current status of antiplatelet therapy in acute coronary ... · current status of antiplatelet...

Robert C. Welsh, MD, FRCPCProfessor of Medicine, University of Alberta

Zone Clinical Department Head, Cardiac Sciences

Current Status of Antiplatelet Therapy in Acute Coronary Syndromes:

Duration of DAPT in 2016

Inspiring Innovation and KnowledgeLeaders in Patient Care

Robert C. Welsh, MD, FRCPC


Faculty Disclosure (12 months):• Research and Clinical Trials: Abbott Vascular, Alere, Astra Zeneca, Bayer,

BMS, Boehringer Ingelheim, CIHR, CSL Behring LLC, Edwards Lifesciences, Eli Lilly, Jansen, Johnson and Johnson, Matrizyme Pharma, Pfizer, Population Health Research Institute, University of Alberta Hospital Foundation

• Honoraria: Astra Zeneca, Bayer

• Advisory Board: Astra Zeneca, Bayer, Bristol Myers-Squibb/Pfizer

• Other: University of Alberta (employee), Alberta Health Services (Clinical privileges) and President, The Canadian Centre for Clinicians and Scientists

Reflections on DAPT therapy

We have to consider patients with Acute Coronary Syndromes separately from those with Elective Revascularization.

1. With available data – is it fair to discuss DAPT as a therapy versus C-DAPT, P-DAPT, T-DAPT?

2. Can we identify patients for prolonged versus short duration of therapy?

3. With upcoming trials – is DAPT going to remain the standard of care versus ticagrelor monotherapy, or dual pathway strategies?


Antiplatelet Therapy with ASA and Clopidogrel Improves Major Outcomes in NSTE ACS

CURE Yusuf S, et al. NEJM. 2001;345:494

Cu

mu

lati

ve H

azar

d R

ate

(%)

Months of Follow-Up

Clopidogrel+ ASA

(n=6,259)

0 3 6 9 12

Placebo+ ASA

(n=6,303) 20% RRR

Primary Endpoint: MI/Stroke/CV Death Major Bleeding

3.7

2.7

RR 1.38 95% CI 1.13–1.67

p<0.001

+ ASA

PlaceboClopidogrel0

1

2

3

4

Inci

den

ce (

%)

RR 0.8095% CI 0.72–0.90p<0.001

11.4

9.3

0

2

4

6

8

12

10

All patients received ASA and UFH or LMWH

Timing of Randomization and Treatment in Dual Oral Antiplatelet Trials

< 24 hrs

NSTE ACS < 72 hrsSTEMI < 12 hrs

CUREClopidogrel

PLATOTicagrelor

Presentation

Selective Invasive

Early Invasive

CoronaryAngiography

CABG

PCI

Medical Management

TRITONPrasugrel

SymptomOnset

James SK et al. BMJ 2011;342:d3527.

Wiviott SD et al. N Engl J Med 2007;357(20):2001–2015. Yusuf S et al. N Engl J Med 2001;345(7):494–502.

CURRENTClopidogrel

Medical

TRILOGYPrasugrel

Collet et al Lancet 2014;384:1577-85

Mortality According to Continuation vs.

Interruption of DAPT After PCI

Major Adverse Cardiac Events: 1.05 (0.87-1.25); p=0.62

Stent Thrombosis: 0.86 (0.53-1.39); p=0.41

Stroke : 1.43 (0.93-2.21); p=0.10

MI: 1.03 (0.79-1.34); p=0.84

Collet et al Lancet 2014;384:1577-85

Major Bleeding According to Continuation vs.

Interruption of DAPT After PCI

“…no apparent benefit but instead harm with extension of DAPT…after stenting. The

consistency between findings from all trials of such interruption suggests the need for a

reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of

treatment.”

Study Design and Patient Population

Enrolled: Subjects treated with FDA-approved DES or BMS

(16% NSTEMI, 10% STEMI)Excluded: Subjects on oral anticoagulant therapy or with life expectancy < 3 years

Randomized: Free from MI, stroke, repeat revascularization, and

moderate or severe bleeding, and adherent with thienopyridine (80% to

120% of doses taken and no interruption > 14 days)

Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:2155-66

Stent and Drug Types


Co-Primary Effectiveness End Point Stent

Thrombosis


65 vs. 19

Co-Primary Effectiveness End Point: Major Adverse

Cardiovascular and Cerebrovascular Events


285 vs. 211

Non-Stent Thrombosis Myocardial Infarction


All-Cause Mortality


Primary Safety Endpoint

GUSTO

Moderate or

severe

bleeding 12-30

Months


All cause mortality

Sammy Elmariah , Laura Mauri et al; The Lancet, 2014

Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis

Figure 3 Bayesian meta-analysis of cardiovascular and non-cardiovascular mortality associated with extended duration DAPT

versus short duration or no DAPT Hazard ratio for cardiovascular mortality, and (B) non-cardiovascular mortality. Results are

present...Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis

Sammy Elmariah , Laura Mauri et al; The Lancet, 2014

■ “Extended” DAPT therapy

■ Decreases the risk of ischemic events -especially stent thrombosis and MI

■Consistent with previous observational findings and randomized clinical trial evidence

■ Increases the risk of bleeding

■ Clopidogrel based DAPT does not improve mortality

Interpretation

PLATO Comparison of Ticagrelor and Clopidogrel in Patients with ACS

Major Bleeding*CV Death/MI/Stroke

Wallentin L, et al. N Engl J Med. 2009;361:1045-1057

Cu

mu

lati

ve In

cid

ence

( %

)

0 6 0 120 180 240 300 360

0

2

4

6

8

10

12 Clopidogrel (n=9,291)

Ticagrelor(n=9,333)

Days after randomization

Median follow-up9.1 months

HR 0.8495% CI 0.77–0.92p<0.001

11.7

9.8

Clopidogrel(n=9186)

Ticagrelor(n=9235)

7.4

HR 0.9595% CI 0.85-1.06p=0.32

7.9

4.5 3.8

HR 1.1995% CI 1.02–1.38p=0.03

CABG Major Bleed Non-CABG Major Bleed

0

2

4

6

8

10

*Total major bleeding (study criteria) for ticagrelor vs clopidogrel 11.6% vs 11.2%, HR 1.04 (0.95–1.13), p=0.43.

Inci

den

ce (

%)

Cardiovascular Death All-Cause Mortality

Wallentin L, et al. N Engl J Med. 2009;361:1045-1057

Clopidogrel (n=9,291)

Ticagrelor(n=9,333)

5.94.5

Incidence at 1 year (%)

HR 0.7895% CI 0.69–0.89

p<0.001(nominal)

Cu

mu

lative

in

cid

en

ce (

%)

Months After Randomization

Clopidogrel (n=9,291)

Ticagrelor(n=9,333)

HR 0.7995% CI 0.69–0.91p=0.001

0 2 4 6 8 1210

0

1

2

3

4

5

6

7

21%RRR

PLATO: Secondary Efficacy OutcomesTicagrelor Reduced Mortality in ACS

Incid

en

ce

(%

)

0

1

2

3

4

5

6

Stable pts with history of MI 1-3 yrs prior

+ 1 additional atherothrombosis risk factor*

Ticagrelor

90 mg bidPlacebo

RANDOMIZE

DOUBLE BLIND

Follow-up Visits

Q4 mos for 1st yr, then Q6 mos

Planned treatment with ASA 75 – 150 mg &

Standard background care

* Age >65 yrs, diabetes, 2nd prior MI, multivessel CAD,

or chronic non-end stage renal dysfunction

Event-driven trial

Ticagrelor

60 mg bid

Trial Design

Bonaca MP et al., NEJM 2015

Months from Randomization

Ticagrelor 60 mg

HR 0.84 (95% CI 0.74 – 0.95)

P=0.004

CV

Death

, M

I, o

r S

troke (

%)

3 6 9 120 15 18 21 24 27 30 33 36

Ticagrelor 90 mg

HR 0.85 (95% CI 0.75 – 0.96)

P=0.008

Placebo (9.0%)

Ticagrelor 90 (7.8%)Ticagrelor 60 (7.8%)

Primary Endpoint

6

5

4

3

10

9

8

7

2

1

0

N = 21,162

Median follow-up 33 months


P value Ticagrelor 90 mg 0.008 0.15 0.01 0.14 0.43 <0.001

Ticagrelor 60 mg 0.004 0.07 0.03 0.03 0.47 <0.001

Ticagrelor 90 mg bid


Outcomes over 1 Year for 10,000 Patients

with Prior MI Initiated on Ticagrelor

Events extrapolated from 3-yr KM rates from ITT population

P values based on Cox regression

Irreversible Damage


PEGASUSPrimary endpoint – landmark (ITT)

3.4%

2.8%

2.9%

2.6%

2.8%

2.4%

Ticagrelor pooled

HR 0.84

(95% CI 0.71 – 0.98)

P=0.029

Ticagrelor pooled

HR 0.86

(95% CI 0.72 –1.03)

P=0.094

Ticagrelor pooled

HR 0.83

(95% CI 0.68 – 1.02)

P=0.084

Median 1.7 y

from index MI

(1.2 – 2.3)

Median 2.7 y

from index MI

(2.2 – 3.3)

Median 3.7 y

from index MI

(3.2 – 4.3)

Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 383)

0

1

2

3

4

0 90 180 270 360 366 456 546 636 726 731 821 911 1001

CV

D/M

I/s

tro

ke

(%

)

0

1

2

3

4

0

1

2

3

4

Time (days) from randomization

Placebo

Ticagrelor pooled doses

Adverse events leading to discontinuationN

um

be

r o

f p

atie

nts

P=NS each for D/C for

arrhythmia or other

AE, adverse event; D/C, discontinuation; NS, not significantBonaca MP et al. Presented at AHA Congress 2015 (Late Breaking Clinical Trial)

Treatment arm Any AE Bleeding Dyspnoea

Ticagrelor 90 mg bid 19.0% 7.8% 6.5%

Ticagrelor 60 mg bid 16.4% 6.2% 4.6%

Placebo 8.9% 1.5% 0.8%

3 year KM rate (%) – P value for each dose vs. Placebo <0.001

Discontinuation over time for dyspnoea by randomization group

Dashed lines represent median time (days) to discontinuation

Bonaca MP et al. Presented at AHA Congress 2015 (Late Breaking Clinical Trial)

Days from randomization

Nu

mb

er o

f p

atie

nts

dis

con

tin

ued

fo

r d

ysp

no

ea

500

450

400

350

300

250

200

150

50

0

0 90 180 270 360

100

450 540 630 720 810 900 990

8

11

P<0.01 for each

dose vs placebo

Ticagrelor 90 mg twice daily


Placebo

53

Median days to discontinuation

Discontinuation over time for bleeding by randomization group

Days from randomization

500

450

400

350

300

250

200

150

50

0

0 90 180 270 360

100

450 540 630 720 810 900 990 1080

86

156

344



Placebo

P<0.01 for each

dose vs placebo

Dashed lines represent median time (days) to discontinuation

Bonaca MP et al. Presented at AHA Congress 2015 (Late Breaking Clinical Trial)

Median days to discontinuationN

um

ber

of

pat

ien

ts

dis

con

tin

ued

fo

r b

leed

ing

PEGASUSEfficacy of ticagrelor – on treatment*

CV, cardiovascular; CVD, CV deathBonaca MP et al. Presented at AHA Congress 2015 (Late Breaking Clinical Trial)

Pooled



*N=20,942 patients who received at least one dose of study drug including events through 7 days from the last dose of study drug.

Results consistent after propensity score adjustment

Ticagrelor better Placebo better1.0

6.6 8.4 0.79 (0.68, 0.91) <0.001

6.8 0.78 (0.68, 0.90) <0.001

6.7 0.78 (0.70, 0.88) <0.001

1.9 2.4 0.78 (0.60, 1.03) 0.076

1.8 0.74 (0.57, 0.97) 0.031

1.9 0.76 (0.61, 0.96) 0.019

1.3 1.6 0.75 (0.54, 1.04) 0.087

1.2 0.72 (0.52, 1.00) 0.052

1.3 0.74 (0.56, 0.97) 0.029

3.8 4.9 0.78 (0.65, 0.94) 0.0080

4.1 0.81 (0.68, 0.97) 0.0236

4.0 0.80 (0.68, 0.93) 0.0036

1.4 1.8 0.77 (0.56, 1.05) 0.094

1.4 0.73 (0.53, 1.00) 0.048

1.4 0.75 (0.58, 0.97) 0.029

Ticagrelor Placebo HR (95% Cl) P value

CVD, MI, stroke

CV death

Coronary heart disease death

Myocardial infarction

Stroke

3-year Kaplan Meier (%)

METHODS: MODELS TO PREDICT ISCHEMIC AND BLEEDING EVENTS

Development of 2 Prediction Models within the randomized DAPT Study population (N=11648).

• Ischemic Model | Myocardial infarction or stent thrombosis between 12-30 months after index PCI. Includes fatal events.

• Bleeding Model | GUSTO moderate or severe bleeding between 12-30 months after index PCI. Includes fatal events.

• Cox regression, stepwise selection among 37 candidate variables, including randomization treatment arm. In addition, several interaction terms with treatment arm evaluated. P value of 0.05 for retention.

• Validated externally within the PROTECT trial population*

AHA 2015, November 10, 2015, Orlando, FL , *Camenzind, Wijns, Mauri et al. Lancet. 380; 9851:1396-1405.

INDIVIDUALIZING TREATMENT DURATION OF DUAL ANTIPLATELET THERAPY AFTER PERCUTANEOUS CORONARY

INTERVENTION: AN ANALYSIS FROM THE DAPT STUDY

THE DAPT SCORE and Distribution within the DAPT Study

AHA 2015, November 10, 2015, Orlando, FL

Variable PatientCharacteristics

Points

Age ≥ 75 -2

Age 65 - < 75 -1

Age < 65 0

Diabetes Mellitus 1

Current Cigarette Smoker 1

Prior PCI or Prior MI 1

CHF or LVEF <30% 2

Index Procedure Characteristic

MI at Presentation 1

Vein Graft PCI 2

Stent Diameter < 3 mm 1

DISTRIBUTION OF DAPT SCORES AMONG ALL RANDOMIZED SUBJECTS IN THE DAT STUDY

CONTINUED THIENOPYRIDINE VS. PLACEBODAPT SCORE <2 (LOW); N=5731


INSERCONTINUED THIENOPYRIDINE VS. PLACEBODAPT SCORE ≥ 2 (HIGH); N=5917


CONCLUSION


Among patients who have not had a major ischemic or bleeding event within the first year after PCI:

The DAPT Score identified patients for whom ischemic benefits outweighed bleeding risks, and patients for whom

bleeding risks outweighed ischemic benefits.

Low DAPT Score (< 2)

NNT to prevent ischemic = 153

NNH to cause bleeding = 64

High DAPT Score (≥ 2)



-2 10

DAPT Score may help clinicians decide who should and who should not be treated with extended DAPT.

CONCLUSION


Among patients who have not had a major ischemic or bleeding event within the first year after PCI:

The DAPT Score identified patients for whom ischemic benefits outweighed bleeding risks, and patients for whom

bleeding risks outweighed ischemic benefits.

Low DAPT Score (< 2)



High DAPT Score (≥ 2)



-2 10

DAPT Score may help clinicians decide who should and who should not be treated with extended DAPT.

Applies to a selected population treated with C-DAPT or P-DAPTACS patients start with a score of 1

Interventional focused – all patients previous PCI

Scores – need to be developed in ACS specific patient population

Novel strategies to improve secondary prevention following ACS

DAPTDiagnosis

One month

Twelve months

OAC

Atrial

Fibrillation

Dual Pathway

or OAC

Ticagrelormonotherapy

Dual pathwayRivaroxaban

+ ADP Rantagonist

http://clinicaltrials.gov/show/NCT01813435

GLOBAL LEADERS Trial

Dual Pathway Strategies

Phase 2 - Study designRecent ACS

Stabilised >48 hours & <10 days from hospitalisation for index event

PRIMARY ENDPOINT: TIMI clinically significant bleeding

EXPLORATORY EFFICACY ENDPOINT: Composite of CV death, MI, ischaemic stroke or stent thrombosis

Stratify by MD decision to use either clopidogrel or ticagrelor

ASA

Ticagrelor

90 mg bid

+

Rivaroxaban

2.5 mg bid

Ticagrelor (n=1500)Clopidogrel (n=1500)

Minimum 180; Maximum 360, Day F/U

R R

ClinicalTrials.gov Identifier: NCT02293395.

Available at: https://clinicaltrials.gov/ct2/show/NCT02293395 (accessed October

2015).

Clopidogrel

75 mg od

+

Rivaroxaban

2.5 mg bid

ACS=acute coronary syndrome; ASA=acetylsalicylic acid; od=once daily; bid=twice daily; F/U=follow up; TIMI=Thrombolysis In Myocardial Infarction; CV=cardiovascular;

MI=myocardial infarction.

Clopidogrel

75 mg od

+

ASA

100 mg od

Ticagrelor

90 mg bid

+

ASA

100 mg od

https://clinicaltrials.gov/ct2/show/NCT02293395

SummaryConsider patients with Acute

Coronary Syndromes separately from those with Elective Revascularization

1. In appropriately selected patients DAPT should be considered beyond 12 months – focus on ACS.

2. Further academic investment is required to develop scores to assist clinical decision for prolonged therapy.

3. The current trials may further adapt the ACS anti-thrombotic landscape.

current status of antiplatelet therapy in acute coronary ... · current status of antiplatelet...

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