Shamir Mehta, MD, MSc, FRCPC Shamir Mehta, MD, MSc, FRCPC Director Interventional Cardiology Associate Professor of Medicine McMaster University Hamilton, Ontario, Canada Continues – But with Better Outcomes? A Critical Appraisal of Recent Clinical Data
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Shamir Mehta, MD, MSc, FRCPC Director Interventional Cardiology Associate Professor of Medicine McMaster University Hamilton, Ontario, Canada The Balancing.
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The Balancing Act in ACS Continues – But with BetterOutcomes? A Critical Appraisal of Recent Clinical Data
Antithrombotics in UA/NSTEMI Patients in the Last Decade: Increased Efficacy at the Price of Increased Bleeding
16-20% 12-15% 8-12% 6-10% 4-8%Dea
th /
MI
BleedingBleeding
1988ASA
1992ASA+
Heparin
1998 ASA+
Heparin+Anti-
GPIIB/IIIA
2003ASA+
LMWH +Clopidogrel +Intervention
Bleeding is Associated with an Increased 30-Day Mortality in NSTEMI Patients
Rao et al. Am J Cardiol 2005;96:1200-1206
N = 26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A&B
Log-rank p values are 0.0001 for all 4 categories, 0.20 for no bleeding vs. mild bleeding, 0.0001 for mild vs. moderate bleeding, and 0.001 for moderate vs. severe bleeding.
Adjusted HR (95% CI)
% Death
2.9% 1.03.5% 1.6 (1.3-1.9)5.9% 2.7 (2.3-3.4)
25.7% 10.6 (8.3-13.6)
GUSTO bleeding None Mild Moderate Severe
0 5 10 15 20 25 30
0.70
0.75
0.80
0.85
0.90
0.95
1.00
Days to Death
Cu
mu
lati
ve s
urv
ival
Procedure-Related and Non-Procedure-Related Bleeds are Associated with an Increased 30-Day Mortality in NSTEMI Patients
Rao et al. Am J Cardiol 2005;96:1200-1206
Procedure-related GUSTO bleeds
Non-procedure-related GUSTO bleeds
Ris
k o
f d
eath
(H
azar
d R
atio
)
None
1.0
Mild
1.3
Severe
16.5
0
5
20
10
15
None
1.0
Mild
2.1
Moderate
2.5
Severe
10.9
Moderate
3.7
N = 26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A & B
OASIS Registry, OASIS-2, CUREStrong, Independent Association
OutcomeMajorBleed
No MajorBleed
Hazard (Adjusted)
P-Value
Death 60/470(12.8%)
833/33676(2.5%)
5.37(3.97-7.26)
<0.0001
MI46/436(10.6%)
1375/33710(4.1%)
4.44(3.16-6.24)
<0.0001
Stroke12/469
(2.6%)
187/33677
(0.6%)
6.46
(3.54-11.79)<0.0001
Eikelboom JW et al. Circulation. 2006;114(8):774-82.
N = 34,126
Increased Mortality at Days 30/180 in Patients with Major Bleeds by Day 9 (All Patients)
Budaj et al. JACC. 2006;abstract 972-224
Adjusted HR (95% CI) at day 30: 5.06 (4.59-5.62); at day 180: 3.16 (2.92-3.44)
0.00
0.05
0.10
0.15
0.20
0 30 60 90 120 150 180
Major Bleed 9 days
No Major Bleed 9 days
Cu
mu
lati
ve
Ha
zard
Days
Increased Risk of MI at Days 30/180 in Patients with Major Bleeds by Day 9 (All Patients)
Adjusted HR (95% CI) at day 30: 5.01 (4.56-5.57); at day 180: 2.99 (2.75-3.28)
Budaj et al. JACC. 2006;abstract 972-224
0 30 60 90 120 150 180
Days
0.00
Cu
mu
lati
ve
Ha
zard
0.05
0.10
0.15
Major Bleed 9 days
No Major Bleed 9 days
Increased Risk of Stroke at Days 30/180 in Patients with Major Bleeds by Day 9 (All Patients)
Adjusted HR (95% CI) at day 30: 4.77 (3.95-6.00); at day 180: 3.30 (2.82-3.97)
Budaj et al. JACC. 2006;abstract 972-224.
0 30 60 90 120 150 180
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Cu
mu
lati
ve
Ha
zard
Days
Major Bleed 9 days
No Major Bleed 9 days
Potential Mechanisms for the Higher Morbidity/Mortality Associated with Bleeding
1. Activation of clotting cascade as a response to bleeding--may lead to recurrent events in at the site of plaque rupture
2. Cessation of antithrombotic therapies (eg. ASA, clopidogrel, heparin) after a bleeding event
3. Adverse effects of hypotension due to the bleed
4. Adverse effects of transfusion
5. Common risk factors for bleeding and adverse outcome
0.4 0.6 0.8 1.2* The median value for creatinine was 88 µmol/L (1.04 mg/dL)
Interaction p value
Major Bleeding at Day 30 and GP IIb/IIIa Use
4.3
8.3
2.7
5.1
0
1
2
3
4
5
6
7
8
9
No GP IIb/IIIa GP IIb/IIIa
Enox
Fonda
HR 0.63P<0.0001
HR 0.60P = 0.0001
N = 16448 N = 3630
Fondaparinux Superior to Enoxaparin for Bleeding Irrespective of Rx Duration
6.8
5.2
3
4.8
2.9
2
0
1
2
3
4
5
6
7
8
0-4 Days 5-6 Days 7-8 Days
Maj
or
Ble
eds
at D
ay30
Enox
Fonda
HR 0.69P = 0.001
HR 0.55P <0.0001
HR 0.67P = 0.018
N = 5581 N = 8712 N = 5785
Incidence of Major Bleeds with Enoxaparin in OASIS-5 is Consistent with Previous Trials
Enoxaparin Enox Fonda Enox Fonda
SYNERGY1
In-hospital
ESSENCE2
Day 30
A to Z3
Day 6
Meta-analysis4
Day 7
OASIS 5
Day 9
OASIS 5
Day 9
OASIS 5
Day 30
OASIS 5
Day 30
TIMI major+fatal bleeds
9.1% - 0.9% - 1.3% 0.7% 1.5% 1.0%
Major bleeds - 6.5% - 4.7% 4.1% 2.2% 5.0% 3.1%
1. SYNERGY Investigators. JAMA. 2004;292:45-54. 2. Cohen et al. N Engl J Med. 337:447-52.
3. Blazing et al. JAMA 2004;292:55-64 • 4. Petersen et al. JAMA. 2004;292:89-96.
Fondaparinux-Associated Reduction of Bleeding Translated into Long-Term Mortality Benefit
Patients with Enoxaparin Fondaparinux Difference
No Bleed 526 523 -3
Minor Bleeds 33 13 -20
Major Bleeds 79 38 -41
Total 638 574 -64
No. of deaths at 180 days
OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.
Days
Cu
mu
lati
ve H
azar
d0.
00.
050.
100.
15
0 20 40 60 80 100 120 140 160 180
Enoxaparin
Fondaparinux
HR 0.8695% CI 0.81-0.93P<<0.00001
Net Clinical Benefits at 6 Months(Death, MI, RI, Major Bleeding)
Efficacy and Safety in PCI PatientsOutcome Day 9 Enox
N = 3072Fonda
N = 3105HR (95% CI) P value
Death, MI or Stroke 190 (6.2) 197 (6.3) 1.03 (0.84-1.25)
0.79
Death 38 (1.2) 37 (1.2) 0.96 (0.61-1.52)
0.87
MI 154 (5.0) 160 (5.2) 1.03 (0.82-1.28)
0.80
Stroke 13 (0.4) 12 (0.4) 0.91 (0.42-2.00)
0.82
Major Bleeding 155 (5.1) 73 (2.4) 0.46 (0.35-0.61)
<0.00001
Death, MI, stroke, major bleeding
318 (10.4) 255 (8.2) 0.78 (0.67-0.93)
0.004
Mehta et al. JACC. 2006;abstract 821-5.
PCI < 24 Hours of RandomizationOutcomeDay 9
EnoxN = 1420
FondaN = 1414
HR (95% CI) P value
Death, MI or Stroke 77 (5.4) 75 (5.3) 0.98 (0.71-1.34)
0.89
Death 19 (1.3) 19 (1.3) 1.01 (0.53-1.90)
0.98
MI 55 (3.9) 53 (3.8) 0.97 (0.66-1.41)
0.86
Stroke 8 (0.6) 6 (0.4) 0.76 (0.23-2.18)
0.60
Major Bleeding 69 (4.9) 33 (2.3) 0.48 (0.31-0.72)
0.0005
Death, MI, stroke, major bleeding
135 (9.5) 103 (7.3) 0.76 (0.59-0.98)
0.035
Mehta et al. JACC. 2006;abstract 821-5
RR 0.4295% CI 0.26-0.65
P <0.0001
RR 0.9695% CI 0.73-1.26
P = 0.78
RR 0.3995% CI 0.22-0.67
P <0.0001
RR 1.4095% CI 1.00-1.97
P = 0.048
Major Bleeding 48 hours after PCI Abrupt/threatened abrupt closure
N = 1277 N = 1275 N =
1633
N = 1648
N = 1275
RR 0.94 95% CI 0.63-1.33
P=0.62
RR 0.70 95% CI 0.51-0.96
P=0.026
OASIS 5: Fonda vs Enox alone and vs UFH + Enox
Mehta et al. Presented at WCC/ESC Hotline Session, Barcelona, 2006
3.83.4
6.2
4.3
1.3
5.9 6
0
2
4
5
6
7
% E
ven
ts
FondaFonda
Enox alone
UFH+
EnoxFonda
Fonda
Enoxalone UFH
+Enox
1
N = 1633
N = 1648
1.6
3 N = 1277
N = 1633
N = 1648
N = 1277
N = 1275
Open Label UFH Prior to PCI Data After Protocol Amendment
No UFH Prior to PCI UFH Prior to PCI
Enox(%)
Fonda(%)
HR (95% CI)
Enox(%)
Fonda(%)
HR(95% CI)
Number randomized 810 793 80 75
Death/MI/Stroke/Major Bleed
90 (11.1) 80 (10.1) 0.90(0.67-1.22)
9 (11.2) 4 (5.3) 0.45(0.14-1.47)
Death/MI/Stroke 60 (7.4) 57 (7.2) 0.97(0.68-1.40)
5 (6.3) 3 (4.0) 0.62(0.15-2.61)
Major Bleed 35 (4.3) 26 (3.3) 0.75(0.45-1.25)
5 (6.2) 1 (1.3) 0.21(0.02-1.79)
Abrupt Closure 13 (1.6) 15 (1.9) 1.18(0.56-2.5)
0 1 (1.3) --
Threatened abrupt closure
38 (4.7) 31 (3.9) 0.83 (0.52-1.32)
2 (2.5) 4 (5.3) 2.13(0.40-11.3)
Catheter Thrombus 4 (0.5) 9 (1.1) 2.30(0.71-7.4)
0 1 (1.3)* --
Vascular Access Site complication
56 (6.9) 22 (2.8) 0.40(0.25-0.65)
5 (6.3) 1 (1.3) 0.21(0.03-1.8)
Final 1758 patients randomized*represents 1 patient with low dose of UFH 5 IU/kg vs mean dose of 47 IU/kg
Mehta et al. JACC. 2006;abstract 821-5
Adding UFH to Fondaparinux is Safe and Preserves the Lower Bleeding with Fondaparinux vs Enoxaparin
Enox Fonda HR CI
No UFH post-Randomization
1.2
(n = 1277)
0.5
(n = 1313)
0.45 0.18-1.11
UFH or equivalent placebo mandated by protocol during PCI
1.1
(n = 1229)
0.4
n = 1279)
0.34 0.12-0.95
Open Label UFH 2.7
(n = 598)
1.3
(n = 543)
0.48 0.20-1.17
Overall 1.5
(n = 3104)
0.6
(n = 3135)
0.42 0.24-0.71
Yusuf S. et al. N Engl J Med. 2006; 354:2829.
PCI-Related Complications and MACE (death, MI or stroke)
16
20.618.1
12.6
16.6
13.7
0
5
10
15
20
25
Any PCI Complication Any PCI Complicationor MACE
Any PCI complicationor Major Bleed
Enox
Fonda
HR 0.79P<<0.0001
HR 0.81P<0.0001
HR 0.75P<<0.0001
Mehta et al. JACC 2006;abstract 821-5
Advantage of a Single Dose with Fondaparinux
The advantage of a single dose for all patients is clear; in this era of recognition of the common
occurrence of medical errors that lead to harm, a single dose would result in fewer medical errors
because complex calculations of the type identified in the CRUSADE registry would not be needed
Califf. JAMA. 2006;295:1579-80.
ACUITY Study Design – Patient Flow
UFH/Enox+ GP IIb/IIIa(N = 4,603)
Bivalirudin+ GP IIb/IIIa(N = 4,604)
BivalirudinAlone
(N = 4,612)
R*
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategyModerate-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
Moderate-high risk
ACS
Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.
ACUITY Primary Outcome: No Difference in Ischemic Outcomes or Major Bleeding with Bivalirudin vs Heparin in Presence of GPI
Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.
Summary
• Fondaparinux reduces bleeding and mortality in patients with NSTEACS compared with enoxaparin including those undergoing early intervention (<24 hours)
• Standard UFH +/- GPI is recommended in those receiving a PCI
• Bivalirudin is no different than UFH/enoxaparin in reducing ischemic outcomes or bleeding in presence of a GPI
• Bivalirudin reduces bleeding compared with UFH/enox + GPI but patients need to be pre-treated with a thienopyridine to maintain efficacy
• The two agents may be complementary—fondaparinux for initial upstream therapy and bivalirudin in those needing a PCI.