ACS Management NSTEMI

Pro DTI “Hook-ster Hoekstra”

Pro Factor Xa “Knockdown Diercks”

James W. “Hook-ster”

Hoekstra, MD

Bivalirudin Use in the ED for NSTEMI:

Maximizing Our Choices to Maximize Our

Patients’ Benefit

James Hoekstra, MDProfessor and ChairmanDepartment of Emergency MedicineWake Forest University

80%

Diagnosis

Diagnosticcatheterization

60%

10%

20% 30%

PCI

CABG

Medicalmanagement

High risk

Low risk

CRUSADE Database.

Average time to catheterization = 21 hours

Current Management of NSTEMI ACS in the United States: Cath Happy!!

ACS, acute coronary syndrome; CABG, coronary artery bypass graft.ACS, acute coronary syndrome; CABG, coronary artery bypass graft.

Invasive Strategy Clinical Criteria (Class IA)– Recurrent chest pain– Elevated troponin level– ST depression– Signs of congestive heart failure– Sustained ventricular tachycardia– Hemodynamic instability– PCI in last month– High-risk noninvasive testing results– Prior CABG– TIMI >3– LVEF <40%– Diabetes

2007 ACC/AHA NSTE ACS Guidelines, available at acc.org.

EM Relevance: Medical Managementin the Pre-PCI Period

Concern Is Recurrent MI/Ischemia

ED PresentationED Presentation Catheterization Catheterization

D/CD/C

PCIPCI

Pre-PCI Period Pre-PCI Period Post-PCI PeriodPost-PCI Period

Cardiologists are vulnerable in the PCI and post-PCI period, where bleeding isa major concern

The Challenge: Balancing Efficacy and Safety

• Old guidelines (2002) emphasize reduction of ischemic risk in NSTE ACS—especially for upstream therapy initiated in the ED

• New guidelines (2007) include data on the harm that bleeding events cause, diminishing ischemic efficacy in some patients, and provide many more options for care upstream

• Emergency physicians are comfortable with the goal of reducing ischemic risk . . . and traditionally have left concern over bleeding to “downstream providers”; this paradigm is changing

IIaS

C

Direct antithrombin

LMWH

ATXa AT

Xa

Pentasaccharide

Bivalirudin and Fondaparinux

= saccharide unit.

Konkle BA, Schafer AI. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds.Braunwald’s Heart Disease. 7th ed. Volume 2. Philadelphia: Elsevier Saunders; 2005:2067–2092.

ATIIaIIa

UFH

LMWH, low-molecular-weight heparin.LMWH, low-molecular-weight heparin.

Moderate-high risk

ACS

Study Design: First Randomization• Moderate-high risk unstable angina or NSTEMI undergoing an

invasive strategy (N = 13,819)

An

gio

gra

ph

y w

ith

in 7

2 h

ou

rs

Aspirin in allAspirin in allClopidogrelClopidogrel

dosing and timingdosing and timingper local practiceper local practice

UFH orEnoxaparin+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

BivalirudinAlone

R*

*Stratified by preangiography thienopyridine use or administration.

ACUITY Design. Stone GW, et al. Am Heart J. 2004;148:764–775.

Medicalmanagement

PCI

CABG

Primary End Point Measures(Intent to Treat)

• Heparin* + IIb/IIIa vs Bivalirudin + IIb/IIIa vs Bivalirudin Alone

7.3%5.7%

11.7%

7.7%

11.8%

5.3%

3.0%

10.1%

7.8%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

Heparin+IIb/IIIa (N=4603) Bivalirudin+IIb/IIIa (N=4604) Bivalirudin alone (N=4612)

PNI <0.001PSup = 0.015

PNI = 0.011 PSup = 0.32

PNI <0.001PSup <0.001

*Heparin=unfractionated or enoxaparin. Stone GW, McLaurin BT. N Engl J Med. 2006;355:2203–2216.

0 1 2

ACUITY: Primary End Point Measures (Intent to Treat)

Bivalirudin Alone BetterBivalirudin Alone Better UFH/Enox + IIb/IIIa BetterUFH/Enox + IIb/IIIa Better

Risk Ratio±95% CI

Risk Ratio±95% CI

PrimaryEnd Point

Bivalalone

UFH/Enox+ IIb/IIIa

RR (95% CI)

Net clinical outcome

Ischemic composite

Major bleeding

Upp

er b

oun

dary

non

-infe

riorit

y11.7%10.1% 0.86 (0.77-0.97)

<0.0010.015

7.3%7.8% 1.08 (0.93-1.24)0.020.32

5.7%3.0% 0.53 (0.43-0.65)<0.001<0.001

P Value(noninferior)

(superior)

UFH/Enoxaparin + GPI vs Bivalirudin Alone

Stone GW, McLaurin BT. N Engl J Med. 2006;355:2203–2216.

0 1 2

UFH/Enoxaparin + IIb/IIIa vs Bivalirudin Alone

Yes (n = 3,197)No (n = 6,008)

Low (0–2) (n = 1,291)Intermed (3–4) (n = 4,407)

High (5–7) (n = 2,449)

Elevated (n = 5,368)Normal (n = 3,841)

Risk Ratio±95% CI

Risk Ratio±95% CI

BivalAlone

UFH/Enox+ IIb/IIIa

9.2%11.3%

12.2%11.1%

P Pint

0.76 (0.65–0.89)1.02 (0.86–1.21)

12.2%7.1%

13.3%9.4%

0.92 (0.80–1.06)0.75 (0.61–0.93)

0.230.01

<0.0010.83

0.35

0.02

0.18

13.0%8.6%

13.7%10.6%

0.96 (0.80–1.14)0.81 (0.69–0.95)

0.610.01 0.42

Biomarkers (CK/Trop)

ST deviation

TIMI risk score

Prethienopyridine

6.4% 10.2% 0.63 (0.43–0.91) 0.019.4% 10.2% 0.92 (0.77–1.10) 0.34

13.9% 15.2% 0.92 (0.76–1.11) 0.36

Yes (n = 5,192)No (n = 4,023)

RR (95% CI)

Bivalirudin Alone BetterBivalirudin Alone Better UFH/Enox + IIb/IIIa BetterUFH/Enox + IIb/IIIa Better

Stone GW, McLaurin BT. N Engl J Med. 2006;355:2203–2216.

ACUITY: Net Clinical Outcome Composite

Enoxaparin or UFH with antiplatelet agents

Fondaparinux or bivalirudin with antiplatelet agents

Invasive Therapy:Initial Antithrombin Therapies

II IIaIIa IIbIIb IIIIII

.

Upstream Hospital Care: Invasive RxAntiplatelet Therapy

A Platelet GP IIb/IIIa inhibitor in addition to ASA and heparin upstream for patients in whom PCI is planned

OR Clopidogrel 300 mg load and 75 mg/day upstream for a month up to a year

Bivalirudin instead of GPI/antithrombin upstream only if clopidogrel is used as well >6 hours prior to PCI

A Platelet GP IIb/IIIa inhibitor in addition to ASA and heparin upstream for patients in whom PCI is planned

OR Clopidogrel 300 mg load and 75 mg/day upstream for a month up to a year

Bivalirudin instead of GPI/antithrombin upstream only if clopidogrel is used as well >6 hours prior to PCI

II IIaIIa IIbIIb IIIIII

Bleeding Among Patients with ACSConclusions

• Antithrombotic therapies are cornerstone Rx– Must balance thrombosis and hemostasis

• Certain patient and PCI procedure characteristics predict bleeding– Age, female gender, chronic kidney disease,

procedure time, sheath dwell time

• Bivalirudin is a GREAT option in these patients

Deborah B. “Knockdown” Diercks, MD

XaBetter Living Through Chemistry

Deborah Diercks, MD

Associate Professor

Department of Emergency Medicine

University of California, Davis Medical Center

My Position

• Agents providing Xa inhibition are more desirable than UFH or direct thrombin inhibition– Xa inhibition is provided

• In balance with IIa (thrombin) inhibition– LMWH (enoxaparin)

• In isolation– Fondaparinux

My Position

• Part I: Enoxaparin and fondaparinux are superior to UFH

• Part II: ACUITY results do not support the superiority of bivalirudin

Part I

Enoxaparin and Fondaparinux Are Superior to UFH

The Enemy and Our Weapons

• Weapons to stop the cascade:– Heparin– LMWH– Special forces

• Xa inhibitors• Direct thrombin

inhibitors

Cascade activation (intrinsic or extrinsic pathway)

Factor X Factor Xa

Prothrombin(factor II)

Thrombin(factor IIa)

Fibrinogen Fibrin

Weapons

Unfractionated Heparin

Enoxaparin

Fondaparinux

Bivalirudin

Xa inhibition

IIa inhibition

PF 4 activity

X X

X X

LMWH: Cleaner

• Dalteparin and enoxaparin– Animal derived– Smaller chains

more selective activity– Anti Xa >> anti IIa– Less PF4 binding

• Less HIT II

At least 2 of 3 required: Age 60 years ST (transient) or (+) CK-MB or troponin

IV Heparin

Primary end point: death or MI at 30 days

High-RiskACS Patients

Randomize(N = 10,027)

Early invasive strategyOther therapy per ACC/AHA guidelines

(ASA, -blocker, ACE-I, clopidogrel, GP IIb/IIIa)

60 U/kg 12 U/kg/hr (aPTT 50–70 seconds)

1 mg/kg SC every 12 hours

SYNERGY: Study Design

Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45–54.

Enoxaparin

aPTT, activated partial thromboplastin time.

SYNERGY: Primary End Point

0 5 10 15 20 25 300.8

0.85

0.9

0.95

1.0

Free

dom

from

Dea

th /

MI

Days from Randomization

UFHEnoxaparin

HR 0.96 (0.87-1.06)

30-Day Death/MI30-Day Death/MI

0.80.8 11 1.21.2

Hazard Ratio (95% CI)

EnoxaparinBetter

UFHBetter

Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45–54.

Death or MI to 30 Days C

umul

ativ

e %

of P

atie

nts

Days from Randomization0 5 10 15 20 25 30

UFH

Enoxaparin

HR = 0.8295% CI: 0.72, 0.94

15.9

13.3P = 0.004RRR = 16.4

20

15

10

5

0

J Am Coll Cardiol. 2006;48:1346–1354.

SYNERGY: Consistent Therapy

Patients with NSTE ACS, chest discomfort <24 hoursPatients with NSTE ACS, chest discomfort <24 hours2 of 3: Age >60 years, ST segment 2 of 3: Age >60 years, ST segment ΔΔ, , cardiac markers cardiac markers

Patients with NSTE ACS, chest discomfort <24 hoursPatients with NSTE ACS, chest discomfort <24 hours2 of 3: Age >60 years, ST segment 2 of 3: Age >60 years, ST segment ΔΔ, , cardiac markers cardiac markers

Fondaparinux2.5 mg SC once daily

Fondaparinux2.5 mg SC once daily

OASIS-5: Study Overview

ASA, clopidogrel, GP IIb/IIIa, planned cath/PCI

as per local practice

ASA, clopidogrel, GP IIb/IIIa, planned cath/PCI

as per local practice

Randomize

Enoxaparin1 mg/kg SC twice daily

Enoxaparin1 mg/kg SC twice daily

Primary: Primary: EfficacyEfficacy: : Death, MI, refractory ischemiaDeath, MI, refractory ischemia at 9 days at 9 days

SafetySafety: : Major bleeding at 9 daysMajor bleeding at 9 daysRisk benefitRisk benefit: Death, MI, refractory ischemia, major bleeds at 9 days: Death, MI, refractory ischemia, major bleeds at 9 days

SecondarySecondary: Above & each component : Above & each component separatelyseparately at day 30 and 6 months at day 30 and 6 monthsHypothesisHypothesis: First test noninferiority, then test superiority: First test noninferiority, then test superiority

Primary: Primary: EfficacyEfficacy: : Death, MI, refractory ischemiaDeath, MI, refractory ischemia at 9 days at 9 days

SafetySafety: : Major bleeding at 9 daysMajor bleeding at 9 daysRisk benefitRisk benefit: Death, MI, refractory ischemia, major bleeds at 9 days: Death, MI, refractory ischemia, major bleeds at 9 days

SecondarySecondary: Above & each component : Above & each component separatelyseparately at day 30 and 6 months at day 30 and 6 monthsHypothesisHypothesis: First test noninferiority, then test superiority: First test noninferiority, then test superiority

OutcomesOutcomes

PCI <6 hours:PCI <6 hours: No additional UFH No additional UFHPCI >6 hours:PCI >6 hours: IV UFH IV UFHWith IIb/IIIa 65 U/kgWith IIb/IIIa 65 U/kgWithout IIb/IIIa 100 U/kgWithout IIb/IIIa 100 U/kg

PCI <6 hours:PCI <6 hours: IV fondaparinux 2.5 mg IV fondaparinux 2.5 mgwithout IIb/IIIa, 0 with IIb/IIIawithout IIb/IIIa, 0 with IIb/IIIaPCI >6 hours:PCI >6 hours: IV fondaparinux 2.5 mg with IV fondaparinux 2.5 mg withand 5.0 mg without IIb/IIIa and 5.0 mg without IIb/IIIa

ExcludeAge <21 yearsAny contraindication to enoxaparinHem stroke <12 monthsCr >3 mg/dL/265 umol/L

N = 20,000

OASIS-5: Efficacy Outcomes at Day 9

Enox Fonda

Death/MI/RI 5.8% 5.9%

Death/MI 4.1% 4.1%

Death 1.9% 1.8%

MI 2.7% 2.7%

Refractory ischemia

1.9% 2.05%

0.8 1 1.2

NoninferiorityMargin = 1.185

Hazard RatioFondaparinux Better Enoxaparin Better

OASIS-5: Bleeding Rates at Day 9

Outcome Enox(%)

Fonda(%)

HR (95% CI) P value

No. randomized 10,021 10,057

Total bleed 7.0 3.2 0.44 (0.39-0.51) <<0.0001

Major bleed 4.0 2.1 0.53 (0.45-0.62) <<0.0001

TIMI major bleed 1.3 0.7 0.54 (0.41-0.73) <<0.0001

Minor bleed 3.1 1.1 0.35 (0.28-0.43) <<0.0001

OASIS-5: Mortality at 6 Months

Days

Cu

mu

lati

ve H

azar

d0.

00.

020.

040.

06

0 20 40 60 80 100 120 140 160 180

HR = 0.8995% CI: 0.79, 0.99

P = 0.037

Enoxaparin

Fondaparinux

Oasis-5

• Summary of Oasis-5– Fondaparinux has similar efficacy to enoxaparin– Fondaparinux (as used in this study) has less

bleeding than enoxaparin (as used in this study)– This lower bleeding rate translated into fewer

adverse outcomes at 6 months

• Critique– Enoxaparin was not used appropriately?

Part II

ACUITY Results Do Not Support the Superiority of Bivalirudin

Moderate-high risk

ACS

ACUITY Study Design• Moderate-high risk unstable angina or NSTEMI undergoing an invasive

strategy (N = 13,800)

An

gio

gra

ph

y w

ith

in 7

2 h

ou

rs

Aspirin in allClopidogrel

dosing and timingper local practice

UFH orenoxaparin+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

Bivalirudinalone

R*

*Stratified by preangiography thienopyridine use or administration.

ACUITY Design. Stone GW, et al. Am Heart J. 2004;148:764–775.

Medicalmanagement

PCI

CABG

ACUITY Major Entry Criteria

ACUITY Design. Stone GW, et al. Am Heart J. 2004;148:764–775.

Inclusion CriteriaAge ≥18 yearsChest pain ≥10 minutes within 24 hours

At least one of:•New ST depression or transient ST elevation ≥1 mm•Troponin I, T, or CKMB •Documented coronary artery disease•All other 4 TIMI risk criteria

- Age ≥65 years- Aspirin within 7 days- ≥2 angina episodes

within 24 hours- ≥3 cardiac risk factors

Written informed consent

Exclusion CriteriaNo angiography within 72 hours

Acute STEMI or shockBleeding diathesis or major bleed within 2 weeks

Platelet count ≤100,000/mm3

International normalized ratio >1.5 control

CrCl level ≤30 mL/minAbciximab or ≥2 prior LMWH doses

• Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed

Allergy to drugs, contrast

Primary Results by Treatment Arm (30 Day)Heparin* + IIb/IIIa vs Bivalirudin + IIb/IIIa vs Bivalirudin Alone

7.3%5.7%

11.7%

7.7%

11.8%

5.3%

3.0%

10.1%

7.8%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

Heparin+IIb/IIIa (N=4603) Bivalirudin+IIb/IIIa (N=4604) Bivalirudin alone (N=4612)

PNI <0.001PSup = 0.015

PNI = 0.01 PSup = 0.32

PNI <0.001PSup <0.001

*Heparin=unfractionated or enoxaparin. Stone GW, et al. N Engl J Med. 2006;335:2203–2216.

Non–CABG-related bleeding

– Intracranial bleeding or intraocular bleeding– Retroperitoneal bleeding– Access site bleed requiring intervention/surgery– Hematoma ≥5 cm– Hemoglobin ≥3 g/dL with an overt source or ≥4 g/dL without overt source– Blood product transfusion– Reoperation for bleeding

1. Superiority was driven by decreased bleeding– Trend toward higher ischemic events– Hematoma does not equal death

7.3%5.7%

11.7%

7.7%

11.8%

5.3%

3.0%

10.1%

7.8%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

Heparin+IIb/IIIa (N=4603)

Bivalirudin+IIb/IIIa (N=4604)

Bivalirudin alone (N=4612)

*Heparin=unfractionated or enoxaparin. Stone GW, et al. N Engl J Med. 2006;335:2203–2216.

2. An unusual and unimportant bleeding scale was used– TIMI-major bleeding rates were low in all arms

TIMI-Major bleeding

0

2

4

6

8

ACUITY

Treatment arm

% o

f p

atie

nts

Bival

Bival + GP

H + GP

3. TIMI major bleeding rates in ACUITY are similar to those seen in all other trials– Superiority due to the “innovative” bleeding scale

0

0.5

1

1.5

2

2.5

3

SYNERGY OASIS-5 ACUITY

Enox

UFH

Fonda

Bival

Bival + GP

H + GP

Comparison of major bleeding rates by arm, by study

4. ACUITY does not reflect practice in the United States– Biomarker-negative patients were receiving

heparin + GPI

Newby KL, et al. Circulation. 2001;103:2891-2896.

TnT-NegativeTnT-Positive

PARAGON-B

PRISM

CAPTURE

Combined

0.125 1 20.5 0.125 1 20.5GP IIb/IIIa

BetterGP IIb/IIIa

WorseGP IIb/IIIa

BetterGP IIb/IIIa

Worse

5. Who is the enemy?

• Cost effectiveness of bivalirudin– GP IIb/IIIa

• Is this an issue for emergency physicians?– New guidelines suggest not every patient

needs one– Registry data says that not every patient is

getting one

My Position

• Follow the evidence-based guidelines– Enoxaparin and

fondaparinux are indicated regardless of the management strategy

– Even in the invasive arm, not all get a GP

• Anti-Xa is the way!!!

BLEEDING IS IMPORTANT

ONE SIZE DOES NOT FIT ALL!!!

Pro DTI “Hook-ster Hoekstra”

Selection of Therapy in the ED Must Include Consideration of

Bleeding Risk

• Age

• Gender

• Renal insufficiency

• Baseline anemia

• Expectation of prolonged medical therapy

0 1 2 3

P valueRR (95% CI)Risk Ratio ± 95% CIRisk Ratio ± 95% CI

Results: The ACUITY Trial PCI PopulationPredictors of Major Bleeding

Age >75 years (vs 55–75)

Anemia

CrCl level <60 mL/min

Diabetes

Female gender

High risk (ST/biomarkers)

Hypertension

Prior PCI

Prior antithrombotic therapy

Heparin(s) + GPI (vs bivalirudin)

1.56 (1.19–2.04) 0.0009

1.89 (1.48–2.41) <0.0001

1.68 (1.29–2.18) <0.0001

1.30 (1.03–1.63) 0.0248

2.08 (1.68–2.57) <0.0001

1.42 (1.06–1.90) 0.0178

1.33 (1.03–1.70) 0.0287

1.47 (1.15–1.88) 0.0019

1.23 (0.98–1.55) 0.0768

2.08 (1.56–2.76) <0.0001

ACUITY: Impact of 30-Day Events on 1-Year Mortality

3.4

8.6

12.5

28.9

0

5

10

15

20

25

30

No MI ormajor bleed

MI only Major bleedonly

Both MI andmajor bleed

Events in first 30 days

1-ye

ar m

ort

alit

y (%

)

Stone GW, McLaurin BT. N Engl J Med. 2006;355:2203–2216.Stone et al. American College of Cardiology Annual Scientific Session; March 24–27, 2007; New Orleans, La.

30-Day Outcomes: Renally Impaired (CrCl <60 mL/min) by Treatment Group

9.2% 9.8%

16.8%

11.1%

16.1%

6.2%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

Heparin+IIb/IIIa (N=826) Bivalirudin alone (N=818)

*Heparin=unfractionated or enoxaparin.

RR 0.64(0.45-0.89)

RR 1.21(0.91-1.61)

RR 0.96(0.77-1.19)

Bivalirudin 30-Day Outcomes in Diabetic Patients: ACUITY Substudy

15.2

9.58.5

4.6

12.1

8.3

0

5

10

15

20

Net clinical outcome Composite ischemia

Heparin(s) + GP IIb/IIIa (n=703) ANGIOMAX alone (n=721)

P = 0.08

P = 0.42P < 0.003

30-D

ay E

ven

ts (

%)

Major bleeding (non-CABG)

Data on file. The Medicines Company, Parsippany, NJ.

Seamless Transition to the Cath Lab: The Ideal Scenario???

Presentation

Early Treatment in the ED

Catheterization

D/C

PCI

Drug Administration

• Bivalirudin is a good antithrombin agent

• It should be used in the patient population that was studied– That is what evidence-based medicine

is all about

Pro Factor Xa “Knockdown Diercks”

Let’s Take a Closer Look

1. Patients were on study drug for a very short time

- Patients were on study drug a median of 3.9–4.1 hours prior to PCI

2. Majority of the patients were treated with a UFH or anti-Xa inhibitor prior to randomization

3. All patients were to undergo an invasive management strategy

Time

Arrival Randomization PCI

0 h 6.1 h 10.1 h

(Median times used for H + GPI arm) (Stone et al., Bival for patients with ACS. NEJM, 2006)

4. Broad inclusion criteria

Inclusion Criteria Age ≥18 years Chest pain ≥10 minutes within 24 hours At least one of:

• New ST depression or transient ST elevation ≥1 mm

• Troponin I, T, or CKMB • Documented coronary artery disease• All other 4 TIMI risk criteria

- Age ≥65 years- Aspirin within 7 days- ≥2 angina episodes within 24 hours- ≥3 cardiac risk factors

• High risk???• Does this reflect

current practice?• What is the

appropriate treatment for this group?

My Final Position

• In high-risk patients:– Enoxaparin or fondaparinux are recommended agents

in patients who will be managed with a conservative or invasive strategy

• In intermediate-risk patients or patients at higher risk for bleeding, who are rapidly going on to cardiac intervention (no long ED stay), who have been treated with an anti-Xa agent prior to initiating bivalirudin, it is a reasonable agent

Why You Should Use Enoxaparin

• Enoxaparin– Similar rates of bleeding to UFH

• Improved clinical outcomes

– Benefit persists regardless of whether invasive or conservative approach used

– Lower resource consumption– Proven

Why You Should Use Fondaparinux

• Fondaparinux– Less bleeding than enoxaparin and bivalirudin

(even in a higher-risk population)– Similar clinical outcomes (to enoxaparin)– Low cost– Ease of dosing

Why Would You Choose Bivalirudin?

• Uncertain performance in high-risk patients– What would ACUITY have looked like if it was

done in the same patient population as SYNERGY or OASIS-5?

• Requires continuous infusion

• $$$$$