TICAGRELOR – The Good, The Bad, and The Ugly…..

Dr Tim Kinnaird Consultant Cardiologist UniversityDr Tim Kinnaird, Consultant Cardiologist, University Hospital of Wales, Lecturer, Cardiff University

A good sermon should be like a woman’s skirt: short enough to rousewoman s skirt: short enough to rouse the interest, but long enough to cover the essentials…(Ronald Knox)(Ronald Knox)

1. What do we make of the PLATO trial?

2. Is BD dosing likely to be a problem?

h l l f h d ?3. The clinical pain of the dyspnoea?

4 Just how much?4. Just how much?

PLATO : Study DesignPatient >18 years hospitalized with documented evidence of non–ST elevation or ST‐elevation ACS in the 24 hours before randomization

PLATO : Study Designin the 24 hours before randomization

Ticagrelor 180mg LD then 90 mg bd (n ~ 9,000)

N = 

Randomisation

Clopidogrel 300mg* LD then 75 mg od (n ~ 9,000)18,000

*patients previously treated with clopidogrel will have placebo

Follow‐up

All patients received aspirin (75‐100mg od) + GPIIb/IIIa antagonistAspirin naive patients received a loading dose (160‐500mg)

Onset of cardiac ischemic symptoms and before any planned or urgent PCI

<24h  1 month  2 month   3 month 6‐12months study lengthMean exposure estimated ~11 monthsScreening

• Patients undergoing percutaneous coronary intervention (PCI) >24h after randomisation to ticagrelor will receive an additional 90mg of ticagrelor. Patients randomised to clopidogrel will be eligible to receive an additional 300mg loading dose of clopidogrel at the discretion of the treating physician

*Of the 990 randomized patients, 984  who received ≥1 dose of study drug and were included in the safety analysis dataset.GP = glycoprotein; LMWH = low‐molecular‐weight heparin.

James et al. Am Heart J 2009; 157: 599‐605

TRITON‐TIMI 38: Study Design and Primary Efficacy End PointsEnd Points

Prasugrel60 LD/ 10 MD

ASAUA/NSTEMI                     (TIMI Risk Score ≥ 3)

60 mg LD/ 10 mg MD

12.0 month planned

N=6813

& Planned PCI

( )

R 14.5 month actual

planned median

Double‐blind treatment                          6 ‐ 15 months planned follow‐up

ASA

STEMI           (Primary PCI ≤ 12 hours of symptoms or post‐STEMI within 14 days)

actual median

N=6795ASASTEMI within 14 days)

Clopidogrel300 mg LD/ 75 mg MD

Primary efficacy end point: a composite of the rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke

=

Key secondary end points at 30 and 90 days included primary efficacy end point and a composite of the rate of death from cardiovascular causes, nonfatal MI, or UTVR

=

f d i C G l d j l diKey safety end point: non‐CABG related TIMI Major Bleeding

Wiviott SD et al. New Engl J Med 2007;357:2001‐2015Wiviott SD et al. Am Heart J 2006;152:627‐635

TRITON‐TIMI 38: Study Drug and Pharmacotherapies

clopidogrel( 6 795)

prasugrel( 6 813)(n=6,795)

%(n=6,813)

%

Ti i f t d d l di dTiming of study drug loading dose

Pre‐PCI (before 1st wire) 25 26Pre PCI (before 1 wire) 25 26

During PCI (1st wire to 1 hr after  74 73g (leaving lab)

Post‐PCI (>1 h after leaving lab) 1 1Post PCI (>1 h after leaving lab)  1 1

PCI = Percutaneous Coronary Intervention

*P=0.03 

Wiviott SD et al. New Engl J Med 2007;357:2001‐2015

PLATO : Primary EndpointTime to first primary efficacy event (composite of CV death, MI or stroke)

1211

13(%

) 11.7Clopidogrel

10987ci

denc

e (

9.8Ticagrelor

7654ul

ativ

e in

HR 0.84 (95% CI 0.77–0.92), p=0.00033210

Cum

u

Days after Randomisation0 60 120 180 240 300 360

0

Wallentin et al. New Eng J Med 2009: 10.1056/NEJMoa09043

PLATO : Secondary EndpointsTime to first myocardial infarction or cardiovascular death

7Clopidogrel 6.9 7

Time to first myocardial infarction or cardiovascular death

6

5

ce (%

)

Ticagrelor

5.86

Clopidogrel 5.15

ce (%

)

4

3

ve in

cide

nc 4

3Ticagrelor

4.0

ve in

cide

nc

2

1Cum

ulat

iv

HR 0.84 (95% CI 0.75–0.95), p=0.005

2

1

Myocardial infarction

Cardiovascular death

Cum

ulat

iv0 60 120 180 240 300 360

0

0 60 120 180 240 300 360

0HR 0.79 (95% CI 0.69–0.91), p=0.001

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,560

8,678

8,405

8,520

8,177

Days after randomisation

6,703

6,796

5,136

5,210

4,109

4,1918,2799,291

9,333

8,865

8,294

8,780

8,822

8,589

Days after randomisation

7079

7119

5,441

5,482

4,364

4,4198,626

Wallentin et al. New Eng J Med  2009: 10.1056/NEJMoa09043 

CURRENT OASIS-7

HIGH RISK PATIENTS IN PLATO?

PLATO : Primary Safety EndpointsNS13

12 11.611.2

TicagrelorClopidogrel

NS

NS

r year)

9

10

1111.2

8.9 8.9

NS

d rate (%

 per

6

7

87.9 7.7

5.8 5.8

M estim

ated

4

5

6

NS

K‐M

1

2

3

0.3 0.3

0PLATO major bleeding

TIMI major bleeding

Red cell transfusion*

PLATO life‐threatening/fatal bleeding

Fatal bleeding

Wallentin et al. New Eng J Med  2009: 10.1056/NEJMoa09043 

PLATO : Secondary Safety EndpointsNS9

8 7.9

TicagrelorClopidogrel

 per year)

NS

8

7

7.4

5 8

ed ra

te  (%

p=0.026

6

54.5

5.3

5.8

M estim

ate

p=0.0254

3

3.8

2.8

2 2

K‐M

2

1

2.2

Non‐CABGPLATO majorbleeding

0Non‐CABGTIMI major bleeding

CABGPLATO major bleeding

CABG TIMI major bleedingg g g g

Wallentin et al. New Eng J Med 2009: 10.1056/NEJMoa09043

“There is no such thing as a free lunch ”free lunch……

Milton Friedman (Nobel‐prize winning economist)Milton Friedman (Nobel‐prize winning economist)

1. What do we make of the PLATO trial?

2. Is BD dosing likely to be a problem?

h l l f h d ?

Control arm reflects contemporary anti‐platelet practice

Absolute mortality benefit3. The clinical pain of the dyspnoea?

4 Just how much?

Absolute mortality benefit

Nagging issues regarding variable outcomes by country

There is a bleeding excess4. Just how much?There is a bleeding excess

100

ONSET/OFFSET Study IPA with ADP 5uM (final extent) 

90

80

Ticagrelor  180mg LD / 90 mg bd (n=54)

Clopidogrel 600mg LD / 75  mg  od (n=50)

*

* **

**

*

* †

//70

*//

60

50

IPA %

* //40

30

‡

20

†

10

0 //

Time (hours)Onset                            Maintenance                                 Offset

0     .5      1      2     4      8     24      6 weeks        0      2     4      8     24    48    72   120 168  240//

Gurbel PA et al. Circulation 2009 

1. What do we make of the PLATO trial?

2. Is BD dosing likely to be a problem?

h l l f h d ?3. The clinical pain of the dyspnoea?

4 Just how much?4. Just how much?

1. What do we make of the PLATO trial?

2. Is BD dosing likely to be a problem?

h l l f h d ?3. The clinical pain of the dyspnoea?

4 Just how much?4. Just how much?

COST EFFECTIVENESSCOST EFFECTIVENESS

£7897 per QALY for all ACS

£8872 per QALY for STEMI

£7215 per QALY for NSTEMI

£9131 per QALY for unstable angina

= £1.31M

I20 - Angina pectoris 6717 4109I20 - Angina pectoris 6717 4109

I21 - Acute myocardial infarction 5922 3194

I22 - Subsequent myocardial infarction 1784 898

High risk patientsHigh risk patients

All for 3 months

Stent‐fest only

Not using

4.12 The Committee heard from the Primary Care Trustexpert that although treatment with ticagrelor relative toclopidogrel appeared cost effective within the rangeclopidogrel appeared cost effective within the rangeconsidered to represent good value for money by NICE, thehigh incidence of ACS in England and Wales means thatg f gticagrelor would have a large impact on budgets andopportunity costs if it was approved for use. The PrimaryCare Trust expert noted that this would invariably lead toreduced spending elsewhere for health, which wouldinclude cardiology services However the Committee notedinclude cardiology services. However, the Committee notedthat the guide to the methods of technology appraisalstates that budget impact and affordability do not formg p ff y fpart of its decision making.