State-of-the-art lecture in the

role of bleeding in
determining DAPT
Prof. Marco Valgimigli
Deputy Chief of Cardiology
Cardiocentro Ticino Institute, EOC
Lugano, Switzerland

27.08.2022
Disclosures
• Grants and/or personal fees from Astra Zeneca, Terumo, Alvimedica/CID,
Abbott Vascular, Daiichi Sankyo, Bayer, CoreFLOW, Idorsia Pharmaceuticals-
Ltd, Universität Basel Department Klinische Forschung, Vifor, Bristol-Myers-
Squib SA, Biotronik, Boston scientific, Medtronic, Vesalio, Novartis, Chiesi,
PhaseBio.
Conventional wisdom: sentences from guidelines

• DAPT duration should be individualized based on

ischemic and bleeding risks

• DAPT duration should be XX long, unless concerns over

bleeding prevail
 The Challenge of treating pts at both high
bleeding and ischemic risks
which risk should I give priory to ?

Proprietary and confidential — do not distribute

 Ischemic and bleeding risks…how do they to intersect each other ?
PARIS risk scores

Long-term
DAPT

? ?
? Short-term
DAPT

J Am Coll Cardiol 2016; 67, 2224

There is risk and risk!

Do we care much the about absolute risk per se?

Or shall we focus on how much of that risk is potentially

modifiable by treatment (e.g. by modulating DAPT duration)?
 PRECISE-DAPT and PCI or Pt complexity

BLEEDING RISK ISCHEMIC RISK

Non-High High Non-High High
Bleeding Risk Bleeding Risk Ischemic Risk Ischemic Risk

Non-High 25 High Non- Complex

PRECISE PRECISE Complex 1 Element
PCI
DAPT PRECISE-DAPT
DAPT PCI Complex
Score SCORE Score PCI / ACS

≥3 stents X
ACS*
X X
Hemoglobin Creat implanted
Clear X 3 vessels
Bifurcation
X X treated
Age WBC stenting
Prior >60mm
≥3 lesions stenting
Bleed CTO
treated

Costa F et al. J Am Coll Cardiol 2019;73(7):741-754.

 Effect of long (12-24m) vs. short (3-6 m) DAPT and
PRECISE-DAPT score in the presence/absence of Complex PCI (alternative definition)

Risk difference for long vs. short DAPT pint

+0.25% p=0.16
Non-HBR

Bleeding
PRECISE-DAPT <25 0.49
(Non-High bleeding risk) +0.01% p=0.98

+3.95%
HBR PRECISE-DAPT ≥25 p=0.004 0.22
(High bleeding risk) +1.78% p=0.12

+0.43%p=0.51
Ischemia

Non-HBR PRECISE-DAPT <25 -3.50% <0.001

(Non-High bleeding risk) p<0.001

PRECISE-DAPT ≥25 +2.28% p=0.22

HBR +1.06% p=0.64
0.68
(High bleeding risk)

+0.70%p=0.31
PRECISE-DAPT <25 -3.45% <0.001
NACE

(Non-High bleeding risk) p<0.001

+4.58%
PRECISE-DAPT ≥25 p=0.03 0.32
(High bleeding risk) +1.37% p=0.56

Non-complex PCI no ACS

–5%–4%–3%–2%–1% 0 +1%+2%+3%+4% +5%
Complex PCI and/or ACS
Long DAPT better Short DAPT better
(% Reduction of events with long DAPT) (% Increase of events with long DAPT)

J Am Coll Cardiol. 2019 Jul 9;74(1):162-163. doi: 10.1016/j.jacc.2019.05.005.

 To sum up…
If HBR…the ischemic risk should not drive longer-
term DAPT duration, as it will not pay back and will
only increase bleeding events
The ischemic risk in HBR pts, even if high, is not modifiable by prolonging DAPT

In non-HBR high ischemic risk patients, long-term

DAPT provides ischemic benefit and an acceptable
bleeding risk
The ischemic risk in non-HBR pts, if high, is modifiable by prolonging DAPT

Proprietary and confidential — do not distribute

 PEGASUS-TIMI 54 Patient Selection: Patient Selection Algorithm
Efficacy and safety evaluated using an algorithm, first excluding patients at high risk of bleeding and then
stratifying by number of high risk features

For medical use only – may contain off label topics

Step 1
PEGASUS-TIMI 54
Assess bleeding risk and exclude patients at
high risk: N=21,162
• Prior hospitalization for bleeding
• Low baseline hemoglobin

High Bleeding Risk

19%

Step 2
Assess number of ischemic risk factors: 0-1 Ischemic Risk Factors
• MI within 2 years or P2Y12 receptor inhibitor 22%
within 1 year
Low Bleeding Risk
• Multi-vessel coronary artery disease
81%
• Diabetes mellitus ≥2 Ischemic Risk Factors
• Peripheral artery disease 59%
• Chronic kidney disease
• Multiple prior MIs
MI = myocardial infarction.
10 Bonaca MP et al. Poster presented at: AHA Scientific Sessions 2018; November 10, 2018; Chicago, IL.
 PEGASUS-TIMI 54 Patient Selection: Primary Endpoint (CV Death, MI or
Stroke) and TIMI Major Bleeding in High Bleeding Risk Group
In the high bleeding risk population, there was no benefit of ticagrelor in reducing the rate of the primary
endpoint, but there was a higher rate of TIMI major bleeding

For medical use only – may contain off label topics

HR 0.99 (95% CI 0.78-1.27)
12 p=0.97*; ARR 0
10.47 10.21
10
Event Rate at 3 years (K-M%)

HR 2.40 (95% CI 1.33-4.33)

6 p=0.0037*; ARI 2.26%

3.95
4

1.69 Ticagrelor 60 mg BID

2
Placebo

0
CV Death, MI or stroke TIMI major bleeding
*Exploratory post-hoc sub-analysis. Findings should be considered hypothesis generating.
ARI = absolute risk increase; ARR = absolute risk reduction; CV = cardiovascular; HR = hazard ratio; K-M = Kaplan Meier; MI = myocardial infarction; TIMI = Thrombolysis
in Myocardial Infarction.
11 Bonaca MP et al. Poster presented at: AHA Scientific Sessions 2018; November 10, 2018; Chicago, IL.
 PEGASUS-TIMI 54 Patient Selection: Primary Endpoint (CV Death, MI or Stroke) and TIMI
Major Bleeding in Low Bleeding Risk Population by Number of Ischemic Risk Factors
The relative benefit of ticagrelor treatment, ARR in ischemic endpoints vs ARI in TIMI major bleeding, varied according to number of
ischemic risk factors present, with greater net benefit observed in patients with low bleeding risk and at least 2 ischemic risk factors

For medical use only – may contain off label topics

12 HR 0.79
(95% CI 0.68-0.92)
12
p=0.0024*; ARR 1.9%
p-interaction = 0.47 9.9 p-interaction = 0.84
10 10

TIMI major bleeding (K-M%)

CV death, MI or stroke (K-

8.0
8 HR 0.88
(95% CI 0.62-1.25)
8
p=0.46*; ARR 0.6%
5.8
M%)

6 5.2 6
4.1 4.0
4 3.5 4 HR 2.18
(95% CI 1.41-3.38)
HR 1.42
p=0.0005*; ARI 1.0%
(95% CI 0.56-3.60)
p=0.46*; ARI 0.3%
2.0
2 2 1.2 0.9 1.0
0.0
0 0
0** 1 ≥2 0** 1 ≥2
n=469 n= 2535 (19%) n= 8231 (59%) n=469 n= 2535 (19%) n= 8231
(3%) Ischemic Risk Factors (3%) Ischemic Risk Factors (59%)
Ticagrelor 60 mg BID Placebo
*Exploratory post-hoc sub-analysis. Findings should be considered hypothesis generating.
**HR and p value not reported.
ARI = absolute risk increase; ARR = absolute risk reduction; CV = cardiovascular; HR = hazard ratio; K-M = Kaplan Meier; MI = myocardial infarction; TIMI = Thrombolysis
in Myocardial Infarction.
12 Bonaca MP et al. Poster presented at: AHA Scientific Sessions 2018; November 10, 2018; Chicago, IL.
 MASTER DAPT Trial
Screened Population: HBR pts, treated exclusively with Ultimaster stent,
with no restriction based on clinical presentation or PCI complexity

Randomization 30 (+14) Days after PCI

and Regimens Free from cardiac and cerebral ischemic events
and active bleeding
No further revascularization planned

Sx: Site
Need for oral anticoagulation
Prior MI within 12 months

Abbreviated DAPT Standard DAPT

Immediate DAPT discontinuation DAPT for ≥ 2 or 5 months in pts with
or without OAC indication, respectively
followed by SAPT for 11 months
or 5 months if OAC is indicated followed by SAPT up to 11 months

HBR: high bleeding risk; DAPT: dual antiplatelet therapy; SAPT: single antiplatelet therapy; MI myocardial infarction: OAC: oral anticoagulation
 ACS at presentation + complex PCI
ACS plus at least one criterion:

3 vessels treated, + Left main stenting

Graft stenting
≥3 stents implanted,

≥3 lesions treated,

Bifurcation with 2 stents implanted,

Total stent length >60 mm,

Chronic total occlusion as target lesion.

Giustino G et al. J Am Coll Cardiol 2016;68(17):1851-1864., Costa F et al. J Am Coll Cardiol 2019;73(7):741-754.
ACS and complex PCI: MASTER DAPT results
 Perceived Risk of Ischemic and Bleeding Events in Acute
Coronary Syndromes

Any bleeding event

n
physician determined: 0.471 (0.426–0.515)

o
ati
Acuity risk score: 0.511 (0.470–0.553)

im
est
er-
Ov
TIMI major/minor bleeding
Over-estimation
physician determined: 0.498 (0.308–0.550)
Acuity risk score: 0.589 (0.487–0.691)
C-statistic for physician determined: 0.652 (0.596–0.708)
C-statistic for GRACE score 0.812 (0.772–0.851) , p<0.001

Chew D, Circ Cardiovasc Qual Outcomes. 2013;6:299-308

DAPT Score: A Decision Tool
For DAPT Duration
Predictors of Predictors of DAPT Score
ischemic bleeding
events events

Predictors of ischemic and bleeding

events (excluded)

Yeh et al. JAMA 2016; 315:1735-49

 PRECISE DAPT score: weight of the single predictors

15 pt 0 pt
100 pts 0 pts
0 pt

25 pts

26 pt

0 pt

0 pts 15 pt
19 pt 0 pt

Costa et al, Lancet 2017; 389: 1025-1034)

 4%

3%
Benefit
Absolute Risk Difference
2%

1%

0%

1%

2%
Ischemia (MI, Def. ST, Stroke, TVR)
Bleeding (TIMI major or minor)
3%
Net Effect

4% Harm
Very Low Low Moderate High
PRECISE DAPT <25 ≥25
Costa et al, Lancet 2017; 389: 1025-1034
 ARC-HBR Criteria for Bleeding Risk
Stratification
ARC-HBR App for
Smartphone

Urban et al. Circulation. 2019;140:240-261.

 ARC –HBR consensus definition

consensus major criterion minor criterion

In isolation, confers: In isolation confers

HBR =
increased bleeding risk,
BARC 3 or 5 bleeding 1) BARC 3 or 5 bleeding
but:
risk of > 4% risk
and/or so… of ≥ 4% at one year and risk of BARC 3 or 5
risk of intracranial bleeding of <4% at one
hemorrhage (ICH) > 1% and/ or year
2 ) risk of ICH of > 1% and
within 1 year after PCI at one year
risk of ICH < 1%

HBR status conferred if: 1 major criterion or 2 minor criteria

 Worldwide Validation of the ARC-HBR Criteria
Among Patients Undergoing PCI

Gargiulo, Esposito. EuroIntervention. 2021 Feb 19;16(14):1126-1128.

 Validation of the ARC-HBR Criteria in the
Bern PCI Registry (n=16,850)
4% BARC 3-5 bleeding

Corpataux, Valgimigli et al. Eur Heart J. 2020;41(38):3743-3749.

 Rates of BARC 3-5 Bleeding at 1 year
according to isolated ARC-HBR Criteria
4% BARC 3-5 bleeding

Corpataux, Valgimigli et al. Eur Heart J. 2020;41(38):3743-3749.

 Sex-Based Differences in Bleeding Risk After
PCI: Implications for the ARC-HBR Criteria

ARC-HBR criteria
modelled
as a risk score

Modified ARC-HBR
criteria: age, creatinine
clearance, and
hemoglobin appraised
as continuous variables

Spirito, Valgimigli et al. J Am Heart Assoc. 2021;10(12):e021965.

 ARC-HBR: pros and cons
PROs
• Captures comorbidity related (liver disease, bleeding diathesis etc) and drug-
related (OAC, CCS, NSAIDs) HBR features unlike the majority of bleeding risk
scores
• No need for score calculation (easy for bedside use)
• HBR is clearly defined based on a bleeding risk threshold
• Based on a contemporary bleeding scale (BARC)

CONs
• Criteria need to be re-weighted
• Dichotomization of continuous into dummy variables leads to less
discrimination >Need for computing a score!
 PRECISE-DAPT and ARC-HBR criteria: Rationale
for Combination into a Comprehensive Risk
Score
PRECISE-DAPT score distribution by ARC-HBR score BARC 3-5 bleeding at 1 year by PRECISE-
in the Bern PCI registry population DAPT score and the ARC-HBR definition

Gragnano, Valgimigli et al. (manuscript in preparation)

 MASTER DAPT Study Design
DAPT stop
No
SAPT ≥ 11 months
Abbreviated Clinical
Patients APT indication
OAC
eligible regimen DAPT stop
following Yes SAPT 5 months
1 month
R Routine
mandatory care
DAPT No DAPT ≥ 5 months
after PCI with SAPT till 11 months
Prolonged Clinical
Ultimaster®
APT indication
OAC
regimen
DAPT ≥ 2 months
Yes
SAPT till 11 months

PCI 1M 1M 3M 6M 12M 15M

Enrolment Follow-up period post PCI
Conclusions
Bleeding assessment should be prioritized over ischemic risk
in the decision for DAPT duration
Ischemic risk should be valued if HBR is low, otherwise it
does not seem to be a treatment modifier (non-modifiable
risk!)
Bleeding risk assessment requires the use of standardized
algorithm.
PRECISE DAPT has been shown to be actionable for deciding
upon DAPT duration and ARC-HBR seems to be a
complementary, potential additive way of assessing risk.
 Thank you

e-mail: marco.valgimigli@eoc.ch

@vlgmrc