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Antithrombotic Drug Therapy in Cardiovascular Disease
Bivalirudin
Bivalirudin is a 20-amino acid synthetic analogue of hirudin. Like hirudin, it bivalently binds with
high affinity to both the catalytic and exosite-1 recognition sites of thrombin (Fig.
2). Unlike hirudin,
thrombin inhibition by bivalirudin is reversible
(1,28). Upon binding to thrombin, bivalirudin is
quickly cleaved into two fragments which only weakly interact with thrombin. The half-life of biva-
lirudin is approximately 25
min, a factor which may contribute to the lower rate of bleeding compli-
cations compared with hirudin. Bivalirudin is administered intravenously and plasma levels are
directly proportional to dosing. For percutaneous coronary intervention, an initial bolus of 0.75
mg/
kg is followed by a continuous infusion of 1.75
mg/kg/h for the duration of the procedure. For man-
agement of ACS outside of percutaneous interventional procedures, the initial dose is 0.1
mg/kg,
followed by a continuous infusion of 0.25
mg/kg/h. Therapeutic steady state is achieved when the
PTT is 1.5–2.5 times the baseline value. Bivalirudin fragments are degraded by endogenous pepti-
dases in the blood, and are primarily excreted by the kidneys. Although clearance is only modestly
effected by decreased renal insufficiency, dose adjustments and careful monitoring is suggested in
patients with creatinine clearance <30 ml/min (decrease infusion rate to 1 mg/kg/h) and dialysis
dependent patients (decrease infusion to 0.25
mg/kg/h). Bivalirudin is approved for use as an anti-
coagulant in patients undergoing percutaneous coronary intervention electively or during an acute
coronary syndrome.
Argatroban
Argatroban is a small synthetic molecule derived from L-arginine, which acts as a reversible uni-
valent thrombin inhibitor. In contrast to bivalirudin or hirudin, argatroban is hepatically metabolized
through the cytokine P450 pathway, and approximately half of a given intravenous dose is bound by
plasma proteins. Dosing precautions are advised in patients with hepatic dysfunction, but are not
required in patients with renal insufficiency
(29). Plasma levels are linearly related to intravenous
dosing, and the half-life of argatroban is approximately 54
min. In percutaneous coronary interven-
tion, an initial bolus dose of 350
mcg/kg is followed by infusion of 25 mcg/kg/min, with additional
boluses of 150
mcg/kg and increase in infusion as necessary to achieve an activated clotting time
(ACT) of 300–450
s. When given for treatment of HIT, dose adjustment should be made until a steady
state aPTT of 1.5–3.0 times the initial baseline value is achieved. Argatroban has not been linked to
immune-mediated responses. Argatroban is approved for use in the treatment of HIT, and during
percutaneous coronary intervention in patients who have or are at risk for HIT.
Orally Active Direct Thrombin Inhibitors
Ximelagatran was the first orally-active DTI (Fig. 2). It is a small molecule which requires metabo-
lization after ingestion to melagatran, a univalent inhibitor of the catalytic site on thrombin. Melagatran
has a half-life of 5 h, and is excreted in the urine. Use of this agent has been limited by an alarming
number of unpredictable incidents of severe hepatotoxicity. In 2004 the FDA Advisory Committee rec-
ommended against its approval, and the sponsoring company terminated its development 2 years later.
Dabigatran etexilate is another orally active DTI under investigation to determine its safety and
efficacy in the treatment of venous and arterial thromboembolic disorders (30).
Clinical Use of Direct Thrombin Inhibitors in Unstable Angina and NSTEMI
Thrombus formation at the site of plaque disruption leading to partial or subtotal occlusion of a
coronary artery is the key step in the pathogenesis of UA and non-transmural myocardial infarction.
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Direct Thrombin Inhibitors in Acute Coronary Syndromes
Coronary artery plaque disruption results in exposure of subendothelial collagen and tissue factor to
circulating clotting factors. The activation of thrombin is a critical early step in the activation of the
clotting cascade, platelet activation and ultimately in the formation of a platelet-fibrin clot. Based on
the limitations of heparins and the advantages of DTIs discussed above, recent investigation has
focused on using DTI as primary anticoagulant agents in the treatment of ACS.
The use of DTIs in the treatment of ACS has been evaluated by a number of clinical trials. Two
large trials the Global Utilization of Strategies to Open Occluded Coronary Arteries (GUSTO-II) (31),
and the Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) trial (32) focused on
the use of recombinant hirudin in the treatment of ACS. GUSTO IIb was a multicenter international
trial that compared heparin to low dose hirudin (0.1 mg/kg bolus followed by 0.1 mg/kg/h infusion;
goal aPTT 60–85 s) in 12,142 patients enrolled in 1994 and 1995 with either ST elevation (4,131
patients) or non-ST elevation (8,011 patients) myocardial infarctions (33). At 24 h, hirudin therapy
was associated with a statistically-significant reduction in the incidence of death or recurrent myocar-
dial infarction (1.3% vs. 2.1% with heparin, p = 0.001). By 30 days, however, this difference was only
marginally significant with 8.9% and 9.8% of patients in the hirudin and heparin arms respectively
reaching the study’s primary endpoint of death or non-fatal myocardial infarction (p = 0.06). Of those
patients who presented without ST elevation, the difference in incidence of death or recurrent ischemia
Hirudin
Bivalirudin
Argatroban
Ximelagatran
Catalytic
Site
Substrate
Recognition Site
Heparin
Binding
T
T
h
h
r
r
o
o
m
m
b
b
i
i
n
n
Fig. 2. Schematic representation of thrombin with substrate recognition sites (exosites 1 and 2) and the active catalytic
site. Binding patterns of bivalent (hirudin and bivalirudin) and univalent (argatroban and Ximelagatran) are shown.
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Antithrombotic Drug Therapy in Cardiovascular Disease
was less impressive and statistically insignificant (8.3% for hirudin vs. 9.1% for heparin, p = 0.22).
The trend toward reduced ischemic events was offset by an increase in the incidence of moderate and
severe bleeding defined as the need for transfusion with hirudin (9.7%) compared to heparin (8.6%,
p
= 0.04).
A subsequent trial, OASIS II, evaluated a similar hypothesis that hirudin would be a superior anti-
coagulant to heparin in patients with UA or non-ST elevation myocardial infarction
(32). In this trial,
10,141 patients were enrolled from August 1996 to April 1998 and randomized to standard dose UFH
vs. high dose hirudin (0.4
mg/kg bolus followed by 0.15 mg/kg/h infusion; goal aPTT 60–100 s). At
7 days, patients treated with hirudin were less likely to develop the primary endpoints of cardiovas-
cular death or new myocardial infarction (3.6% vs. 4.2% with heparin, p
= 0.077). Moreover, hirudin
therapy was associated with a statistically significant reduction in the secondary composite endpoint
of cardiovascular death, myocardial infarction or refractory angina at 7 days (5.6% vs. 6.7% with
heparin, p
= 0.0125). Differences were particularly apparent in higher risk patients for whom an inter-
vention was eventually required. Similar to GUSTO II, the risk of major bleed was higher in the
hirudin group than in the heparin treated group (1.2% vs. 0.7%, p = 0.01).
A meta-analysis performed by the Direct Thrombin Inhibitor Trialists’ Collaborative Group com-
pared safety and efficacy of four different DTIs from 11 randomized trials and 35,970 patients who
presented with UA, NSTEMI, and STEMI
(34). Compared with heparin, patients treated with DTIs
had a significant reduction in the primary efficacy endpoint of death or myocardial infarction (4.3%
vs. 5.1%) at 30 days. Notably the treatment benefit was seen with bivalent DTIs, hirudin and bivaliru-
din, but not with the univalent DTIs, inogatran or argatroban. This finding held true in the subset of
patients who presented without ST elevation with primary endpoint occurring in 3.7% with DTIs
versus 4.6% with heparin (Odds Ratio 0.80 (0.70–0.92)). Perhaps most significant given the results
of the OASIS II and GUSTO II trials, there was an increase in major bleeding with hirudin but an
actual reduction in bleeding with bivalirudin.
The finding that improved antithrombotic efficacy may be obtained without an associated increase
in major bleeding was first demonstrated in the Bivalirudin Angioplasty Trial (BAT). The BAT trial
enrolled 4,098 patients with either UA or postinfarction angina between March 1993 and July 1994
(35). Patients were randomly assigned to receive either heparin or bivalirudin prior to angiography.
Although there was no difference in the primary endpoint of death in the hospital, myocardial infarc-
tion, abrupt vessel closure or cardiac derived clinical decline between bivalirudin and heparin (11.4%
vs. 12.2%, p
= 0.44), there was a significant reduction in incidence of major hemorrhage seen in
patients treated with bivalirudin compared with heparin (3.8% vs. 9.8%, p < 0.001). Although the
mechanism is unclear, it has been suggested that the reduction in bleeding seen with bivalirudin is due
to its reversible binding of thrombin and shorter half-life (35). The results of the BAT trial suggested
bivalirudin could provide at least equal reduction in ischemic complications without resulting in an
increased risk of bleeding.
Taken together, the results of the individual trials and the meta-analysis comparing DTIs to heparin
in the setting of ACS suggest a modest superiority of DTIs over heparin in reducing ischemic events,
which in the case of hirudin is achieved at the cost of increased bleeding. The meta-analysis demon-
strated heterogeneity of DTIs both in terms of clinical benefit and incidence of major bleeding. The
greatest benefit in the meta analysis appeared to be derived from patients treated with bivalirudin who
later underwent percutaneous coronary intervention (34), in whom the BAT trial revealed bivalirudin
could actually reduce bleeding rates.
The relevance of the results from early studies to current clinical practice is limited. Overall
management strategies during the majority of these trials were conservative in contrast to current
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Direct Thrombin Inhibitors in Acute Coronary Syndromes
strategies of early angiography and aggressive percutaneous coronary intervention. Additionally,
when the effectiveness of DTIs could be evaluated in the setting of percutaneous intervention, it
was in an era prior to the widespread use of coronary stents. Another limitation is that newer anti-
coagulants such as thienopyridines and glycoprotein IIb/IIIa inhibitors which have been shown to
be clearly beneficial were not yet part of the treatment strategy for ACS at the time of the early
trials. Moreover, despite the notable benefit of reduced bleeding with bivalirudin noted in the BAT
trial and the DTI meta-analysis, the majority of the initial investigations were focused on huridin.
Based on its favorable safety profile compared with other DTIs and the results of the BAT trial,
bivalirudin received approval for use as an anticoagulation strategy in percutaneous intervention.
However, widespread use of bivalirudin in this setting did not occur until The Randomized Evaluation
in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial suggested bivalirudin could
be used as an alternative anticoagulation strategy instead of heparin and GPIIa/IIIb inhibition
(36).
The REPLACE-2 trial demonstrated bivalirudin to be non-inferior to heparin plus glycoprotein IIb/
IIIa blockade in reducing ischemic complications associated with PCI, while significantly reducing
rate of major in-hospital bleeding (4.1% in heparin plus GPIIa/IIIb vs. 2.4% in bivalirudin alone,
p = 0.001).
The intent of the REPLACE-2 trial was to evaluate the use of bivalirudin during elective or urgent
PCI, and the study did not include patients with acute myocardial infarctions or who were given
antithrombotic therapy prior to PCI for high-risk acute coronary syndrome
(36). Therefore, to assess
the role of bivalirudin across the spectrum of care from contemporary medical pretreatment through
early angiography and PCI in the setting of moderate- or high-risk ACS, the Acute Catheterization
and Urgent Intervention Triage Strategy (ACUITY) trial was performed
(37). This trial enrolled
13,819 patients, all of whom were to receive immediate aspirin and undergo angiography within 72
h
of presentation; the administration of clopidogrel was at the discretion of the local investigator.
Patients were assigned to one of three arms for anticoagulation: unfractionated or low molecular
weight heparin plus a glycoprotein IIb/IIIa inhibitor (heparin plus GpIIb/IIIa inhibitor), bivalirudin
plus a glycoprotein IIb/IIIa inhibitor (bivalirudin plus GpIIb/IIIa inhibitor), or bivalrudin plus provi-
sional use of a glycoprotein IIb/IIIa inhibitor (per the discretion of the investigator; bivalirudin
alone). Both bivalirudin alone and with GpIIb/IIIa inhibition, compared to heparin plus a GpIIb/IIIa
inhibitor, were associated with non-inferior 30 day rates of the primary endpoint of death, myocar-
dial infarction, or unplanned revascularization (Fig.
3). Rates of major hemorrhage were similar for
the bivalirudin plus GpIIb/IIIa inhibitor arm and the heparin plus GpIIb/IIIa inhibitor arm (5.3% vs.
5.7%, respectively, p
= 0.38), while bivalirudin alone was associated with significantly less major
bleeding (3.0%, p < 0.001). In a subgroup analysis, it is worth noting that treatment with bivalirudin
alone without pretreatment with clopidogrel prior to angiography showed a marginally significant
increase in ischemic events (9.1% vs. 7.1% with heparin plus GpIIb/IIIa inhibition, p = 0.054)
Subsequent more detailed post hoc analysis suggested that outcomes in the bivalirudin monotherapy
arm were similar to those in the heparin plus GP IIb/IIIa inhibitor group as long as clopidogrel was
administered before or within 30
min of completing the PCI procedure (38). Thus, while the data
from ACUITY were by no means conclusive that bivalirudin monotherapy without clopidogrel pre-
treatment is inferior to treatment with heparin plus a GpIIb/IIIa inhibitor, the apparent relationship
was noted and led to the recommendation in the ACC/AHA 2007 Guidelines for the Management of
Unstable Angina/Non-ST Elevation Myocardial Infarction that bivalirudin monotherapy be used
with clopidogrel loading (39). The results from ACUITY support those from REPLACE-2 in dem-
onstrating that the use of bivalirudin is associated with a similar incidence of ischemic events, yet
significantly less major bleeding complications when compared to treatment with heparin and a
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Fig. 3. Kaplan–Meier Time-to-Event Curves for the end points of net clinical outcome (a), composite ischemia (b),
and major bleeding (c). Outcomes at 30 days in the ACUITY trial comparing bivalirudin with and without glycopro-
tein IIb/IIIa to heparin and glycoprotein IIb/IIIa blockade in the treatment of acute coronary syndromes. The primary
end points were measured at 30 + 5 days; thus, follow-up is reported to 35 days. The event rate for each curve refers
to the cumulative rate at 35 days. P values are for comparisons with the control group (unfractionated heparin or
enoxaparin plus glycoprotein IIb/IIIa inhibitors). GP denotes glycoprotein. The thick solid line represents heparin plus
GP IIb/IIIa inhibitor; the dotted line, bivalirudin plus GP IIb/IIIa inhibitor; and the thin solid line, bivalirudin alone.
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Direct Thrombin Inhibitors in Acute Coronary Syndromes
glycoprotein IIb/IIIa inhibitor, and thus is an acceptable alternative for the management of UA,
NSTEMI and during elective or urgent PCI
(36,37).
Clinical Use of Direct Thrombin Inhibitors in STEMI
In contrast to UA or NSTEMI, the majority of patients with STEMIs have occlusive coronary
thrombi with little or no blood flow to the effected area of myocardium (40). Therapy for this condi-
tion is therefore focused on immediate reperfusion with either fibrinolysis or percutaneous interven-
tion. Early trials focused on the usefulness of DTIs in conjunction with fibrinolytics in the treatment
of STEMIs. GUSTO-IIa
(31,33) and TIMI-9a (41) assessed hirudin in this setting, but both studies
were terminated early after initial analysis revealed higher bleeding rates within the hirudin treatment
arms. Although, the trials were restarted with lower doses of hirudin, treatment with hirudin was
associated with similar rates of ischemic events compared with heparin
(31,33)(42). Moreover, pri-
mary endpoints of death or myocardial re-infarction at 30 days were not significantly different
between the hirudin and heparin groups in GUSTO-IIb (hirudin 9.9% vs. heparin 11.3%) or TIMI 9b
(hirudin 9.7% vs. heparin 9.5%). As was the case for patients with UA and NSTEMIs, hirudin treat-
ment was associated with a higher rate of bleeding in patients with STEMI. The Hirulog and Early
Reperfusion or Occlusion (HERO-2) trial compared the use of bivalirudin to heparin in patients with
ST elevation myocardial infarctions undergoing fibinolysis with streptokinase
(43). The results were
similarly disappointing with no difference in the primary endpoint of 30 day mortality in patients
treated with bivalirudin (10.8%) compared to heparin (10.9%), and there were higher rates of bleeding
in the bivalirudin arm. Taken together, these studies demonstrate that the use of DTIs appear to offer
no benefit over heparin in the setting of fibrinolysis for treatment of acute STEMI.
The results of these trials evaluating the use of DTIs in the treatment of ST-segment elevation
myocardial infarctions thus suggested that DTI’s do not provide a net benefit over heparin among
patients undergoing fibrinolysis. The Harmonizing Outcomes with Revascularization and Stents in
Acute Myocardial Infarction (HORIZONS-AMI) study was designed to test whether direct thrombin
inhibition could provide a benefit in patients with ST elevation myocardial infarctions who underwent
early percutaneous intervention
(44). A total of 3,602 patients presenting with STEMI were randomly
assigned to receive heparin plus glycoprotein IIb/IIIa blockade or bivalirudin alone and then under-
went emergent percutaneous coronary intervention (Fig. 4) (44). All patients were treated with opti-
mal platelet inhibition including aspirin and clopidogrel. At 30 days, those treated with bivalirudin
monotherapy showed similar rates of major cardiovascular events when compared to heparin plus a
GpIIa/IIIb inhibitor. However, bivalirudin monotherapy resulted in significantly lower 30 day rates of
death from cardiovascular causes (1.8% vs. 2.9% with heparin plus GpIIb/IIIa inhibition, p = 0.03) and
death from all causes (2.1% vs. 3.1% with heparin plus GIIb/IIIa inhibition, p = 0.047). Equally nota-
ble was that bivalirudin monotherapy was associated with significantly less major hemorrhage (5.0%
vs. 8.4% with heparin plus GpIIb/IIIa inhibition, p < 0.001, Fig. 4). As shown in Fig. 4, there was an
apparent initial increase in ischemic cardiovascular endpoints (death, reinfarction, target vessel revas-
cularization for ischemia, and stroke) in the bivalirudin arm, however, this difference was no longer
evident at 30 days when overall rates were similar (5.4% vs. 5.5% with heparin and GpIIb/IIIa inhibi-
tion, respectively, p = 0.95). In addition, the authors note that in the 3,124 patients in whom stents were
implanted, stent thrombosis occurred in 17 more patients within the first 24 h in the bivalirudin arm.
However, that trend was later reversed with seven fewer incidents of stent thrombosis in the bivaliru-
din arm during the period from the 24 h to 30 days. At 30 days, there was no significant difference in
stent thrombosis between the bivalirudin group (2.5%) and the heparin and glycoprotein group (1.9%,
p = 0.30).
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Antithrombotic Drug Therapy in Cardiovascular Disease
Safety and Efficacy of Switching Anticoagulant Therapy
Most patients presenting with ACS are currently treated with UFH or LMWH initiated in the ambu-
lance, the emergency department, or in a transferring hospital before PCI. In such patients, it has been
suggested that switching from UFH to LMWH or vice versa may be associated with an increased rate
of death or myocardial infarction at 30 days and an increase in the need for blood transfusion
(19).
Thus, the safety of changing antithrombin therapy from a heparin to a DTI once therapy has been initi-
ated has been called into question. The small randomized SWITCH trial among 91 patients with non-
ST elevation ACS treated with enoxaparin demonstrated that subsequent switching to bivalirudin for
PCI was not associated with increased risk of major bleeding when compared to those who did not
have a change in antithrombin therapy (45). This finding was independent of the duration of time
between the last administration of enoxaparin and PCI.
A subsequent analysis of the REPLACE-2 study evaluated the incidence of hemorrhage among
patients who were pretreated with UFH or LWMH during the 48 h prior to PCI (46). When compared
to those who did not receive pretreatment, there was no difference in the rates of major or minor bleeding
nor non-CABG related blood transfusion in patients who received bivalirudin during PCI (Table 6).
Interestingly, those who received heparin pretreatment and then received heparin and additional glyco-
protein IIb/IIIa inhibition did have a significant increase in bleeding complications when compared to
Fig. 4. HORIZONS-AMI: Time to event curves through 30 days. Outcomes at 30days in the HORIZONS-AMI trial
comparing bivalirudin to heparin and glycoprotein IIb/IIIa in the treatment of STEMI.
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Direct Thrombin Inhibitors in Acute Coronary Syndromes
Table 4
Major trials of DTIs in ST-elevation acute myocardial infarction
TIMI 9B GUSTO IIb HERO-2 HORIZONS-AMI
Number of patients 3,002 4,131 17,073 3,602
Direct thrombin
inhibitor
Hirudin Hirudin Bivalirudin Bivalirudin
Dose DTI 0.1 mg/kg bolus 0.25 mg/kg bolus 0.1 mg/kg bolus 0.75 mg/kg bolus
0.1 mg/kg-h × 4 days 0.5 mg/kg-h × 12 h, then
0.25 mg/kg-h × 36 h
0.1 mg/kg-h × 3–5
days
1.75 mg/kg/h until completion
of PCI
UH 5000 U bolus 5000 U bolus 5000 U bolus 60 IU/kg bolus
1000 U/h × 4 days,
aPTT = 55–85 s
1000 U/h × 48 h,
aPTT = 50–75 s
1000 U/h × 3–5 days,
aPTT = 60–85 s
rebolused as necessary for
goal ACT 200–250 s.
Fibrinolytic agent TPA – 64%
SK – 36%
30 days
TPA – 69%
SK – 31%
SK – 100%
96h
N/A
(Primary PCI used)
Endpoint follow-up 30 days 30 days
Death (%) DTI 6.1 10.8 5.9 2.1
UH 5.0 10.9 6.2 3.1
Reinfarction (%) DTI 4.3 1.6* 5.0 1.8
UH 5.0 2.3* 6.0 1.8
Death or reinfar-
ction (%)
DTI
UH
9.7
9.3
12.6
13.6
9.9
11.3
5.4
5.5
Intracranial
hemorrhage
(%, in-
hospital)
DTI
UH
0.4
0.7
0.6
0.4
0.5
0.4
Not repored
Not repored
Major bleeding (%,
in-hospital)
DTI
UH
3.4
3.8
0.7
0.5
1.1
1.5
3.1**
5.0**
All p = N.S. except *p = 0.001, **p = 0.002
DTI direct thrombin inhibitor, SK streptokinase, TPA tissue plasminogen activator, UFH unfractionated heparin. GUSTO Global Use of Strategies to Open Occluded
Coronary Arteries (21), HERO Hirulog and Early Reperfusion or Occlusion (23), TIMI Thrombolysis and Thrombin Inhibition in Myocardial Infarction (22),
HORIZONS-AMI Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction Trial
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Antithrombotic Drug Therapy in Cardiovascular Disease
Table 5
Major trials of DTIs in non-ST-elevation acute coronary syndromes
Gusto IIb Oasis-2 Acuity
Number of patients 8,011 10,141 13,819
Direct thrombin inhibitor (DTI) Hirudin Hirudin Bivalirudin
Dose DTI 0.1 mg/kg bolus 0.4 mg/kg bolus 0.1 mg/kg bolus
0.25 mg/kg/h until PCI
¶
0.15 mg/kg-h × 3 days
0.1 mg/kg-h × 3–5 days
UFH 5,000 U bolus 5,000 U bolus 60 U/kg bolus
1000 U/h × 3–5 days,
aPTT = 60–85 s
15 U/kg-h × 3 days,
aPTT = 60–105 s
12 U/kg-h until PCI
b
,
aPTT = 50–75 s
LMWH N/A N/A 1 mg/kg q12 h
a
Endpoint
follow-up
30 days 7 days 30 days
Death (%) DTI 3.7 NR 1.6
UFH 3.9 NR 1.3
c
Reinfarction (%) DTI 5.6 NR 5.4
UFH 6.4 NR 4.9
c
Death or reinfarc-
tion (%)
DTI 8.3 3.6** 7.8
UFH 9.1 4.2** 7.3
c
Intracranial
hemorrhage
(%, in-hospital)
DTI 0.2* 0 <0.1
UFH 0.02* 0 <0.1
c
Major bleeding
(%, in-hospital)
DTI 1.3* 1.2*** 0.9
‡
UFH 0.9* 0.7*** 1.9
c,‡
a
Additional 0.3 mg/kg LMWH given if last dose given >8 h. before PCI
b
Anticoagulation could be continued past completion of PCI at the discretion of the physician
c
Number represents percentage of patients in whom endpoint occurred while receiving either UFH or LMWH and a
GpIIbIIa inhibitor in the ACUITY trial
All p = N.S. except *p = 0.06,**p = 0.066, ***p = 0.01, ‡ p £ 0.001
DTI direct thrombin inhibitor, NR not reported, UFH unfractionated heparin
those who received no pretreatment (Table 6). It is worth noting that patients in this study could not
receive bivalirudin within 8
h of administration of LMWH or 6 h of administration of UFH unless the
ACT was less than 175 s. Nevertheless, there was no association between time of discontinuation of
heparin therapy to the time of PCI and incidence of major or minor bleeding (Fig. 5).
More recently, an analysis of patients who received heparin prior to randomization in the ACUITY
trial assessed the safety of switching from prerandomization UFH or enoxaparin to bivalirudin as
compared with continuation of their heparin therapy in the setting of non-ST elevation ACS managed
with an invasive strategy (47). Here the authors found that patients switching to bivalirudin had simi-
lar rates of ischemia (6.9% vs. 7.4%, p = 0.52), less major bleeding (2.8% vs. 5.8%, p < 0.01), and
improved net clinical outcomes (9.2% vs. 11.9%, p < 0.01) compared with those who had been rand-
omized to continue their prerandomization heparin.
To date, there are no published studies that evaluate the safety and efficacy of switching from
heparin therapy to a DTI in the setting of STEMI. However, in HORIZONS-AMI, approximately
two-thirds of patients randomized to treatment with bivalirudin received UFH prior to PCI. There was
no significant difference in bleeding between those who received preprocedural heparin and those
who did not (4.8% with preprocedural heparin vs. 5.2% without, p = 0.47).
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Direct Thrombin Inhibitors in Acute Coronary Syndromes
Table 6
Bleeding rates associated with different antithrombin transitions (Adapted with permission)
Variable
Naive→bivalirudin*
(n = 2,345)
UFH→bivalirudin
(n = 287)
LMWH→bivalirudin
(n = 258)
Naive→GP IIb/IIIa/
UFH (n = 2,325)
UFH→GP IIb/IIIa/
UFH (n = 349)
LMWH→GP IIb/
IIIa/UFH
(n = 313)
Protocol major
bleeding
2.3%* 1.7% 2.7% 3.6% 4.9% 5.8%
Protocol minor
bleeding
13.4%* 13.6% 14.0% 25.0% 28.9% 29.1%
Protocol major/
minor bleeding
15.6%* 15.3% 16.7% 28.6%
†
33.8% 34.8%
TIMI major/minor
bleeding
1.9%* 1.4% 1.9% 3.5% 4.3% 5.4%
³2 Non-CABG
transfusions
0.8%* 1.1% 1.2% 1.0%
†
2.3% 2.9%
*p = NS for all three-way comparisons versus bivalirudin alone
†
p < 0.05 for two-way comparison versus GP IIb/IIIa, UFH-naive as well as two-way comparisons of UFH- naive versus either preceding UFH or preceding
LMWH
CABG coronary artery bypass grafting; GP glycoprotein; LMWH low molecular weight heparin; UFH unfractionated heparin
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