Medical management after PCI Ma Hong 1 st affiliated hospital of Sun Yat-sen University.

Medical management after PCI

Ma Hong1st affiliated hospital

of Sun Yat-sen University

Successful PCI is

just the beginning

of another long

journey

Goals of medical management after PCI

• To prevent acute/sub-acute stent thrombosis

• To prevent other coronary events

(improve survival)

• To improve symptoms

Medical management after PCI

• Antiplatelet therapy

• Beta-blocade

• ACEI / ARB

• Statins

• others

After PCI, aspirin should be continued indefinitely.

Postprocedural Antiplatelet Therapy

I IIa IIb III

2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, JACC 2011:58(24)

After PCI, it is reasonable to use 81 mg per day of aspirin in preference to higher maintenance doses.

I IIa IIb III


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).

I IIa IIb III


Continuation of clopidogrel, prasugrel or ticagrelor beyond 12 months may be considered in patients undergoing DES placement.


I IIa IIb III

If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by a recommended duration of P2Y12 inhibitor therapy after stent implantation, earlier discontinuation (e.g., <12 months) of P2Y12 inhibitor therapy is reasonable.

I IIa IIb III


New P2Y12 inhibitor-- prasugrel, ticagrelor

• Prasugrel– Phase 2 PCI: JUMBO – TIMI 26

– Phase 3 PCI in ACS: TRITON – TIMI 38

– TRIGGER-PCI– ……

• Ticagrelor– PLATO– PLATO-INVASIVE– ……

NNSS

OO

ClCl

OO CHCH33CC

Clopidogrel

Prodrug

Prasugrel

NN

SS

OO

CCOO

FFOO

CHCH33

85% Inactive Metabolites

hCE1hCE1

LiverLiver Hydrolysis(Esterases)

NN

SS

OO

FFOO

hCE2

GutGut

HOOCHOOC* HS* HS

NN

OO

FF

CYPs:CYPs: 3A4/5 3A4/5 2B6 2B6 2C9 2C9 2C19 2C19

GutGut

and

LiverLiver

Oxidation(Cytochrome P450)

Active Metabolite

CYPs: 1A2 2B6 2C19

LiverLiver

HOOCHOOC* HS* HS

NN

OO

ClCl

OCHOCH33

CYPs: 3A4/5 2B6 2C9 2C19

LiverLiver

Clopidogrel Prasugrel

Wiviott SD et al. NEJM 2007; 357: 2001-2015

TRITONEfficacy and Safety in Patients with ACS

≥ 60 kg, < 75 years, no previous stroke/ TIA

0

2

4

6

8

10

12

14

16

0 30 90 180 270 360 450

End

poin

t (%

)

Hazard Ratio, 1.240(95% CI, 0.91 - 1.69)P = 0.17

Hazard Ratio, 0.75(95% CI, 0.66 - 0.84)P < 0.001

Clopidogrel 11.0%

Prasugrel 8.3%

Clopidogrel 1.50%

Prasugrel 2.0%

Days

Cardiovascular Death, MI, StrokeCardiovascular Death, MI, Stroke

Major BleedingMajor Bleeding

ITT= 13,608ITT= 13,608 LTFU = 14 (0.1%)LTFU = 14 (0.1%)

Ticagrelor - An Oral Reversible P2Y12 Antagonist

Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)

OH

OH

O

OH

N

F

S

NH

NN

NN

F

Direct acting Direct acting Not a prodrug; does not require metabolic activationNot a prodrug; does not require metabolic activation Rapid onset of inhibitory effect on the P2YRapid onset of inhibitory effect on the P2Y1212 receptor receptor Greater inhibition of platelet aggregation than clopidogrelGreater inhibition of platelet aggregation than clopidogrel

Reversibly boundReversibly bound Degree of inhibition reflects plasma concentrationDegree of inhibition reflects plasma concentration Faster offset of effect than clopidogrel Faster offset of effect than clopidogrel Functional recovery of all circulating plateletsFunctional recovery of all circulating platelets

PLATO study design

Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding

6–12-month exposure

ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,

then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)

Ticagrelor180 mg loading dose, then90 mg bid maintenance;

(additional 90 mg pre-PCI)

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;

randomised within 24 hours of index event (N=18,624)

PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

PLATO – INVASIVE study design

6–12 months treatment

PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator

NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624)Clopidogrel-treated or -naive; randomized <24 hours of index event

At randomization, 13,408 (72%) of patients were specified by the Investigator: intent for invasive strategy

Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding

Clopidogrel (n=6,676)If pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,

then 75 mg qd maintenance;(additional 300 mg allowed pre-PCI)

Ticagrelor (n=6,732)180 mg loading dose, then

90 mg bid maintenance;(additional 90 mg pre-PCI)

Primary endpoint: CV death, MI or stroke

00

5

10

15

60 120 180 240 300 360Days after randomization

K-M

est

imat

ed ra

te (%

per

yea

r)

HR: 0.84 (95% CI = 0.75–0.94), p=0.0025

9.02

10.65Clopidogrel

Ticagrelor

No. at risk

ClopidogrelTicagrelor

6,6766,732

6,1296,236

6,0346,134

5,881 4,8154,889

3,6803,735

2,9653,0485,972

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Stent thrombosis

Ticagrelor(n=6,732)

Clopidogrel (n=6,676)

HR for ticagrelor (95% CI)

p value*

Stent thrombosis, %

Definite

Probable or definite

Possible, probable, or definite

1.0

1.7

2.2

1.6

2.3

3.1

0.62 (0.45–0.85)

0.72 (0.56–0.93)

0.72 (0.58–0.90)

0.003

0.01

0.003

¶ Evaluated in patients with any stent during the studyTime-at-risk is calculated from the date of first stent insertion in the study or date of randomization* By univariate Cox model

Primary safety event: Major bleeding*

No. at risk

ClopidogrelTicagrelor

6,5856,651

5,2155,235

4,9844,947

4,786

Days after randomization

3,7533,726

2,7542,741

2,4962,503

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor11.611.5

4,755

K-M

est

imat

ed ra

te (%

per

yea

r)

HR 0.99 (95% CI = 0.89–1.10), p=0.88

* PLATO definitions

Before we have the new

P2Y12 Inhibitors, what we can

do for high risk patients ?

Low Dose ASA

(75-100 mg)

Mehta SR et al. Am Heart J 2008

25,000 ACS or STEMI PatientsAngiography with intended PCI <72 hrs

No restriction on use of GP IIb/IIIa inhibitors

DOUBLE DOSEClopidogrel 600mgthen 150 mg OD x 6d then 75 mg OD

STANDARD DOSEClopidogrel 300 mg followed by 75 mg

daily

Randomized

High Dose ASA

(300-325 mg)

High Dose ASA

(300-325 mg)

Low Dose ASA

(75-100 mg)

A Randomized, Double-Blind, 2X2 Factorial Trial of Clopidogrel A Randomized, Double-Blind, 2X2 Factorial Trial of Clopidogrel Double vs. Standard Dose and High versus Low Dose ASA in ACS Double vs. Standard Dose and High versus Low Dose ASA in ACS

or STEMI with an Early Invasive Strategy or STEMI with an Early Invasive Strategy and intent for PCIand intent for PCI

Primary Efficacy Outcome CV Death / MI /stroke at 30 days

Secodary OutcomeARC defined STENT THROMBOSIS

CVD/MI/Stroke + Rec Ischemia

Rational for high dose clopidogrel therapyCURRENT -- OASIS 7

23

Definite Stent Thrombosis in 4 Groups (Angiographically Proven)

Days

Cum

ulat

ive

Haz

ard

0.0

0.00

40.

008

0.01

2

0 3 6 9 12 15 18 21 24 27 30

C Standard, A Low

C Standard, A High

C Double, A Low

C Double, A High

Standard Clop

Double Clop HR P

PIntn

High ASA 1.2 0.6 0.49 0.003

Low ASA 1.2 0.8 0.6 0.058 0.35

24

Days

Cum

ulat

ive

Haz

ard

0.0

0.00

50.

010

0.01

5

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard

Clopidogrel Double

HR 0.5495% CI 0.35-0.84

P=0.006

STEMI-PCI: Definite Stent Thrombosis

46%RRR

Mehta SR. TCT 2009 LBCT

DAPT – the longer the better ?

• Duration of DAPT after DES : at least 12

months, possibly longer

• await for RCT

Others – prevention of GIB

Interaction of PPI and Clopidogrel :

what we have known ?

Scientific Basis

Juhász et al. Digestion 2010 ; Taubert D et al. Clin Pharmacol Ther 2006;80:486–501

Lab. result

Observational Data

Randomized Data

The Cogent Trial

• Randomized to Clopidogrel + Omeprazole (CGT

2168) or Clopidogrel + Placebo

• 3627 patients (above the initial target of 3200)

• 393 sites

• Median follow-up 133 days (maximum 362 days)

• 136 adjudicated cardiovascular events (preliminary)

• 105 adjudicated GI events (preliminary)

CONGENT – Primary Endpoint

Bhatt DL. Presented at: NEJM OCTOBER 2010

Prevention of GIB -- guidelines PPI should be used in patients with history of prior

GIB who require DAPT.

PPI use is reasonable in patients with increased risk of gastrointestinal bleeding (advanced age, concomitant use of warfarin, steroids, nonsteroidal anti-inflammatory drugs, H pylori infection, etc.) who require DAPT.

Routine use of a PPI is not recommended for patients at low risk of gastrointestinal bleeding, who have much less potential to benefit from prophylactic therapy.

I IIa IIb III

I IIa IIb III

I IIa IIb III


Second prevention


THANK YOU

Antiplatelet therapy for polymer-free stent and biodegenerable

stents ?

We are not clear need more trials

38

1. Overall, the primary outcome was neutral between the clopidogrel and aspirin dose groups.1

2. In patients undergoing PCI, the double-dose clopidogrel regimen reduced the primary outcome (CV death, MI or stroke) and stent thrombosis

3. The reduction in stent thrombosis was robust and observed in those receiving DES and BMS and in those presenting with STEMI

4. There was a modest excess in major bleeds, but no difference in ICH, fatal bleeds or CABG-related bleeds with the double-dose regimen. No difference in major bleeds between aspirin dose groups.

5. There was an interaction between clopidogrel and aspirin such that the lowest event rates were observed in those receiving double-dose clopidogrel and high-dose aspirin.

2. Mehta et al. Lancet 2010; Online First Sept 11. CURRENT Investigators. N Engl J Med 2010;363:930-42

Rational for high dose clopidogrel therapyCURRENT -- OASIS 7

Medical management after PCI Ma Hong 1 st affiliated hospital of Sun Yat-sen University.

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