Diabetic Patients: Current Evidence of Revascularization

Transcription

1 Diabetic Patients: Current Evidence of Revascularization Alexandra J. Lansky, MD Yale University School of Medicine University College of London

2 The Problem with Diabetic Patients Endothelial dysfunction 1 Increased platelet reactivity 2 Increased number of activated circulating platelets 3 Higher levels of fibrinogen and factor VII 1 Lower levels of endogenous fibrinolytic activity and antithrombin III 1 Higher levels of plasminogen activator inhibitor-1 4 More diffuse disease Smaller vessels by angiography Less collaterals Exaggerated cellular and matrix proliferation 1. Moreno PR, Fuster V. J Am Coll Cardiol 24;44: Schneider DJ. Diabetes Care 29;32: Davi G, Patrono C. N Engl J Med 27;357: Mak K-H, Faxon DP. Eur Heart J 23;24:

3 vs. PCI trials In Diabetes Pre-Stent BARI RITA CABRI Stent ARTS I+II ERACI II SOS with Drug-eluting Stent CARDia FREEDOM SYNTAX

4 Mortality (%) BARI: 5 year mortality Diabetic vs non diabetic patients Non-CV death CV death PTCA PTCA Diabetics Non diabetics Adapted from: Circulation 1997;96:

5 Survival BARI: survival at 1 years focus on patients with diabetes ND PTCA vs : p =.59 D PTCA vs : p = Follow-up Time in Years No. of Patients ND ND PTCA D D PTCA ND (77.3) ND PTCA (77.) D (57.9) D PTCA (45.5) No Diabetes No Diabetes PTCA Diabetes Diabetes PTCA Key: PTCA, percutaneous transluminal coronary angioplasty. Adapted from: BARI Investigators. J Am Coll Cardiol 27;49:

6 ARTS-I&II : Diabetic Population ARTS II (n=159) ARTS I () (n=96) ARTS I (PCI) (n=112) Death 2.5% 3.1% 6.3% CVA.% 5.2% 1.8% AMI.6% 2.1% 6.3% Re- 3.1% 1.% 8.% Re-PCI 9.4% 3.1% 14.3% Any MACCE 15.7% 14.6% 36.6% No significant difference in MACCE (p=.86) between ARTS II and ARTS I () Significant difference in MACCE (p=<.1) between ARTS II and ARTS I (PCI) Adapted from: Euro Interv 25;1:

7 CARDIA - 1 Year Outcomes 55 diabetic patients with multi-vessel disease or complex single-vessel disease (not left main disease) randomized to either or PCI. Primary Outcome Death Primary Endpoint Death, MI, 1 year NI design: Upper 95% CI 1.3 Was not met MI PCI: Cypher 69% BMS: 31% Stroke Hazard Ratio Favours PCI Favours Adapted from: Kapur A et al. JACC 21.

8 SYNTAX: Outcome According to Diabetic Status at 1 year Diabetes (Medical Treatment) (N = 452) Non-Diabetic (N = 1348) P=.96 P=.25 P=.8 P=.97 Death/CVA/MI MACCE Death/CVA/MI MACCE TAXUS Adapted from: Banning AP et al. J Am Coll Cardiol 21;55:167-75

9 Syntax: Death (all-cause) at 12 months in patients with 3VD and/or LM Lesions 2 Non-Diabetic P=.68 TAXUS Medically treated diabetes P= Oral Hypoglycemics 6.8 P= /117 8/139 Insulin Treated P=.12 17/645 2/664 P=.1 13/24 19/ P<.1 5/87 11/88 Adapted from: Banning AP et al. J Am Coll Cardiol 21;55:167-75

10 Mortality (% Pts.) Mortality (% Pts.) Mortality by SYNTAX score in 3VD/LM diabetic and non-diabetic patients 2 Non-Diabetic P=.26 P=.48 P=.4 TAXUS Diabetic 2 P=.51 P>.99 P= SYNTAX Score: (n=437) (n=454) >33 (n=449) (n=136) (n=156) >33 (n=157) Adapted from: Banning AP et al. J Am Coll Cardiol 21;55:167-75

11 Log HR SYNTAX Score I vs II: The SYNTAX Trial NO Interaction with Diabetes P interaction =.67 PCI Diabetes was not an independent predictor of mortality or MACE in either the or PCI arm, and had a negative interaction effect No Yes It is not Diabetes but the complexity of CAD that drives events! Farooq V et al. Lancet 213;381:639 5

12 Low < 22 Lesion complexity Medium High > 33 SYNTAX Conclusion Both diabetic status and lesion complexity impact the relative safety between and TAXUS Express stents and should be considered when evaluating treatment options in patients with left main and/or 3- vessel disease Retroactive weighting of syntax score against 1- and 5-year SYNTAX outcomes will provide treatment algorithms to help determine the best revascularisation option for each patient Non Diabetic TAXUS or TAXUS or Diabetes Oral Meds TAXUS or TAXUS or Insulin?? Adapted from: Banning AP et al. J Am Coll Cardiol 21;55:167-75

13 FREEDOM Design Eligibility: DM patients with MV-CAD eligible for stent or surgery Exclude: Patients with acute STEMI Randomized 1:1 MV-Stenting With Drug-eluting With or Without CPB All concomitant Meds shown to be beneficial were encouraged, including: clopidogrel, ACE inhib., ARBs, b-blockers, statins

14 FREEDOM Trial Design Design: Superiority trial of 7 yrs (min 2 yrs, median 3.8yrs) Sample Size: N= 19 (953 DES vs. 947 ; 131 sites) Primary Outcome: All cause death, MI and Stroke Secondary Outcomes: MACCE (Death, MI, Stroke, Repeat Revasc.) at 1 Year Survival at 1,2,3 Years MACCE Components at 3 Days Post-Procedure Cost-Effectiveness Quality of Life at 3 Days, 6 Months, 1, 2 & 3 Years Original Power: Power 85% to detect at least an 18% reduction from 4-year rates ranging from 3-38 %, a =.5.

15 FREEDOM Screening and Enrollment 32,966 Patients were screened for eligibility 3,39 were eligible (1%) 1,49 did not consent 1,9 consented (57%) 953 Randomized to PCI/DES* 5 underwent 3 withdrew prior to procedure 3 died prior to procedure 3 underwent neither PCI/DES or 16 withdrew post-procedure 43 were lost to follow-up 947 Randomized to 18 underwent PCI/DES 26 withdrew prior to procedure 3 died prior to procedure 7 underwent neither PCI/DES or 36 withdrew post-procedure 51 were lost to follow-up

16 FREEDOM Primary Endpoint (Death, MI, Stroke) Death/Stroke/MI, % 3 2 PCI/DES Logrank P=.5 PCI/DES 1 5-Year Event Rates: 26.6% vs. 18.7% Years post-randomization PCI/DES N N

17 FREEDOM Myocardial Infarction Myocardial Infarction, % PCI/DES Logrank P<.1 PCI/DES 13.9 % 6.% Years post-randomization PCI/DES N N

18 All-Cause Mortality, % FREEDOM All Cause Death 3 PCI/DES 2 Logrank P=.49 PCI/DES 1 5-Year Event Rates: 16.3% vs. 1.9% Years post-randomization PCI/DES N N

19 Stroke, % FREEDOM Stroke 3 2 Severely Disabling Scale PCI/DES NIH > 4 55% 27% Rankin >1 7% 6% PCI/DES Logrank P= % PCI/DES 2.4% PCI/DES N N Years post-randomization

20 Repeat Revascularization, % FREEDOM Repeat Revascualrization 3 PCI/DES Log rank P< % 1 PCI/DES 5% Months post-procedure PCI/DES N N

21 FREEDOM MACCE (Death, MI, Stroke, Revasc) MACCE, % 3 PCI/DES 2 Logrank P=.4 17% PCI/DES 1 12% Months post-procedure PCI/DES N N

22 Freedom from Event (%) FREEDOM Primary Endpoint (Death, MI, Stroke) Treatment/ SYNTAX Interaction p=.58 Freedom from Event (%) Freedom from Event (%) SYNTAX Score 22 (N=669) Year Event Rates: 23.2% 17.2% PCI/DES SYNTAX Score (N=844) Year Event Rates: 27.2% 17.7% PCI/DES Years post-randomization SYNTAX Score 33 (N=374) 5-Year Event Rates: 3.6% 22.8% Years post-randomization Years post-randomization PCI/DES

23 FREEDOM HR for Death/MI/Stroke by Subgroups Worse ALL SUBJECTS 19 SYNTAX SYNTAX SYNTAX Males 1356 Females 544 Caucasian 1452 African-American Vessel Disease Vessel Disease 1573 LVEF < 4% 32 LVEF 4% 1259 No LAD involved 151 LAD involved 1737 Hx stroke 65 No Hx stroke 1835 Renal insuff. 129 No Renal insuff HbA1c < 7% 63 HbA1c 7% 1119 N. American Site 77 Non-N. American 113 PCI/DES Worse Treatment x Subgroup Interaction P=.58 P=.46 P=.55 P=.75 P=.37 P=.83 P=.57 P=.62 P=.99 P= yr Rate (%) PCI/DES

24 Quality of Life Angina frequency, physical limitations, and quality-of-life domains of the SAQ assessed at baseline, at 1, 6, and 12 months, and annually thereafter. SAQ Angina Frequency SAQ Physical Limitations SAQ Quality of Life Adjusted: * P<.5 favoring PCI *P<.5 favoring Abdallah MS et al. JAMA 213;on-line

25 FREEDOM: Insulin vs non-insulin Therapy Primary Endpoint

26 FREEDOM: ITDM vs. Non-ITDM ITDM vs. Non-ITDM HR 95 % CI P Value Death/Stroke/MI 1.63 (1.32, 2.2) <.1 Death 1.54 (1.16, 2.5).3 Stroke 1.86 (1.7, 3.2).26 MI 1.64 (1.18, 2.3).4 CV death 1.58 (1.11, 2.26).12 3-Day MACCE 1.54 (1.2, 2.33).4 1-Year MACCE 1.51 (1.18, 1.92).1 3-Day revascularization 1.2 (.64, 2.27).57 1-Year revascularization 1.44 (1.5, 1.97).25 Death/Stroke/MI 1.63 (1.32, 2.2) <.1 Death 1.54 (1.16, 2.5).3 Stroke 1.86 (1.7, 3.2).26

27 FREEDOM: Risk associated with ITDM Non-ITDM n = 1248 ITDM n = 62 P Value Age 63.2 ± ± Male sex 76.5% 61.3% <.1 Body mass index (g/m2) 29.3 ± ± 5.9 <.1 Duration of diabetes (years) 7.7 ± ± 9.9 <.1 Hemoglobin A1c (%) 7.5 ± ± 1.8 <.1 Glucose on day of procedure 144. (118.8,18.) 16. (126.,18.) <.1 Blood Urea Nitrogen mg/dl 21. (15.4,32.) 23.1 (16.1,36.).2 History of hypertension 83.2% 87.5%.2 Peripheral neuropathy 5.2% 14.3% <.1 Congestive heart failure 24.3% 32.1%.4 NYHA class % 67.9%.4 Acute Coronary Syndrome 28.6% 35.1%.5

28 5-Year Kaplan-Meier Event-Free Estimated Event Rates for primary endpoint and Treatment effect Non-ITDM 1.5 Hazard Ratio ITDM

29 The Treatment effect between and PCI is similar in Diabetics irrespective of Insulin Therapy Interaction P-value for treatment by insulin dependency status

30 FREEDOM: Interaction of SYNTAX score and Insulin Therapy on outcomes by randomized treatment allocation Non-ITDM ITDM Treatment x Insulin Group PCI HR PCI vs. PCI HR PCI vs. Interaction P-value SYNTAX ( ) 14.1 ( ) 1.18 ( ) 29.7 ( ) 26.3 ( ) 1.16 ( ).39 SYNTAX ( ) 14.3 (1.1-2.) 1.61 ( ) 35.5 ( ) 21.8 ( ) 1.56 ( ).93 SYNTAX ( ) 2. ( ) 1.58 ( ) 28.9 ( ) 25.9 ( ) 1.27 ( ).65

31 Lesion complexity Low Medium High FREEDOM Conclusions For Diabetics with multivessel CAD (non-lm), was superior to 1 st Generation DES (TAXUS Express 43%, Cypher 57%) Among patients with lesion complexity (Syntax <22) DES may be an alternative to Non Diabetic Diabetes Oral Meds Insulin Question still remains: Diabetic with single vessel CAD Outcomes with 2nd and 3 rd generation DES Outcomes with more potent antiplatelet TAXUS or TAXUS or TAXUS or

32 More stroke in PCI ARTS (ARTS 2) CARDia (DES subset) 5.2% 1.8% (.%) 2.4%.4% (.%) SYNTAX 2.2%.6% FREEDOM (2yrs) 1.9%.9%

33 PCI is improving faster in MV Diabetes 1 year mortality in patients with diabetes BARI ,% 13,% ARTS CARDia ,3% 3,1% 3,2% 3,3% PCI FREEDOM 25-1,9% 1,3%,% 5,% 1,% 15,%

34 Repeat Revascularisation at 1 year CABRI 5% 3% ARTS 4,1% 21,9% SYNTAX CARDia 2,% 5,9% 9,9% 13,7% PCI FREEDOM 4,8% 12,6% % 5% 1% 15% 2% 25% 3% 35%

35 Disease progression in nonstented lesions causes most CV events N = 1228 in 2nd-generation coronary stent trials* 25 CV event rate Average event rate, years Target lesion % Non-target lesion Year Target lesion Cutlip DE et al. Circulation. 24;11: Non-target lesion

36 We can improve PCI further?

37 Primary endpoint (%) Primary efficacy endpoint in TRITON-TIMI 38 stratified by diabetic status Diabetes mellitus No diabetes mellitus 18 HR.7 ( ), P<.1 Clopidogrel HR.86 ( ), P = Clopidogrel Prasugrel Prasugrel Days P interaction =.9 Days (Clopidogrel and prasugrel coadministered with aspirin) Adapted from: Wiviott SD et al. Circulation. 28;118:

38 SPIRIT V Diabetic RCT: 1-Year Clinical Results Composite Endpoints XIENCE V TAXUS Liberté p value N = 215 N = 14 Cardiac death, MI* and CI TLR % Cardiac death, MI * % Event adjudication according to Academic Research Consortium (ARC) Definitions *Not clearly attributed to a non target vessel p-values are not from formal hypothesis testing and are displayed for descriptive purposes only

39 All-cause mortality All-cause mortality EES in Patients with Diabetes: SCAAR HR: 2.2; 95% CI: HR 1.69; 95% CI: No. at risk SES PES EES EES Kedhi et al. JACC Card Int 212;5:1141-9

40 Conclusion With new generation DES, the benefits of PCI compared to in terms of lesser invasiveness, fewer major peri-procedural complications, reduced stroke, better early QOL, more rapid return to work, etc., outweigh the greater rate of repeat revascularization, as long as mortality is not increased. It is reasonable to perform PCI in nearly all pts with a SYNTAX score 22 irrespective of insulin therapy, and select with SYNTAX score Most pts with SYNTAX score 33 who are good surgical candidates should be referred to