Adults With Diagnosed Diabetes

19901990

No dataavailable

Less than 4% 4%-6% Above

6%

Mokdad AH, et al. Diabetes Care. 2000;23(9):1278-1283.

Adults With Diagnosed Diabetes

20002000

4%-6% Above 6%

Mokdad AH, et al. JAMA. 2001;286(10):1195-1200.

Epidemiology:Epidemiology: Clinical Impact of Clinical Impact of Diabetes MellitusDiabetes Mellitus

DiabetesDiabetes

The leading cause of new cases of end stage renal

disease

A 2- to 4-fold

increase in cardio-

vascular mortality

The leading cause of new

cases of blindness in

working-aged adults

The leading cause of

nontraumaticlower

extremity amputations

Diabetes Adversely Affects SurvivalDiabetes Adversely Affects Survival

NEJM 1999;339:229-234

N=1059 diabetics and 1373 non-diabetics with and without MI followed for 7 years

Observational study

Diabetic vascular pathology and PCI

Decreased endothelial thromboresistance

Platelet hyperreactivity (diabetic thrombocytopathy)

Platelet size ↑

GP IIb/IIIa receptor number ↑

Increased platelet aggregation and adhesion

Diminished fibrinolysis

Altered response to arterial injury

Increased plasma coagulation

Levels of fibrinogen ↑

UA/NSTEMI

EarlyInvasive

EarlyConservative

PCI/ CABG

Cath/ PCI/ CABG

Medical Rx

Medical Rx

Endpoints

6 mosRandomize

-24 hrs

Chest pain

4- 48 108hrs hrs

ASA, Hep,Tirofiban

Angio

Hour0

ETT

+ischemia

BaselineTroponin

TACTICS TACTICS –– TIMI 18TIMI 18

N= 2,220 ACS patients

Death/MI/Death/MI/RehospitalizationRehospitalization for ACSfor ACS

Cannon et al NEJM 2001;344:1879-1887

N= 2220 patients with ACS

0

5

10

15

20

25

30

diabetes no diabetes

conservativeinvasive

n=613n=613p=0.028p=0.028

n=1607n=1607p=0.232p=0.232

Bypass Angioplasty Bypass Angioplasty RevascularizatonRevascularizatonInvestigationInvestigation-- BARIBARI

NHLBI-sponsored PTCA vs CABGn=1829 pts with multivesseldisease5 year follow-upn=353 treated diabetics

NEJM 1996;335:217-225

diabetics

Non-diabetics

CABG

PTCA

BARI BARI -- 5 year cardiac death rates5 year cardiac death rates

0

5

10

15

20

IMA graftingSVG onlyPTCA

2.9%

18.2%

20.6%

Circulation 1997;96:1761-1769

RestenosisRestenosis in Diabetics May be Lethalin Diabetics May be Lethal

N=604 consecutive diabetic patientssuccessfully treated with PTCA were enrolled in a follow-up program including repeated angiography at 6 months

N=604 consecutive diabetic patientssuccessfully treated with PTCA were enrolled in a follow-up program including repeated angiography at 6 months

Van Belle et al Circulation 2001;103:1218-1224

Does Does StentingStenting Help?: ARTS TrialHelp?: ARTS Trial

Multicenter (67 countries) randomized and prospective study performed from April 1997 to June 1998Multicenter (67 countries) randomized and prospective study performed from April 1997 to June 1998

1,2051,205

Stentn= 600Stent

n= 600CABG

n= 605CABG

n= 605

n= 112n= 112 n= 96n= 96

Randomized

Diabetics

Abizaid et al Circulation 2001;104: 533-538

Stent:Stent: DiabeticsDiabeticsStent:Stent: Non diabeticsNon diabetics

CABG :CABG : DiabeticsDiabeticsCABG:CABG: Non diabeticsNon diabetics

100100

6060

6565

7070

7575

8080

8585

9090

9595

00 6060 120120 180180 240240 300300 360360

Even

tEv

ent --

free

su

r viv

al (

%)

free

su

r viv

al (

%)

88.488.484.484.4

76.276.2

63.463.4

ARTS TrialARTS Trial1 Year Major Events Survival Free Curve1 Year Major Events Survival Free Curve

0

5

10

15

20

25

30

35

non-insulin-treated

insulin-treated

PCICABG

Dea

th %

N=6033 patients treated with PCI or CABG at Cleveland Clinic followed for 5 years

N=6033 patients treated with PCI or CABG at Cleveland Clinic followed for 5 years

P=0.008 P<0.0001

N=2,319 Diabetic Patients

Brener et al Circulation 2004;109

Drug Delivery PlatformDrug Delivery PlatformUnique Combination

Closed Cell Design

•Consistent & uniform coverage

Polymer

•Ensures controlled, sustained release of therapeutic levels of drug over the critical healing period

•Biocompatible & antithrombogenic

MV-stentingWith Sirolimus-eluting

And ReoPro

MV-stentingWith Sirolimus-eluting

And ReoPro

FREEDOM TrialFREEDOM TrialFREEDOM Trial

Eligibility: DM patients with MV-CAD eligible for stent or surgeryExclude: Patients with acute STEMI, cardiogenic shockEligibility: DM patients with MVEligibility: DM patients with MV--CAD eligible for stent or surgeryCAD eligible for stent or surgeryExclude:Exclude: Patients with acute STEMI, cardiogenic shockPatients with acute STEMI, cardiogenic shock

CABGWith or without CPB

CABGWith or without CPB

All concomitant Meds shown to be beneficial are encouraged, including: Plavix, ACE inhibitors, b-blockers, statins etc

All concomitant Meds shown to be beneficial are encouraged, including: Plavix, ACE inhibitors, b-blockers, statins etc

PRIMARY: 5-year mortalitySECONDARY: 12-month MACCE, 5-year Quality of Life

Randomized 1:1Randomized 1:1

Fuster V and the FREEDOM Steering CommitteeFuster V and the FREEDOM Steering Committee

Roffi et al Circulation 2001;104:2767-2771

Meta-analysis of 6458 diabetic patients, and 23,072 nondiabetic patients

PCI

Oral AntiOral Anti--platelet Agents platelet Agents –– Sites of ActionSites of Action

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Cum

ulat

ive

Haz

ard

Rat

e

Clopidogrel Clopidogrel + ASA*+ ASA*

1010 2020 3030

Placebo Placebo + ASA*+ ASA*

Days of FollowDays of Follow--UpUp00

PP = 0.003= 0.003N = 12,562N = 12,562

* In addition to other standard therapies.

The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

MI/Stroke/CV Death Within 30 DaysMI/Stroke/CV Death Within 30 Days

21%21%Relative RiskRelative Risk

ReductionReduction

Overall 12562 9.3 11.4

Associated MI 3283 11.3 13.7No associated MI 9279 8.6 10.6Male sex 7726 9.1 11.9

Female sex 4836 9.5 10.7≤65 yr old 6354 5.4 7.6

> 65 yr old 6208 13.3 15.3ST-segment deviation 6275 11.5 14.3

No ST-segment deviation 6287 7.0 8.6Enzymes elevated at entry 3176 10.7 13.0Enzymes not elevated at entry 9386 8.8 10.9Diabetes 2840 14.2 16.7No diabetes 9722 7.9 9.9Low risk 4187 5.1 6.7Intermediate risk 4185 6.5 9.4High risk 4184 16.3 18.0History of revascularization 2246 8.4 14.4No history of revascularization 10316 9.5 10.7Revascularization after randomization 4577 11.5 13.9No revascularization after randomization 7985 8.1 10.0

Placebo + ASA*Characteristic

No. ofPatients

Clopidogrel + ASA*

Percentage of Patients with Event

Placebo BetterClopidogrel Better

Relative Risk (95% CI)

1.21.00.80.60.4

CURE Outcomes in Various Subgroups

Major/LifeMajor/Life--Threatening Bleeds within Threatening Bleeds within 77 Days of CABG SurgeryDays of CABG Surgery

N = 456N = 454Stopped > 5 days prior to Stopped > 5 days prior to CABGCABG

0.530.834.4%5.3%Pts with Maj/LT Bleeds

0.061.539.6%6.3%Pts with Maj/LT Bleeds

N = 436N = 476Stopped Stopped << 5 days prior to 5 days prior to CABGCABG

Placebo ClopidogrelEndpoint +ASA* +ASA* P Value

(n=6303) (n=6259)

PlaceboPlacebo+ ASA*+ ASA*

ClopidogrelClopidogrel+ ASA*+ ASA*

Major Bleeding by ASA DoseMajor Bleeding by ASA Dose

<100 mg 2.6% 2.0%

100-200 mg 3.5% 2.3%

>200 mg 4.9% 4.0%

ASA DoseASA Dose

McGuire DK et al Am Heart J 2004;147:246-252

To evaluate the associations of diabetes and hypoglycemic strategies with clinical outcomes after acute coronary syndromes, data was analyzed from 15,800 patients enrolled in the SYMPHONY and 2nd SYMPHONY trials

To evaluate the associations of diabetes and hypoglycemic strategies with clinical outcomes after acute coronary syndromes, data was analyzed from 15,800 patients enrolled in the SYMPHONY and 2nd SYMPHONY trials

n=3,101

n=12,699

n=1473

n=100

McGuire DK et al Am Heart J 2004;147:246-252

InsulinInsulin--sensitizing sensitizing vsvs ––providingproviding

Cannon et al N Engl J Med 2004;350:1495-1504

N = 4,162 ACS patients Compared 40 mg of pravastatindaily (standard therapy)with 80 mg of atorvastatin daily (intensive therapy)Primary end point: composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization and stroke

Cannon et al N Engl J Med 2004;350:1495-1504

Intensive versus Moderate Lipid Lowering with Intensive versus Moderate Lipid Lowering with StatinsStatins after Acute Coronary Syndromesafter Acute Coronary Syndromes

Nissen et al JAMA 2004;291:1071-1080

REVERSAL

N = 654 stable angina patients Randomized to 40 mg of pravastatin daily (standard therapy) versus 80 mg of atorvastatindaily (intensive therapy)

Diabetes and ACSDiabetes and ACS

• Early cath is the default mode for ACS management in all patients, particularly in diabetics (TACTICS TIMI-18).

• Major upgrade in the early initiation and sustained use (in patients with definite atherosclerotic disease) of clopidogrel (CURE, COMMIT, CLARITY, CHARISMA).

• Until the results of FREEDOM are known, we should err on the side of CABG for diabetic patients with 3 vessel disease and LV dysfunction.

• Statins and insulin-sensitizing drugs appear to be particularly beneficial.