ACS: Are Timing-related Strategies a Critical Issue? Timing to Reperfusion, Timing of Culprit vs.

Multivessel Approach, Timing of DAPT

Christopher B. Granger

Duke University

Disclosures

Research contracts: Armetheon, AstraZeneca, Bayer, Novartis, GSK, BMS, Pfizer, The Medicines Company, and

Boehringer Ingelheim

Consulting/Honoraria: AstraZeneca, GSK, BMS, Pfizer, Lilly, Daiichi Sankyo, Novartis, Boehringer Ingelheim, The

Medicines Company, and Sanofi-Aventis

For full listing see www.dcri.duke.edu/research/coi.jsp

Time is a critical element in care of ACS

Time to reperfusion for STEMI

Time to cath following fibrinolytics

Timing of non-culprit artery PCI

Time to cath for ACS according to risk

Timing of starting P2Y12 antagonists in ACS

3

The wavefront phenomenon of ischemic cell death

Reimer KA, … Jennings RB. Circulation 1977; 56:786

Rao M. J Int Cardiol 2014

PCI vs none:

53% RRR

Importance of Time

Boersma. Lancet 1996; 348:771-5.

Absolu

te b

enefit

per

1000 p

atients

tre

ate

d

Treatment delay (hours)

35 day mortality

In first 1-2 hours, up

to 40 lives per 1000

saved per hour of

faster treatment

Mortality reduction versus treatment delay

Presentation Delay and Outcome

5.1%6.1%

6.7%

0%

5%

10%

15%

< 2hr 2-4hr > 4hr

Sx Onset to Presentation

Primary Angioplasty

-- Zijlstra, EHJ, 2002

6-M

on

th M

ort

alit

y

5.4%

7.3%

14.6%

0%

5%

10%

15%

< 2hr 2-4hr > 4hr

Sx Onset to Presentation

Fibrinolysis

D2B and Mortality in NCDR

Rathore BMJ 2009;338: b1807

N= 43,801 NCDR STEMI Patients

2005-2006

P <0.001 for trend

Primary PCI

Median D2B 83 min

Overall mortality 4.6%

Contradictory studies from the same dataset

Lancet. 2014 Nov 19

N Engl J Med. 2013;369:901-9.

System Delay (First Medical Contact to Wire) and Long-Term Mortality

Each hour of delay associated with 10% risk of death

Terkelsen JAMA. 2010;304(7):763-771

Regional Systems of STEMI Care,

Reperfusion Therapy, and Time-to-

Treatment Goals

All communities should create and maintain a regional system of

STEMI care that includes assessment and continuous quality

improvement of EMS and hospital-based activities. Performance

can be facilitated by participating in programs such as Mission:

Lifeline and the D2B Alliance.

I IIa IIb III

Performance of a 12-lead ECG by EMS personnel at the site of

FMC is recommended in patients with symptoms consistent with

STEMI.

I IIa IIb III

STEMI Regional Systems

11 12/17/2015 ©2011, American Heart Association

Onset of

symptom

of STEMI

GOALS†

Patient

5 min after

symptom onset

9-1-1

EMS

dispatch

Dispatch

1 min

EMS on-scene

• Encourage 12-lead ECGs

• Consider prehospital fibrinolytic if

capable and EMS-to-needle within 30 min

EMS on scene EMS transport

within 8 min Prehospital fibrinolysis:

EMS-to-needle within 30 min

STEMI-receiving hospital

(PCI-capable)

EMS transport:

EMS-to-balloon within 90 min

Patient self-transport:

Hospital door-to-balloon within 90 min

Total ischemic time: Within 120 min* * Golden Hour = First 60 minutes

Hospital fibrinolysis:

Door-to-needle within 30 min

EMS

Triage

Plan

STEMI-referral hospital

(non PCI-capable)

Baseline characteristics and reperfusion strategy

Variable Year

Baseline characteristics 2008 2009 2010 2011 2012

Age (yrs)* 60 (52,71)

60 (52,71)

60 (52,71)

61 (52,71)

61 (52,70)

Female sex (%) 30 30 30 30 30

Time symptom onset to FMC (minutes)*

50 (21,120)

50 (23,120)

50 (23,120)

52 (24,120)

49 (23,115)

Reperfusion strategy 2008 2009 2010 2011 2012

Primary PCI for transfer-in (%) 62 68 72 85 90

Fibrinolytic therapy (%) 13.4 11.1 9.0 7.4 7.0

*median (25th, 75th percentile)

150,000 patients at 485 hospitals

representing 46 states

Sorin Brener

Marty Leon Alice Jacobs

Roxanna Mehran Kirk Garratt

Timing of cath after fibrinolytic therapy

15

Primary Outcome of 7 Trials of Routine vs Ischemia-

driven Catheterization and PCI After Fibrinolytic Therapy

3.5 hr 16.7 hr 2.2 hr 4.9 hr

N

Risk

Follow-up

Composite

500

All

12 mo

D,MI,revasc

163

All

6 mo

D,MI,RI,TVR

170

High

6 mo

D,MI,RI,

stroke

600

High

30 d

D, MI, RI

204

All

30 d

D,MI,RI,CHF,

shock, arrhy

3.9 hr

266

All

12 mo

D, MI, RI,

stroke

2.7 hr 1.6 hr

1059

High

30 d

D,MI,RI,CHF,

shock

Time (median or average) from Fibrinolytic to PCI

Practice and timing of non-infarct vessel PCI

17

PRAMI Trial Non-culprit vessel PCI at time of primary PCI vs only for refractory angina/ ischemia (74 D/MI/RI events)

Wald DS et al. N Engl J Med 2013;369:1115-1123.

CvLPRIT Trial Non-culprit vessel PCI at time of primary PCI vs only for refractory angina/ ischemia (46 MACE events)

Gershlick J Am Coll Cardiol. 2015; 65: 963–972.

Non-Culprit Lesion PCI: CvLPRIT and PRAMI

Bhatt J Am Coll Cardiol. 2015

DANAMI 3 – PRIMULTI Trial: FFR-Guided PCI reduced revasc with no difference in death or MI

IRA only

(n = 313)

Complete

revascularisation

(n = 314)

HR [95% CI] p

Primary endpoint 68 (22%) 40 (13%) 0·56 [0·38 – 0·83] 0·004

All-cause death 11 (4%) 15 (5%) 1·4 [0·63 – 3·0] 0·43

Nonfatal MI 16 (5%) 15 (5%) 0·94 [0·47 – 1·9] 0·87

Ischemia-driven

revascularisation* 52 (17%) 17 (5%) 0·31 [0·18 – 0·53] <0·001

Engstrøm, Lancet 2015

Culprit Artery Only vs Mutivessel PCI

21 Levine 2015 ACC/AHA/SCAI Focused Update on Primary PCI

STEMI with successful culprit lesion PCI (primary, rescue or pharmacoinvasive) +

≥ 70% stenosis or ≥ 50% with FFR < 0.80

Staged Non-culprit lesion PCI+OMT

Staged PCI of all suitable

non-culprit lesions

N=1950

COMPLETE Trial: Trial Design

RANDOMIZED

Within 72 h of index

Primary PCI

Primary Outcome: CV Death / MI

Key Secondary Outcome: CV Death/MI/Ischemia driven revascularization

Optimal Medical Therapy Alone

No further revsac of non-culprit lesions

(OMT Alone)

N=1950

ALL patients receive OMT (ASA, Ticagrelor, Statin, Beta Blocker, RF Modification)

Follow-up: Discharge, 30 Days, 6 mos, then Annually

Clinicaltrials.gov NCT0174049 Funded by CIHR, AstraZeneca and Boston Scientific

Summary (of evidence to date) pending the COMPLETE trial

1. PCI is effective in reducing angina and subsequent revascularization.

This is true in patients with and without ACS, including patients with

STEMI who have multivessel disease (PRAMI, Cvlprit and DANAMI-3).

2. Current evidence is encouraging, but insufficient to determine

whether non-culprit lesion PCI reliably reduces death or MI.

3. The COMPLETE trial is powered to detect differences in death or MI

and is designed to determine whether staged PCI reliably reduces

these events in patients with STEMI and multivessel disease.

Timing of cath and PCI in NSTE ACS

24

TIMACS

Preliminary Results AHA Nov 7, 2008

Interventions and Timing

Early

N=1,593

Delayed

N=1,438

Coronary Angiography (%)

97.6 95.5

Median time (h ± iqr) 14 (3-21) 50 (41-81)

PCI (%) 59.6 55.1

Median time (h ± iqr) 16 (3-23) 52 (41-101)

CABG (%) 14.8 13.6

Median time (d ± iqr) 7.7 (4.7-17.4) 10.8 (6.7-19.8)

Iqr=interquartile range Mehta SR et al. N Engl J Med 2009;360:2165-2175

TIMACS

Preliminary Results AHA Nov 7, 2008

Death, MI, Stroke at 6 Months Pre-specified Subgroups

Overall

Age < 65

>=65

Female Male

No ST deviation

ST deviation

No elevated marker

Elevated Marker

GRACE 0-140

GRACE >=141

3031

1293

1736

1052 1976

1523

1508

668

2363

2070

961

9.7

6.5

12.3

9.7 9.8

7.6

11.7

10.5

9.5

7.7

14.1

0.463

0.540

0.722

0.423

0.0097

0.85 ( 0.68 - 1.06 )

0.98 ( 0.64 - 1.52 )

0.83 ( 0.64 - 1.07 )

0.77 ( 0.54 - 1.12 )

0.89 ( 0.68 - 1.18 )

0.88 ( 0.62 - 1.26 )

0.81 ( 0.61 - 1.07 )

1.00 ( 0.62 - 1.60 )

0.81 ( 0.63 - 1.04 )

1.14 ( 0.82 - 1.58 )

0.65 ( 0.48 - 0.88 )

N Characteristic HR (95% CI) Interaction

p-Value

0.33 0.5 0.7 1.00 1.5 2.0 3.0

Early better Delayed better Hazard Ratio (95% CI)

Early

%

11.4

6.5

14.8

12.3 10.9

8.7

14.3

10.5

11.7

6.7

21.6

Delayed

%

Mehta SR et al. N Engl J Med 2009;360:2165-2175

26

TIMACS

Preliminary Results AHA Nov 7, 2008

GRACE Risk Score: Primary Outcome

6.7

21.6

7.7

14.1

0

5

10

15

20

25

Dea

th/M

I/Str

oke

at

6 m

o. (

%)

Delayed

Early

HR 1.14

95% CI 0.82-1.58

P=0.43

HR 0.65

95% CI 0.48-0.88

P=0.005

Interaction P=0.01

High Risk

GRACE Score >= 140

N=961

Death, MI or Stroke at 6 mo.

Mehta SR N Engl J Med 2009;360:2165-2175

Low/Int Risk

GRACE Score < 140

N=2070

(>3%

inhospital

death)

Which P2Y12 antagonist in acute ACS, and when?

28

ACCOAST design

Prasugrel 30 mg

Prasugrel 60 mg Prasugrel 30 mg

Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days

PCI

1° Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa bailout, at 7 days

Placebo

Coronary

Angiography

n~4100 (event driven)

Coronary

Angiography

PCI

CABG

or

Medical

Management

(no prasugrel)

CABG

or

Medical

Management

(no more prasugrel)

Montalescot G et al. Am Heart J 2011;161:650-656

Randomize 1:1 Double-blind

NSTEMI + Troponin ≥ 1.5 times ULN local lab value Clopidogrel naive or on long term clopidogrel 75 mg

All TIMI (CABG or non-CABG) Major Bleeding

(All Treated patients)

Days From First Dose

0 5 10 15 20 25 30

En

dp

oin

t (%

)

0

1

2

3

4

5

All TIMI Major Bleeding

Pre-treatment 2.9

Pre-treatment 2.6

No Pre-treatment 1.5

No Pre-treatment 1.4

Hazard Ratio, 1.97 (95% 1.26, 3.08) P=0.002

Hazard Ratio, 1.90 (95% 1.19, 3.02) P=0.006

Montalescot N Engl J Med 2013; 369:999-1010

Duke ACS Algorithm: NSTE ACS

NSSTT s,

neg. cardiac markers

Dynamic STs,

pos. cardiac markers

GRACE > 3% death

Antithrombotic Rx

Fonda UFH

cath in 12 h no cath

in 12 h

Anticoagulant Rx

Ticagrelor 180 mg load; 90 mg twice daily or Clopidogrel 600 mg load

Cath <24 hrs Cath >24 hrs No or delayed cath

Or bivalirudin**

Fondaparinux or enoxaparin UFH †

†GP IIb/IIIa at time of PCI or if refractory ischemia

**Consider bivalirudin for cath <12 hours

A common mistake in management of ACS: stopping anticoagulation prior to

revascularization

FRISC II: Open + double-blind treatment period

180 150 120 90 60 30 0

Pro

ba

bil

ity

of

dea

th o

r M

I

,14

,12

,10

,08

,06

,04

,02

0,00

Dalteparin - Noninv

Placebo - Noninv

Placebo - Invasive

Dalteparin - Invasive

FRISC II. Lancet , August 1999

Time as an adjunct in ACS management

Reperfusion is the most important way to save lives in acute STEMI, and faster reperfusion saves more lives, with regional systems as key to accomplishing this

Non-infarct PCI, acutely or during the initial hospitalization, reduces ischemia and need for subsequent revascularization, and may reduce reMI

Early cath and PCI results in better outcome for high risk NSTEMI

Start P2Y12 early (at first hospital), but very early (prehospital) does not help

For NSTEMI, continue anticoagulation until planned CABG revascularization