Gender Differences in Long-Term Outcomes Following PCI of Patients with Non-ST

Elevation ACS: Results from the ACUITY Trial

Alexandra J. Lansky on behalf of the ACUITY InvestigatorsAlexandra J. Lansky on behalf of the ACUITY Investigators

DisclosuresDisclosures Alexandra J. Lansky

• Insert disclosures here

Alexandra J. Lansky• Insert disclosures here

Moderateand highrisk ACS

(n=13,819)

Study Design – First RandomizationStudy Design – First Randomization

An

gio

gra

ph

y w

ith

in 7

2h

Aspirin in allClopidogrel

dosing and timingper local practice

Aspirin in allClopidogrel

dosing and timingper local practice

UFH/Enox+ GP IIb/IIIa(n=4,603)

Bivalirudin+ GP IIb/IIIa(n=4,604)

BivalirudinAlone

(n=4,612)

R*

*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)

Medicalmanagement

PCI

CABG

Study Design – Second RandomizationStudy Design – Second Randomization

UFH/Enox+ GP IIb/IIIa

(N=4,603)

Bivalirudin+ GP IIb/IIIa

(N=4,604)

BivalirudinAlone

(N=4,612)

R*

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy

GPI upstream (N=2294)

GPI CCL for PCI (N=2309)

GPI upstream (N=2311)

GPI CCL for PCI (N=2293)

Aspirin in allClopidogrel

dosing and timingper local practice

Aspirin in allClopidogrel

dosing and timingper local practice

*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration

Moderateand highrisk ACS

(n=13,819)

Management Strategy (N=13,819)Management Strategy (N=13,819)

56.4%

11.4%32.2%CABG (n=1,539)CABG (n=1,539)

Medical Rx (n=4,491)Medical Rx (n=4,491)

PCI (n=7,789)PCI (n=7,789)

Heparin + IIb/IIIaN = 2,561

Bivalirudin + IIb/IIIaN = 2,609

Bivalirudin aloneN = 2,619

UF Heparin Enoxaparin Bivalirudin

U/Kg mg/Kg mg/kg

Bolus 60 1.0 sc bid 0.1 iv

Infusion/h 121 0.25 iv

PCIACT

200-250s

0.30 iv bolus2

0.75 iv bolus3

0.50 bolus iv

1.75/h infusion iv4

CABG Per institution Per institution Per institution5

Medical mgt None6 None6 None6

Study MedicationsStudy Medications Anti-thrombin agents (started pre angiography) Anti-thrombin agents (started pre angiography)

1 Target aPTT 50-75 seconds2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion

3 Primary Endpoints (at 30 Days)3 Primary Endpoints (at 30 Days)

Composite ischemia Death, MI, or unplanned revascularization for ischemia

Major bleeding (non-CABG) Intracranial bleeding or intraocular bleeding Retroperitoneal bleeding Access site bleed requiring intervention/surgery Hematoma ≥5 cm Hgb ≥3g/dL with an overt source or ≥4g/dL w/o overt source Blood product transfusion Reoperation for bleeding

Net clinical outcome composite ischemia or major bleeding

Composite ischemia Death, MI, or unplanned revascularization for ischemia

Major bleeding (non-CABG) Intracranial bleeding or intraocular bleeding Retroperitoneal bleeding Access site bleed requiring intervention/surgery Hematoma ≥5 cm Hgb ≥3g/dL with an overt source or ≥4g/dL w/o overt source Blood product transfusion Reoperation for bleeding

Net clinical outcome composite ischemia or major bleeding

BackgroundBackground Women with non-ST elevation acute coronary

syndromes are at increased risk for ischemic and bleeding complications compared to men, especially among those undergoing PCI.

In the ACUITY Trial, women undergoing PCI had similar ischemic event rates but significantly higher major bleeding complications compared to men at 30 days.

Among women, treatment with bivalirudin resulted in significantly less major bleeding and similar ischemic outcomes at 30 days compared with heparin + GP IIb/IIIa inhibitors

Women with non-ST elevation acute coronary syndromes are at increased risk for ischemic and bleeding complications compared to men, especially among those undergoing PCI.

In the ACUITY Trial, women undergoing PCI had similar ischemic event rates but significantly higher major bleeding complications compared to men at 30 days.

Among women, treatment with bivalirudin resulted in significantly less major bleeding and similar ischemic outcomes at 30 days compared with heparin + GP IIb/IIIa inhibitors

ObjectivesObjectives

To examine the impact of gender and antithrombotic therapy on early and late outcomes in patients with moderate and high risk ACS undergoing PCI in the ACUITY Trial

We evaluated 30-day non-CABG Major Bleeding and 1-year Composite Ischemia and Mortality among: Male vs female patients undergoing PCI

Female patients undergoing PCI and being treated with bivalirudin ± GP IIb/IIIa inhibition vs heparin plus GP IIb/IIIa inhibition

To examine the impact of gender and antithrombotic therapy on early and late outcomes in patients with moderate and high risk ACS undergoing PCI in the ACUITY Trial

We evaluated 30-day non-CABG Major Bleeding and 1-year Composite Ischemia and Mortality among: Male vs female patients undergoing PCI

Female patients undergoing PCI and being treated with bivalirudin ± GP IIb/IIIa inhibition vs heparin plus GP IIb/IIIa inhibition

Baseline Characteristics by GenderBaseline Characteristics by GenderMales vs. FemalesMales vs. Females

Women(N=2091)

Men(N=5698)

P-value

Age (median [range], yrs) 67 (25-95) 61 (20-93) <0.0001

Weight (median [IQR], kg) 75 (65, 87) 86 (78, 98) <0.0001

Diabetes 34.5% 25.1% <0.0001

Hypertension 74.8% 62.1% <0.0001

Hyperlipidemia 59.1% 55.0% 0.002

Current smoker 26.9% 32.4% <0.0001

Prior MI 26.2% 32.0% <0.0001

Prior PCI 37.7% 39.0% 0.27

Prior CABG 13.1% 19.1% <0.0001

Renal insufficiency* 31.0% 13.9% <0.0001

Anemia† 19.5% 14.4% <0.0001

*Calculated creatinine clearance <60 mL/min using the Cockcroft-Gault equation.†Anemia was defined using the World Health Organization criteria (Hemoglobin ≤13 g/dL for men and ≤12 g/dL for women).

Clinical Outcomes by GenderClinical Outcomes by GenderMales vs. FemalesMales vs. Females

Women(N=2091)

Men(N=5698)

P-value

30-Day Major Bleeding

10.7% 4.2% <0.0001

1-Year Composite Ischemia

19.6% 18.5% 0.27

1-Year Mortality 3.5% 3.1% 0.31

Baseline Characteristics – Female PCI ptsBaseline Characteristics – Female PCI ptsHeparin + IIb/IIIa(N=701)

Bivalirudin + IIb/IIIa(N=690)

Bivalirudin alone

(N=700)

Age (median [range], yrs) 68 [25, 91] 67 [37, 95] 66 [34, 92]

Weight (median [IQR], kg) 74 [64, 88] 74 [65, 86] 76 [65, 88]

Diabetes 36.1% 33.2% 34.1%

Hypertension 73.7% 77.7% 73.1%

Hyperlipidemia 57.6% 62.9% 56.8%

Current smoker 27.4% 26.7% 26.5%

Prior MI 23.9% 28.9% 25.8%

Prior PCI 36.3% 38.0% 38.6%

Prior CABG 13.3% 13.3% 12.8%

Renal insufficiency* 5.5% 5.6% 5.5%

Anemia† 17.8% 18.3% 18.9%

*Calculated creatinine clearance <60 mL/min using the Cockcroft-Gault equation.†Anemia was defined using the World Health Organization criteria (Hemoglobin ≤13 g/dL for men and ≤12 g/dL for women).

Baseline High Risk Features – Female PCI ptsBaseline High Risk Features – Female PCI pts

Heparin + IIb/IIIa(N=701)

Bivalirudin + IIb/IIIa

(N=690)

Bivalirudin

alone(N=700)

Cardiac biomarker (MB or trop) 62.6% 61.7% 64.5%

- Troponin 63.5% 62.3% 65.6%

ST-segment ≥1mm 74.1% 68.3% 72.9%

Cardiac biomarker or ST-segments 75.2% 71.6% 74.4%

TIMI Risk Score

0-2 11.9% 11.1% 10.2%

3-4 50.6% 52.9% 54.7%

5-7 37.5% 36.0% 35.1%

Antiplatelet Medications – Female PCI ptsAntiplatelet Medications – Female PCI pts

Heparin + IIb/IIIa(N=701)

Bivalirudin + IIb/IIIa

(N=690)

Bivalirudin alone

(N=700)

Aspirin use or administration pre-angiography or PCI

- Yes 97.9% 97.4% 98.0%

Thienopyridine use or administration pre PCI

- Yes 66.0% 66.7% 67.4%

- Clopidogrel 65.2% 66.6% 67.1%

- Ticlopidine 1.0% 0.9% 0.9%

Procedural Characteristics – Female PCI ptsProcedural Characteristics – Female PCI ptsHeparin + IIb/IIIa(N=701)

Bivalirudin + IIb/IIIa

(N=690)

Bivalirudin alone

(N=700)

Attempted lesions per pt 1.47 ± 0.81 1.43 ± 0.77 1.42 ± 0.71

- 1 65.7% 67.3% 68.8%

- 2 25.2% 25.8% 22.4%

- ≥3 9.1% 6.8% 8.9%

Attempted vessels per pt 1.18 ± 0.45 1.16 ± 0.41 1.15 ± 0.38

- ≥2 15.4% 14.9% 14.3%

Target Vessel

- Left main 1.2% 0.8% 1.4%

- LAD 39.8% 40.1% 39.8%

- LCX 27.6% 26.3% 27.0%

- RCA 31.4% 32.9% 31.8%

Device Use – Female PCI ptsDevice Use – Female PCI pts

Heparin + IIb/IIIa(N=701)

Bivalirudin + IIb/IIIa

(N=690)

Bivalirudin

alone(N=700)

Stent implanted 94.7% 95.8% 95.3%

Drug-eluting stents 62.8% 62.2% 61.2%

- ≥1 Cypher implanted 42.5% 43.2% 41.5%

- ≥1 Taxus implanted 48.2% 48.1% 50.2%

- ≥1 other DES implanted 6.8% 8.9% 6.6%

Non-drug-eluting stent 31.9% 33.6% 34.1%

Thrombectomy 1.7% 0.7% 1.4%

Distal Protection 1.1% 1.5% 1.1%

Atherectomy 0.7% 0.9% 0.3%

Cutting Balloon 3.0% 4.4% 3.0%

1-Year Composite Ischemia – Female PCI pts1-Year Composite Ischemia – Female PCI pts

*Heparin=unfractionated or enoxaparin*Heparin=unfractionated or enoxaparin

Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin AloneHeparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone

0 30 60 90 120 150 180 210 240 270 300 330 360 3950

5

15

25

10

20

UFH/Enox + GP IIb/IIIaBivalirudin + GP IIb/IIIa

Bivalirudin alone

p=0.18

Mo

rtal

ity

(%)

Days from Randomization

0 30 60 90 120 150 180 210 240 270 300 330 360 3950

1

3

5

2

4

UFH/Enox + GP IIb/IIIaBivalirudin + GP IIb/IIIa

Bivalirudin alone

p=0.23

Mo

rtal

ity

(%)

Days from Randomization

1-Year Mortality – Female PCI pts1-Year Mortality – Female PCI pts

*Heparin=unfractionated or enoxaparin*Heparin=unfractionated or enoxaparin

Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin AloneHeparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone

30-Day Major Bleeding (non-CABG) – Female PCI pts30-Day Major Bleeding (non-CABG) – Female PCI pts

Heparin + IIb/IIIa(N=701)

Bivalirudin + IIb/IIIa

(N=690)

Bivalirudin

alone(N=700)

P value*

Major bleeding 11.8% 13.9% 6.3% <0.001

Intracranial 0% 0% (1) 0% 1.00

Retroperitoneal 1.9% 1.9% 0.3% 0.004

Access site 5.7% 5.9% 1.9% <0.001

- req interv/surgery 1.3% 1.7% 0.9% 0.44

- hematoma ≥5 cm 5.0% 4.8% 1.6% <0.001

Hgb ≥3 g/dL with overt source 5.6% 5.4% 1.7% <0.0001

Hgb ≥4 g/dL with no overt source 1.4% 2.5% 1.7% 0.66

Blood transfusion 6.1% 8.1% 3.7% 0.04

Reoperation for bleed 0% 0.1% 0.1% 0.32

*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor

Bleeding Endpoints – Female PCI ptsBleeding Endpoints – Female PCI pts

Heparin + IIb/IIIa(N=701)

Bivalirudin + IIb/IIIa

(N=690)

Bivalirudin

alone(N=700)

PValue

ACUITY Scale

- Major Bleed, all 12.1% 14.1% 6.9% <0.001

- Major, non-CABG 11.8% 13.9% 6.3% <0.001

- Minor, non-CABG 32.5% 34.2% 17.1% <0.001

TIMI Scale

- Any 12.0% 12.8% 6.7% <0.001

- Major 4.0% 4.2% 1.3% <0.001

- Minor 11.8% 12.3% 6.3% <0.001

Transfusions, non-CABG 6.1% 8.1% 3.7% 0.04

*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor

Study LimitationsStudy Limitations

Even though the baseline characteristics of the 3 groups were well matched, the ACUITY PCI Gender sub-study is not a randomized trial

The ACUITY PCI Gender sub-study was under-powered for non-inferiority testing and subgroups All analyses should be considered hypothesis generating

Given the complexity of the trial, the study design was open label, and as such bias cannot be excluded

Even though the baseline characteristics of the 3 groups were well matched, the ACUITY PCI Gender sub-study is not a randomized trial

The ACUITY PCI Gender sub-study was under-powered for non-inferiority testing and subgroups All analyses should be considered hypothesis generating

Given the complexity of the trial, the study design was open label, and as such bias cannot be excluded

Conclusions and Clinical ImplicationsConclusions and Clinical Implications

In patients with moderate and high risk ACS undergoing PCI Women undergoing PCI have similar long-

term ischemia outcomes as men but with significantly increased major bleeding at 30 days.

Among women, treatment with bivalirudin alone resulted in significantly reduced 30 day major bleeding and similar rates of 1-year composite ischemia and mortality compared to heparin + GP IIb/IIIa inhibitors.

In patients with moderate and high risk ACS undergoing PCI Women undergoing PCI have similar long-

term ischemia outcomes as men but with significantly increased major bleeding at 30 days.

Among women, treatment with bivalirudin alone resulted in significantly reduced 30 day major bleeding and similar rates of 1-year composite ischemia and mortality compared to heparin + GP IIb/IIIa inhibitors.