1. Would you recommend extending DAPT >1 year post-MI?
66 year old man, 78 kg
NSTEMI 1 year ago
80% proximal LAD, multiple 30-40% proximal and mid Circumflex, 30-50% proximal, mid, and distal RCA stenoses; preserved LV function
2nd generation DES placed in the proximal LAD
Discharged on ASA and ticagrelor 90 mg BID
Diabetes mellitus (Type 2)
- On metformin 1 g BID, empagliflozin 10 mg daily → A1C 6.9%
Dyslipidemia
- On atorvastatin 80 mg/day and ezetimibe 10 mg/day → LDL-C 1.6 mmol/L
Moderate renal dysfunction
Creatinine 150 mol/L; eGFR 47 ml/min/1.73m2 (by Cockcroft-Gault),43 ml/min/1.73m2 (by MDRD)
Ramipril 2.5 mg daily at discharge titrated up by family MD to 5 mg/day (for vascular protection)
Would you recommend extending DAPT >1 year post-MI?
Yes No

2. Previous Myocardial Infarction
Mean duration 27 months
~ 36 (5) fewer MIs/Strokes/Vascular Deaths per 1000 patients
(~16 per 1000 per year)
~ 3 excess major extracranial bleeds per 1000 patients
(~1 per 1000 per year)
Antithrombotic Trialists’ Collaboration BMJ 2002;324:71-86

3. CV Death/MI/Stroke CV Death/MI/Stroke RR 0.81 (0.73-0.90)
ACS patients undergoing PCI
Moderate-to-high risk ACS patients (except those receiving fibrinolysis)
CV Death/MI/Stroke
CV Death/MI/Stroke 12 12
12.1
All-cause Mortality:
5.9% vs. 4.5%
HR 0.78 (0.69–0.89); p<0.001
11.7 10 10
9.9
9.2 8 8
RR 0.81 ( )
HR 0.84 ( ) % 6 6
p=0.0004
p=0.0003 4
TIMI Major Bleeding:
1.8% vs. 2.4%, p=0.03
Non-CABG PLATO Bleeding:
3.8% vs. 4.5%, p=0.026 4 2
Clopidogrel (n=6795) 2
Clopidogrel (n=9291)
Prasugrel (n=6813)
Ticagrelor (n=9333) 3 6 9 12 15 3 6 9 12
Months
Months
Wiviott et al N Engl J Med 2007;357:
Wallentin et al N Engl J Med 2009;361:

4. Primary Efficacy Outcome: Time to MI, Stroke, or Cardiovascular Death
Overall Trial Population (N=15,603)
Qualifying CAD, CVD or PAD (n=9,478) 10 10
RRR: 7.1% (95% CI: -4.5%, 17.5%)
p=0.22
RRR: 17.1% (95% CI: 4.4%, 28.1%)
p=0.01
8.8 8
7.3 8
Moderate bleeding (requiring transfusion)
1.3% vs. 2%, p=0.004
7.3
6.8 6 6
Primary outcome event rate (%)
Primary outcome event rate (%) 4 4
The primary efficacy endpoint in CHARISMA was a cluster of the first occurrence of fatal or nonfatal MI, or fatal or nonfatal stroke (of any cause), or cardiovascular death (including haemorrhagic death)
With a median of 28 months of follow-up, the primary event rate was 6.8% in the clopidogrel plus aspirin arm and 7.3% in the placebo plus aspirin arm (p=0.22, relative risk [RR] 0.93, 95% confidence interval [CI] 0.83, 1.05) (Figure 1). This reduction was not statistically significant (p=0.217) 1
The yearly primary outcome events rates were 3.12% and 3.36% for clopidogrel plus ASA vs. placebo plus ASA, respectively
Clopidogrel plus ASA prevented 39 primary events overall during the study follow-up1
The Kaplan-Meier curve of the primary endpoint shows that the curves separate very early after randomization, and continue diverging over time, which indicates a continuous trend in favor of the clopidogrel and ASA treatment arm. 1
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press. 2 2
Placebo + ASA
Clopidogrel + ASA
Placebo + ASA
Clopidogrel + ASA 6 12 18 24 30 6 12 18 24 30
Months since randomization
Months since randomization
Bhatt et al N Engl J Med 2006;354:
Bhatt et al J Am Coll Cardiol 2007;49:1982-8

5. Co-Primary Effectiveness Endpoints/Components
55% of the MI benefit with extended DAPT not related to stent thrombosis
12-30 Months
Largest benefit in stent thrombosis and MACE reductions seen with 1st (vs. 2nd) generation stents
Patients free from ischemic/bleeding events + thieopyridine adherent; 43% post-ACS
Cardiac/Vascular: 1.0% vs. 1.1%; p=0.98
Non-Cardiovascular: 1.0% vs. 0.5%; p=0.002
Numerically higher bleeding-, trauma-, or statistically higher cancer-related (not mutually exclusive) deaths with thienopyridine *
* Major Adverse Cardiovascular and Cerebrovascular Events (Death, MI, or Stroke)
Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:

6. Primary Safety Endpoint GUSTO Moderate or Severe bleeding
12-30 Months
Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:

7. Stable pts ≥50 yrs with MI 1-3 yrs prior
Primary Endpoint
Stable pts ≥50 yrs with MI 1-3 yrs prior
+ tolerating ASA mg/d
+ ≥1 additional atherothrombosis risk factor (age ≥65 yrs, diabetes, 2nd prior MI >1 yr ago, multivessel CAD, CrCl <60 ml/min)
Bonaca et al N Engl J Med 2015;372:

8. Components of Primary Endpoint
All-cause Death:
Placebo 5.2% vs. T % vs. T %
p=NS
Bonaca et al N Engl J Med 2015;372:

9. Primary Endpoint: On-Treatment Analysis
Bonaca et al Circulation 2015;Abstract and JAMA Cardiol 2016;1:425-32

10. Bleeding
Bonaca et al N Engl J Med 2015;372:

11. Events Prevented and Caused
Events Prevented and Caused for 1000 Patients
Initiated on Ticagrelor 60 mg BID and Followed for 3 Years
Bonaca et al J Am Coll Cardiol 2017;70:

12. Primary Endpoint: CV Death/MI/Stroke
Patients Withdrawn from ADP Receptor Inhibition
≤30 Days from Randomization by Treatment
Bonaca et al Eur Heart J 2016;37:

13. Primary Endpoint: CV Death/MI/Stroke
27% RRR
14% RRR
 RRR
P-interaction
Greater benefit in continuation of ADPri therapy without interruption after MI vs. re-initiating in patients who have remained stable for an extended period
Bonaca et al Eur Heart J 2016;37:

14. Efficacy and Safety of Ticagrelor: European Label Subgroup*
PEGASUS-TIMI 54 randomized 21,162 patients →10,779 patients were ≤2 years from qualifying MI or ≤1 year from prior ADP receptor inhibitor treatment* 10
Ticagrelor 60 mg bid, EU label (373/5388)
Placebo, EU label (463/5391)
9.56% 8
7.85%
HR 0.80 (0.70–0.91); p=0.001 6
CV Death:
Placebo 3.6% vs. Ticagrelor 2.6%
HR 0.71 ( ); p=0.004
All-cause Death:
Placebo 5.4% vs. Ticagrelor 4.4%
HR 0.80 ( ); p=0.018
CV Death/MI/Stroke (%) 4 2
180
360
540
720
900
1080
Number at risk (EU*):
Placebo
Ticagrelor 60 mg BID
Days from Randomization
5391
5388
5246
5280
5138
5187
4914
4999
4380
4436
3177
3253
1485
1507
Dellborg et al Eur Heart J 2017;Abstract P3670

15. Ticagrelor* vs. Placebo
Summary of PEGASUS Trial and Subgroup Primary Efficacy Analyses with Ticagrelor 60 mg BID*
Ticagrelor* vs. Placebo
1 Bonaca et al N Engl J Med 2015;372: ; 2 Bonaca et al Eur Heart J 2016;37: ;
3 Dellborg et al Eur Heart J 2017;Abstract P3670

16. PEGASUS* in Context: Statin, ACE Inhibition, Anticoagulation
(Lipid-lowering by 1 mmol/L)1,2
Ramipril (ACE Inhibition; HOPE)3
Rivaroxaban 2.5 mg BID + ASA (COMPASS)4
Ticagrelor 60 mg BID + ASA (PEGASUS)5*
MACE
21%
22%
24%
25%
Death 9%
16%
18%
20%
Stroke
15%
32%
42%
36% MI
14%
1CTT Collaboration Lancet 2015;385: ; 2Collins et al Lancet 2016;388: ; 3HOPE Investigators N Engl J Med 2000;342:145-53; 4Eikelboom et al N Engl J Med 2017;377: ; 5 Bonaca et al Eur Heart J 2016;37: * Post-hoc subgroup analyses vs. placebo (n=6258); patients randomized to ticagrelor 60 mg BID (n=6258) ≤30 days from prior ADP receptor inhibitor treatment

17. Consistency of Benefit
With vs. Without Diabetes
Bonaca et al J Am Coll Cardiol 2016;67:
n=1,143 (5%)
n=20,017
With vs. Without PAD
n=6,806 (32%)
Ticagrelor in DM requiring pharmacological therapy (n=5,960)
ARR 1.9%
3-yr NNT=53
* Ticagrelor 60 mg BID
CV Death: 3.9% vs. 5%
p=0.05
All-Cause Death: 8.2%* vs. 14%
p=0.007
n=14,355
Bhatt et al J Am Coll Cardiol 2016;67:

18. Consistency of Benefit
Renal Dysfunction
Bonaca et al Circulation 2016;in press
n=213
85% ischemic
3-Yr Risk of Stroke
n=4,849 (23%)
n=20,898
Reduced severity of stroke with
Ticagrelor 60 mg BID (p=0.05)
No increase in ICH or fatal bleeding
Magnani et al Eur Heart J 2016;37:400-8

19. Consistency of Benefit
Multivessel Disease (MVD)
12,558 patients (59.4%) had MVD
Coronary Death:
Ticagrelor 60 mg
HR 0.64 ( )
Ticagrelor 90 mg
HR 0.64 ( ) *
* Coronary death, MI, or stent thrombosis
Bansilal et al J Am Coll Cardiol 2018;71:489-96

20. Primary Endpoint – CV Death, MI, or Stroke
Extended Aspirin Risk Ratio
DAPT Alone (95% CI)
Study Events Total Events Total
CHARISMA
PRODIGY
ARCTIC-Int’n
DAPT
DES-LATE
PEGASUS
TOTAL
6.4% %
0.77 ( )
0.91 ( )
0.79 ( )
0.52 ( )
0.85 ( )
0.84 ( )
0.78 ( )
P = 0.001
Extended DAPT Better
Aspirin Alone Better
More Major Bleeding but NO increase in Fatal Bleeding, ICH, non-CV or all-cause death
Pts that presented with, or had a history of, a prior MI
Udell et al Eur Heart J 2016;37: and Can J Cardiol 2015;31:S3

21. Mortality Benefit of Prolonged Dual Antiplatelet Therapy
Patients with Prior Myocardial Infarction
All-Cause Mortality
0.84 ( )
0.92 ( )
0.87 ( )
0.89 ( )
0.89 ( )
P=0.037
Trial
CHARISMA1
TRA2P-TIMI 502
DAPT3
PEGASUS-TIMI 544
TOTAL
Subgroup
MI (n=4,441)
MI (n=17,779)
MI (n=3,576)
60 mg BID (n=14,112)
CV Mortality
0.82 ( )
0.84 ( )
0.67 ( )
0.83 ( )
0.81 ( )
P=0.010
Aspirin + Clopidogrel + Prasugrel /2160=(6.3%)
Aspirin + Clopidogrel + Ticagrelor /2160 (9.4%)
1 Bhatt et al J Am Coll Cardiol 2007;49:1982-8; 2 Scirica et al Lancet 2012;380: ; 3 Yeh et al J Am Coll Cardiol 2015;65: ; 4 Bonaca et al N Engl J Med 2015;372:

22. Fitchett et al Can J Cardiol 2016;32:S15-34

23. Recommendations for Individualizing Duration of DAPT After ACS
At least 1 year unless very high bleeding risk (e.g., recent GI bleed, prior ICH, concomitant anticoagulant) or significant bleeding in first year
Minimum 1-month for BMS or 3 months for 2nd generation DES
If increased risk of bleeding (e.g. age>75, prior stroke/TIA, weight<60kg), 1 year is sufficient
All others extend beyond 1 year, particularly if additional atherothrombotic risk features (e.g., previous MI, multivessel disease, diabetes, PAD, etc.) or high risk angiographic features (e.g., left main or bifurcation stenting)
Ticagrelor 60 mg BID (or clopidogrel 75 mg daily) recommended >1 year
Ongoing (at least annual) assessment of ischemic and bleeding risk
Bagai et al Circulation 2016;133:

24. Mehta et al Can J Cardiol 2018; doi: 10.1016/j.cjca.2017.12.012

25. Mehta et al Can J Cardiol 2018; doi: 10.1016/j.cjca.2017.12.012

26. Mehta et al Can J Cardiol 2018; doi: 10.1016/j.cjca.2017.12.012

27. Mehta et al Can J Cardiol 2018; doi: 10.1016/j.cjca.2017.12.012

28. Mehta et al Can J Cardiol 2018; doi: 10.1016/j.cjca.2017.12.012

29. Would you recommend extending DAPT >1 year post-MI?
66 year old man, 78 kg
NSTEMI 1 year ago
80% proximal LAD, multiple 30-40% proximal and mid Circumflex, 30-50% proximal, mid, and distal RCA stenoses; preserved LV function
2nd generation DES placed in the proximal LAD
Discharged on ASA and ticagrelor 90 mg BID
Diabetes mellitus (Type 2)
- On metformin 1 g BID, empagliflozin 10 mg daily → A1C 6.9%
Dyslipidemia
- On atorvastatin 80 mg/day and ezetimibe 10 mg/day → LDL-C 1.6 mmol/L
Moderate renal dysfunction
Creatinine 150 mol/L; eGFR 47 ml/min/1.73m2 (by Cockcroft-Gault),43 ml/min/1.73m2 (by MDRD)
Ramipril 2.5 mg daily at discharge titrated up by family MD to 5 mg/day (for vascular protection)
Would you recommend extending DAPT >1 year post-MI?
Yes No
→Ticagrelor 60 mg BID