following ACS in High Risk Patients Reducing Outcomes in your - PowerPoint PPT Presentation

Optimal Secondary Prevention following ACS in High Risk Patients Reducing Outcomes in your Diabetic Patient David Fitchett MD St Michael’s Hospital Toronto

David Fitchett MD Disclosures • Received CME / consultation honoraria from – Merck – Boehringer Ingelheim – Lilly – Astra Zeneca • Steering committee member for EMPA Reg • DMC chair for SUSTAIN 6 and PIONEER

Reducing Adverse Outcomes after ACS in Patients with Diabetes Goals To show: • Diabetes increases risk of CV events • Strategies to reduce adverse outcomes • Changing landscape with new therapies

Why Should Cardiologists Care About Diabetes? • DM is present in 40-50% of patients with CHD • 70% mortality in DM due to CVD • DM worsens impact of other CV risk factors • DM worsens outcome of all CV syndromes • DM impacts all aspects of CV practice • Treatments now available with large impact on CV outcomes

Mortality following Myocardial Infarction in Patients with and without Diabetes DM STEM I DM STEMI 62,000 Patients in TIMI trials Non DM STEMI Non DM STEMI Donohoe et al JAMA 2007;298:765

Life Expectancy Is Reduced by ~12 Years in Diabetes Patients with Previous CVD 60 yrs End of life No diabetes – 6 yrs Diabetes yrs – 12 Diabetes + MI The Emerging Risk Factors Collaboration. JAMA 2015;314:52

Diabetes has Major Impact on MI Recurrence Non Diabetic Patients Diabetic Patients

Impact of Diabetes on Outcomes after ACS 1 year outcomes Diabetes New Diabetes No Diabetes Aguilar et al Circulation 2004;110;1572 VALIANT

In-Hospital Management of ACS in the DM Patients and Long-Term Outcomes • Choice of revascularisation PCI vs CABG – Preference for CABG in multivessel CAD (FREEDOM) • Anti-platelet agent – Preferential use of ticagrelor / prasugrel – Use of DAPT in patients managed without PCI • Initiation / dose optimisation of – Statins, BP control, Use of ACEi /ARB, beta blocker • Glycemic management – Glucose control – Need for referral? – Choice of drug with CV benefit / known safety • Facilitate lifestyle change Treatment strategies initiated during admission – Smoking cessation • Patient more likely to remain adherent – Refer to Rehabilitation Clinic • Value of structured orders (admission and discharge)

Optimal Secondary Prevention on Patient with Type 2 Diabetes after ACS Anti-platelet therapy • Vascular Protection Lipid lowering ACE inhibition /ARB Prevention of vascular events Liraglutide Beta blockers • Cardiac protection ACE I / ARB Mineralo corticoid inhibition Prevention of heart failure / Saccubitril / Valsartan Ivabradine Sudden death ICD and or CRT Empagliflozin • Risk factor management Smoking cessation Lipid and BP control Limit CAD progression Glycemia control ? Rehabilitation and lifestyle

Dysfunctional Platelets in Diabetes Diminished platelet inhibition in patients with DM • ASA • Clopidogrel Ferreiro J and Angiolillo D Circulation 2011;123:798

Ticagrelor and ACS Impact of Diabetes CV Death MI or stroke James et al Eur Heart J (2010) 31, 3006

PEGASUS: Longer Term (up to 3yrs) Ticagrelor in Patients with Diabetes Bleeding TIMI major HR 2.5 p<0.001 No increase in fata lbleeding , ICH or Haemorhagic stroke Diabetes Bonaca et al N Engl J Med 2015

Beta-blockers and Diabetes – Implications in MI Concerns Enhanced Treatment Benefit in Diabetes • Masking hypoglycemia 70 • Impaired glycogenolysis % Mortality Reduction 60 Non-DM DM • Worse Glucose % reduction of mortality intolerance 50 • Hyperosmolar 40 hyperglycemic coma • Susceptibility to heart 30 failure 20 10 Mortality reduction • Non DM 33% 0 BHRT NMTS GMT • DM 48% BHRT = Beta-blocker Heart Attack Trial NMTS = Norwegian Multicentre Timolol Study GMT = Goteburg Metoprolol Trial Sawicki et al J Int Med 2001;250:11

Mortality Reduced 26% by ACE Inhibtion after MI in Patients with LVEF < 40% Mortality  26% Readmission for CHF  27% Reinfarction  20% Years Flather et al Lancet 2000;355:1575

TRAndolapril Cardiac Evaluation Study: Increased Survival in High-Risk Patients 80 120% 70 97% 60 Median Lifetime 56% 50 (months) 104% 40 30 20 10 0 Diabetes CHF Angina Hypertension N=237 N=1025 N=795 N=400 Trandolapril Placebo Torp-Pedersen et al ,. Lancet . 1999;354:9-12.

Association between Mean Blood Glucose and In-Hospital Mortality. Reference Mean BG 100-<110 No diabetes All Diabetes Kosiborod et al Circulation 2008;117:1018

Benefit of Tight Glycemic Control after Acute Myocardial Infarction • STE and Non STE MI RR 0.72 (95% CI 0.55-0.92) • Blood glucose > 11 mmol/L • N=1240 • Randomised to: – Intensive insulin for 24 h + multi dose insulin for 3 months NNT=9 – Early glucose target 7-10 mm/l or – Usual care • Mean FU 3.4 years DIGAMI Malmberg et al JACC 1995;26:57 Malmberg BMJ 1997;314:1512

Benefit of Tight Glycemic Control after Acute Myocardial Infarction • STE and Non STE MI RR 0.72 (95% CI 0.55-0.92) • Blood glucose > 11 mmol/L Patients with ACS and blood glucose > 11mmol/l • N=1240 • Randomised to: may receive glycemic control to 7-10mmol/l – Intensive insulin for 24 h + followed by strategies to achieve long-term multi dose insulin for 3 months NNT=9 glucose targets. Grade C level 2 – Early glucose target 7-10 mm/l or CDA Clinical Practice Guidelines 2013 – Usual care • Mean FU 3.4 years DIGAMI Malmberg et al JACC 1995;26:57 Malmberg BMJ 1997;314:1512

Early Incretin Trials and CVD Outcomes Primary HbA 1c End point Duration of Treatment (as part of usual care) Range, % Alogliptin Non Inferior CV death, EXAMINE 1 6.5 – 11.0 R Nonfatal MI, or Placebo Nonfatal stroke Post MI Heart failure hospitalization Saxagliptin Non Inferior SAVOR- Saxagliptin 3.5%; Placebo 2.8% 6.5 – 12.0 R CV death, HR 1.27 (95% CI 1.07 – 1.58) TIMI 2 Nonfatal MI, or Placebo NNH = 142 Nonfatal stroke Sitagliptin Non Inferior TECOS 3 6.5 – 8.0 R CV death, MI, stroke, or UA Placebo Randomization Year 1 Year 2 Year 3 Up to Year 4 Median Duration of Follow-up a Non Inferior Lixisenatide ELIXA Median Duration of Follow-up a CV death, 7.0 – 11.0 R Nonfatal MI, or Post MI Nonfatal stroke or Placebo Hosp for Unstable Angina

EMPA-REG OUTCOME Placebo Trial design (n=2333) Randomised Empagliflozin 10 mg Screening and treated (n=2345) (n=11531) (n=7020) Empagliflozin 25 mg 590 Sites 42 Countries (n=2342) • T2DM (A 1 C >7-10%) + high CV risk (prior MI, CAD, CVA, PVD) • Included patients 2 months post ACS • Prior MI in 46.5% • Study medication given in addition to standard of care • Primary outcome: Triple MACE: CV death, nonfatal MI, non fatal stroke • On treatment median 2.6 years Observation median 3.2 years Zinman et al N Engl J Med 2015 DOI: 10.1056/NEJMoa1504720 21

CV death HR 0.62 (95% CI 0.49, 0.77) p <0.0001 Cumulative incidence function. CI, confidence interval; HR, hazard ratio. Zinman et al . N Engl J Med 2015:373:2117-2128. 22

Hospitalisation for heart failure HR 0.65 (95% CI 0.50, 0.85) p =0.0017 Cumulative incidence function. HR, hazard ratio 23

Incident or worsening nephropathy and its components Empagliflozi Placebo n n with event/ Hazard ratio N analyzed (95% CI) p-value Incident or 0.61 (0.53, 525/4124 388/2061 <0.0001 worsening 0.70) nephropathy New onset 0.62 (0.54, 459/4091 330/2033 <0.0001 macroalbuminuria 0.72) Doubling of serum- 0.56 (0.39, 70/4645 60/2323 0.0009 creatinine * 0.79) Initiation of renal 0.45 (0.21, replacement 13/4687 14/2333 0.0409 0.97) therapy 0.13 0.25 0.50 1.00 2.00 0.5 1 2 Favors empagliflozin Favors placebo * Accompanied by eGFR (MDRD) ≤45 mL/min/1.73m 2 . Cox regression analyses. 24

LEADER: Liraglutide in High Risk Patients with T2 DM • Inclusion criteria – Established CVD including prior MI after14 days (31%) • Included 17% patients with heart failure – High risk for CVD LEADER Marso et al N Engl J Med 2016 June 13 2016

LEADER Liraglutide Cardiovascular Outcome Tria l CV death, MI, Stroke Non-fatal MI HR 0.88 (95% CI 0.75-1.03) Patients with an event % Non-fatal Stroke HR 0.89 (95% CI 0.72-.11) Heart failure HR 0.87 (95% CI 0.73-1.05) CV Mortality Months Patients with an event % Months LEADER Marso et al N Engl J Med 2016 June 13 2016

SUSTAIN 6, LEADER and EMPA REG Comparisons 1 o Outcome Paitents FU Yrs Mortality HFH Hosp enrolled ARR p ARR p ARR p RRR RRR RRR SUSTAIN 6 2.1 2.3% 0.02 -0.2% ns -0.3% ns 26% T2 DM + LEADER 3.8 1.9% 0.01 1.4% 0.02 0.6% ns CVD or High CV risk 13% 15% EMPA REG T2 DM + 3 1.6% 0.04 2.6% <0.001 1.4% <0.002 CVD 14% 32% 35% ARR Absolute risk reduction, RRR Relative risk reduction HFH Heart failure hospitalisation 27