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Antithrombotic Drug Therapy in Cardiovascular Disease
ACUITY-PCI (80) was made up of the 7,789 patients from the ACUITY trial who underwent
PCI during the trial. Drug-eluting-stent use in these patients was roughly 60% in all three groups:
those receiving UFH/enoxaparin plus GP IIb/IIIa inhibitors; those receiving bivalirudin plus GP
IIb/IIIa inhibitors; and those receiving bivalirudin monotherapy, with randomization roughly
equal among the three groups. In an intention-to-treat analysis, the 30-day primary endpoints –
composite ischemia (death, MI, or unplanned revascularization for ischemia), major bleeding or
net clinical outcomes (major bleeding or composite ischemia) –were not significantly different
between the groups receiving bivalirudin plus GP IIb/IIIa inhibitor or a heparin plus GP IIb/IIIa
inhibitors. Composite ischemia rates were similar between the two groups; however, major
bleeding was significantly lower in the bivalirudin-only group at 30 days, as compared with the
group receiving either heparin plus GP IIb/IIIa inhibitors. Unlike the main ACUITY trial, the net
clinical benefit (combining ischemic and bleeding events) was no different between the UFH/enoxa-
parin plus GP-IIb/IIIa-inhibitor and the bivalirudin-only groups. However, in troponin-positive
patients, and in patients who received clopidogrel pretreatment, rates of composite ischemic
events tended to be higher in the bivalirudin-only group versus the UFH/enoxaparin plus GP-IIb/
IIIa-inhibitor group.
HORIZONS AMI
(81) randomized more than 3,600 patients (123 centers in 11 countries) with
STEMI with symptom onset
< 12 h in a 1:1 fashion to UFH 60 U/kg IV, with subsequent boluses
titrated by nomogram to ACT of 200–250
s, plus a GP IIb/IIIa inhibitor (abciximab or eptifibatide),
or to bivalirudin monotherapy (0.75
mg/kg bolus; infusion 1.75 mg/kg per h), stopped at the end of
the procedure, plus provisional GP IIb/IIIa inhibitors for large thrombus or refractory no-flow. Only
7.2% of patients in the bivalirudin-treated group received provisional GP IIb/IIIa inhibitors in the cath
lab. Bivalirudin significantly reduced net adverse clinical events by 24% at 30
days (a composite of
major bleeding and MACE) as well as major bleeding alone by 40%, as compared with UFH plus a
GP IIb/IIIa inhibitor.
Bivalirudin has not consistently demonstrated superiority to heparins in providing protection
against cardiovascular ischemic events, but it has reduced bleeding complications. In fact, a recent
meta-analysis (82) incorporating five randomized controlled trials comparing bivalirudin to the
heparins in 25,457 patients with ACS, including those patients undergoing PCI, demonstrated a
significantly lower risk of major bleeding (defined as intracranial, intraocular, or retroperitoneal
hemorrhage; clinically overt blood loss leading to a hemoglobin drop exceeding 3
g/dL or transfu-
sion of 2 or more units of whole blood or packed red blood cells) with bivalirudin. Compared to the
heparins, the risk of death, MI, revascularization, and composite ischemic endpoints were similar
with bivalirudin monotherapy.
Bivalirudin may be particularly appropriate in higher-risk populations, specifically women, the
elderly (>65 years), and in patients with renal impairment (serum creatinine > 1.2 mg/dL). It may be
an alternative to heparin plus planned GP IIb/IIIa inhibition in any patient undergoing urgent or elec-
tive PCI, especially in any patient with a high risk of bleeding complications. In addition, bivalirudin
is usually the anticoagulant of choice in patients with a history of HIT/HITTS (83). Up to 5% of
patients administered UFH develop HIT/HITTS, which is associated with a dramatic increase in mor-
bidity and mortality (52). The ATBAT trial (84) evaluated the safety and efficacy of direct thrombin
inhibition with bivalirudin during PCI in patients with HIT or HITTS. Over 4 years, this multicenter
trial recruited 52 patients; the investigators reported a low incidence of major (1 patient) and minor
(7 patients) bleeding complications. None of the patients developed thrombocytopenia. In December
2005 the U.S. Food and Drug Administration (FDA) approved the use of bivalirudin in patients with
or at risk of HIT/HITTS undergoing PCI (83).
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SPECIAL POPULATIONS
Women
Even though more women than men die each year from heart disease (85), women tend to be
referred less frequently for diagnostic cardiac catheterization
(86). As a result, only about one-third of
the 1.2 million patients undergoing PCIs annually in the United States are women
(87). More worrisome
yet, women tend to have higher rates of complications and in-hospital mortality after PCI
(88), both
elective and emergent, albeit much of this difference is attributable to higher-risk clinical characteris-
tics. Fortunately, once beyond the acute hospitalization, adjusted long-term mortality rates after PCI
are roughly equivalent
(89–91).
Compared to men, women have a twofold to fourfold increased risk of vascular complications such
as arteriotomy-associated hematomas, retroperitoneal bleeds, and need for blood transfusions
(92).
Proceduralists are generally aware of this discrepancy and attempt to attenuate bleeding risk by whatever
means possible. Paradoxically, in an effort to prevent major bleeding, especially intracranial hemorrhage,
women might receive subtherapeutic antiplatelet and antithrombotic dosing, thereby increasing their
risk for ischemic complications.
The ACC/AHA guidelines (9) advise that lower doses of UFH should be used in patients undergo-
ing PCI at high risk of bleeding, including women and older adults. Although LMWH and UFH have
not been formally compared in an exclusively female population, about 30% of the patients enrolled
in the SYNERGY
(65) and A-to-Z (66) ACS trials were female. Again, neither study noted a benefit
for either therapy in either men or women, but LMWH was associated with a small increase in risk
of bleeding.
Similarly, bivalirudin has not been evaluated in an exclusively female cohort, but about 26% of the
patients in the REPLACE-2 trial (62) were women. The use of bivalirudin was associated with a signifi-
cant reduction in major bleeding complications in women. Both major and minor bleeding was signifi-
cantly reduced (p < 0.0001) from 34.1% with UFH plus GP IIb/IIIa inhibitor to 19.7% with bivalirudin.
Antiplatelet therapy should not be specifically modified for women undergoing PCI. The CREDO
trial (20) (n = 2,116, 29% female) which treated patients undergoing PCI with clopidogrel for up to
1
year noted a nonsignificant 32% relative risk reduction in the combined endpoint of stroke, MI, or
death in women. In the ISAR-REACT trial
(22) (n = 2,159, 24% women), no additional benefit for the
GP IIb/IIIa inhibitor abciximab was found among low-risk PCI patients pretreated with a 600-mg
loading dose of clopidogrel. The combined endpoint, comprising of death, MI, and target vessel revas-
cularization at 30
days, did not differ between the two groups in either the entire cohort or specifically
in the female subset.
As in the general population, GP IIb/IIIa inhibitor administration is usually beneficial in women
undergoing PCI. A meta-analysis (93) of ten randomized, placebo-controlled trials of GP IIb/IIIa
inhibitors as periprocedural antiplatelet therapy (n
= 13 166, 26% women) noted a significant reduc-
tion in the combined endpoint of death or nonfatal MI 6 months after PCI. Importantly higher-risk
patients, including elderly women, appeared to derive the greatest benefit. Contrary to conventional
belief, GP IIb/IIIa inhibitors are not associated with an increase in major bleeding or vascular com-
plications in women (94,95). They do confer increased risk for minor bleeding, however.
Renal Failure
Patients with renal failure are at increased risk of both thrombotic and bleeding complications
(96–98). Whenever these patients undergo primary PCI in the setting of an acute MI, they incur an
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increased risk of acute reocclusion and major hemorrhage, thereby increasing their risk of mortality
significantly. As such, a creatinine clearance should be calculated as a matter of routine for every
patient who presents for a catheterization laboratory procedure. Estimation of renal function is needed
when prescribing certain drugs to any patient with renal dysfunction. Specifically, dose adjustment of
many anticoagulants is indicated when the creatinine clearance falls below 30 mL/min. While dosing
is usually appropriately made in patient with elevated serum creatinine, elderly patients, due to age-
related renal dysfunction and smaller body mass index, often have reduced creatinine clearance and
may be inadvertently overlooked.
UFH generally does not require dose adjustment. Careful monitoring of ACT level is recom-
mended, however, because these patients are vulnerable to bleeding complications with higher levels
of anticoagulation. By contrast, LMWH, danaparoid sodium, hirudins, and bivalirudin all undergo
renal clearance. Conservative dosing is advised whenever these agents are used in patients with renal
failure. LMWHs are excreted nearly completely via the kidneys. The serum half-life of LMWH aver-
ages about 2–4 h after IV injection, and 3–6 h following a SC injection. Dosing of the subcutaneous
LMWH enoxaparin in ACS patients undergoing coronary angiogram and coronary angioplasty should
be reduced by at least 50% (1 mg/kg per 24 h) in patients with severe renal failure (99).
A modestly sized (n
= 170) single hospital pharmacokinetic study (100) attempted to adjust enoxaparin
dosing in response to serum anti-Xa levels. After a bolus of enoxaparin 1
mg/kg SC, patients with a
creatinine clearance of 30–60
mL received subsequent boluses of 0.75 mg/kg SC every 12 h, while those
with a creatinine clearance
< or = 30 mL/min received a 0.50 mg/kg per dose SC every 12 h. The investiga-
tors noted that about 80% of percent of patients with moderate renal failure and 60% of the patients with
severe renal failure were in the therapeutic anti-Xa range after the third dose. A dose-adjustment ratio
New dose
= [(Current dose) × (Goal anti-Xa level)]/(Current anti-Xa level) was used to adjust doses in
patients whose levels were outside the therapeutic range. This formulation reliably placed patients in the
therapeutic range established by consensus guidelines; the incidence of bleeding was noted to be equiva-
lent to normal controls. Obviously, this cleverly designed protocol will need to be validated in larger
studies, but the concept of pharmacokinetic-based adjustments based on renal failure seems logical.
Clinical trials specifically addressing the efficacy of aspirin among patients with renal failure under-
going PCI have not been performed. Aspirin is largely hepatically metabolized, but a fraction is also
renally excreted (1). Given aspirin’s proven track record, however, one should refrain from adjusting
the dose in renally impaired patients. Importantly, ASA is dialyzed significantly. Postdialysis dosing is
recommended in patient acutely requiring consistent aspirin therapy (i.e., recent stent placement).
Clopidogrel and ticlopidine are hepatically metabolized; dose adjustment is not required
(13).
There exist few data supporting the efficacy and safety of GP IIb/IIIa inhibitors use in patients with
significant renal failure. The small molecule agents (i.e., tirofiban and eptifibatide) are excreted
predominantly via the kidneys, and randomized trials have largely excluded patients with renal dys-
function. In contrast, abciximab, a monoclonal antibody fragment, undergoes almost no renal excretion
and is eliminated through platelet degradation by the reticuloendothelial system. In the EPIC (38) and
EPISTENT (101) trials, abciximab therapy did not confer a significant bleeding risk for patients with
mild renal dysfunction; however, safety data among patients with marked reductions in creatinine
clearance are not available from these trials. A retrospective analysis of the TARGET trial (102) noted
that both ischemic and bleeding complications are highest in the lowest creatinine clearance quartile of
patients treated with either tirofiban or abciximab. Of particular interest, no interaction between these
GP IIb/IIIa inhibitors and creatinine clearance on ischemic or bleeding events was appreciated.
Bivalirudin undergoes partial elimination through renal excretion; dose adjustment is required in
patients with moderate-to-severe renal failure (creatinine clearance < 60 mL/dL) (78). The half-life of
bivalirudin is about 25 min in patients with normal renal function, about 34 min in those with moderate
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renal failure, and 57 min in those with severe renal failure. Clinical support for the use of bivalirudin
in patients with renal failure may be derived from a retrospective analysis of the Bivalirudin
Angioplasty Trial (BAT)
(103) in which bivalirudin was compared with UFH therapy among 4,312
patients undergoing angioplasty. Nearly 75% of the enrolled patients had some degree of renal failure.
No matter the degree, bivalirudin-treated patients experienced both fewer bleeding complications and
fewer ischemic complications than patients treated with UFH. Considering the pathological derange-
ments associated with renal impairment, including evidence of ongoing thrombin generation, a
particular emphasis on direct thrombin inhibition seems justified in the renal failure patient.
FUTURE DIRECTIONS
The last decade has seen a remarkable increase in the clinical evaluation and therapeutic applica-
tion of varied platelet inhibitor pharmaceuticals. Prasugrel is a novel platelet inhibitor that has been
tested in patients with ACS planned for PCI. The TRITON-TIMI 38 study (104) randomized 13,608
patients with moderate-to-high-risk ACS and planned PCI to receive prasugrel (a 60-mg loading dose
and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily main-
tenance dose), for 6–15
months. The primary efficacy endpoint was death from cardiovascular causes,
nonfatal myocardial infarction, or nonfatal stroke. The key safety endpoint was major bleeding. The
investigators found that, as a more potent antiplatelet agent, prasugrel reduced the combined rate of
death from cardiovascular causes, acute stent thrombosis, nonfatal myocardial infarction, or nonfatal
stroke (12.1% for clopidogrel vs. 9.9% for prasugrel); however, this was at the expense of increased
major (1.4%, vs. 0.9% in the clopidogrel group) and fatal bleeding (0.4% vs. 0.1%). Overall, a net
clinical benefit in favor of prasugrel remained. Nonetheless, uncertainty remains about the optimal
duration and dosing of this agent.
Cangrelor (AR-C69931MX) is a potent, selective, reversible inhibitor of ADP-induced platelet aggrega-
tion
(105). It is being studied for ACS as an ultrafast acting IV antithrombotic agent. A distinct theoretical
advantage is the agent’s short plasma half-life, which yields a rapid loss of activity following discontinua-
tion of the infusion and may allow for a significant safety advantage. Phase II trials have shown safety and
a greater inhibition of platelet aggregation over clopidogrel. Phase III trials should provide more definitive
information on clinical efficacy and safety; preliminary results are due in late 2008.
In the antithrombotic arena, there is intense interest in the development and application of newer
antithrombotics that inhibit upstream targets in the coagulation cascade. A number of direct factor Xa
inhibitors (DX-9065a and otamixiban), as well as other novel antithrombin inhibitors, are in clinical
development; whether or not they will lend themselves to periprocedural anticoagulation remains to
be seen
(106–108).
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15 Antithrombotic Therapy in Carotid
and Peripheral Intervention
Thomas J. Helton and Samir R. Kapadia
Co n t e n t s
Introduction
Peripheral Intervention (Non-Carotid)
Fibri
nolytics
Reference
Ab s t r A c t Peripheral arterial disease is a spectrum of disease processes involving the non-coronary arterial
system that is primarily the result of atherothrombosis. Although the field of peripheral intervention is older
than coronary intervention, the evolution of this field has lagged behind that of its coronary counterpart.
Adjunctive therapies demonstrated to be beneficial in the realm of percutaneous coronary interventions (PCI)
have not been as systematically assessed within the peripheral arena. Nevertheless, current opinion rests with
the belief that adjunctive antiplatelet and antithrombotic agents improve outcomes for patients undergoing
peripheral interventional procedures. Future studies will foster a better understanding of the idiosyncrasies
related to peripheral interventions and the optimal utilization of currently available and developing antithrom-
botic agents in order to further advance this field.
Key words:
Antiplatelet; Antithrombin; Carotid; Intervention; Peripheral; Renals
INTRODUCTION
Peripheral arterial disease is a spectrum of disease processes involving the non-coronary arterial
system that is primarily the result of atherothrombosis. In 1964, Dotter and Judkins pioneered “trans-
luminal angioplasty” for the treatment of peripheral arterial disease
(1). Early procedures were fraught
with complications (distal emboli and puncture site hematomas). After a decade of growing skepticism
and mounting complications Andreas Gruentzig was able to refine the multiple catheter system of
Dotter to a single double-lumen catheter with a low compliance balloon. This new system allowed for
smaller bore catheters and thus reduced the number of puncture site hematomas prompting the emer-
gence of percutaneous intervention (2). Although reasonably successful at the time (initial patency rate
of 86%), there were still many problems with reocclusions and embolic complications (2). The catheters
were felt to be thrombogenic and it was speculated that anticoagulation might improve outcomes.
From: Contemporary Cardiology: Antithrombotic Drug Therapy in Cardiovascular Disease
Edited by: A.T. Askari and A.M. Lincoff (eds.), DOI 10.1007/978-1-60327-235-3_15
© Humana Press, a part of Springer Science+Business Media, LLC 2010
283
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