Issues in the Management of Diabetic Patients with Cardiovascular Disease

Transcription

1 Issues in the Management of Diabetic Patients with Cardiovascular Disease Elliot Rapaport, MD December 13,

2 Hyperglycemia and Acute Coronary Syndromes 2

3 Effect of Hyperglycemia in STEMI Impairs microvascular perfusion Increases endothelial dysfunction Decreases NO production Increases oxidative stress Promotes a pro-thrombotic state Abolishes ischemic reconditioning experimentally Increases inflammatory markers Increases free fatty acid concentration 3

4 Association between Mean Blood Glucose and In- Hospital Mortality. No Diabetes Reference Mean BG 100-<110 No diabetes All All Diabetes Diabetes < Mean Blood Glucose (mm / l) (90 mg/dl) (270 mg/dl) Kosiborod et al et al Circulation 2008;117:1018 4

5 Relationship of blood glucose level (BGL) and death at 30 days stratified by Thrombolysis In Myocardial Infarction (TIMI) risk score (TRS) Pinto, D. S. et al. J Am Coll Cardiol 2005;46: Copyright 2005 American College of Cardiology Foundation. Restrictions may apply. 5

6 Stress hyperglycemia in AMI: Association with mortality risk in patients without known diabetes Reference Hyperglycemia definition (mg/dl) O Sullivan 1991 >144 Lewandowicz Soler Oswald Bellodi 1989 >121 Ravid 1975 >121 Sewdarsen Pooled (3.9-fold higher risk ) Unadjusted RR of in-hospital mortality after MI* *vs patients with normoglycemia Capes SE et al. Lancet. 2000;355:

7 Admission glucose and glucose change within 24 hours predict mortality risk N = 1469 with AMI (n = 1219 without DM) day mortality (%) % in 30-day mortality per 11 mg/dl glucose in first 24 hr (P = 0.002)* < < < Baseline glucose (mg/dl) Glucose (24 hr vs baseline) 30 mg/dl decrease No change to <30 mg/dl decrease Increase *Multivariate analysis Goyal A et al. Eur Heart J. 2006;27:

8 Potential beneficial effects of insulin Anti-inflammatory NF-κB MCP-1 ICAM-1 CRP IκB Antithrombotic TF PAI-1 Anti-oxidative ROS Mechanistic benefits of insulin Vasodilatory + Platelet inhibitory NO release enos camp Cardioprotective Neuroprotective Antiapoptotic Glucose lowering Dandona P et al. Am J Cardiol. 2007;99(suppl):15B-26. 8

9 Early impact of insulin on mortality for hyperglycaemic patients without known diabetes with ACS Registry in 201 UK hospitals 38,864 ACS patients with no hx diabetes 3835 with glucose > 11 mmol/l (198 mg/dl) 31% received insulin Mortality 7 days 30 days Received insulin 11.6% 15.8% No insulin 16.5% 22.1% HR (95% CI) 1.56 ( ) 1.51 ( ) p < O.OO1 < O.OO1 Weston et al Heart 2007;93:1542 9

10 CREATE-ECLA: Effect of GIK on mortality, glucose N = 20, Mortality, cumulative events (%) GIK infusion Control* Mean glucose (mg/dl) Days 0 Baseline (both groups) GIK group Control* *Usual care only 6 hours after randomization CREATE-ECLA Trial Group Investigators. JAMA. 2005;293:

11 ACC/AHA STEMI guidelines: Strict glucose control Class and level of evidence I B IIa IIb III Insulin infusion to normalize BG recommended for patients with STEMI + complicated courses B C During acute management of STEMI in patients with hyperglycemia, it is reasonable to administer insulin infusion to normalize BG, even in those with an uncomplicated course After acute phase of STEMI, individualize diabetes treatment; select combinations of agents that achieve optimal glycemic control and are well tolerated Antman EM et al. J Am Coll Cardiol. 2004;44:

12 SWEET SWEET ACS ACS Trial trial 12

13 General Management of the Diabetic Undergoing an ACS or STEMI 13

14 Diabetes and Fibrinolysis % of Patients Day Mortality Placebo/Control Fibrinolysis 8.7 Non-Diabetic 17.3 Lives Saved per Patients Treated Diabetic 13.6 Fibrinolytic Therapy Trialists (FTT) Collaborative Group Lancet 1994;343:

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16 Meta-Analysislsis:: Stenting vs Balloon for STEMI(13RCT s; n=6921) 12- month MORTALITY STUDY WITHOUT ABCIXIMAB I II STENTING BALLOON n/n (%) n/n (%) OR (fixed) 95% CI Weight % OR 95% CI P value CADILLAC 17/512 (3.3%) 28/518 (5.4%) [0.32, 1.11] 1.0 FRESCO 1/75 (1.3%) 4/75 (5.3%) [0.03, 2.20] 0.36 Jacksch et al 5/231 (2.2%) 7/231 (3.0%) [0.22, 2.26] 0.56 PAMI 26/452 (5.8%) 14/448 (3.1%) [0.97, 3.67] PASTA 3/67 (4.5%) 6/69 (8.7%) [0.12, 2.05] 0.49 PSAAMI 4/44 (9.1%) 8/44 (18.2%) [0.12, 1.62] 0.35 STENTIM-2 3/101 (3.0%) 2/110 (1.8%) [0.27, 10.1] 0.58 ZWOLLE-5 3/112 (2.7%) 4/115 (3.5%) [0.17, 3.49] 1.0 ZWOLLE-6 47/785 (6.0%) 45/763 (5.9%) [0.67, 1.55] 0.94 WITHI ABCIXIMAB II STOPAMI-3 25/305 (8.2%) 28/306 (9.2%) [0.50, 1.56] 0.67 STOPAMI-4 7/90 (7.8%) 11/91 (12.1%) [0.23, 1.66] 0.33 CADILLAC 28/524 (5.3%) 16/528 (3.0%) [0.97, 3.38] ABCIXIMAB 60/919 (6.5%) 55/925 (5.9%) [0.76, 1.61] 0.6 CONTROL 109/2379 (4.6%) 118/2373 (5.0%) [0.70, 1.20] 0.5 TOTAL (95% CI) 169/3298 (5.1%) 173/3298 (5.2%) [0.78, 1.21] 0.81 De De Luca, Luca, Suryapranatarrt, Suryapranatarrt et al. et al. JACC 2006t l STENT BETTER BALLOON I BETTER JACC 2006t l. STENT BETTER BALLOON BETTER 16

17 Diabetes Remains a Major Risk Factor for Mortality after AMI for Patients Managed by an Invasive Strategy Independent Predictors FRISC 2 Norhammer et al J Am Coll Cardiol 2004;43:585 17

18 Outcomes in Patients with UA/NSTEMI Invasive vs Noninvasive Strategy Death or MI FRISC 2 Norhammer et al J Am Coll Cardiol 2004;43:585 18

19 % of Patients Underutilization of an Invasive Management Strategy in Canadian Non-ST ST ACS Diabetic Patients: The Problem Still Remains 36.1 p ACS I ( ) Diabetes 25.9% ACS II ( ) 2004) Diabetes 27.2% p p Non-diabetic ACS I DM ACS II DM 20 0 n= ACS I ACS II Angiography ACS I ACS II PCI p ACS I ACS II CABG 14.8 p< ACS I ACS II ACS I ACS II Any Revasc. Death Yan R et al Circulation 2005;112(Suppl II):

20 GP IIb/IIIa Inhibition for Non-ST ST-Elevation ACS 30-Day Death or Nonfatal MI Trial n Risk Ratio & 95% CI Placebo GP IIb/IIIa PRISM 3, % 5.8% PRISM PLUS 1, % 10.2% PARAGON A 2, % 11.3% PURSUIT 9, % 14.2% PARAGON B 5, % 10.5% GUSTO-IV ACS Pooled Boersma,, Lancet ,800 29, (0.86, 0.995) p = GP IIb/IIIa Better Placebo Better 8.0% 8.7% 11.5% 10.7% 20

21 Trial Non-ST ST ACS GP IIb/IIIa Agents N PURSUIT 2, Day Death Diabetic Patients Odds Ratio & 95% CI 0.74 (0.59, 0.92) p= , % 4.6% IIb/III /IIIa Better Placebo Better Placebo IIb/III /IIIa 6.1% 5.1% PRISM 687 p= % 1.8% PRISM-PLUS PLUS 362 p= % 3.6% GUSTO IV 1,677 p= % 5.0% PARAGON A 412 p= % 4.6% PARAGON B 1,157 p= % 4.9% Pooled 6,458 Note: Pooled mortality for Non-diabetics was 3.0% in both groups p=0.33 Roffi et al Circulation 2000;104:

22 NAPLES (Novel Approaches for Preventing or Limiting Event Study) DESIGN: Prospective, randomized, double-arm, single-center clinical study ASA Clopidogrel (loading dose 300 mg the day before procedure) Diabetic Patients Elective PCI Biomarker negative UFH + Tirofiban Bivalirudin alone N = 168 Elective PCI N = day endpoints Death, MI, IUR, ACUITY major bleeding (net clinical outcome) 22

23 30 25 P = OR, % CI, % P = OR, % CI, P = OR, % CI, Non Q-wave MI UFH plus tirofiban (n = 168) Bleeding Bivalirudin (n = 167) Composite End Point 23

24 Adjunctive Pharmacologic Management of the Diabetic Patient Undergoing an ACS 24

25 TNT: Intensive Atorvastatin Treatment Reduces Cardiovascular Events in Patients With CHD and Diabetes LDL-C 98.6 mg/dl LDL-C 76.7 mg/dl 25

26 STUDY DESIGN ACS (STEMI or UA/NSTEMI) & Planned PCI ASA N= 13,600 Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1 o endpoint: CV death, MI, Stroke 2 o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis Key Substudies: Pharmacokinetic, Genomic 26

27 Balance of Efficacy and Safety Endpoint (%) CV Death / MI / Stroke Clopidogrel Prasugrel events HR 0.81 ( ) P= NNT = TIMI Major NonCABG Bleeds Prasugrel Clopidogrel Days events HR 1.32 ( ) P=0.03 NNH =

28 CV Death, Non-fatal MI and Non-fatal Stroke and Major Bleeds among Diabetic Subjects in TRITON-TIMI 38 Primary End Point Diabetics Non-diabetics ( n = 3,148 ) ( n = 10,462 ) Prasugrel Clopidogrel RR Reduction Major Bleeds Prasugrel Clopidogrel RR Increase 12.2% 17.0% 30.0% 2.5% 2.6% +6.0% 9.2% 10.6% 14.0% 2.4% 1.6% +43.0% 28

29 PROactive: Ti me to Pri mar y Composite End Point (all-cause death, nonfatal MI [including silent MI], stroke, ACS, leg amputation, coronary revascularization, leg revascularization) 29

30 PROactive: Ti me to Death, MI (Excluding Silent), or Stro ke ( maim secondary endpoint ) 30

31 Endpoint Cardiovascular Impact of Pioglitazone Therapy: A Meta-analysis Pioglitazone (n=8,554) (%) Control (n=7,836) (%) Hazard Ratio (95% CI) P Death, myocardial infarction, stroke ( ) Death Myocardial infarction Stroke Serious heart failure ( ) 0.81 ( ) 0.80 ( ) 1.41 ( ) Lincoff AM et al. JAMA. 2007;298(10):

32 DAIS: Final Results in CAD Patients With Type 2 Diabetes (200 mg/d Fenofibrate v plac.) CAD Treatment with fenofibrate resulted in 40% reduction in rate of progression of localized CAD (by prior angiography) versus placebo 23% reduction in combined coronary events following fenofibrate treatment (P=NS*) Lipids Average reductions with fenofibrate: TC, 10%; LDL-C, 6%; TG, 29%; average increase in HDL-C, 6% Safety Very few serious adverse events; no significant differences in tolerability between fenofibrate and placebo treatments; TM 95% compliance *Researchers report that results suggest benefit to patients. N = 418 Steiner G. XIIth International Symposium 1999 Professional on Atherosclerosis; Postgraduate Services June 27, 2000; Stockholm, Sweden. 32

33 CABG or PCI in Diabetics with Multivessel CAD 33

34 BARI I: Poorer Outcome with Revascularization in Diabetics Percent Survival Treatment Comparisons Non-diabetics: p=0.72 Diabetics: p= Non Diabetic PTCA 86.8% Non Diabetic CABG 86.4% Diabetic CABG 76.4% Diabetic PTCA 55.7% Years 34

35 Coronary Revascularization in Diabetes Trial Design 510 patients recruited between Jan 2002 and May 2007 ESC Congress Munich Sep1,

36 Death, Non-fatal MI, Non-fatal Stroke 36

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42 Note: Propensity score matching based on 67 patient, procedural and hospital variables 42

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44 Long Term Therapy Following DES Use in AMI Patients with Diabetics High dose HMG Co-A Reductase Inhibitors with LDL-C target < 70 mg/dl ACE Inhibitors or Angiotensin-Receptor Blockers Beta-Receptor Blockers Eplerenone if LV failure at onset and LVEF <40 Low dose aspirin Extended Thienopyridine Therapy Diabetes Control 44