Optimal Duration of Dual Antiplatelet...

Luis A Guzman, MD, FACC, FSCAI

Associate Professor of Medicine

Director, Cardiac and Vascular Cath Lab

University of Florida College of Medicine - Jacksonville

Optimal Duration of Dual Antiplatelet

Therapy

Current Controversies on DAPT in PCI

• Which drug?

• When to start?

• Which dose?

• How long?

Is shorter DAPT better?

• Less bleeding

• Less cost

• Current DES are safer than I

generation DES

• Many patients do fine with short DAPT

duration

After PCI, aspirin should be continued indefinitely.

The duration of P2Y12 inhibitor therapy after stent implantation

should generally be as follows:

a) In patients receiving a stent (BMS or DES) during PCI for ACS,

P2Y12 inhibitor therapy should be given for at least 12 months

(clopidogrel 75 mg daily); prasugrel 10 mg daily; and ticagrelor

90 mg twice daily.

b) In patients receiving a DES for a non–ACS indication,

clopidogrel 75 mg daily should be given for at least 12 months

if patients are not at high risk of bleeding.

c) In patients receiving a BMS for a non-ACS indication,

clopidogrel should be given for a minimum of 1 month and

ideally up to 12 months (unless the patient is at increased risk

of bleeding; then it should be given for a minimum of 2 weeks).

Postprocedural Antiplatelet Therapy

I IIa IIb III

I IIa IIb III

2011 ACCF/AHA/SCAI Guideline for PCI

DES and Prolonged DAPT

What are we treating?

The patient or the stent?

NSTE-ACS: Evidence for Clopidogrel Use

0

2

4

6

8

10

12

14

Death

, M

I, o

r S

tro

ke (

%)

Clopidogrel

+ ASA

3 6 9

Placebo

+ ASA

Months of Follow Up

11.4%

9.3%

20% RRR

P<0.001

0 12

CURE Primary Results (N=12,562)

NSTE-ACS = non-ST segment elevation-acute coronary syndrome. RRR = relative risk ratio.

Yusuf S, et al. N Engl J Med. 2001;345:494-502.

TRITON TIMI 38 (prasugrel vs clopidogrel)

PLATO

(ticagrelor vs clopidogrel)

TRITON TIMI 38 (prasugrel vs clopidogrel)

PLATO

(ticagrelor vs clopidogrel)

DES and Prolonged DAPT

In the setting of ACS (across the spectrum: UA, NSTEMI, STEMI) dual antiplatelet

therapy with aspirin and a P2Y12 receptor inhibitor is the standard of care irrespective

of management (medical therapy, percutaneous revascularization with

POBA/BMS/DES, surgical revascularization)

Guideline recommendations since 2002 based on

robust large scale clinical trial data.

Little room to debate shorter duration of DAPT in DES

treated patients with ACS.

DES and Prolonged DAPT

What are we treating?

The patient or the stent?

Incidence, Predictors, and Outcome of Thrombosis

After Successful Implantation of Drug-Eluding Stents

Univariate Predictors of Cumulative Stent Thrombosis

Iakovou, I, et al. JAMA. 2005;293:2126-30.

0 10 20 30 40

Incidence of Stent Thrombosis

Premature Antiplatelet Therapy Discontinuation

Prior Brachytherapy

Renal Failure

Bifurcation with 2 Stents

Bifurcation Lesion

Unprotected Left Main Artery

Diabetes

Hazard Ratio for ATP Discontinuation = 89

Basket Late

Pfisterer et al. JACC 2006

Duke registry

Eisenstein et al. JAMA 2007

Challenging the guidelines

Duration of dual antiplatelet therapy is:

Too long!

Not long enough!

DES and Prolonged DAPT

Are we overreacting to ST data from first generation DES?

Does DES type make a difference on duration on DAPT?

1st vs 2nd

DES

Thin strut BMS, thick BMS, and drug-eluting stent (XIENCE V)

Kolandaivelu K et al. Circulation 2011;123:1400-1409

Relative ex vivo Thrombogenicity between

Different Stent Designs

Single Stent Overlapping Stent

Palmerini et al. Lancet 2012;379:1393-402

Stent Thrombosis Network Meta-

analysis

Palmerini et al. Lancet 2012;379:1393-402

Stent Thrombosis Network Meta-

analysis

Palmerini et al. Lancet 2012;379:1393-402

Stent Thrombosis Network Meta-

analysis

PRODIGY Study Design

Valgimigli M et al, Circulation. 2012;125:2015-26

1,970 patients with BMS, ZES,

PES, EES (1:1:1:1)

Short-term of DAPT

6 months*

Long-term of DAPT

24 months

24 months of follow up after randomization

Primary Endpoint: Composite of death, myocardial infarction,

cerebrovascular accidents

R

30 days of DAPT

6 months vs 24 months

*<6 months clopidogrel was allowed in BMS pts with stable CAD at the time of PCI

OPTIMIZE Study Design

Feres F et al, JAMA. 2013;

3.119 patients with, ZES

Short-term of DAPT

3 months*

Long-term of DAPT

12 months

12 months of follow up after randomization

Primary Endpoint: Composite of death, myocardial infarction,

cerebrovascular accidents

R

3 months vs 12 months

*<6 months clopidogrel was allowed in BMS pts with stable CAD at the time of PCI

SECURITY Study Design

Colombo A et al, TCT 2014

1,399 patients

with 2 nd generation DES

Short-term of DAPT

6 months

Long-term of DAPT

12 months

24 months of follow up after randomization

Primary Endpoint: Composite of death, myocardial infarction,

cerebrovascular accidents

R

6 months vs 12 months

Courtesy Dr Tullio Palmereni

Can we consider these data

conclusive? Open label trials

Underpowered for ischemic events

Randomization performed at the time of PCI and not at the time of platelet discontinuation

Inclusion of discordant endpoint in the PE

May apply to low risk patients

Different DES included

…but they point all to the

same direction!

With Second Generation DES

3-6 months appears to be sufficient

Challenging the guidelines

Duration of dual antiplatelet therapy is:

Too long!

Not long enough!

Stone et al. N Engl J Med. 2011;364:226-35

Arguments for DAPT prolongation:

Benefits of prolonging DAPT could be other than stent related

MA

CE

(%

)

Time in Years 0 1 2 3

All

Culprit lesion (CL) related

Non culprit lesion (NCL) related

Indeterminate

0

5

10

15

20

25

12.9%

20.4%

11.6%

2.7%

18 mo 12 mo

Dual Antiplatelet Therapy (DAPT) Study

50% of patients continue on

dual antiplatelet therapy

(clopidogrel or prasugrel)

50% of patients receive

aspirin + placebo

Total 33-month patient evaluation including additional 3-month follow-up

All patients on

aspirin + open-label

thienopyridine

therapy for

12 months

DES

n=15,245

BMS

n=5400 1:1 Randomization

at month 12

PCI and the Need for oral Anticoagulation

The Triple Therapy Dilemma

The US perspective

Faxon D, et al. Circ Cardiovasc Interv. 2011;4:522-534

Low ST

and

Bleeding

Risk

High ST

and low

Bleeding

Risk

Any ST and

High

Bleeding

Risk

BMS –Triple Tx

for 1 months

OAC + 1 AP for

12 months

DES –Triple Tx

for 6 months

OAC + 1 AP

for 12 months

BMS –Triple

Tx for 6

months

OAC + 1 AP

for 12 months

DES –Triple

Tx for 12

months

BMS –Triple

Tx for 1

months

OAC + 1 AP

for 12 months

NO

DES

After 12 months. Single OAC

The US perspective

Faxon D, et al. Circ Cardiovasc Interv. 2011;4:522-534

Low ST

and

Bleeding

Risk

High ST

and low

Bleeding

Risk

Any ST and

High

Bleeding

Risk

DES –Triple Tx

for 6 months

OAC + 1 AP

for 12 months

DES –Triple

Tx for 12

months NO DES

After 12 months. Single OAC

North American Consensus Statement Regarding Antithrombotic Therapy in AF

Requiring Stent (2011)

• Aspirin in a dose < 100 mg daily

• Clopidogrel is preferred in combination with

aspirin and warfarin

• Prasugrel or Ticagrelor are not recommended

• Warfarin adjusted to 2.0-2.5 INR

• Not unreasonable to use Dabigatran in place of

warfarin based on PETRO trial

Faxon D, et al. Circ Cardiovasc Interv. 2011;4:522-534

100

90

80

70

60

50

0 200 300 450 600

%

Dual therapy

Triple therapy (INR: 2.0-2.5)

95.1 %

95.1 %

Days

Ble

ed

ing e

ve

nt fr

ee

su

rviv

al

Triple therapy (INR > 2.5)

66.7 %

†

‡

† Log Rank, p<0.0001 vs dual therapy

‡ Log Rank, p<0.0001 vs triple therapy (INR: 2.0-2.5)

Rossini & Angiolillo, Am J Cardiol. 2008;102:1618-23

Bleeding risk in PCI patients on dual antiplatelet

therapy requiring oral anticoagulation

Risk of Bleeding with Single, Dual, or Triple

Therapy With Warfarin, Aspirin, and Clopidogrel in

Patients With Atrial Fibrillation: Risk of nonfatal (n = 12 191) and fatal (n = 1381) bleeding

Hansen et al. Arch Intern Med. 2010;170(16):1433-1441.

Risk of Stroke with Single, Dual, or Triple Therapy

With Warfarin, Aspirin, and Clopidogrel in Patients

With Atrial Fibrillation: Risk of nonfatal (n = 9785) and fatal (n = 3537) ischemic stroke

Hansen et al. Arch Intern Med. 2010;170(16):1433-1441.

Warfarin

Dabigatran

150 mg

Dabigatran

110 mg

No APT

SAPT

DAPT No APT

SAPT

DAPT

No APT

SAPT

DAPT

Major Bleeding in Patient with Oral Anticoagulation and Dual, Single or no

Antiplatelet Treatment in RE-LY

Dans A, et al. Circulation 2013;127:634-40

Similar trends were found for minor bleeding and no intracranial

bleeding. No increase risk of intracranial bleeding was noted.

Oral Anticoagulation and Antiplatelets in Atrial

Fibrillation Patients After MI and PCI

Denmark National Registry: 12,965 pts

Lambert M, et al JACC, Volume 62, Issue 11, 2013, 981 - 989

Triple therapy is used as

reference (hazard ratio =1.00).

Triple Therapy With Aspirin, Prasugrel, and VKA’s

Sarafoff N et al. J Am Coll Cardiol. 2013;61:2060-2066.

Kaplan-Meier analysis for the primary endpoint

(TIMI major and minor bleeding) at 6 months.

6 [28.6%) vs. 24 [6.7%];

unadjusted HR: 4.6, CI: 1.9-11.4,

p 0.001;

adjusted HR: 3.2, CI: 1.1 to 9.1, p

0.03

377 DES treated pts

of whom 21

switched to

prasugrel because

of HPR

Bleeding Risk

Atherothrombotic Events

ST and Stroke

PCI and the Need for oral Anticoagulation

The Triple Therapy Dilemma

Bleeding Risk

Atherothrombotic Events

ST and Stroke

Oral Anticoagulants

Triple Therapy

PCI and the Need for oral Anticoagulation

The Triple Therapy Dilemma

How long Triple? (0 or 1 month)

Double Therapy

• No Aspirin?

• No Clopidogrel?

• Either one?

• How long? (3, 6, 12 months)

Role of New anticoagulants

PCI and the Need for oral Anticoagulation

The Triple Therapy Dilemma

The WOEST Trial: Randomised trial with or without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting

Dewilde WJ et al. Lancet. 2013;381(9872):1107-15

ISAR-TRIPLE Study Randomized 600 patients

Fiedler KA, et al. Presented at TCT September 2014.

XARELTO® (rivaroxaban) Use in Patients With AF Undergoing PCI: PIONEER AF-PCI

• Primary endpoint: TIMI major, minor, and bleeding requiring medical attention

• Secondary endpoint: CV death, MI, stroke, and stent thrombosis

*XARELTO® dosed at 10 mg once daily in patients with CrCl of 30 to <50 mL/min.

†Alternative P2Y12 inhibitors: 10 mg once-daily prasugrel or 90 mg twice-daily ticagrelor.

‡Low-dose aspirin (75-100 mg/d).

Data on File. Janssen Pharmaceuticals, Inc.

2100 patients

with NVAF

No prior

stroke/TIA

PCI with stent

placement

R

A

N

D

O

M

I

Z

E

1,6, or 12 months

XARELTO® 15 mg qd*

Clopidogrel 75 mg qd†

XARELTO® 15mg QD

Aspirin 75-100 mg qd

XARELTO® 2.5 mg bid

Clopidogrel 75 mg qd†

Aspirin 75-100 mg qd‡

VKA (target INR 2.0-3.0)

Aspirin 75-100 mg qd

VKA (target INR 2.0-3.0)

Clopidogrel 75 mg qd†

Aspirin 75-100 mg qd

≤72

hours

After

Sheath

removal

1,6, or 12 months

End of treatment at 12 months

PCI and the Need for oral Anticoagulation

ESC 2014 Guidelines

1) Which stent?

- Define if PCI/stenting is “appropriate”

- 2nd generation DES is the prefer stent (no BMS)

- Preferential use of radial approach during PCI

2) Which antiplatelet agent?

- Clopidogrel (± low dose aspirin)

- Avoid prasugrel/ticagrelor; avoind/limit NSAIDs

- Add PPI (preferably non CYP2C19 interfering)

3) Always OAC. Which OAC?

- I prefer VKA (more data; antidote), targeting an INR 2.0-2.5

- If already on NOAC, continue with same NOAC

- Limited data on NOACs (no antidote; negative press; patients concerned)

4) For how long?

- Triple Rx for 1 Month. May consider longer (6 months) if low bleeding risk

- After: Dual Rx with OAC + clopidogrel (stop aspirin) up to 12 month

- >1 year: Dual Rx with OAC ± aspirin (depending on patient risk)

What do I do in my practice?

MUCHAS GRACIAS

Lip G, et al. Eur Heart J 2010; 31, 1311–1318 / ESC Guidelines for AF 2010

Antithrombotic strategies following coronary artery stenting

in patients with AF at moderate to high thrombo-embolic risk

(in whom oral anticoagulation therapy is required): HAS-BLED 0-2

Elective BMS 1 month: triple therapy of VKA (INR 2.0–2.5) + aspirin

≤100 mg/day + clopidogrel 75 mg/day

Lifelong: VKA (INR 2.0–3.0) alone

Elective DES 3 (-olimus group) to 6 (paclitaxel) months: triple

therapy of VKA (INR 2.0–2.5) + aspirin ≤100 mg/day +

clopidogrel 75 mg/day

Up to 12th month: combination of VKA (INR 2.0–2.5) +

clopidogrel 75 mg/day (or aspirin 100 mg/day)

Lifelong: VKA (INR 2.0–3.0) alone

ACS BMS/DES 6 months: triple therapy of VKA (INR 2.0–2.5) + aspirin

≤100 mg/day + clopidogrel 75 mg/day

Up to 12th month: combination of VKA (INR 2.0–2.5) +

clopidogrel 75 mg/day (or aspirin 100 mg/day)

Lifelong: VKA (INR 2.0–3.0) alone

Antithrombotic strategies following coronary artery stenting in patients with AF at moderate to high thrombo-embolic risk (in whom oral anticoagulation therapy is required): HAS-BLED ≥3

Elective BMS 2–4 weeks: triple therapy of VKA (INR 2.0–2.5) +

aspirin ≤100 mg/day + clopidogrel 75 mg/day

Lifelong: VKA (INR 2.0–3.0) alone

ACS BMS 4 weeks: triple therapy of VKA (INR 2.0–2.5) +

aspirin ≤100 mg/day + clopidogrel 75 mg/day

Up to 12th month: combination of VKA (INR 2.0–

2.5) + clopidogrel 75 mg/day (or aspirin 100

mg/day)

Lifelong: VKA (INR 2.0–3.0) alone

Lip G, et al. Eur Heart J 2010; 31, 1311–1318 / ESC Guidelines for AF 2010