A changing paradigm in ACS

management
 Activated platelets are central to
thrombus formation in ACS
• Platelets do 3 things that promote thrombus formation
– Adhesion
Activated platelets aggregate
– Activation and assemble a critical mass
– Aggregation of activated, pro-thrombotic
3 platelet membrane at the site
of injury

Adherent platelet become activated

2

1
Plaque rupture leads
to platelet adhesion
to the exposed
subendothelium

Vorchheimer DA, et al. Mayo Clin Proc. 2006;81:59-68; Davies MJ. Heart. 2000;83:361-366.
 Targets for platelet inhibition
ASPIRIN
HEPARINS 5HT
5HT
FONDAPARINUX
BIVALIRUDIN Coagulation
Thromboxane
A
2 x
Collagen ADP ADP ADP TICLOPIDINE
CLOPIDOGREL
RIVAROXABAN
APIXABAN
DABIGATRAN
x
Thrombin x TPa
GPVI 5HT2A P2Y
1
ATP ATP PRASUGREL

P2X1
x PAR-1
PAR-4 ACTIVE
METABOLITE

VORAPAXAR
E5555 PLATELET
Dense
granule x
P2Y12
TICAGRELOR
CANGRELOR
Thrombin ELINOGREL
ACTIVATION
generation

Shape Amplification
change Alpha
granule
Aggregation
a b
a b
IIb 3
IIb 3

Fibrinogen
x a b
IIb 3
Coagulation factors
Inflammatory mediators
GP IIb/IIIa ANTAGONISTS
GP, glycoprotein; PAR, protease-activated receptor;
TP, thromboxane A2 / prostaglandin H2

Storey RF Curr Pharm Des 2006;12:1255–1259

 The P2Y12 receptor and platelet activation
ADP

P2Y12 receptor ADP binds and activates Conformational change

the receptor and signalling

• P2Y12 is a seven transmembrane spanning receptor

• ADP binding activates the P2Y12 receptor
•Conformational changes leads to signaling through a G-protein coupled
mechanism
- Potentiates further ADP secretion
- Recruits additional platelets
- Facilitates platelet adhesion
ADP, adenosine diphosphate
van Giezen JJ et al. J Thromb Haemost 2009;7:1556–1565
Angiolillo DJ & Ueno M. JACC: Cardiology Interventions 2011;4 (4):411–414
 Ticagrelor
HO
N
N
N
HO H
N F Ticagrelor is a cyclo-pentyl-
O N
N triazolo-pyrimidine (CPTP)
F
S
OH

• Direct-acting P2Y12 receptor antagonist

– Direct-acting; does not require metabolic activation
– Faster onset of inhibitory effect on the P2Y12 receptor than
clopidogrel
• First reversibly binding oral ADP receptor antagonist
– Active in systemic circulation throughout dosing interval
– Higher and more consistent platelet inhibition than clopidogrel
Deeks ED. Drugs 2011;71(7):909-933
Husted S. Van Giezen JJJ. Cardiovascular Therapeutics 2009;27:259-274
 Ticagrelor P2Y12 receptor binding
ADP

P2Y12 receptor ADP binds and activates Conformational change

the receptor and signalling

Ticagrelor binds away ADP can bind reversibly Receptor remains intact
from ADP pocket but no conformational upon dissociation
change or signalling

ADP, adenosine diphosphate

Adapted from Husted S. Van Giezen JJJ. Cardiovascular Therapeutics 2009;27:259-274
 Ticagrelor: Does Not Require Hepatic
Metabolism for Activation
Ticagrelor:
Does NOT require metabolic activation to
become active drug

Ticagrelor
Binding

Platelet

P2Y12
Clopidogrel
CYP-dependent CYP-dependent
oxidation oxidation
CYP1A2 CYP2C19
Active compound CYP2B6 CYP3A4/5
CYP2C19 CYP2B6
Intermediate metabolite
Prodrug
Clopidogrel:
A prodrug; requires metabolism to
become active drug

Adapted from Schomig A. N Engl J Med. 2009;361:1108–1111.

 Clinical Pharmacology: Ticagrelor and Clopidogrel

Ticagrelor Clopidogrel

Chemical class CPTP Thienopyridine

Reversible Inhibition of P2Y12 receptor Yes No

PD variability with CYP2C19 genotype No Yes

Dosing Twice daily (bid) Once daily (qd)

Mean inhibition of platelet aggregation

(IPA) at 30 minutes
41% 8%

Mean IPA at 2 hours 89% 38%

Gurbel PA, et al. Circulation. 2009;120:2577–2585.

BRILINTA Indonesia Prescribing Information 2012.
PLAVIX Indonesia Prescribing Information (latest version).
 ONSET/OFFSET: Study Design
Patients with stable CHD (n=123) on aspirin treatment

Onset, Day 1
Randomization
Platelet function testing at predose and 0.5, 1, 2 , 4, 8, and 24 hours post dose

Loading
Ticagrelor 180 mg Clopidogrel 600 mg Placebo

Maintenance, 6 weeks
Ticagrelor 90 mg twice Clopidogrel 75 mg once
daily Placebo
daily

Offset, 10 days
Platelet function testing at 0 (last dose), 2, 4, and 8 hours after last dose and at days 1
to 3, 5, 7, and 10 after last dose

[Gurbel 2009:I,K]
Primary endpoints:
• ONSET: IPA (20 μM ADP, final extent) at 2 hours after the first dose of study drug
• OFFSET: SLOPE of IPA between 4 and 72 hours after the last dose of study drug
Gurbel PA, et al. Circulation. 2009;120:2577-2585.
DISCLAIMER: BRILINTA is not indicated in stable CAD
 ONSET/OFFSET: Pharmacodynamics in Stable
CAD Patients Last
Maintenance
Dose
Loading 90 mg bid
100 75 mg qd Ticagrelor (n=54)
Dose
90
* * * * * †
180 mg
600 mg
* * Clopidogrel (n=50)
80
 * *
†
P<0.0001
70 P<0.005
‡ P<0.05

60
IPA %

50
* 
40
‡
30
†
20

10


0

0 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240

Onset Maintenance Offset

Time (Hours) Time (Hours)
Adapted from Gurbel PA, et al. Circulation. 2009;120:2577–2585.
 RESPOND: Study Design
Patients with stable CHD (n=98) on aspirin treatment
AZD6140 90 mg bd

Partial crossover
AZD6140 180/90 mg bd

Clopidogrel 600/75 mg od
All subjects (n=57) are
R clopidogrel responders
AZD6140 180/90 mg bd
Responders*

Clopidogrel 600/75 mg od
Clopidogrel 75 mg od
Randomisation
V2 V3 V4 V5
Screening
V1* ≥14-day
2 weeks 4 weeks
Nonresponders*

washout 0 weeks V3 + 1 day

(±2 days) (±2 days)
– 14–28 days
AZD6140 180/90 mg bd Clopidogrel 600/75 mg od

R
All subjects (n=41) are Crossover
clopidogrel nonresponders

Clopidogrel 600/75 mg od AZD6140 180/90 mg bd

Incl clopidogrel responsiveness, to 300-mg clopidogrel load.

Gurbel PA, et al. Circulation. 2010;121:1188-1199.
Nonresponders absolute change in platelet ≤10%; Responders absolute change in platelet >10%
 RESPOND: Primary analysis – inhibition of platelet
aggregation in clopidogrel non-responders
[Gurbel 2010:M]
maximum aggregation) (%)

≈40% mean increase in IPA

IPA (20 μM ADP-induced

among nonresponders, when

switched to ticagrelor

Greater IPA was achieved in clopidogrel non-responders

treated with ticagrelor compared with clopidogrel[Gurbel 2010:M]
*p<0.0001, †p<0.001, ‡p<0.05.
ADP, adenosine diphosphate; IPA, inhibition of platelet aggregation.
Gurbel PA, et al. Circulation 2010;121:1188–1199.
 RESPOND: Primary analysis – inhibition of
platelet aggregation in clopidogrel responders
≈20% mean
maximum aggregation) (%)

increase in IPA
IPA (20 μM ADP-induced

among
responders,
Crossover

when switched
to ticagrelor

≈25% mean
decrease in IPA
among
responders,
when switched
to clopidogrel
maximum aggregation) (%)
IPA (20 μM ADP-induced
Continue

Greater IPA was achieved in clopidogrel responders

treated with ticagrelor compared with clopidogrel
*p<0.0001, †p<0.001, ‡p<0.05.
ADP, adenosine diphosphate; IPA, inhibition of platelet aggregation.
Gurbel PA, et al. Circulation 2010;121:1188–1199.
 • Active drug
Key points from
• Reversibly binding
the molecule
• Fast Onset – ONSET/OFFSET trial
• Benefit over clopidogrel for both
responders and non responders –
RESPOND Trial
 PLATO Study

PLATO study tested the hypothesis that…

ticagrelor will result in a lower risk of recurrent thrombotic events in a broad
patient population with ACS as compared to clopidogrel and this would be
achieved with a clinically acceptable bleeding rate and overall safety profile1

PLATO Study2:
• 43 countries
• 862 sites 18,624
43862
countries
patients
sites
• 18,624 patients

1. James S et al. Am Heart J 2009;157: 599 – 605

2. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
 PLATO: Study Population

ACS Patient

STEMI UA/NSTEMI

Initial Invasive Initial Non-Invasive

Primary PCI
Management Management

No Reperf PCI PCI

Fibrinolytic Rx No revascularisation CABG

Only STEMI patients

intended for primary PCI
included CABG No revascularisation

Adapted from James S, et al. Am Heart J. 2009;157:599–605.

 PLATO: Study Design

Primary efficacy
Ticagrelor (n=9,333) endpoint:
Composite of CV
death, MI (excluding
silent MI), or stroke
180-mg loading dose 90 mg bid + ASA maintenance dose

• All patients were hospitalised with symptom onset <24 hours

N=18,624 • Patients could be taking clopidogrel at time of randomisation
Patients with ACS
(UA, NSTEMI, or Primary safety
STEMI*) 300-mg loading dose† 75 mg qd + ASA maintenance dose endpoint:
Total PLATO major
bleeding‡
Clopidogrel (n=9,291)

Randomisation
Visit 2 Visit 3 Visit 4 Visit 5 Visit 6

Screening <24h Month 1 Month 3 Month 6 Month 9 Month 12

*STEMI patients scheduled for primary PCI were randomised; however, they may not have received PCI.
Initial Treatment approaches †A loading dose of 300-mg clopidogrel was permitted in patients not previously treated with clopidogrel,
• Medically managed (n=5,216 — 28.0%) with an additional 300 mg allowed at the discretion of the investigator.
• Invasively managed (n=13,408 — 72.0%) ‡The PLATO study expanded the definition of major bleeding to be more inclusive compared with

previous studies in ACS patients. The primary safety endpoint was the first occurrence of any major
bleeding event.

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

James S, et al. Am Heart J. 2009;157:599–605.
 PLATO Main: Inclusion Criteria

• Hospitalisation for STEMI or NSTEMI/UA ACS, with onset during previous

24 hours
• With STEMI, the following 2 inclusion criteria were required
– Persistent ST elevation of at least 0.1 mV in ≥2 contiguous leads or new LBBB
– Primary PCI planned
• With NSTEMI, at least 2 of the following 3 were required
– ST changes on ECG indicating ischaemia
– Positive biomarker indicating myocardial necrosis
– One of the following risk indicators
• ≥60 years of age
• Previous MI or CABG
• CAD with ≥50% stenosis in ≥2 vessels
• Previous ischaemic stroke, TIA, carotid stenosis (≥50%), or cerebral
revascularisation
• Diabetes mellitus
• Peripheral artery disease
• Chronic renal dysfunction (creatinine clearance <60 mL/min)

James S, et al. Am Heart J. 2009;157:599–605.

 PLATO Main: Key Exclusion Criteria

• Contraindication to clopidogrel
• Fibrinolytic therapy within 24 hours
• Oral anticoagulation therapy that cannot be stopped
• ACS event was a complication of previous PCI
• PCI after index event (initial clinical signs and symptoms)
and before first study dose
• Increased risk for bradycardic events
• Concomitant therapy with strong CYP3A
inhibitors/inducers
• Patients requiring dialysis

James S, et al. Am Heart J. 2009;157:599–605.

 PLATO Study

Summary
• PLATO was a pivotal clinical study, comparing ticagrelor to the
current standard of care, clopidogrel
• A total of 18,624 patients with ACS were randomised early after
admission to the hospital─within 24 hours of symptom onset and
generally prior to angiography
• The study was designed to reflect clinical practice
– Allowed prior clopidogrel use
– Included both intent for invasive management (72%) and intent for
medical management (28%)
– PLATO allowed up to 600-mg clopidogrel loading dose pre-PCI
• PLATO enrolled a broad spectrum of patients with ACS (UA,
NSTEMI, or STEMI)

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; James S, et al. Am Heart J. 2009;157:599–605.;

Cannon CP, et al. Lancet. 2010;375:283–293.
So…
How is the result
Efficacy Results
 PLATO: Baseline Characteristics
Ticagrelor Clopidogrel
Characteristic
(n=9,333) (n=9,291)
Median age, years 62.0 62.0

Age ≥75 years, n (%) 1,396 (15.0) 1,482 (16.0)

Women, n (%) 2,655 (28.4) 2,633 (28.3)

CV risk factors, n (%)

Habitual smoker 3,360 (36.0) 3,318 (35.7)

Hypertension 6,139 (65.8) 6,044 (65.1)

Dyslipidemia 4,347 (46.6) 4,342 (46.7)

Diabetes mellitus 2,326 (24.9) 2,336 (25.1)

History, n (%)

MI 1,900 (20.4) 1,924 (20.7)

PCI 1,272 (13.6) 1,220 (13.1)

CABG 532 (5.7) 574 (6.2)

ECG at study entry, n (%)

ST-segment elevation, persistent 3,497 (37.5) 3,511 (37.8)

ST-depression 4,730 (50.7) 4,756 (51.2)

T-wave inversion 2,970 (31.8) 2,975 (32.0)

Troponin-I positive, n (%) 7,965 (85.3) 7,999 (86.0)

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

 PLATO: Primary Efficacy Endpoint
(Composite of CV Death, MI, or Stroke)

13 0–30 Days 0–12 Months

12 11.7 Clopidogrel
Cumulative Incidence (%)

11
10 9.8 Ticagrelor
9 Clopidogrel
8 5.4
7
6
5
4 ARR=0.6% ARR=1.9%
4.8
RRR=12% RRR=16%
3 Ticagrelor
P=0.045 NNT=54*
2 HR: 0.88 (95% CI, 0.77−1.00) P<0.001
1 HR: 0.84 (95% CI, 0.77–0.92)
0
0 2 4 6 8 10 12
No. at risk Months After Randomization
Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147

Clopidogrel 9,291 8,521 8,362 8,124 6,650 5,096 4,047

Both groups included aspirin.
*NNT at one year.

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

 PLATO: Predefined Testing of Primary and
Major Secondary Efficacy Endpoints

Ticagrelor Clopidogrel HR for Ticagrelor

All Patients* P Value**
(n=9,333) (n=9,291) (95% CI)
Primary endpoint, n (%/year)

Death from vascular cause + MI† + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001

Secondary endpoints, n (%/yr)

Death from any cause + MI† + stroke 901 (10.2) 1,065 (12.3) 0.84 (0.77–0.92) <0.001

Death from vascular causes + MI† + stroke 1,290 (14.6) 1,456 (16.7) 0.88 (0.81–0.95) <0.001
+ severe recurrent ischemia + recurrent
ischemia + TIA + arterial thrombus
MI† 504 (5.8) 593 (6.9) 0.84 (0.75–0.95) 0.005
Death from vascular causes 353 (4.0) 442 (5.1) 0.79 (0.69–0.91) 0.001
Stroke 125 (1.5) 106 (1.3) 1.17 (0.91–1.52) 0.22
Death from any cause 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001‡
Nominal
Significance

* Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded
from the CV death category. ** By Cox regression analysis using treatment as factor; †Excluding silent MI; ‡Death from any cause was tested after
stroke, which was non-significant, so the results should be considered nominally significant.

Both groups included aspirin.

The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months.

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

 PLATO: Secondary Efficacy Endpoints

Myocardial Infarction Cardiovascular Death

7 6.9 7
Clopidogrel

6 5.8 6
Cumulative Incidence (%)

Cumulative Incidence (%)

Clopidogrel 5.1
5 Ticagrelor 5

4.0
4 4
Ticagrelor
3 3

ARR=1.1% ARR=1.1%
2 2
RRR=16% RRR=21%
Calculated NNT=91 NNT=91
1 1
P=0.005 P=0.001
HR: 0.84 (95% CI, 0.75–0.95) HR: 0.79 (95% CI, 0.69–0.91)
0
0

0 2 4 6 8 10 12 0 2 4 6 8 10 12
Months After Randomisation Months After Randomisation

Rate of stroke for Ticagrelor was not different from clopidogrel (1.3% vs 1.1% ), P=0.225.

Both groups included aspirin.

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

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplement.
 Stent Thrombosis ticagrelor vs clopidogrel

Definite* Stent thrombosis at 12 month

2 1.9
0,6%
% stent thrombosis

ARR
1.3
33%
1
RRR
P = 0.009

0
Ticagrelor Clopidogrel
n= 5640 n = 5649
* Definition by Academic Research Consortium criteria

Wallentin L, et al. N Engl J Med 2009;361:1045-57

 PLATO Efficacy Results

Summary
• In PLATO, ticagrelor significantly reduced the composite of CV
death, MI or stroke vs clopidogrel at 1 year (1.9% ARR, 16% RRR,
P<0.001, NNT=54)
• Ticagrelor significantly reduced CV mortality vs clopidogrel
(1.1% ARR, 21% RRR, P=0.001)
– Risk of CV death and MI were both significantly reduced
– Risk of stroke was not significantly different
• The absolute risk reduction with ticagrelor vs clopidogrel starts early
and continues to build over the full 1 year treatment period
• In PLATO, for every 91 ACS patients treated with ticagrelor for 1
year, instead of clopidogrel, 1 CV death was prevented (NNT=91)
• The effect of ticagrelor over clopidogrel appears consistent across
many subgroups

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

Supplement to: Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
BRILINTA. Indonesia Prescribing Information 2012.
A balance is important
Safety Results
 PLATO: Primary Safety Endpoint

15

Ticagrelor
PLATO-defined Total

11.6%
Major Bleeding (%)

P=NS
11.2%
10 Clopidogrel

P=0.43
HR: 1.04 (95% CI, 0.95–1.13)
0
0 60 120 180 240 300 360

Days From First Dose

No. at risk
Ticagrelor 9,235 7,246 6,826 6,545 5,129 3,783 3,433

Clopidogrel 9,186 7,305 6,930 6,670 5,209 3,841 3,479

Both groups included aspirin.

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

 PLATO: Safety Endpoints - bleeding

*Both groups included aspirin; **Proportion of patients (%)

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

 PLATO: Bleeding

BRILINTA (n=9,235)
18 P = 0.008
16.1 Clopidogrel (n=9,186)
16
K-M Estimated Rate (% Per Year)

14.6
14 NS
11.6
12 11.2

10 NS
7.9
8 7.4
NS
5.8 5.8 P = 0.03
6
4.5
3.8
4
2 NS
0.3 0.3
0
Major Bleeding Life-threatening/ Fatal Bleeding Major and Non-CABG- CABG-Major
Fatal Bleeding Minor Bleeding Major Bleeding Bleeding

All values presented by PLATO criteria.

Both groups included aspirin.

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

 PLATO: Dyspnoea

Dyspnoea in the PLATO trial Ticagrelor Clopidogrel P Value

Incidence of dyspnoea adverse events (%) 13.8 7.8 <0.001

Patients who discontinued treatment due to

0.9 0.1 <0.001
dyspnoea (%)

• Ticagrelor-associated dyspnoea was mostly mild to moderate in severity

and did not reduce efficacy
• Most events were reported as single episode occurring early after starting
treatment
• Not associated with new or worsening heart or lung disease

BRILINTA. Indonesia Prescribing Information 2012.

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Storey R, et al. Eur Heart J 2011;32:2945-2953
 PLATO: Bradycardia-related Events

Ticagrelor Clopidogrel
All Patients (n=9,235) (n=9,186) P Value
Bradycardia-related event, n (%)

Pacemaker insertion 82 (0.9) 79 (0.9) 0.87

Syncope 100 (1.1) 76 (0.8) 0.08

Bradycardia 409 (4.4) 372 (4.0) 0.21

Heart Block 67 (0.7) 66 (0.7) 1.00

• Ventricular pauses ≥3 seconds occurred in 5.8% of Ticagrelor-treated patients vs 3.6% of

clopidogrel-treated patients in the acute phase, and 2.1% and 1.7% after 1 month, respectively
• There were no differences in adverse clinical consequences (ie, pacemaker insertion, syncope,
bradycardia, and heart block)

1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.2. Scirica BM et al. J Am Coll Cardiol 2011;57:1908-1916
3. BRILINTA Indonesia Prescribing Information 2012.
 PLATO: Laboratory Parameters

Ticagrelor Clopidogrel
All Patients (n=9,235) (n=9,186) P Value
Mean % increase (± SD) in serum creatinine from
baseline
At 1 month 10 ± 22 8 ± 21 <0.001

At 12 months 11 ± 22 9 ± 22 <0.001

1 month after end of treatment 10 ± 22 10 ± 22 0.59

Mean % increase (± SD) in serum uric acid from
baseline
At 1 month 14 ± 46 7 ± 44 <0.001

At 12 months 15 ± 52 7 ± 31 <0.001

1 month after end of treatment 7 ± 43 8 ± 48 0.56

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

 PLATO Safety Results

Summary
• No increase in overall major bleeding with ticagrelor vs clopidogrel
• Non-CABG major bleeding and major + minor bleeding were more frequent
with ticagrelor vs clopidogrel
• No increase in overall fatal/life-threatening bleeding with ticagrelor vs
clopidogrel
• There are more dyspnoea-related events associated with ticagrelor vs
clopidogrel, however most events were mild to moderate in intensity and
often resolved without a need for treatment
• Please refer the label for all precautions and warnings

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

BRILINTA Indonesia Prescribing Information 2012
• Ticagrelor an active drug with reversible binding to
P2Y12 receptor
• Ticagrelor provide fast onset and fast offset
• Ticagrelor significantly reduces the combined risk
of CV death, MI, or stroke vs clopidogrel in patients
with ACS
• Ticagrelor significantly reduced CV mortality vs
clopidogrel
• Ticagrelor is effective in a broad spectrum of ACS
patients
• There is no increase of overall major bleeding with
Ticagrelor vs clopidogrel
• Ticagrelor has been recommended in ACS
guidelines both in initial management , before PCI
procedure and at discharge
Safety End Point: PLATO Major
PLATO scale TIMI scale
Major
Major fatal/life-threatening’ Intracranial, or clinically significant overt signs of
Any of the following: hemorrhage associated with a drop in Hg of >5 g/dL (or,
Fatal when Hg is not available, an absolute drop in hematocrit
Intracranial of > 15%)
Note: TRITON used ≥5 g/dL; not all fatal or life-threatening etc bleeds
Intrapericardial bleed with cardiac tamponade are included in the TIMI-Major category.
Hypovolemic shock or severe hypotension due to Life-threatening
bleeding and requiring pressors or surgery
Is fatal; leads to hypotension requiring treatment with
Clinically overt or apparent bleeding associated with a intravenous inotropic agents; requires surgical intervention
decrease in Hg of more than 50 g/L for ongoing bleeding; necessitates the transfusion of 4 or
Transfusion of 4 or more units (whole blood or PRBCs) more units of blood (whole blood or packed red blood
for bleeding cells) over a 48-hour period; is a symptomatic intracranial
hemorrhage
Major other
Any of the following:
Minor
Significantly disabling (e.g. intraocular with permanent
Any clinically overt sign of hemorrhage (including imaging)
vision loss)
that is associated with a fall in Hg of 3 to ≤5 g/dL (or, when
Clinically overt or apparent bleeding associated with a Hg is not available, a fall in hematocrit of 9 to ≤15%)
decrease in Hg of 30 to 50 g/L
Note: TRITON used 3 to <5 g/dL
Transfusion of 2-3 units (whole blood or PRBCs) for
bleeding
Minimal
Minor Any clinically overt sign of hemorrhage (including imaging)
Requires medical intervention to stop or treat bleeding that is associated with a fall in hemoglobin <3 g/dL (or,
(e.g. epistaxis requiring visit to medical facility for packing) when hemoglobin is not available, a fall in hematocrit of
<9%)d
Minimal
-
All others not requiring intervention or treatment