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Assoc.Prof.Dilok Piyayotai
Division of Cardiology
Thammasat University Hospital
ACS guidelines -Choose the right drugs and strategies before referal
เครือข่ายบริการสาธารณสุขที ่6
Guidelines Pertaining to ACS An Expanding Portfolio
ACC/AHA guidelines • 2011 ACC/AHA/SCAI Guideline on PCI • 2013 ACC/AHA Guideline on STEMI • 2014 ACC/AHA Guideline on NSTE-ACS • 2015 ACC/AHA/SCAI Focused Update on Primary PCI
for STEMI • 2016 ACC/AHA Focused Update on DAPT Duration ESC guidelines • 2012 STEMI Guideline • 2015 NSTEMI Guideline
* O’Connor RE, Brady W, Brooks SC, Diercks D, Egan J, Ghaemmaghami C, Menon V, O’Neil BJ, Travers AH, Yannopoulos D. “Part 10: acute coronary
syndromes: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care”. Circulation.
2010;122(suppl 3):S787-S817. http://circ.ahajoumals.org/content/122/18_suppl_3/S787
**Afolabi BA, Novaro GM, Pinski SL, Fromkin KR, Bush HS. Use of the prehoapital ECG improves door to balloon times in ST segment elevation myocardial
infarction irrespective of time of day or day of week. Emerg Med J. 2007;24:588-591
*** O’Connor, RE AL, Ali, brady , WJ, Ghaemmaghami CA, Menon V, Welsford M, shuster M. . Part 9: acute coronary syndromes: 2015 American Heart
Association Guidelines Update for Cardiopulmonary Resuscitation
and Emergency Cardiovascular Care. Circulation 2015;132(suppl2):S483-S500
• STEMI intervention
• Fibrinolytics
• Use of appropriate antiplatelet agents
• Use of appepropriate anticoagulants
The interesting topics in STEMI
The Goal of STEMI Intervention
• Restore flow in the culprit artery and optimize myocardial perfusion
• Preserve LV function.
• Reduce MI complications
• Reduce mortality.
Geoffrey Hartzler, M.D. First Primary Angioplasty in AMI, 1979
1946 - 2012
Angioplasty reduces mortality and morbidity
Primary PCI vs. Thrombolysis in ST-Elevation Myocardial Infarction: Meta-analysis (23 Randomised controlled trials, N=7,739)
Death Nonfatal MI
Short-term Outcomes (4-6 weeks)
Fre
qu
ency
(%
)
P<.0001
P<.0001
P=.0002
P<.0001 PPCI
Thrombolytic therapy
Recurrent Ischemia
Death, Nonfatal, Reinfarction, or Stroke
Based on Keeley EC, et al. Lancet. 2003;361:13-20.
11
Time from symptom onset to treatment predicts 1 Year Mortality—Primary PCI
The relative risk of 1 year mortality increases by 7.5% for each 30 minute delay.
De Luca G, et al. Circulation. 2004;109:1223-1225.
Y=2.86 (± 1.45) + 0.0045X1 + 0.000043X2 P<.001
Roughly 1% every 3 minutes
Primary PCI in STEMI
ACC/AHA STEMI guidelines 2015
Immediate transfer⟸Failed
Routine transfer 3-24 hr⟸Successful
Pharmaco-invasive Strategy for STEMI Transfer to a PCI-Capable Hospital After Fibrinolytic Therapy
Transfer of Patients With STEMI to a PCI-Capable Hospital for Coronary Angiography After Fibrinolytic Therapy
Transfer to a PCI-capable hospital for coronary angiography
is reasonable for patients with STEMI who have received
fibrinolytic therapy even when hemodynamically stable* and
with clinical evidence of successful reperfusion.
Angiography can be performed as soon as logistically
feasible at the receiving hospital, and ideally within 24
hours, but should not be performed within the first
2 to 3 hours after administration of fibrinolytic
therapy.
I IIa IIb III B
*Although individual circumstances will vary, clinical stability is defined by the absence of low output, hypotension, persistent tachycardia, apparent shock, high-grade ventricular or symptomatic supraventricular tachyarrhythmias, and
spontaneous recurrent ischemia.
Prefer 3-24 Hr after fibrinolysis
Indications for Transfer for Angiography After Fibrinolytic Therapy
*Although individual circumstances will vary, clinical stability is defined by the absence of low output, hypotension, persistent tachycardia, apparent shock, high-grade ventricular or symptomatic supraventricular tachyarrhythmias, and spontaneous recurrent ischemia.
ACC/AHA STEMI guidelines 2015
Immediate transfer⟸Failed
Routine transfer 3-24 hr⟸Successful
ACC/AHA STEMI guidelines 2015
Risk-Benefits of N-IRA PCI
? Benefits
• Decrease infarct size by increasing collateral flow
• Reduce recurrent MI – Plaque stabilisation
• ? Reduce length of stay
• Reduce recurrent ischaemia – ? Improve prognosis
? Risks
• Increase infarct size – N-IRA PCI related
• Contrast induced nephropathy
• Bleeding
• Increase cost with no clinical benefit
Culprit artery–only versus multivessel PCI
PCI-CLARITY: Event rates following PCI
Sabatine MS et al. JAMA 2005; 294:1224-1232.
End point Clopidogrel pretreatment (%)
No pretreatment (%)
Adjusted odds ratio (95% CI)
p
CV death/MI/stroke*
3.6 6.2 0.54 (0.35-0.85)
0.008
CV death/MI 3.3 5.4 0.58 (0.36-0.94)
0.03
CV death 1.4 2.6 0.49 (0.24-1.03)
MI 1.9 3.1 0.60 (0.33-1.11)
Stroke 0.4 1.2 0.35 (0.11-1.11)
*Primary end point
PLATO STEMI-Hierarchical testing of major efficacy endpoints
Endpoint* Ticagrelor (n=4,201)
Clopidogrel (n=4,229)
HR for ticagrelor (95% CI)
p-value†
Primary endpoint, %
CV death + MI + stroke
9.3
11.0
0.85 (0.74–0.97)
0.02
Secondary endpoints, %
Total death + MI + stroke
CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events
MI
CV death
Stroke
9.7
13.4
4.7
4.5
1.6
11.5
15.4
6.1
5.4
1.0
0.84 (0.73–0.96)
0.86 (0.76–0.96)
0.77 (0.63–0.93)
0.84 (0.69–1.03)
1.45 (0.98–2.17)
0.01
0.01
0.01
0.09
0.07
All-cause mortality 4.9 6.0 0.82 (0.68–0.99) 0.04
The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint.
†By univariate Cox model
Adjunctive Antithrombotic Therapy to
Support Reperfusion With Primary PCI
‡The recommended ACT with planned GP IIb/IIIa receptor antagonist treatment is 200 to 250 s.
§The recommended ACT with no planned GP IIb/IIIa receptor antagonist treatment is 250 to 300 s (HemoTec device) or 300
to 350 s (Hemochron device).
Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI with symptom onset ≤12 hours
Emergent angiography, followed by triage to…
Primary PCI CABG – Medical Rx –
UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide)
Bivalirudin monotherapy
(± provisional GP IIb/IIIa)
Aspirin, thienopyridine R
1:1
3006 pts eligible for stent randomization R
3:1
Bare metal EXPRESS stent Paclitaxel-eluting TAXUS stent
Clinical FU at 30 days, 6 months, 1 year, and then yearly through 3 years; angio FU at 13 months
Stone, GW N Engl J Med 2008;358:2218-30.
0
5
10
15
20
Horizons-Primary PCI Cohort (N=3,340)
30-day Event rates
RR = 0.99 [0.75, 1.32]
Psup = 1.00
RR = 0.59 [0.46, 0.77]
PNI ≤ 0.0001 Psup ≤ 0.0001
RR = 0.75 [0.62, 0.92]
PNI ≤ 0.0001 Psup = 0.005
*Not related to CABG
**MACE = All cause death, reinfarction, ischemic TVR or stroke
Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678)
Net adverse clinical Major bleeding* MACE** events
% 12.3
9.2 8.6
5.1 5.5 5.4
3-year MACE Components*
UFH + GPI (N=1802)
Bivalirudin (N=1800)
HR [95%CI] P Value Number
needed to treat
Death 7.7% 5.9% 0.75 (0.58,0.97) 0.03 54
- Cardiac 5.1% 2.9% 0.56 (0.40,0.80) 0.001 45
- Non cardiac 2.8% 3.1% 0.62
Reinfarction 8.2% 6.2% 0.76 (0.59,0.92) 0.04 52
- Q-wave 3.8% 3.4% 0.61
- Non Q-wave 4.9% 3.2% 0.009 58
Death or reinfarction 14.5% 11.3% 0.72 (0.58,0.91) 0.005 31
Ischemic TVR 12.1% 14.2% 0.06
Stroke 2.0% 1.7% 0.50
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
3-year Bleeding Endpoints UFH + GPI (N=1802)
Bivalirudin (N=1800)
HR (95% CI) P Value Number needed to treat
Major bleeding, non-CABG
10.5% 6.9% 0.64 (0.51-0.80) 0.0001 28
Major bleeding, including CABG
12.8% 8.9% <0.0001 25
Blood transfusion 5.1% 3.5% 0.01 61
TIMI Major or Minor 10.9% 7.0% <0.0001 26
TIMI Major 6.1% 4.1% 0.007 51
TIMI Minor 5.0% 3.2% 0.007 56
GUSTO (any) 12.7% 8.8% 0.0001 26
GUSTO severe/life-threatening
0.9% 1.0% 0.74
GUSTO moderate 6.3% 4.7% 0.03 63
GUSTO mild 6.2% 4.0% 0.003
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
How Effective are Antithrombotic Therapies in PPCI
Characteristic Bivalirudin (%) Heparin (%)
P2Y12 use - Any 99.6 99.5
- Clopidogrel 11.8 10.0
- Prasugrel 27.3 27.6
- Ticagrelor 61.2 62.7
GPI use 13.5 15.5
Radial arterial access 80.3 82.0
PCI performed 83.0 81.6
Event curve shows first event experienced
Bivalirudin Heparin n % % n
Minor Bleed 83 9.2 % v 10.8 % 98
Major or Minor 113 12.5 % v 13.5 % 122
Minor Bleed P=0.25 Major or Minor P=0.54
Major Bleed BARC grade 3-5 Minor Bleed BARC grade 2
Reperfusion at a Non–PCI-Capable Hospital
Guideline for STEMI
Indications for Fibrinolytic Therapy When There Is a >120-Minute Delay From FMC to Primary PCI
Adjunctive Antithrombotic Therapy to Support Reperfusion With Fibrinolytic Therapy
Adjunctive Antithrombotic Therapy to Support Reperfusion With Fibrinolytic Therapy (cont.)
New NSTE-ACS guidelines
The most confusing issues in NSTE-ACS management
• Diagnosis : rule-in & rule-out protocol
• Risk stratification
• Invasive vs ischemia-driven management
• Use of appropriate antiplatelet agents
• Use of appropriate anticoagulants
The most confusing issues in NSTE-ACS management
• Diagnosis : rule-in & rule-out protocol
• Risk stratification
• Invasive vs ischemia-driven management
• Use of appropriate antiplatelet agents
• Use of appepropriate anticoagulants
Marco Roffi* et al. Eur Heart J 2015,
0 h/3 h rule-out algorithm of of NSTEMI using hs-troponin
Marco Roffi* et al. Eur Heart J 2015,
Marco Roffi* et al. Eur Heart J 2015,
Marco Roffi* et al. Eur Heart J 2015,
5 12
3
52
5
The most confusing issues in NSTE-ACS management
• Diagnosis : rule-in & rule-out protocol
• Risk stratification
• Invasive vs ischemia-driven management
• Use of appropriate antiplatelet agents
• Use of appepropriate anticoagulants
Benefit of Risk Stratification in NSTE-ACS patients
1) selection of the site of care:
- coronary care unit
- monitored step-down unit
- outpatient setting
2) selection of therapy:
- GP IIb/IIIa inhibitors
- invasive management strategy
Rationale for Risk Stratification in NSTE-ACS patients
- Focuses on history
- Physical findings
- ECG findings
- Biomarkers of cardiac injury
(Cardiac specific Troponin)
- Scoring system e.g. TIMI score, GRACE risk score
Summary of recommendations for prognosis early risk stratification
✔
✔
✔
✔
EKG • Transient ST changes (>0.5 mm.)during
symptom at rest strongly suggest ischemia and underlying severe CAD
• Marked symmetrical precordial T-wave inversion (> 2 mm) suggests acute ischemia, particular due to critical stenosis of LAD
EKG
• Completely normal ECG does not exclude NSTE-ACS, 1-6% will have MI
• Nonspecific ST-T changes (defined as ST deviation of < 0.5 mm. or T-wave inversion of < 2 mm. are less helpful diagnostically
Troponin Predicts Mortality
Antman TM, Tenasijevic MJ, Thompson B, et al. Cardiac-specific troponin I
levels to predict the risk of mortality in patients with acute coronary
syndromes. N Engl J Med 1996;335:1342-1349.
Risk Assessment Tools
• The TIMI risk score
• The GRACE risk model
• The PURSUIT risk score
• Etc.
TIMI Risk Score* for NSTE-ACS
TIMI Risk
Score
All-Cause Mortality, New or Recurrent MI, or
Severe Recurrent Ischemia Requiring Urgent
Revascularization Through 14 d After
Randomization, %
0–1 4.7
2 8.3
3 13.2
4 19.9
5 26.2
6–7 40.9
*The TIMI risk score is determined by the sum of the presence of 7
variables at admission; 1 point is given for each of the following variables:
≥65 y of age; ≥3 risk factors for CAD; prior coronary stenosis ≥50%; ST
deviation on ECG; ≥2 anginal events in prior 24 h; use of aspirin in prior 7
d; and elevated cardiac biomarkers.
Calibration of Simplified Global Registry of ACS
Mortality Model
The most confusing issues in NSTE-ACS management
• Diagnosis : rule-in & rule-out protocol
• Risk stratification
• Invasive vs ischemia-driven management
• Use of appropriate antiplatelet agents
• Use of appepropriate anticoagulants
Invasive vs Conservative Strategy Clinical Trials
TIMI IIIB (94)
Conservative Strategy Favored
N=920
Invasive Strategy Favored
N=7,018
VANQWISH (98)
MATE
FRISC II (99)
TACTICS- TIMI 18 (01)
VINO
RITA-3 (02)
TRUCS
ISAR- COOL
ICTUS (05)
No difference N=2,874
Weight of the evidence
Risk criteria mandating invasive strategy
Marco Roffi* et al. Eur Heart J 2015,
Rx strategy Action at non-PCI hospital
Immediate Invasive ( < 2 hours)
Immediate Transfer to PCI center
Early invasive (< 24 hours)
Same day Transfer to PCI center
Invasive (< 72 hours)
Transfer to PCI center
Marco Roffi* et al. Eur Heart J 2015,
The most confusing issues in NSTE-ACS management
• Diagnosis : rule-in & rule-out protocol
• Risk stratification
• Invasive vs ischemia-driven management
• Use of appropriate antiplatelet agents
• Use of appepropriate anticoagulants
74
NB: Continuation of ticagrelor or prasugrel beyond 12 months is outside the label of both drugs
Recommended treatment algorithm in NSTE-ACS
• Early management (angiography or initial medical management)
• Invasive management (PCI)
• Late/post- hospital care
Pathway stage
• Initiate ticagrelor or clopidogrel, preferably ticagrelor
• (NB: prasugrel is not a recommended option at this stage)
• Initiate/continue ticagrelor or clopidogrel, or initiate prasugrel (only after coronary anatomy has been defined)
P2Y12 recommendation
• Medically managed: Ticagrelor or clopidogrel for up to 12 months, preferably ticagrelor
• Stent: Ticagrelor, prasugrel or clopidogrel for at least 12 months, preferably ticagrelor or prasugrel
NSTE-ACS:
Definite or Likely
Ischemia-Guided strategy Early Invasive Strategy
Initiate DAPT and Anticoagulant Therapy
1. ASA (Class I; LOE: A)
2. P2Y12 inhibitor (in addition to ASA) (Class I; LOE B):
● Clopidogrel or
● Ticagrelor
3. Anticoagulant:
● UFH (Class I; LOE B) or
● Enoxaparin (Class I; LOE: A) or
● Fondaparinux (Class I; LOE: B)
Initiate DAPT and Anticoagulant Therapy
1. ASA (Class I; LOE: A)
2. P2Y12 inhibitor (in addition to ASA) (Class I; LOE: B):
● Clopidogrel or
● Ticagrelor
3. Anticoagulant:
● UFH (Class I; LOE B) or
● Enoxaparin (Class I; LOE: A) or
● Fondaparinux (Class I; LOE B) or
● Bivalirudin (Class I; LOE B)
Can consider GPI in addition to ASA and P2Y12 inhibitor in
high-risk (eg, troponin positive) patients (Class IIb; LOE B)
● Eptifibatide
● Tirofiban
Medical therapy
chosen based on cath
findings
Therapy
Ineffective Therapy
Effective
PCI with stenting
Initiate/continue antiplatelet and anticoagulant
therapy
1. ASA (Class I; LOE: B)
2. P2Y12 inhibitor (in addition to ASA):
● Clopidogrel (Class I; LOE: B) or
● Prasugrel (Class I; LOE: B) or
● Ticagrelor (Class I: LOE: B)
3. GPI (if not treated with bivalirudin at time of
PCI)
● High risk features, not adequately pretreated
with clopidogrel (Class I; LOE: A)
● High-risk features adequately pretreated
with clopidogrel (Class IIa; LOE: B)
4. Anticoagulant:
● Enoxaparin (Class I; LOE: A) or
● Bivalirudin (Class I; LOE: B) or
● Fondaparinux as the sole anticoagulant
(Class III: Harm; LOE: B) or
● UFH (Class I; LOE: B)
Late hospital/post hospital care 1. ASA indefinitely (Class I; LOE: A) 2. P2Y12 inhibitor (clopidogrel or ticagrelor), in addition to ASA, up to 12 mo if medically treated (Class I; LOE: B) 3. P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor), in addition to ASA, at least 12 mo if treated with coronary stenting (Class I; LOE: B)
CABG
Initiate/continue ASA therapy and
discontinue P2Y12 and/or GPI therapy
1. ASA (Class I; LOE: B)
2. Discontinue clopidogrel/ticagrelor 5
d before, and prasugrel at least
7 d before elective CABG
3. Discontinue clopidogrel/ticagrelor up
to 24 h before urgent CABG (Class I;
LOE: B). May perform urgent CABG
<5 d after clopidogrel/ticagrelor and
<7 d after prasugrel discontinued
4. Discontinue eptifibatide/tirofiban at
least 2–4 h before, and abciximab
≥12 h before CABG (Class I; LOE: B)
GP IIb/IIIa inhibitors
The most confusing issues in NSTE-ACS management
• Diagnosis : rule-in & rule-out protocol
• Risk stratification
• Invasive vs ischemia-driven management
• Use of appropriate antiplatelet agents
• Use of appepropriate anticoagulants
Anticoagulants
• Unfractionated heparin vs LMWH
– TIMI 11B, ESSENCE
• Bivalirudin
– ACUITY
• Fondaparinux
– OASIS-5
Moderate and high risk ACS
(n=13,819)
ACUITY: Study Design – First Randomization
An
gio
grap
hy
wit
hin
72
h
Aspirin in all Clopidogrel
dosing and timing per local practice
UFH/Enox + GP IIb/IIIa (n=4,603)
Bivalirudin + GP IIb/IIIa (n=4,604)
Bivalirudin Alone
(n=4,612)
R*
*Stratified by pre-angiography thienopyridine use or administration
Moderate and high risk unstable angina or NSTEMI
undergoing an invasive strategy (N = 13,819)
Medical management
PCI
CABG
Composite Ischemia – All pts
0
5
10
15
0 5 10 15 20 25 30 35
Cu
mu
lati
ve E
ven
ts (
%)
Days from Randomization
Estimate P (log rank) 7.4% UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604) 0.37 7.9%
Bivalirudin alone (N=4612) 0.30 8.0%
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
Major Bleeding (Non CABG) – All pts
0
5
10
15
0 5 10 15 20 25 30 35
Cu
mu
lati
ve E
ven
ts (
%)
Days from Randomization
Estimate P (log rank) 5.7% UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604) 0.41 5.3%
Bivalirudin alone (N=4612) <0.0001 3.1%
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
OASIS 5:
An International, Multicenter, Randomized, Double-Blind,
Double-Dummy Trial in 41 Countries
20,078 patients with UA/NSTEMI
Fondaparinux 2.5 mg s.c. od up to 8 days
Aspirin, Clopidogrel, anti-GPIIb/IIIa, planned
Cath/PCI as per local practice
Randomization
Enoxaparin 1 mg/kg s.c. bid for 2-8 days
1 mg/kg s.c. od if ClCr<30mL/min
1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10
2. OASIS 5 Investigators. N Engl J Med 1464-76
Vital status ascertained in 20,066 (99.9%) Lost to follow-up at day 9: fondaparinux: n=7 and enoxaparin: n=5
Death/MI/RI: Day 9
Days
Cu
mu
lati
ve
Ha
za
rd
0.0
0.0
10
.02
0.0
30
.04
0.0
50
.06
0 1 2 3 4 5 6 7 8 9
Enoxaparin
Fondaparinux
HR 1.01
95% CI 0.90-1.13
Major Bleeding: 9 Days
Days
Cu
mu
lati
ve
Ha
za
rd
0.0
0.0
10
.02
0.0
30
.04
0 1 2 3 4 5 6 7 8 9
HR 0.53
95% CI 0.45-0.62
P<<0.00001
Enoxaparin
Fondaparinux
ACS guidelines -Choose the right drugs and strategies before referal