Managing High Bleeding Risk patients with short DAPTtsc2019.tamduchearthospital.com/pdf/p1/105-tam-duc-high-bleeding … · Managing High Bleeding Risk patients with short DAPT DR

The 16th Malaysian Cardiovascular Interventional

Symposium with Live Transmission

25th – 27th July 2019, Sheraton Petaling Jaya

Managing High Bleeding Risk patients with

short DAPT

DR AL FAZIR OMAR MBCHB FNHAM FAsCC FSCAI

CONSULTANT CARDIOLOGIST GLENEAGLES KUALA LUMPUR




I will start my last slide as my first slide

• How long would you keep his DAPT

– 1 month

– 3 months

– 12 months

– >12 months




• 67 yrs

• Diabetes Mellitus

• ESKD – Renal replacement therapy

• IHD




• IHD – PCI RCA in Jan 2013 – CTO LAD – told to manage medically unless

symptomatic as very complex and then patient defaulted

– Multiple NSTEMI since end of last year with deteriorating LV function

– Recent admission with NSTEMI 7/5/2019 with Trop T 1500




24th May 2019

• Admitted with drowsiness, weak, hypotensive

• Right middle zone/ lower zone pneumonia

• IV meropenem / IV insulin / IV Norad







ECG










• LVDD 6.4cm • LVSD 5.3cm • IVSD 1.4cm

• LV severely reduced • Simpson 23% Visual EF 30% • Mild moderate MR




Called by a colleague May 2019 to discuss about revascularization




Code Blue in HDU during dialysis




Discussed with hematologist Dr Jay Suria – started hydrocortisone plus Eltrombopag 50mg od for ITP













What is the plan?

• Issues:

• Low platelets

• However, becoming hemodynamically unstable

• Complex anatomy




• Duration of DAPT ?

DAPT Duration:

It’s all about balance

Ischemic

events Bleeding

MI Stroke ST

Death Death

GI Access ICH

Study

Year

Randomization

DAPT

duratio

n

median

Primary

Endpoin

t* Exp

Arm

Primary

Endpoin

t* Cnt

Arm

(PCI-) ASA/Clopidogrel x12m

CURE 2001 vs. 9 mo 4.5% 6.4%

(n=2658) ASA/Clopidogrel x1m

+ ASA alone x11m

TRITON ASA/Prasugrel

(n=13,608) 2007 vs. 14 mo 9.9% 12.1%

ASA/Clopidogrel

PLATO ASA/Ticacrelor

(n=18,624) 2009 vs. 9 mo 9.8% 11.7%

ASA/Clopidogrel

12-Month DAPT Duration After PCI with

Stents: What is the evidence? 3 RCTs in ACS

*CVD, MI or urgTVR in PCI-CURE; CVD, MI or stroke in TRITON and PLATO

Why Short DAPT? The high bleeding risk pt

Elderly

Rx with OAC or NOAC

Previous bleeding

Anemia or other

hematologic disorders

Coagulation disorders

Chronic Rx with

steroids or NSAIDs

Renal dysfunction

Bleeding

Risk Factors

VKA NOACs

PCI-CURE BMS (n=2658)

STOPDAPT-2 (n=3009)

SENIOR (n=1200)

SMART-CHOICE (n=2993)

REDUCE (n=1496)

RESET (n=2117)

OPTIMIZE (n=3119) IVUS-XPL (n=1400)

SECURITY (n=1399)

EXCELLENT (n=1443)

ISAR-SAFE (n=4000) I LOVE IT 2 (n=1829)

OPTIMA-C (n=1367)

SMART-DATE (n=2712)

NIPPON (n=3307)

ITALIC (n=1850)

PRODIGY (n=2014)

ARCTIC-Interruption (n=1259) DAPT BMS (n=1687)

DAPT DES (n=9961)

DES Late (n=5045)

OPTIDUAL (n=1385)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Months after PCI

22 RCTs of DAPT Duration after DES/BMS Timing of SAPT vs. DAPT

*1 vs. 12 mo in SIHD; 6 vs. 12 mo in ACS; **Primary endpoint at 12 mo

**

57,250 randomized pts!

*

Network Meta-analysis of Short (≤6 mo) vs. Standard

(12 mo) vs. Long (≥12 mo) Duration DAPT After DES

17 RCTs and 46,864 Pts

Yin SHL et al.

BMJ 2019;365:l2222

Short DAPT

(3-6 mo; n=13,234)

Standard DAPT

(12 mo; n=18,473)

Long DAPT

(>12 mo; n=15,157)

3-6 mo vs >12 mo

• Greater MI and ST

• Less bleeding and

non-cardiac death

• No ∆ in cardiac or

all-cause death

3-6 mo vs 12 mo

• Less bleeding

• No ∆ in MI, ST,

non-cardiac,

cardiac or all-cause

death

Odds ratio

(95% CI)

DAPT duration comparisons

>12 mo vs 3-6 mo

All cause mortality

Cardiac death Non-cardiac death

Major bleeding

Any bleeding

MI

Definite or probable stent thrombosis

Odds ratio

(95% CI)

1.18 (0.93 to 1.49)

1.28 (0.88 to 1.86)

1.63 (1.03 to 2.59)

1.78 (1.27 to 2.49)

2.13 (1.46 to 3.10)

0.63 (0.46 to 0.86)

0.57 (0.34 to 0.95)

1.08 (0.77 to 1.51)

0.88 (0.67 to 1.15) Stroke

Net adverse clinical events

12 mo vs 3-6 mo

All cause mortality

Cardiac death

Non-cardiac death

Major bleeding

Any bleeding

MI

Definite or probable stent thrombosis

Stroke

Net adverse clinical events

1.08 (0.82 to 1.43)

1.12 (0.80 to 1.58)

1.09 (0.67 to 1.77)

1.28 (0.91 to 1.80)

1.39 (1.01 to 1.92)

0.92 (0.70 to 1.21)

0.98 (0.59 to 1.64)

1.04 (0.74 to 1.47)

0.91 (0.77 to 1.08)

0.2 0.4 0.8 1 Favors longer duration

1.6 3.2 5 Favors shorter duration

Utility of Risk

Scores

Short-term

1 vs. 3 vs. 6 vs. 12 months

Long-term

1 year vs. longer

Key Factors That Affect

Optimal DAPT Duration after PCI

Risk Scores for DAPT Duration

Capodanno D et al. Lancet 2017;389:987-9

Score

Setting

Predicted

outcome(s)

Developme nt

cohort (design,

pts)

Number of

variables in the

risk score

Validation cohort(s) (c-

index, pts)

DAPT

PCI patients on

DAPT who were

event- free at 12

months

Ischemia and

bleeding

between 12

and 30 months

after PCI

RCT

(N=11,648)

Ischemia: 8

clinical and

procedural

Major

bleeding: 1

clinical

0.64 for ischemia

0.64 for bleeding

(N=8,136)

PARIS

PCI patients on

DAPT at

discharge

Ischemia and

bleeding at 24

months after PCI

Multicenter

registry

(N=4,190)

Ischemia: 6

clinical

Major

bleeding: 6

clinical

0.65 for ischemia

0.64 for bleeding

(N=8,665)

PRECIS

E-DAPT

PCI patients on

DAPT at

discharge

Bleeding at 12

months after PCI

Pooled RCTs

(N=14,963)

5 clinical

0.70 for bleeding

(N=8,595)

0.66 for bleeding

(N=6,172)

DAPT Trial: Continued Thienopyridine vs.

Placebo According to High vs. Low DAPT Score

-0,66%

0,92%

-3,02%

0,37%

-2,70%

-4,0%

-3,0%

-2,0%

-1,0%

0,0%

1,0%

2,0%

3,0%

4,0%

DAPT Score < 2

DAPT Score ≥ 2

ST or MI

NNT NNT

153 34

GUSTO mod/sev bleed Net adverse events

NNH NNH NNH NNT

109 37

P<0.001

64 272

P=0.02

1,55%

P<0.001

Ris

k D

iffere

nce (

Co

ntinued T

hie

nopyri

din

e

– P

lacebo

), 1

2-3

0M

Yeh R et al. JAMA. 2016;315:1735-1749

Yeh R et al. JAMA 2016;315:1735-1749

Pa

tie

nts

, %

7 8 9 10

30

25

20

15

10

5

0

Clinical Prediction Score

Variable Points

Age, years

≥75 -2

65-<75 -1

<65 0

Cigarette smoking 1

Diabetes mellitus 1

MI at presentation 1

Prior PCI or prior MI 1

Paclitaxel-eluting

stent

1

Stent diameter <3 mm 1

CHF or LVEF <30% 2

Vein graft stent 2

Total score range: -2 to 10

1 2 3 4 5 6

Clinical Prediction Score

-2 -1 0

DAPT Score: Multivariable prediction models unified

into a single integer score to predict clinical benefit

- N = 11,648 -

Prior

bleed

WBC

Age

CrCl

0 pt

26 pt

0 pt

15 pt

0 pt

0 pts

19 pt

25 pts

0 pt Hgb

15 pt

100 pts 0 pts

Costa F et al. Lancet 2017;389:1025-34

PRECISE-DAPT Score: Post-discharge

bleeding risk prediction model (n=14,963) multiple RCTs

PRECISE-DAPT Score: Post-discharge

bleeding risk prediction model (n=14,963)

Very low

Bleeding score quartiles

# o

f P

ati

en

ts

1-Y

ear B

lee

din

g R

isk

(%)

TIMI major o(rC mindienx o= 0r.7b1)leeding (C index = 0.73)

TIMI major bleeding

>4.15

3.85

2.67

1.84

1.27

0.88

0.60 0.42

0.26 0.37 0.51

0.71

0.99

1.38

>2.05

1.93

700

525

350

175

0 0 5 10 15 20

Low Mod

25 30

High

35 ≥36 0

1

2

3

4

5 Risk factors and score

derivation 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Points

≤90

Creatinine clearance (mL/min)

20 0

≥12.0 11.5 11.0 10.5 ≤10.0

Hemoglobin (g/dL)

≤5 8 10 12 14 16 18 ≥20

White blood cell (x103 cells per µL)

≥50 60 70 80

Age (years)

≥100 80 60 40

Previous Bleed

No Yes

Costa F et al. Lancet 2017;389:1025-34

PRECISE-DAPT SCORE

Calculation

July 23, 2019, 4:24 pm

Patient ID number: Stent implanted (type): DES

Stent implanted (brand):

Total number of stent implanted: 3

Intended DAPT duration: 6

Antiplatelet agents implemented: ASA+Clopidogrel

Did score calculation change

your treatment duration strategy? Yes

Haemoglobin value 11.3 (g/dl)

Age 63 (years)

White blood cell count 9.1 (units/mcL)

Creatinine clearance 15 (ml/min)

Prior Bleeding No

PRECISE-DAPT Score 33

Risk category High

DISCLAIMER

This risk scoring tool is intended for use by clinicians, in conjunction with individual patient assessment.

We assume no responsibility for how you use or interpret the PRECISE-DAPT score or any other information provided on this website.

ACS (troponin +)

vs. Stable CAD









Stent Type



Extended Duration DAPT After DES:

Second vs. First Generation DES

Giustino G et al. JACC 2015;65:1298–310

Stent Thrombosis Trial Name

Shorter DAPT Better Longer DAPT Better

Subtotal heterogeneity; p=0.21

Odds Ratio (95% CI)

Overall

Pint = 0.008

1

Second Generation DES

DAPT

ITALIC

SECURITY

PRODIGY

EXCELLENT

OPTIMIZE

First Generation DES

DAPT

PRODIGY EXCELLENT

Subtotal heterogeneity; p=0.59

2.64 (1.17, 5.98)

7.01 (0.36, 135.86)

0.70 (0.12, 4.20)

0.25 (0.03, 2.25)

3.01 (0.31, 28.99)

1.08 (0.49, 2.37)

1.54 (0.96, 2.47)

4.44 (2.22, 8.87)

2.30 (0.70, 7.56)

7.12 (0.37, 138.77)

3.94 (2.20, 7.05)

2.33 (1.63, 3.34)

DAPT Duration According to Ds Complexity Individual patient data meta-analysis comparing short-term (3 or 6 months) vs. long-term

(≥12 mo) DAPT from 6 RCTs; 9,577 randomized pts; 1,680 (17.5%) underwent complex

PCI (3 vessels or ≥3 lesions treated or ≥3 stents implanted or total stent length >60 mm

or 2-stent bifurcation or CTO). Median 392 day FU.

Impact of DAPT duration on MACE (CD, MI or ST):

0

No. at risk

0

90 180

Days After Procedure

270 360

Non-complex PCI – Short DAPT 3938 3875 3816 3782 3511

Non-complex PCI – Long DAPT 3932 3874 3824 3794 3520

Complex PCI – Short DAPT 802 777 768 759 668

Complex PCI – Long DAPT 840 816 805 796 693

Non-complex PCI –

Short DAPT

Non-complex PCI –

Long DAPT

Complex PCI –

Short DAPT

Complex PCI –

Long DAPT

MA

CE

(%

)

2

4

6

8

10

Complex PCI

Non-complex PCI

Long

DAPT

2.8%

2.0%

Short

DAPT

4.4%

2.0%

Adjusted HR

∆ (95% CI)

-1.6% 0.56 (0.35-0.89)

+0.0% 1.01 (0.75-1.35) int

Giustino G et al. JACC 2016;68:1851-64

P =0.01

2000 patients*

Up to 90 global sites

1:1 randomization

1m

o

2mo 6 mo 1 yr 2 yr

Prospective, multicenter, single-blind

randomized trial in high bleeding-risk

patients undergoing PCI*

Resolute ONYX DES

with 1-month DAPT

(N=1000)

BioFreedom DCS with

1-month DAPT

(N=1000)

Onyx ONE Global RCT Short-Term (1-Month) DAPT

*Pts with ACS and stable angina undergoing PCI who are at increased risk of bleeding

or in whom DAPT >1 month is undesirable (criteria similar to LEADERS FREE)

Antiplatelet Therapy: DAPT for 1 month, SAPT after 1 month

Follow-up:

Primary endpoint: Composite of cardiac death, MI or stent thrombosis (def/prob) at 1 year

Major secondary endpoint (powered): Target lesion failure at 1 year

Other secondary endpoints: Acute procedural, device and lesion success; BARC bleeding;

target vessel failure; all death, MI, stroke, revascularizations, TLF and MACE at all timepoints

Principal Investigator: Stephan Windecker

Co-principal Investigators: Elvin Kedhi and Azeem Latib Study Chair: Gregg W. Stone

Sponsor: Medtronic







© AstraZeneca 2019

TWILIGHT

Ticagrelor With aspIrin or aLone In hiGH-risk patients after coronary inTervention

© AstraZeneca 2019

TWILIGHT: Study Design Overview1

cOther secondary ischemic endpoints included time to first occurrence of: (i) CV death, non-fatal MI, ischemic stroke or clinically-driven revascularization; (ii) CV death, non-fatal MI or ischemic stroke; (iii) definite or probable stent thrombosis; (iv) CV death.

1. Baber U et al. Am Heart J. 2016;182:125-134; 2. Mehran R et al. Online ahead of print. N Engl J Med. 2019.

Primary composite endpoint (ITT): Clinically relevant (BARC type 2, 3, or 5) bleeding during months 3-15 Key secondary endpoint (per protocol): Composite of all-cause death, non-fatal MI, stroke during months 3-15c

aHigh-risk patients must meet ≥1 criteria from both clinical and angiographic criteria (Inclusion criteria):

• Clinical: ≥65 years of age, female, troponin positive ACS, established vascular disease (previous MI, documented PAD or CAD/PAD revascularization),

DM treated with medications, CKD (eGFR <60 mL/min/1.73 m2 or CrCl <60 mLmin)

• Angiographic: multivessel CAD, target lesion total stent length >30 mm, thrombotic target lesion, bifurcation lesions with Medina X, 1, 1 classification requiring ≥2 stents, left main ≥50%

or proximal LAD ≥70% lesion, calcified target lesion requiring atherectomy

Open-label ticagrelor; double-blinded ASA or placebo

Ticagrelor 90 mg BID + PBO

Ticagrelor Monotherapy

(Ticagrelor 90 mg BID

+ Placebo)

Standard of care therapy at

the discretion of treating

physician

Observation period Open-label after index PCI

Ticagrelor 90 mg

BID + ASA 81-100

mg QD

Randomized if event-

freeb and adherent

(N=7119)2

Enrollment

(N=9006)2

Ticagrelor DAPT

(Ticagrelor 90 mg BID

+ ASA 81-100 mg QD)

High-riska

patients aged

≥18 years

undergoing

PCI with

≥1 DES

placement

15 mo 18 mo 3 mo

42

bEvent-free if none of the following:

• Major bleeding (BARC type 3b); ischemic event after PCI (eg, non-fatal MI, definite or probable stent thrombosis, ischemic stroke, coronary revascularization with DES); no longer

taking DAPT with ticagrelor + ASA; non physician-guided cessation of ASA or ticagrelor of 5 consecutive days; current indication for oral anticoagulation or high dose ASA; renal failure

requiring dialysis; woman of child bearing potential; refusal of randomization by patient or treating physician; withdrawal of consent; lost to follow-up

Exclusion Criteria

© AstraZeneca 2019

TWILIGHT: Primary Endpoint1

43

Note: The primary endpoint analysis was performed in the ITT cohort, including those who were successfully randomized at the 3-month visit.2

1. Mehran R et al. Online ahead of print. N Engl J Med. 2019; 2. Baber U et al. Am Heart J. 2016;182:125-134.

0

2

4

6

8

10

3555 3474 3424 3366 3321 Ticagrelor Monotherapy

3564 3454 3357 3277 3213 Ticagrelor DAPT

Number at risk

0 3 6 9 12

BARC 2, 3 or 5 Bleeding

Monotherapy vs. DAPT

HR 0.56 (95% CI 0.45-0.68)

p<0.001

Cu

mu

lati

ve In

cid

en

ce (

%)

Months Since Randomization

Ticagrelor Monotherapy 4.0%

Ticagrelor DAPT 7.1%

Definitions of BARC Bleeding

© AstraZeneca 2019

Note: The key secondary endpoint was performed in the per protocol cohort, including those who were randomized and completed all study-related contacts without any major protocol deviations.2 aNon-inferiority was tested at a one-sided alpha level of 0.025 using 1.6% as the absolute upper limit of the 95% CI.2

1. Mehran R et al. Online ahead of print. N Engl J Med. 2019; 2. Baber U et al. Am Heart J. 2016;182:125-134.

TWILIGHT: Key Secondary Endpoint1

44

Cu

mu

lati

ve

In

cid

en

ce

(%

)

0

2

4

6

8

10

0 3 6 9 12

Ticagrelor Monotherapy: 3.9%

Ticagrelor DAPT: 3.9%

Composite of All-Cause Death, MI or Stroke

Monotherapy vs. DAPT

HR 0.99 (95% CI 0.78-1.25)

Non-inferiority p<0.001a

3524 3457 3412 3365 3330

3515 3466 3415 3361 3320

Ticagrelor Monotherapy

Ticagrelor DAPT

Number at risk Months Since Randomization




GAIA 2 changes to Conquest PRO










Multiple predilatation balloons 1.0, 1.5, 2.0, 2.5 NSE Balloon 2.5, 3.0 NC balloons 3.0, 3.5 Used Guide extension










3 DES ONYX 2.75mmx26 ONYX 3.5x38mm ONYX 3.5x38mm

DAPT Duration: Factors to be weighed

HIGH

ISCHEMIC RISK

•High-risk ACS

•Recurrent ischemic events on DAPT

•Peripheral vascular disease

•Prior MI

•Diabetes

•Chronic renal dysfunction

•Complex/multivessel CAD

•Stent-related factors (multiple stents, overlapping stents,

long stents, small-sized stents,

double stents in bifurcations)

•First generation DES

PCI with DES

HIGH

BLEEDING

RISK

LOW

ISCHEMIC

RISK

•Clinically significant bleeding

on DAPT

•Bleeding diathesis

•Prior bleeding

•Female gender

•Elderly

•Liver disease

•Chronic renal dysfunction

•Anemia or thrombocytopenia

•Chronic anticoagulation therapy

•Diabetes

•Second generation DES

• Stable CAD

• Troponin negative ACS

• Single vessel disease

• Simple stenting

(single, short, large stent)

INTERMEDIATE

ISCHEMIC RISK

•Troponin positive ACS

Favors 3 or 6-month DAPT Favors 1-year DAPT Favors >1-year DAPT

When assessing ischemic and bleeding risk, clinical presentation (ACS vs SIHD),

age, disease/PCI complexity and stent type are important factors to consider

Palmerini T and Stone GW. Eur Heart J 2016;37:353-64




Recently seen 12th July 2019

• Tolerating dialysis well

• Current platelets 200 (eltrombopag 50mg od)

• Still on DAPT – 2 months now




I will start my last slide as my first slide

• How long would you keep his DAPT

– 1 month

– 3 months

– 12 months

– >12 months




Thank you




Documents

Managing High Bleeding Risk patients with short DAPTtsc2019.tamduchearthospital.com/pdf/p1/105-tam-duc-high-bleeding … · Managing High Bleeding Risk patients with short DAPT DR