Acute Coronary Syndrome in Diabetes :

Insights from Latest Guidelines &

Role of Potent Oral Antiplatelet

M Yusuf Alsagaff, MD PhD FESC FAsCC FIHA

Outline
Antiplatelets in ACS
• The Need
• Choosing
• Sweet Spot
• Certain Populations : Diabetes & Asian
STEMI
• Guidelines ( PPCI, Fibrinolytic, Conservative)
• Evidence
• Switching
NSTE-ACS
• Guidelines (Risk Stratification, Ischemic Driven )
• Evidence
Take Home Messages
• Summary
• Future
N Engl J Med 2017;376:2053-64
 Acute thrombosis induced by a ruptured or eroded atherosclerotic
coronary plaque, with or without concomitant vasoconstriction, causing a
sudden and critical reduction in blood flow

Bentzon JF et al. Circ Res. 2014;114:1852-1866

For more than 10 years, dual antiplatelet therapy with aspirin and clopidogrel
has remained the Cornerstone of treatment for patients with ACS

Franchi, F. & Angiolillo, D. J. Nat. Rev. Cardiol. 12, 30–47 (2015)

Franchi, F. & Angiolillo, D. J. Nat. Rev. Cardiol. 12, 30–47 (2015)
PLATO: Study Design
Primary efficacy
Ticagrelor (n=9,333) endpoint:
Composite of CV
death, MI (excluding
silent MI), or stroke
180-mg loading dose 90 mg bid + ASA maintenance dose

• All patients were hospitalised with symptom onset <24 hours

• Patients could be taking clopidogrel at time of randomisation
N=18,624
Patients with ACS
(UA, NSTEMI, or Primary safety
STEMI*) 300-mg loading dose† 75 mg qd + ASA maintenance dose endpoint:
Total PLATO major
bleeding‡
Clopidogrel (n=9,291)

Randomisation
Visit 2 Visit 3 Visit 4 Visit 5 Visit 6

Screening <24h Month 1 Month 3 Month 6 Month 9 Month 12

*STEMI patients scheduled for primary PCI were randomised; however, they may not have received PCI.
Initial Treatment approaches †A loading dose of 300-mg clopidogrel was permitted in patients not previously treated with clopidogrel,
• Medically managed (n=5,216 — 28.0%) with an additional 300 mg allowed at the discretion of the investigator.
• Invasively managed (n=13,408 — 72.0%) ‡The PLATO study expanded the definition of major bleeding to be more inclusive compared with

previous studies in ACS patients. The primary safety endpoint was the first occurrence of any major
bleeding event.

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

James S, et al. Am Heart J. 2009;157:599–605.
 Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes
Platelet Inhibition and Patient Outcomes (PLATO)

13 0–30 Days 0–12 Months

(Composite of CV Death, MI, or

12 11.7 Clopidogrel
11
Cumulative Incidence of

10 9.8 Ticagrelor
9 Clopidogrel
Stroke) %

8 5.4 at 12 months
7
6 at 1 month ARR=1.9% 54 NNT
5 ARR=0.6% RRR=16% ( primary composite
4 4.8 RRR=12% endpoint)
3 Ticagrelor
2 HR: 0.84 (95% CI, 0.77–0.92); P<0.001
1 HR: 0.88 (95% CI, 0.77−1.00); P=0.045
0
0 2 4 6 8 10 12
No. at risk Months After Randomization
Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147
Clopidogrel 9,291 8,521 8,362 8,124 6,650 5,096 4,047

Reduction CV event of ticagrelor starts early and continue until

12 months in ACS Patients vs. clopidogrel

Reference: 1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

 250 NNH
(Primary safety endpoint –
total major bleeding)

without an increase in the rate of overall major bleeding

but with an increase in the rate of non–procedure-related bleeding

10
Net Clinical Benefit was greater for ticagrelor compared with
clopidogrel and The greatest relative difference was observed after
30 days
PLATO Study: Net clinical benefit*1
Exploratory post hoc analysis using primary efficacy and safety endpoints (31 days –12 months)

14
Ticagrelor
12
Clopidogrel
Net Clinical Benefit (%)

p = 0.026
10

8 8,97
7,86
6

-
*Net clinical benefit was defined as the composite of CV death, MI, stroke and major bleeding (CABG or non-CABG related)1
†Net clinical benefit favoured ticagrelor both within the initial 30 days of treatment and after1

Becker R et al. Eur Heart J 2011;32:2933-2944.

 Proposed Mechanism of Atherothrombosis in Diabetes Mellitus

Diabetes

Excess free fatty Insulin resistance Hyperglycaemia Lipoproteins

acids

Oxidative stress, PKC activation, RAGE activation

Endothelial dysfunction

Nitric oxide Nitric oxide Nitric oxide

Endothelin-1 NF–kB Tissue factor Hypercoagulability
Angiotensin II Angiotensin II PAI-1 Fibrinogen
Activator protein- Prostacyclin Fibrinogen Platelet activation
1 oxidation
Factors VII & VIII
Antithrombin
Vasoconstriction Inflammation
Hypertension Chemokines
VSMC growth Cytokines
Adhesion Atherothrombosis
molecules

NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PAI-1, plasminogen activator inhibitor-1; PKC, Jung JH et al. Diabetes Metab J. 2015;39:95-113
protein kinase C; RAGE, receptor for advanced glycation endproducts; VSMC, vascular smooth muscle cell
 Diabetes among ACS in China Type 2 Diabetes and CV Disease

Zhou et al. Cardiovasc Diabetol (2018) 17:147 Cosentino F et al. European Heart Journal (2019) 00, 169
 Ticagrelor, when compared with clopidogrel,
reduced ischaemic events in ACS patients
irrespective of diabetic status and glycaemic control,
without an increase in major bleeding events
 East Asian Paradox

It is a time to consider the paradigm shift from

"one-guideline-fits-all races" to "race-tailored antiplatelet therapy"
in treating ACS patients.

Curr Cardiol Rep 2014 May;16(5):485 Y. Huo et al. / Science Bulletin 64 (2019) 166–179
The effects of ticagrelor versus clopidogrel were not significantly different between Asians and non-Asians
with respect to the primary efficacy outcome
(hazard ratio for Asians vs non-Asians, 0.84 [95% CI 0.61-1.17] vs 0.85 [95% CI 0.77-0.93], P = .974)

Am Heart J 2015;169:899-905.e1
Outline
Antiplatelets in ACS
• The Need
• Choosing
• Sweet Spot
• Certain Populations : Diabetes & Asian
STEMI
• Guidelines ( PPCI, Fibrinolytic, Conservative)
• Evidence
• Switching
NSTE-ACS
• Guidelines (Risk Stratification, Ischemic Driven )
• Evidence
Take Home Messages
• Summary
• Future
 ACS Spectrum

1. Roffi M et al. Eur Heart J 2016;37(3):267-315;

18 2. Ibanez B et al. European Heart Journal 2017; 00; 1–66
Primary PCI

Should not be used :

➢ Previous Hemorrhagic Stroke
➢ Oral anticoagulation
➢ Moderate-severe liver diseases

European Heart Journal (2017) 00, 1–66

 MI, stroke, or vascular death; HR, 0.98; 95% CI, 0.83to 1.14; P0.76
HR, 0.87; 95% CI, 0.75 to 1.01; P0.07

HR, 0.80; 95% CI, 0.65 to 0.98; P0.03

HR, 1.63; 95% CI, 1.07 to 2.48; P0.02

Ticagrelor Vs Clopidogrel in STEMI Intended for PPCI : PLATO Trial Subgroup Analysis
PPK PERKI SKA 2019
 Fibrinolytic

➢ clopidogrel should be started immediately on presentation

➢ Clopidogrel is the only P2Y12 inhibitor that has been properly
investigated in patients with STEMI undergoing initial treatment with
thrombolysis.

Switch ±

More Potent P2Y12 Inhibitor

( Ticagrelor )
- Median 11.4 hour
(12 – 24 hours )

Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612 European Heart Journal (2017) 00, 1–66
 Explore safety of ticagrelor vs
clopidogrel after thrombolytic therapy
The TREAT study:
Multinational,*open-label, randomized, Phase III trial to assess safety and efficacy of ticagrelor vs
clopidogrel in patients aged 18–75 years, diagnosed with STEMI ≤24 hours prior to randomization, with
documented cardiac ischaemic symptoms due to atherosclerosis >10 minutes duration at rest and treated
with pharmacological thrombolysis† (N=~3794)1

TICAGRELOR LD administered as early as Clopidogrel

180 mg LD, possible after index event and not 300 mg LD,‡
then 90 mg BID MD >24 hours post-event then 75 mg QD MD
Duration of follow-up: 12 months
All patients will receive ASA at hospitalization
and continue at discharge2

Primary safety endpoint:

Time to TIMI-defined first major bleeding
Secondary endpoints:
Composite of MACE§ , All-cause mortality, need for rescue PCI, individual components of the
composite, PLATO-, TIMI- and BARC-defined bleeding events

Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612

 Ticagrelor 90 mg did not increase TIMI major bleeding at
30 days compared with clopidogrel in STEMI patients
treated with fibrinolysis*1,2

2.5 Clopid
Ticagrelor ogrel P value
Cumulative incidence of primary outcome,

Difference
Endpoint (N=1913) (N=188 for non-
2 (95% CI)
n (%) 6) inferiority
TIMI major bleeding (KM%)

Ticagrelor
Clopidogrel
n (%)
1.5

TIMI major
1 0.04%
bleeding 13
14 (0.73%) (-0.49 to <0.001
(primary (0.69%)
0.58%)
0.5 endpoint)

P value<0.001 for non-inferiority

0 PLATO major
0 3 6 9 12 15 18 21 24 27 30 bleeding/ BARC -0.18%
26
Time (days) 3–5 bleeding 23 (1.2%) (-0.89 to 0.001
No. at risk (1.38%)
BRILINTA 1913 1879 1870 1863 1858 1855 1853 1848 1835 1795 1642
(secondary 0.54%)
Clopidogrel 1886 1860 1850 1840 1838 1834 1831 1830 1822 1776 1606 endpoints)

1. Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612; 2. Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612
Supplementary Appendix
 Among patients age <75 years with STEMI,
administration of ticagrelor after fibrinolytic therapy
did not significantly reduce the frequency of
cardiovascular events when compared with clopidogrel
 ESC 2017 Focused Update DAPT in CAD :
Algorithm for switching between oral P2Y12 inhibitors
in ACUTE setting 1

Class I LOE B
Class Iib LOE C

Switch from Clopidogrel to Ticagrelor in Acute Setting is allowed

irrespective of prior clopidogrel timing and dosing (1B)
Reference: 1. Valgimigli M et al. European Heart Journal (2017) 0, 1–48 26
 27
PPK PERKI SKA 2018
 No Reperfusion

www.uptodate.com ©2020 UpToDate COMMIT Study. Lancet 2005;366(9497):1607–1621

BMJ 2011;342:d3527 doi: 10.1136/bmj.d3527
Outline
Antiplatelets in ACS
• The Need
• Choosing
• Sweet Spot
• Certain Populations : Diabetes & Asian
STEMI
• Guidelines ( PPCI, Fibrinolytic, Conservative)
• Evidence
• Switching
NSTE-ACS
• Guidelines (Risk Stratification, Ischemic Driven )
• Evidence
Take Home Messages
• Summary
• Future
 ACS Spectrum

1. Roffi M et al. Eur Heart J 2016;37(3):267-315;

31 2. Ibanez B et al. European Heart Journal 2017; 00; 1–66
 NSTEMI patients remain at high and persistent risk
of CV events post discharge from hospital1

2-year rate of MI, stroke or all-cause mortality in NSTEMI and STEMI

patients ≥65 years of age.

32
Both NSTEMI and STEMI patients are at high risk of recurrent CV events, NSTEMI
is associated with greater long-term risk than STEMI

Vora AN et al. Circ Cardiovasc Qual Outcomes 2016;9:513–522.

 Incidence Trend STEMI vs NSTEMI (1990 -2006)

33
Ruff CT, Braunwald E. Nature Review Cardiology.2011;8: 140-147 European Heart Journal (2020) 00, 179
34
35
European Heart Journal (2016) 37, 267–315
36
European Heart Journal (2020) 00, 179
 In specific clinical scenarios, DAPT duration can
be shortened (<12 months), extended (>12 months), or modified

37
European Heart Journal (2020) 00, 179
European Heart Journal (2020) 00, 179
[10.0 vs. 12.3%; hazard ratio (HR) 0.83; 95% 13.4 vs. 12.6%; HR1.07;95%CI ¼ 0.95–1.19 3.4 vs. 12.6%; HR 1.07;95%CI ¼ 0.95–1.19
confidence interval (CI) ( 0.74–0.93]

In patients with NSTE-ACS, benefit of ticagrelor over clopidogrel

in reducing ischaemic events and total mortality was
consistent with the overall PLATO trial, independent of actually
performed revascularization during the initial 10 days

PLATO : NSTE-ACS Sub Analysis, with/out Revasc40EHJ 2011

 Class of recommendation IB Class of recommendation IIb C

SWITCH in Acute SWITCH in Chronic

European Heart Journal (2020) 00, 179 Reference: Valgimigli M et al. European Heart Journal (2017) 0, 1–48
European Heart Journal (2020) 00, 179
European Heart Journal (2020) 00, 179
Outline
Antiplatelets in ACS
• The Need
• Choosing
• Sweet Spot
• Certain Populations : Diabetes & Asian
STEMI
• Guidelines ( PPCI, Fibrinolytic, Conservative)
• Evidence
• Switching
NSTE-ACS
• Guidelines (Risk Stratification, Ischemic Driven )
• Evidence
Take Home Messages
• Summary
• Future
STEMI
Take Home Messagess
• There is no such one DAPT combination fits all
• The efficacy to prevent CV Events and The safety from bleeding
should always be balanced, both eventually contributes to mortality
• ACS and Diabetes are two clinical entities that represents high
thrombotic burdens, nevertheless they carry substantial risk of
bleeding
• Guideline directed decision making, based on reliable trials, should
always be kept in mind