Journal club : dual antiplatelets therapy Post AMI

Mahajna MuhammadSackler faculty of medicine

Tel-Aviv-Uni2015

This article was published on March 14,2015, at NEJM.org.

DOI: 10.1056/NEJMoa1500857

This article was published on March 14,2015, at NEJM.org.

DOI: 10.1056/NEJMoa1500857

Introduction and background

N=18,000

TRIAL ORGANIZATION

An Academic Research Organization ofBrigham and Women’s Hospital and Harvard Medical School

TIMI Study GroupEugene Braunwald (Chair) Marc P. Bonaca (Co-PI)S Morin & P Fish (Operations)

Executive CmteEugene Braunwald (Chair) Deepak L. BhattPh. Gabriel Steg

Sponsor: AstraZenecaPeter Held Per JohansonBarbro Boberg

Independent Data Monitoring CmteJeffrey L. Anderson (Chair) Freek W.A.VerheugtDavid L. DeMets

Marc S. Sabatine (PI)Stephen D. Wiviott (CEC Chair) SA Murphy & Kelly Im (Statistics)

Marc S. Sabatine Marc Cohen Robert Storey

Eva JensenAnn Maxe Ahlbom Olof Bengtsson

Terje R. Pedersen Harvey D. White

Hypothesis

The addition of ticagrelor to standard therapy

(including low-dose aspirin) would reduce the

incidence of major adverse cardiovascular

events during long-term follow-upin patients with a history of MI

Global enrollment

MethodsStudy design and oversightStudy populationRandomization and study treatment End pointsStatistical analysis

Trial design

Overall 33 months follow up

Bonaca MP et al. Am Heart J 2014;167:437-44

Ascertainment for primary endpoint was complete for 99% of potential patient-years of follow up

Randomized 21,162 patients

Ticagrelor 90 mg bid (N=7050)

Ticagrelor 60 mg bid (N=7045)

Placebo (N=7067)

Follow-up median 33 months (IQR 28-37)Minimum 16 months, maximum 47 months

Premature perm. drug discontinuation

12%/yr 11%/yr 8%/yr

Withdrew consent 0.7%

total 0.7% total 0.7% total

Lost to follow-up 3 patients 6 patients 1 patient

Follow up

~65~24%

~82

~54%

~40%

~6%

Key Inclusion & Exclusion Criteria

Bonaca MP et al. Am Heart J 2014;167:437-44

Endpoints

Efficacy : hierarchical testingPrimary : cardiovascular death , myocardial

infarction , stroke Secondary : all cause mortality + non-

coronary ischemic events , individual ischemic events

Safety : Primary : TIMI major bleeding Other : intracranial hemorrhage , fatal bleeding

[ death >7d]

TIMI major bleeding scale

http://spo.escardio.org/eslides/view.aspx?eevtid=33&id=5017

ResultsEfficacy vs

safety

Ticagrelor at any dose >placebo 60 mg as good as 90 mg ~ 15 %-19% relative risk reduction

10.1056/NEJMoa1500857

10.1056/NEJMoa1500857

Duration

Relative risk reduction

RR -REDUCTIO

N

Pooled Ticagrelor dose > placebo at coronary,cardiovascular,infarction,stroke prevention

90 mg > 60 mg at MI prevention 60 mg > 90 mg for stoke prevention

Bleeding

Discussion : limitation , comparison

All trials agree on the benefits of dual anti- platelet therapy after MI

DAPT trial : 1)Randomly assigned pts to continuing vs stopping a P2Y12

receptor antagonist after 12 moths2)Included pts who had not had clinically significant bleeding.3)Included pts who were able to keep taking a P2Y12 receptor

antagonist .4)All above minimize their bleeding complication In PEGASUS-TIMI 54 all Pts began treatment with Brilinta

after they complete the guidelines duration of therapy .They enrolled close to 2 years after MI

Considering side effects [ mainly dyspnea] : PLATO trial > PEGASUS-TIMI 541.Less stable Pts in PLATO study [ dyspnea is common during 1 year after MI ].2. PEGASUS-TIMI 54 had more stable Pts [ 3 years after MI] 3. PEGASUS-TIMI 54 reflects the real dyspnea ratio as a complication

PEGASUS-TIMI 54 : safety profile should not be generalized for all population

1)High risk of bleeding , previous stroke , anticoagulants usage were among the exclusion criteria

summary

• Adding ticagrelor to low-dose aspirin in stable patients with a history of MI reduced

the risk of CV death, MI or stroke

• The benefit of Ticagrelor was consistent at all major groups and sub groups

• Ticagrelor increased the risk of TIMI major bleeding, but not fatal bleeding or ICH

• The two doses of Ticagrelor had similar overall efficacy, but bleeding and other side

effects tended to be less frequent with 60 mg bid dose

Thanks