Ticagrelor With AspIrin or ALone In HiGH-

Risk Patients After Coronary InTervention

for Acute Coronary Syndrome
TWILIGHT-ACS
Usman Baber, MD MS
on behalf of Roxana Mehran, MD and the TWILIGHT Investigators
Icahn School of Medicine at Mount Sinai, New York, NY
ClinicalTrials.gov Number: NCT02270242
 Disclosures

Affiliation/Financial Relationship Company

Advisory board/personal fees Amgen; AstraZeneca; Boston Scientific

Research Funding to Institution AstraZeneca

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 Background
• The prevailing construct of dual antiplatelet therapy (DAPT) as the preferred
treatment for patients with acute coronary syndromes (ACS) originated from
clinical trials showing that the addition of an oral P2Y12 inhibitor to aspirin
significantly lowers recurrent ischemic events as compared with aspirin alone.1,2

• The benefits, or harms, of maintaining aspirin as a long-term component of DAPT

in the setting of ACS remains unknown, however, as aspirin served as a
background agent in earlier studies.

• Recent studies have suggested that aspirin-free strategies lower bleeding without
increasing ischemic risk as compared with conventional DAPT in select patients
undergoing percutaneous coronary intervention (PCI).3,4,5
1Mehta et al., Lancet 2001; 2Levine et al., JACC 2016; 3Mehran et al., NEJM 2019; 4Watanabe et al., JAMA 2019; 5Hahn et al., JAMA 2019

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 Study Objective

To examine the effect of antiplatelet monotherapy with

ticagrelor alone versus ticagrelor plus aspirin among
patients with non-ST elevation acute coronary syndromes
(NSTE-ACS) undergoing PCI with drug eluting stents who
had already completed a 3-month course of DAPT

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 Study Design
• Randomized, double-blind placebo controlled trial in 187 sites and 11 countries

• High-risk patients underwent PCI and were treated with ticagrelor plus aspirin for 3
months

• Event-free and adherent patients were randomized to aspirin versus placebo and
continued ticagrelor for an additional year

High-Risk PCI Patients

(N=9006) Ticagrelor + Aspirin Standard of Care

ACS= 4614
Ticagrelor + Placebo Standard of Care

Enrollment Period 3M Randomization Period 15 M Observation Period 18 M

3 Months 12 Months 3 Months
 Inclusion/Exclusion Criteria
Must meet at least one clinical AND one angiographic criterion

Clinical criteria Angiographic criteria

Age ≥65 years Multivessel CAD

Female gender Target lesion requiring total stent length >30mm

Troponin positive ACS Thrombotic target lesion

Established vascular disease (previous MI, Bifurcation lesion(s) with Medina X,1,1
documented PAD or CAD/PAD revasc) classification requiring ≥2 stents
DM treated with medications or insulin Left main (≥50%) or proximal LAD (≥70%) lesions

CKD (eGFR <60ml/min/1.73m2 or CrCl <60ml/min) Calcified target lesion(s) requiring atherectomy

Key Exclusions: STEMI; Salvage PCI; need for chronic oral anticoagulation;
planned coronary revascularization
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 TWILIGHT-ACS: Methods
Target Population
Randomized TWILIGHT participants presenting with unstable angina or non-ST elevation MI
(NSTE-ACS)

Endpoints
Primary: BARC 2, 3 or 5 bleeding between 0 - 12 months after randomization
Secondary: Non-fatal MI, stroke or all-cause death between 0 - 12 months after
randomization

Analytic Approach
Survival analyses using the Kaplan-Meier method
Hazard ratios and 95% confidence intervals (CI) generated using Cox regression
Treatment effect examined in relation to number of clinical and angiographic risk factors
Stratified analyses among those with unstable angina or NSTEMI

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 Total Enrolled
(N = 9006)
Excluded (n = 3267)
• Clinical Presentation missing (5)
• Stable Syndrome (3262)
Enrolled with NSTE-ACS
(N = 5739) Not randomized (n = 1125)
• Lost to follow-up (76)
• Adverse events (173)
• DAPT non-adherence (637)
• Consent withdrawal/refusal (158)
• Other reasons (81)
Randomized (N = 4614)
Unstable Angina (n=2494)
NSTEMI (n=2120)

Ticagrelor + Placebo Ticagrelor + Aspirin

(N = 2273) (N = 2341)

10 withdrew consent 16 withdrew consent

27 lost to follow-up 20 lost to follow-up

15 Month Follow-up 15 Month Follow-up

Includes 22 deaths Includes 34 deaths
(N = 2236; 98.4%) (N = 2305; 98.5%)

15 M Vital status 15 M Vital status

(N = 2265; 99.6%) (N = 2332; 99.6%)
TWILIGHT-ACS: Distribution of Pre-Specified Clinical and
Angiographic High-Risk Features
30%
Number of patients 27.5%

25%
21.9%
21.1%
20%

15%

11.3% 11.4%
10%

5% 4.3%

1.0% 1.4%
0.2%
0%
1 2 3 4 5 6 7 8 9

Number of Clinical and Angiographic High-Risk Features

 TWILIGHT-ACS: Patient Characteristics
Baseline Demographics
Tica + Placebo Tica + Aspirin
Variable p-value
(n=2273) (n=2341)
Age, years [Mean ± SD] 64.2 ± 10.5 64.2 ± 10.6 0.99
Female sex 25.5% 24.8% 0.56
Nonwhite race 38.4% 36.5% 0.62
BMI, kg/m2 28.4 ± 5.5 28.4 ± 5.7 0.85
Diabetes Mellitus 35.6% 34.3% 0.36
Insulin requiring 9.7% 10.1% 0.47
NSTEMI 45.1% 46.8% 0.23
Chronic Kidney Disease 14.6% 15.1% 0.68
Anemia 19.9% 19.5% 0.76
Current Smoker 23.3% 26.6% 0.02
Previous MI 25.4% 25.2% 0.83
Previous PCI 34.2% 34.4% 0.91
Previous CABG 8.8% 8.5% 0.68

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 TWILIGHT-ACS: Patient Characteristics
Procedural Details
Tica + Placebo Tica + Aspirin
Variable p-value
(n=2273) (n=2341)
Radial access 76.7% 76.3% 0.78
Multivessel CAD 61.9% 59.5% 0.08
Target vessel
LAD 57.7% 58.4% 0.6
RCA 34.9% 33.9% 0.47
LCX 32.6% 32.9% 0.83
Number of lesions treated 1.5 ± 0.7 1.5 ± 0.7 0.52
Lesion morphology
Thrombus 14.9% 15.4% 0.60
Calcification (Moderate/Severe) 12.0% 11.9% 0.92
Any bifurcation 12.5% 12.6% 0.98
Chronic total occlusion 5.6% 6.1% 0.49
Total stent length 40.5 ± 24.5 39.8 ± 24.6 0.35

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 TWILIGHT-ACS: Adherence by Treatment Allocation
Ticagrelor + Placebo Ticagrelor + Aspirin
100
87.8 86.4
Adherence to medication (%)

83.7 82.9
80

60

40

20

0
Ticagrelor Study Drug

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 TWILIGHT-ACS: BARC 2, 3 or 5
10% Ticagrelor + Placebo
Ticagrelor + Aspirin

Placebo vs Aspirin
7.6%
Cumulative Incidence 8%
HR (95%CI): 0.47 (0.36 to 0.61)
p <0.001
6%

4% 3.6%

2%

0%

0 60 120 180 240 300 360

Days after randomization
Number at risk
Ticagrelor plus Aspirin 2338 2285 2240 2197 2160 2129 2095
Ticagrelor plus Placebo 2269 2238 2215 2190 2159 2142 2130
TWILIGHT-ACS: BARC 2, 3 or 5 in Relation to Risk Factor Burden
Number of Risk One-year rate (%)
Hazard ratio (95% CI)
Factors
T+P T+A

1–3
3.5% 7.0% 0.49 (0.31-0.77)
(n=1579)

4, 5
3.7% 7.3% 0.50 (0.34-0.72) pint = 0.69
(n=2239)

6–9
3.6% 9.4% 0.37 (0.20-0.68)
(n=796)

0.1 1 10

Ticagrelor monotherapy better Ticagrelor monotherapy worse

 TWILIGHT-ACS: Pre-Specified Bleeding Endpoints
4%

Ticagrelor + Placebo Ticagrelor + Aspirin

One-Year Event Rate, %

3%
p < .0001 p = 0.001

2.2%
2.1%
p = 0.002
2%
1.6%
p = 0.08

1.0%
1% 0.9%
0.8%
0.6%
0.5%

0%
BARC 3 or 5 TIMI major GUSTO moderate or severe ISTH major

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 TWILIGHT-ACS: Death, MI or Stroke
10% Ticagrelor + Placebo
Ticagrelor + Aspirin

Placebo vs Aspirin
8%
Cumulative Incidence HR (95%CI): 0.97 (0.74 to 1.28)
p = 0.84
6%

4.4%
4%
4.3%

2%

0%

0 60 120 180 240 300 360

Days after randomization
Number at risk
Ticagrelor plus Aspirin 2338 2208 2292 2169 2242 2223 2201
Ticagrelor plus Placebo 2269 2235 2215 2195 2167 2158 2143
TWILIGHT-ACS: Death, MI or Stroke in Relation to Risk Factor Burden
Number of Risk One-year rate (%)
Hazard ratio (95% CI)
Factors
T+P T+A

1–3
1.9% 3.0% 0.63 (0.33 – 1.22)
(n=1579)

4, 5
4.4% 3.5% 1.27 (0.83 – 1.93) pint = 0.18
(n=2239)

6–9
8.4% 9.8% 0.86 (0.54 – 1.36)
(n=796)

0.1 1 10

Ticagrelor monotherapy better Ticagrelor monotherapy worse

 TWILIGHT-ACS: Pre-specified Ischemic Endpoints
6%
Ticagrelor + Placebo Ticagrelor + Aspirin
One-Year Event Rate, %

p = 0.77

4.2%
4.0%
4% p = 0.99

3.1% 3.1%

p = 0.14
2%
1.5%
p = 0.21 p = 0.38
1.0%
0.5% 0.6%
0.3% 0.4%

0%
CV Death, MI or All-cause Death MI, any Ischemic Stroke Stent thrombosis
Ischemic Stroke (definite/probable)

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 TWILIGHT-ACS: Adjusted Hazards for Death, MI, Stroke
Variable HR (95% CI)

Ticagrelor plus Placebo 1.02 (0.74-1.41)

Age, per year increase 1.01 (0.99-1.03)
Female sex 0.92 (0.62-1.36)
Troponin (+) 1.77 (1.23-2.55)
Established vascular disease 2.77 (1.94-3.97)
Diabetes Mellitus 1.38 (0.99-1.93)
Chronic Kidney Disease 1.35 (0.88-2.06)
Multivessel CAD 1.25 (0.86-1.82)
Lesion requiring stent length > 30 mm 1.30 (0.94-1.81)
Bifurcation requiring 2 stents 1.32 (0.61-2.83)
Atherectomy use 2.46 (1.19-5.1)
Thrombotic lesion 1.09 (0.67-1.77)
Left main or LAD lesion 0.90 (0.61-1.34)
BARC type 3 or 5 Bleeding (time-updated covariate) 6.7 (3.1-14.6)
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TWILIGHT-ACS: Stratified Analysis According to UA or NSTEMI
Ticagrelor + Placebo Ticagrelor + Aspirin
pint = 0.90
9% 9%
HR (95% CI) 0.47 (0.33-0.68) HR (95% CI) 0.46 (0.31-0.67)
pint = 0.33

HR (95% CI) 1.13 (0.75-1.68) HR (95% CI) 0.85 (0.58-1.26)

6% 6%

3% 3%

0% 0%
UA NSTEMI UA NSTEMI
BARC 2, 3 or 5 Death, MI or Stroke
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 Limitations
• Extrapolating results to STEMI patients not possible given trial design.

• Generalizing to broader population of PCI patients without high-risk

features pre-specified in TWILIGHT is limited.

• Use of ticagrelor as background antiplatelet agent thereby precluding

inference for other P2Y12 inhibitors.

• Lack of power to detect differences in the risk of important yet rare

clinical events, such as stent thrombosis and stroke.

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 Conclusions
• Among patients with NSTE-ACS undergoing PCI with DES and who have completed
a 3-month course of DAPT with ticagrelor plus aspirin, continued treatment with
ticagrelor alone significantly lowers clinically relevant and major bleeding without
increasing risk for ischemic events over one year.

• The effect of ticagrelor monotherapy with respect to bleeding and ischemic events is
uniform across different levels of risk.

• Results are unchanged for patients presenting with UA or NSTEMI.

• Overall findings are concordant with the results of the primary trial.

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 Acknowledgement

We thank all country leaders,

investigators, coordinators and study
participants who made TWILIGHT
possible!

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 Thank you!

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