tct presentation october 2006 outcomes in elderly patients undergoing pci treated with bivalirudin...

TCT PresentationOctober 2006

Outcomes in Elderly Patients Undergoing Outcomes in Elderly Patients Undergoing PCI Treated with Bivalirudin Monotherapy PCI Treated with Bivalirudin Monotherapy versus Glycoprotein IIb/IIIa Inhibitors with versus Glycoprotein IIb/IIIa Inhibitors with

Heparin or LMWH: Results from the Heparin or LMWH: Results from the Randomized ACUITY TrialRandomized ACUITY Trial

Karen P. Alexander, E. Magnus Ohman, Karen P. Alexander, E. Magnus Ohman, Michel E. Bertrand, Frederic Feit, Charles V. Michel E. Bertrand, Frederic Feit, Charles V.

Pollack Jr, James Hoekstra, Bernard J. Pollack Jr, James Hoekstra, Bernard J. Gersh, Harvey D. White, Gregg W. Stone for Gersh, Harvey D. White, Gregg W. Stone for

the ACUITY Investigatorsthe ACUITY Investigators


DisclosuresDisclosures

Research Funding (Minor): Schering Plough, Research Funding (Minor): Schering Plough, BMS, Amgen, CV TherapeuticsBMS, Amgen, CV Therapeutics

Speakers Bureau: PfizerSpeakers Bureau: Pfizer


BackgroundBackground

Elderly patients presenting with NSTE ACS are at Elderly patients presenting with NSTE ACS are at high risk for recurrent ischemic events high risk for recurrent ischemic events Use of antithrombotic therapy and an early Use of antithrombotic therapy and an early

invasive strategy are beneficialinvasive strategy are beneficial

Elderly patients are at high risk for bleeding with Elderly patients are at high risk for bleeding with antithrombotic therapy and catheter interventionsantithrombotic therapy and catheter interventions Major bleeding is associated with adverse Major bleeding is associated with adverse

outcomesoutcomes

Therapy for NSTEACS has become multi-tiered, Therapy for NSTEACS has become multi-tiered, particularly in pts undergoing PCIparticularly in pts undergoing PCI


BivalirudinBivalirudin

Bivalirudin is a direct thrombin inhibitor with Bivalirudin is a direct thrombin inhibitor with certain advantagescertain advantages Circulating and clot bound thrombin, no requirement for AT Circulating and clot bound thrombin, no requirement for AT

III, may reduce thrombin mediated platelet activity III, may reduce thrombin mediated platelet activity Clearance by proteolysis, with minor renal contributionClearance by proteolysis, with minor renal contribution Short half life, no required monitoringShort half life, no required monitoring

Studied in trials which enrolled PCI pts with Studied in trials which enrolled PCI pts with various comparison groups *various comparison groups * Similar protection from ischemic events Similar protection from ischemic events Superior bleeding profile compared to standard Superior bleeding profile compared to standard

combination therapycombination therapy

* Replace-2, Protect TIMI 30, ACUITY, BAT


Chest pain ≥10’ within 24h

At least one of: New ST depression or

transient ST elevation ≥1 mm Troponin I, T, or CKMB Documented CAD All other 4 TIMI risk criteria

Age ≥65 years Aspirin within 7

days ≥2 angina

episodes w/i 24h ≥3 cardiac risk

factors

ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

No angiography within 72h

Acute STEMI or shock

Bleeding diathesis or major bleed within 2 weeks

Platelet count ≤100,000/mm3

INR >1.5 control

CrCl ≤30 ml/min

Abcx or ≥2 prior LMWH doses Prior UFH, LMWH (1 dose),

eptifibatide and tirofiban OK

Inclusion CriteriaInclusion Criteria Exclusion CriteriaExclusion Criteria

ACUITY TrialACUITY Trial

Moderate-high risk NSTE ACS undergoing invasive care Moderate-high risk NSTE ACS undergoing invasive care (13, 819 patients, 448 centers,17 countries)(13, 819 patients, 448 centers,17 countries)


Moderate-high risk

ACS

ACUITY Design –RandomizationACUITY Design –Randomization

An

gio

gra

ph

y w

ith

in 7

2h

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

ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

Aspirin in allClopidogrel

dosing and timingper local practice*

Aspirin in allClopidogrel

dosing and timingper local practice*

Medicalmanagement

PCI

CABG

BivalirudinAlone

UFH or EnoxaparinUFH or EnoxaparinRoutine upstream

GPI in all ptsGPI started in

CCL for PCI only

BivalirudinBivalirudin

R2

R2

Routine upstream GPI in all ptsGPI started in

CCL for PCI only

R1

*Stratified by pre-angiography thienopyridine use or administration


ACUITY Primary Endpoint at 30 daysACUITY Primary Endpoint at 30 days

Net Clinical EndpointNet Clinical Endpoint Composite ischemic and non-CABG major bleeding endpointsComposite ischemic and non-CABG major bleeding endpoints

Ischemic EndpointIschemic Endpoint Death, MI, or unplanned revascularizationDeath, MI, or unplanned revascularization

Non-CABG Major Bleeding EndpointNon-CABG Major Bleeding Endpoint Intracranial, intraocular, or retroperitoneal bleedingIntracranial, intraocular, or retroperitoneal bleeding Access site bleed requiring intervention/surgeryAccess site bleed requiring intervention/surgery Hematoma ≥5 cmHematoma ≥5 cm Hgb Hgb ≥3g/dL with an overt source or ≥3g/dL with an overt source or ≥4g/dL w/o overt source≥4g/dL w/o overt source Blood transfusionBlood transfusion


ACUITY Primary Results by TreatmentACUITY Primary Results by Treatment

Heparin + Heparin + GP IIb/IIIaGP IIb/IIIa

(4603)(4603)

Bivalirudin +Bivalirudin +GP IIb/IIIaGP IIb/IIIa

(4604)(4604)

BivalirudinBivalirudinalonealone(4612)(4612)

EndpointEndpoint RateRate RateRate P ValueP Value RateRate P ValueP Value

Net clinical Net clinical outcomeoutcome 11.7%11.7% 11.8%11.8% <0.001 NI<0.001 NI 10.1%10.1% 0.015 0.015

SupSup

Ischemic Ischemic eventsevents 7.3%7.3% 7.7%7.7% 0.007 NI0.007 NI 7.8%7.8% 0.011 NI0.011 NI

Major Major bleedingbleeding 5.7%5.7% 5.3%5.3% <0.001 NI<0.001 NI 3.0%3.0% <0.001 <0.001

SupSup

NI = non-inferiority; Sup = superiority

Dr. Gregg Stone, ACC 2006 Presentation


PurposePurpose

To compare age subgroup results with To compare age subgroup results with Bivalirudin monotherapy, heparin/GPI and Bivalirudin monotherapy, heparin/GPI and Bival/GPI in PCI patients in ACUITYBival/GPI in PCI patients in ACUITY Ischemic EndpointsIschemic Endpoints Major and Minor BleedingMajor and Minor Bleeding

Describe differences across age Describe differences across age In terms of absolute risk reductionIn terms of absolute risk reduction Among those with preserved renal functionAmong those with preserved renal function


Baseline Characteristics by Age Subgroups Baseline Characteristics by Age Subgroups PCI Cohort n=7,789; 56%PCI Cohort n=7,789; 56%

<55 55-64 65-74 ≥75N (%) 2,052 (26.3) 2,240 (28.8) 2,121 (27.2) 1,376 (17.7)

Age (yrs) 48.0 ±4.9 59.6 ±2.8 69.3 ±2.9 79.3 ±3.5

Weight (kg) 92.1 ±19.9 88.4 ±17.7 83.4 ±16.0 76.4 ±14.1

Female (%) 18.4 23.3 29.8 40.6

HTN 50.7 63.4 73.4 77.0

DM 22.0 28.1 30.7 29.4

CVA 2.5 5.0 6.9 9.4

Renal Insuff 2.1 4.5 7.3 11.0

EF <30% 2.5 3.6 3.4 4.3

Continuous Variables as Means ± SD


Cardiac Markers and Creatinine Clearance Cardiac Markers and Creatinine Clearance PCI Cohort n=7,789; 56%PCI Cohort n=7,789; 56%

<55 55-64 65-74 ≥75N (%) 2,052 (26.2) 2,240 (28.8) 2,121 (27.2) 1,376 (17.7)

Hgb (mg/dl) 14.6 ±1.5 14.3±1.5 13.9 ±1.6 13.4 ±1.6

Troponin I (>ULN) 65.2 63.9 63.8 62.8

CrCl (ml/min) 127 ±62 107 ±318 79 ±36 59 ±36

CrCl ≥ 90 (%) 84.8 60.9 25.8 4.7

CrCl 60-90 (%) 13.4 33.0 53.0 36.3

CrCl 30-60 (%) 1.0 5.4 20.6 55.2

CrCl <30 (%) 0.8 0.7 0.6 3.7

Continuous Variables as Means ± SD


Combined Ischemic EndpointCombined Ischemic EndpointPCI Cohort by Age GroupsPCI Cohort by Age Groups

0%

2%

4%

6%

8%

10%

12%

14%

<55 55-64 65-74 >=75

Hep + GPI Biv + GPI Biv alone

6.5

9.3

7.0 7.1

8.3 8.6 9.08.2 8.6

11.0

12.3 12.2

Patient Age

N=2052 N=2240 N=2121 N=1376

P for all comparisons = NS


Major Bleeding EndpointMajor Bleeding EndpointPCI CohortPCI Cohort

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

<55 55-64 65-74 >=75


4.3 4.2

1.7

5.76.6

3.0

6.7

5.54.2

12.3

16.5

6.1

Patient AgeN=1376N=2121N=2240N=2052

P=0.006

P=0.001P=NS

P<0.001

P=0.007

P=0.010 P=0.033

P=0.001

Excluding CABG-related bleeding


0

5

10

15

20

25

30

35

40

45

<55 55-64 65-74 >=75

Major Bleeding with GPI/HepNNT

Patient Age

38 3740

16

Implication for Number Needed to Treat (NNT) Implication for Number Needed to Treat (NNT) Given the Absolute Risk Reduction (ARR) in Given the Absolute Risk Reduction (ARR) in

Major Bleeding with Bivalirudin vs. Heparin/GPIMajor Bleeding with Bivalirudin vs. Heparin/GPI


Minor BleedingMinor BleedingPCI CohortPCI Cohort

0%

5%

10%

15%

20%

25%

30%

35%

40%

<55 55-64 65-74 >=75


19.5

22.5

12.5

24.7

28.9

14.3

28.6 28.8

14.4

33.235.5

20.6

Patient AgeN=1376N=2121N=2240N=2052

**

** **

**

*

** **

**

*P<0.001; ** P<0.0001

Excluding CABG-related bleeding


0

5

10

15

20

25

30

35

<55 55-64 65-74 >=75

Minor Bleeding with GPI/Hep

NNT

Patient Age

1410

7 8

Implication for NNT given the ARR in Minor Implication for NNT given the ARR in Minor Bleeding with Bivalirudin vs. Heparin/GPIBleeding with Bivalirudin vs. Heparin/GPI

Maj

or B

leed

ing

Rat

e w

ith H

epar

in/G

PI


Limiting Cohort to CrCl >50cc/minLimiting Cohort to CrCl >50cc/minaddressing the question of renal dosingaddressing the question of renal dosing

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

<55 55-64 65-74 >=75

93%

Patient Age

92%85.5%

62%


Combined Ischemic EndpointsCombined Ischemic Endpoints PCI Cohort with CrCl >50 cc/min

0%

2%

4%

6%

8%

10%

12%

14%

<55 55-64 65-74 >=75


6.7

9.6

6.67.4

7.88.5

8.0 8.08.7

9.3

10.4

12.3

Patient Age

N=1909 N=2063 N=1813 N=849

All other P = NS

P=0.04


Non-CABG Major Bleeding Endpoint Non-CABG Major Bleeding Endpoint PCI Cohort with CrCl >50 cc/minPCI Cohort with CrCl >50 cc/min

0%

2%

4%

6%

8%

10%

12%

14%

<55 55-64 65-74 >=75


4.1

12.7

Patient Age

N=849N=1813N=2063N=1909

4.3

1.9

5.76.3

2.8

5.9

5.0

3.5

9.6

4.5

Patient Age

P=0.012

P=0.002

P=NS

P<0.001

P=0.021

P=0.008=0.049

P=0.019


0

5

10

15

20

25

30

35

40

45

50

<55 55-64 65-74 >=75

Major Bleeding

NNT

Patient Age

45 34

42

20

Maj

or B

leed

ing

Rat

e w

ith H

epar

in/G

PI

Implication for NNT Given ARR in Major Bleeding Implication for NNT Given ARR in Major Bleeding with Bivalirudin vs. Heparin/GPIwith Bivalirudin vs. Heparin/GPIPCI Cohort with CrCl >50 cc/minPCI Cohort with CrCl >50 cc/min


ConclusionsConclusions

Ischemic and hemorrhagic events increase with Ischemic and hemorrhagic events increase with ageage

Across all age groups, bivalirudin is associated Across all age groups, bivalirudin is associated with significantly less major and minor bleeding with significantly less major and minor bleeding and similar ischemic outcomesand similar ischemic outcomes Even among those with preserved renal functionEven among those with preserved renal function ARR for major bleeding was greatest in the elderly (age >75)ARR for major bleeding was greatest in the elderly (age >75)

NNT of 16 to prevent one major bleedNNT of 16 to prevent one major bleedNNT of 8 to prevent one minor bleedNNT of 8 to prevent one minor bleed

Dose all agents carefully, fewer agents may be Dose all agents carefully, fewer agents may be betterbetter

tct presentation october 2006 outcomes in elderly patients undergoing pci treated with bivalirudin...

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