cardiovascular events only in the high (≥ 33) SYNTAX score compared to PCI at 3 year follow-up.
Initial strategy of medical therapy may be reasonable in diabetics with stable coronary artery disease and low SYTNAX score; however, 42% of patients assigned to medical therapy required revascularization during the 5-year follow-up.
- J Am Coll Cardiol SYNTAX (5-year follow-up): Low SYNTAX major cardiovascular events did not differ significantly between revascularization and medical therapy, either in the CABG stratum (26.1% vs. 29.9%, p=0.41) or in the PCI stratum (17.8% vs %, p=0.84).
- Ann Thorac Surg SYNTAX (3-year follow-up): Overall study MACCE (22.9% CABG, 37.0% PES; p=0.002) driven by decrease revascularization rate in CABG (12.9% CABG, 28.0% PES; p<0.001).
- Ann Thorac Surg SYNTAX (3-year follow-up) in mid and high subgroups driven by composite events death/CVA/MI and repeat revascularization
BARI 2D Trial. N Engl J Med. 2009;360:
Mack MJ, et al. Ann Thorac Surg. 2011;92:2140–6.
BARI 2D Study Group. J Am Coll Cardiol. 2017;69:395–403.

17. PCI vs. CABG in Diabetics
All-Cause Mortality
Meta-Analysis of Randomized Controlled Trials
5-Year (or longest) Follow-up
1st generation
Verma, S, et al. Lancet Diabetes Endocrinol Dec;1(4):

18. Drug Eluting Stents (DES) vs. Bare Metal Stents (BMS) Diabetes Mellitus
DES provide better results compared to BMS.
No significant increase risk of stent thrombosis with DES compared to BMS.
Second generation DES may be superior to first generation DES.
Diabetics requiring insulin therapy have the highest rates of restenosis regardless of stent type.
Bangalore S, et al. BMJ. 2012;345:e5170.
Bavishi C, et al. Int J Cardiol. 2017;230:
Piccolo R, et al. J Am Coll Cardiol Intv. 2015;8:1657–66.

19. Cumulative Incidence of
Resolute (zotarolimus) Drug Eluting Stent Death and Target Vessel Myocardial Infarction (TVMI)
Cumulative Incidence of
Cardiac Death / TVMI
- first DES to gain a FDA labeling indication for patients with DM
- In the whole population, including complex patients, rates of stent thrombosis were not significantly different between patients with and without diabetes (1.2% vs. 0.8%).
Time After Initial Procedure (months)
Silber S, et al. JACC Cardiovasc Interv. 2013;6:357–368.

20. Revascularization Modality in Diabetic Patients
CABG is a superior form of revascularization in diabetics mostly due to the utilization of the LIMA to the left anterior descending artery decreasing major cardiovascular events including mortality.
Bangalore S, et al. BMJ. 2012;345:e5170.

21. Hybrid Coronary Revascularization
Modified from

22. Hybrid Approach to Coronary Revascularization Advantages
Less invasive than standard CABG using minimal invasive access and off-pump.
Utilize LIMA to the LAD (most survival benefit).
Decreases cardiopulmonary bypass (if used) and surgical times; avoids clamping aorta.
Substitutes coronary artery stents for grafts; drug eluting stents provide a good form of revascularization.
Allows close collaboration between interventional cardiologist and cardiothoracic surgeon.
LIMA angiogram can be performed immediately post-surgery (prior to chest closure) if using the Hybrid Cardiovascular Operating Room.

23. Hybrid Cardiovascular Operating Room
Vanderbilt University Adult Hybrid OR/Lab First in USA (2005)

24. Hybrid Cardiovascular Operating Room Major Key Advantage
LIMA angiogram can be performed immediately post-surgery (prior to chest closure) with ability to revise defect if present prior to patient leaving the Hybrid Cardiovascular Operating Room.

25. Immediately Post-Surgery LIMA Graft Defects
Total LIMA Used
345
LIMA with Defects Requiring Repair 7%
Conduit Defects (3%)
Distal Anastamosis Defects (4%)
Zhao DX, Leacche M, Balaguer JM, Boudoulas KD, et al. J Am Coll Cardiol. 2009; 53:232–41.

26. Detection and Revision of Angiographic Bypass Defect
LIMA
Hemoclip
Revised
Stenosis
LAD
Before Revision
After Revision

27. Patients Undergoing Coronary Revascularization
3-Year Follow-up
n=423
p<0.05
Death, Myocardial Infarction, Stroke or Repeat Revascularization (%)
22.7
- CABG increase CVA; PCI increase rep revasc
13.5
6.4
Hybrid
(LIMA + PCI) *
CABG
PCI
* Performed in the Hybrid
Cardiovascular Operating Room
Data from Shen L et al (J Am Coll Cardiol. 2013;61:2525–33) was used to construct slide.

28. Optimal Revascularization of the Diabetic Patient with Coronary Artery Disease Summary
Diabetics have an increase risk of coronary artery disease compared to non-diabetics.
Diabetics have increased risk of target vessel failure after coronary artery revascularization and repeat coronary artery interventions.
Insulin treated diabetics have higher rates of major adverse cardiovascular events after revascularization compared to non- insulin treated diabetics.

29. Optimal Revascularization of the Diabetic Patient with Coronary Artery Disease Summary
Medical therapy initially may be reasonable in diabetics with stable coronary artery disease and low SYTNAX score; however, a substantial number of patients will require revascularization within 5- years.
Mid and high SYNTAX scores have decrease in major cardiovascular events with CABG compared to PCI.
CABG is a superior form of revascularization in diabetics mostly due to the utilization of the LIMA to the left anterior descending artery decreasing major cardiovascular events including mortality.

30. Optimal Revascularization of the Diabetic Patient with Coronary Artery Disease Summary
Hybrid approach for coronary revascularization may be considered providing a less invasive approach to revascularization utilizing the LIMA to the LAD (survival benefit) and PCI to other vessels.
Medical management is critical to provide therapy for the plaque, preserve/improve left ventricular function, treat angina/ischemia and prevent sudden cardiac death.

32. Accelerated Atherosclerosis in Diabetes Mellitus
Armstrong EJ, et al. Circulation. 2013;128:

33. Saphenous Vein Grafts Diabetes Mellitus
Saphenous vein graft occlusion is more common among diabetics versus non-diabetics.
- The proportion of small-sized target vessels was greater in diabetics.
- At 1 year, grafts 14.4% were occluded in the diabetics versus 9.7% (p=0.052).
- Multivariable regression found diabetes to be a significant independent predictor of 1-year graft occlusion along with female gender, SV conduit, and small target-vessel size.
- A significantly higher proportion of SV grafts were occluded in the diabetics (19% versus 12%, P=0.04).
- Diabetics occlusion radial artery 9.5% vs. SVG 19.1%
- Non-diabetics occlusion radial artery 7.7% vs SVG 11.7%
Singh SK, et al. Circulation. 2008;118[suppl 1]:S222–25.

34. Modified from BARI 2D Study Group. N Engl J Med. 2009;360:2503-15.
Revascularization vs. Medical Therapy in Type 2 Diabetics with Stable Coronary Artery Disease BARI 2D Trial
n=2368
PCI vs. Medical Therapy
CABG vs. Medical Therapy
- First generation DES with only 35%, 56% BMS, and 9% no stent
- major cardiovascular events (death, myocardial infarction, or stroke)
Modified from BARI 2D Study Group. N Engl J Med. 2009;360:

35. SYNTAX Score and 5-Year Outcomes BARI 2D Trial
CABG group had significantly higher SYNTAX scores compared to PCI group (36% vs. 13% had mid/high scores, respectively; p < ).
Patients with low SYNTAX scores (≤ 22) there was no significant difference in major cardiovascular events between medical therapy and revascularization for both CABG and PCI.
Patients with mid/high SYNTAX scores major cardiovascular events were significantly lower after revascularization than with medical therapy in the CABG group, but not in the PCI group.
- Low SYNTAX scores (≤ 22), major cardiovascular events did not differ significantly between revascularization and medical therapy, either in the CABG stratum (26.1% vs. 29.9%, p=0.41) or in the PCI stratum (17.8% vs. 19.2%, p=0.84).
- Patients with mid/high SYNTAX scores major cardiovascular events were lower after revascularization than with medical therapy in the CABG stratum (15.3% vs. 30.3%, p= 0.02), but not in the PCI stratum (35.6% vs. 26.5%, p=0.12).
BARI 2D Study Group. J Am Coll Cardiol. 2017;69:395–403.

36. PCI vs. CABG Outcomes at 3-Years In Diabetics Based on SYTNAX Score
Diabetes Mellitus
Non-Diabetes Mellitus
- Overall: MACCE (22.9% CABG, 37.0% PES; p=0.002) driven by decrease revascularization rate in CABG (12.9% CABG, 28.0% PES; p<0.001).
Mack MJ, et al. Ann Thorac Surg. 2011;92:2140–6.

37. Coronary Artery Bypass Graft (CABG) Surgery
20 Year Follow-up The Cleveland Clinic Foundation
SVD with IMA 75%
SVD no IMA 58%
DVD with IMA 57%
TVD with IMA 44%
DVD no IMA 43%
TVD no IMA 30%
LIMA was used in 94 patients *
*IMA=left internal mammary artery
Hurst’s The Heart. 11th Edition. p

38. PCI vs. CABG in Diabetics and Non-Diabetics
All-Cause Mortality
Meta-Analysis of Randomized Controlled Trials
5-Year (or longest) Follow-up
Verma, S, et al. Lancet Diabetes Endocrinol Dec;1(4):

39. Bioresorbable Vascular Scaffold (BVS) Diabetes Mellitus
Limited information in diabetic patients.
BVS showed similar rates of target vessel failure compared with non- diabetics patients at 1-year.
BVS showed similar rates of target vessel failure compared with diabetics treated with 2nd generation drug eluting stent (Xience everolimus) at 1-year.
ABSORB and SPIRIT Trial Investigators. JACC Cardiovasc Interv. 2014;7:482–93.

40. Anti-Platelet Therapy Diabetes Mellitus
Prasugrel (TRITON-TIMI 38) and ticagrelor (PLATO) overall showed clinical improvement compared with clopidogrel after PCI.
Subgroup analyses showed diabetics had relative reductions in major cardiovascular events ≥ than reductions in non-diabetics.
A large proportion of patients treated with enteric coated aspirin did not achieve complete inhibition of thromboxane B2 due to incomplete absorption; reduced bioavailability of enteric coated aspirin may contribute to aspirin resistance in diabetics.
No significant difference in cardiovascular or bleeding outcomes with aspirin monotherapy vs. dual antiplatelet therapy post-CABG.
James S, et al. Eur Heart J. 2010;31:3006–16.
Wiviott SD, et al. Circulation. 2008;118:1626–36.
Bhatt, Dl, et al . J Am Coll Cardiol. 2017;69:603–12.
van Diepen S, et al. J Am Coll Cardiol. 2017;69:119–27.

41. Frequency of clinical manifestations of coronary atherosclerosis
Coronary Atherosclerosis: Early Treatment may Prevent the Clinical Manifestations of the Disease
No therapy
↓ LDL-C (Statin), Other
Frequency of clinical manifestations of coronary atherosclerosis
LDL-C
< 45 mg/dl (Statin)
ATHEROSCLEROSIS
Statin + PCSK9i
Vaccine, Other
0 –
Birth 20 40 60 80
Age (years)
Boudoulas KD, et al. Prog Cardiovasc Dis. 2016;58:
Boudoulas KD, et al. Prog Cardiovasc Dis. 2016;58: