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Antithrombotic Drug Therapy in Cardiovascular Disease
Alternative Therapies
Fondaparinux
Fondaparinux is a synthetic pentasaccharide metabolized in the kidneys. It has a half-life of
17–21
h and is administered subcutaneously with 100% bioavailability. Its elimination is prolonged
in patients with renal impairment and is not advised in patients with a creatinine clearance of less than
30
ml/min. Fondaparinux is a selective indirect factor Xa inhibitor that binds specifically to anti-
thrombin. It inhibits thrombin generation, does not prolong the prothrombin time (PT), INR, or aPTT,
and no laboratory monitoring is usually needed.
Fondaparinux is currently approved for the prophylaxis of DVT and PE for orthopedic and abdominal
surgery as well as for treatment of DVT and PE. It has also been used “off-label” in a number of
patients with HIT
(40). Warkentin et al reported similar immunogenicity between fondaparinux and
LMWH in a study of 2,726 patients; however, PF4/fondaparinux was poorly recognized by the HIT
antibodies leading the authors to rationalize that the risk of HIT was very low
(41). Recently,
Warkentin and colleagues published the first reported case of HIT associated with fondaparinux in a
patient with no previous UFH or LWMH exposure and advised that it can cause a disorder resembling
HIT on rare occasions
(40–42).
Danaparoid
Danaparoid is a non-heparin low molecular weight glycosaminoglycan derived from porcine intes-
tinal mucosa. It is approved for the treatment and prevention of HIT-associated thrombosis outside the
United States. However,it is no longer available in this country.
None of the currently available alternative anticoagulants used in the US have an antidote. If clinically
significant bleeding occurs, the agent should be discontinued immediately and supportive therapy
initiated. A comparison of the current alternative anticoagulants available for the treatment of HIT is
found in Table
3.
Warfarin
Warfarin should be avoided in patients with acute HIT to avoid coumarin-induced-VLG or coumarin-
induced skin necrosis. Current ACCP guidelines advise that warfarin only be initiated in lower doses
Table 3
Comparison of available agents used in the treatment of HIT
Argatroban Bivalirudin Fondaparinux Lepirudin
Monitoring aPTT, ACT aPTT, ACT, ECT Anti-Xa level aPTT, ACT, ECT
Half-life 39–51 min 25 min 17 h 80 min
Clearance Hepatic Enzymic and renal Renal Renal
Dose adjustment Hepatic
insufficiency
Moderate to severe
renal insufficiency
Renal insufficiency Renal insufficiency
Cross-reaction with
HIT antibodies
No No Yes No
Antibody
development
No May cross-react with
anti-hirudin
antibodies
No Anti-hirudin
antibodies in up to
60% of patients
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Heparin-Induced Thrombocytopenia
(£5 mg); overlapped concurrently with a DTI for a minimum of 5 days, only started once the patient
has improved clinically and the platelets have recovered to ³100,000
mm
3
and preferably 150,000 mm
3
;
and the DTI discontinued only when the INR is ³2 for two consecutive days
(5,17,18). Reversal with
oral or intravenous vitamin K is advised to prevent VLG or coumarin-induced skin necrosis if warfarin
has already been started before HIT is recognized
(3).
All DTIs prolong the INR because of differences in their molar concentrations required to achieve the
desired inhibition of thrombin
(43). Argatroban causes the most pronounced increase in the INR and
the manufacturer recommends a INR ³4.0 during cotherapy. The INR is least affected by lepirudin
(44).
Once the INR is within the targeted range (and only after a minimum 5-day overlap), the INR and
aPTT should be checked after holding the DTI 4–6
h. If the INR is between 2 and 3 (or) and the aPTT
is at baseline, the DTI can be safely discontinued
(44). The recommended length of therapy with
warfarin following acute HIT is 3–6 months.
Reducing the Incidence of HIT
Low molecular weight heparin or fondaparinux are alternatives to UFH for prophylaxis and/or
treatment of DVT and PE and should reduce the incidence of HIT as they are less likely to trigger this
condition. Early transition to warfarin (before HIT has a chance to develop) in patients receiving UFH
or LMWH for acute DVT or PE is also recommended. Porcine UFH preparation should be used rather
than bovine products, and all patients receiving UFH should have their platelet count monitored regu-
larly. Current ACCP guidelines recommend monitoring platelet counts at baseline and every other day
from days 4 to 14. If there is no recent exposure however, patients with exposure within the previous
100 days must be monitored within 24
h of administration (5,45). The ACCP guidelines do not recom-
mend routine platelet count monitoring for LMWH. This is however recommended by the British
Committee for Standards in Haematology (46).
Special Conditions
Isolated HIT
Isolated HIT was previously treated by just discontinuing UFH or LMWH. However, this approach
places patients at an increased risk of new thromboembolic rates of 20–50%
(5,16,32,46). Current
ACCP guidelines recommend treatment with a DTI followed by a short course of warfarin and per-
forming a venous duplex ultrasound of the lower extremities due to the high frequency of asymptomatic
DVT’s in this situation (5).
HIT and PCI
Argatroban and bivalirudin are the only agents currently approved by the FDA for PCI and HIT,
although there is limited experience with lepirudin, and all three agents have been used successfully
in previous trials (32,47). The Anticoagulant Therapy with Bivalirudin to Assist in the performance
of PCI in patients with heparin-induced Thrombocytopenia trial (ATBAT) used bivalirudin in 52
patients (34). Clinical success was defined as procedural success without death, emergency bypass
surgery, or q wave MI, and procedural and clinical successes were achieved in 98 and 96% of patients.
Only one death was reported - a cardiac arrest 46 h after a successful PCI (34).
Lewis and colleagues analyzed 91 patients who underwent 112 PCIs in three prospective rand-
omized trials (ARG-261, ARG-310, and ARG-311) using Argatroban (48). Satisfactory outcomes of
the procedure and adequate anticoagulation were primary efficacy endpoints and were achieved in
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Antithrombotic Drug Therapy in Cardiovascular Disease
94.5 and 97.8% of patients respectively. There was only one major bleeding event, four MIs, and
revascularization was necessary in seven patients. Results were comparable to historical heparin con-
trols
(48).
Percutaneous coronary intervention was also performed using lepirudin in 25 HIT patients by
Cochran et
al. Many of their patients received GPIIb/IIIa inhibitors and clinical success - defined as
freedom from death, MI, stroke, or revascularization -was achieved in 92% of the patients
(47).
According to Jolicoeur et
al ,who recommend bivalirudin, experience with PCI and HIT is limited
(to only 228 patients)
(49). The ACCP guidelines recommend using any of the three DTIs for patients
with acute or previous HIT who require cardiac catheterization or PCI
(5).
Fondaparinux has also been used in PCI, but not in patients with HIT
(50). In the recently published
Sixth Organization to Assess Strategies in Acute Ischemic Syndromes trial or OASIS, an increase in
catheter-related thromboses was reported. Based on this finding, the authors recommended adjunctive
therapy with UFH to prevent this complication, thereby eliminating fondaparinux as a suitable alternative
for HIT patients (50).
HIT AND CARDIAC SURGERY
Several issues confront the cardiac surgical patient with HIT, including difficulty in making the
postoperative diagnosis of HIT and how best to manage the patient with acute HIT who requires
urgent CABG.
The incidence of HIT approaches 2–3% following CABG; however, antibody formation is much
higher approaching 50% by 1 week postoperatively. If routine HIT testing is done after surgery
(because of thrombocytopenia), there is often a potential to over diagnose HIT based on laboratory
results alone (14).There are several clues helpful in making the diagnosis of “postoperative HIT.” One,
it classically presents as a biphasic pattern of platelet recovery; with an initial postoperative decline
followed by recovery and then a second decline (14). Other clues may include unusual or unexpected
thromboembolic events, prolonged thrombocytopenia, and immunoassay values >1.0 or positive
functional testing (51).
Anticoagulation for the acute HIT patient who requires urgent CABG presents a difficult problem
because currently available alternative anticoagulants are limited by their lack of an antidote and their
need for special intraoperative monitoring using the ecarin clotting time (ECT). Several recent trials
using bivalirudin in both “on-pump” and “off-pump” cardiac surgery have been described however
(35,36). The CABGHIT/TS On and Off Pump Safety and Efficacy (CHOOSE-ON and CHOOSE-
OFF) trials reported satisfactory procedural success and an acceptable incidence of bleeding (35,36).
If surgery cannot wait, recent data appears to favor bivalirudin in this setting, although lepirudin has
been successfully used as well (5,35,36).
Reexposure to UFH in patients with HIT is an area of controversy, although this approach has been
used successfully for CABG and vascular surgery, when the surgeon feels alternative anticoagulants
are not acceptable. Current strategies advise waiting approximately 100 days after the last UFH or
LMWH exposure, thus allowing time for transient HIT antibodies to disappear. If testing confirms
their absence, re-administration of UFH (during the procedure) appears to be safe (22,45,52). A DTI
should be considered postoperatively if the clinical situation warrants it.
The ACCP and the task force of the British Committee for Standards in Haematology guide-
lines recommend delaying surgery if possible, until the HIT antibody disappears., If however
surgery is urgently needed, options include bivalirudin and lepirudin using the ECT for monitor-
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Heparin-Induced Thrombocytopenia
ing, or UFH plus the antiplatelet agents tirofiban (not recommended by the manufacturer) or
epoprostenol
(5,45).
PLATELET FACTOR 4 HEPARIN ANTIBODIES IN PATIENTS WITHOUT HIT
Several recently published studies have suggested that the mere presence of “heparin antibodies”
(without evidence for thrombocytopenia or overt HIT) may lead to adverse outcomes for cardiovas-
cular patients
(53,54). Mattioli and colleagues reviewed the composite end point of death, MI, recur-
rent angina, and need for revascularization in 124 patients presenting with unstable angina who
received at least 5 days of UFH
(53). The combined incidence of new thrombotic events including
death, MI, recurrent angina, urgent revascularization, and stroke was more common (66% in patients
with positive HIT antibodies and 44% in those without) at one year follow up
(53). Williams et al also
reported adverse outcomes in 109 patients from the GUSTO IV-ACS trial who also received UFH
exposure. They found that patients with PF4/heparin antibodies (without thrombocytopenia and no
evidence for HIT) had a significantly higher rate of 30-day MI compared to those without antibodies
(54).
Arnold and Kelton suggested that although these patients likely have what should be considered “false
positive HIT”, these antibodies, in certain populations may result in thrombosis (55). Although these and
other reports are intriguing, their significance is unknown and will need further research.
CONCLUSION
Heparin-induced thrombocytopenia is a serious complication of UFH or LMWH preparations that
affects both the venous and arterial circulation. Although thrombocytopenia is the most common
presentation, bleeding is an unusual complication. Thrombosis develops in over one half of all
patients and lower extremity DVT and PE are the most common events, while acute limb occlusion
involving the arterial circulation occurs more often than stroke or myocardial infarction.
HIT is an immune-mediated process that requires both clinical and laboratory findings to confirm
the diagnosis. It is commonly referred to as a clinicopathologic syndrome. A high clinical suspicion,
a pre-test probability score using the 4T’s (thrombocytopenia, timing of the platelet count drop,
thrombosis, and exclusion of other diagnostic possibilities) and positive laboratory testing will help
confirm the diagnosis. Immediate discontinuation of UFH or LMWH,and the initiation of a DTI fol-
lowed by warfarin therapy once the platelet count has recovered, is recommended.
Prevention is best achieved by close monitoring of the platelet count while the patient is receiving
UFH. The use of alternatives to UFH (LMWH or fondaparinux) as primary prevention or treatment
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24
Resistance to Antiplatelet Drugs
Gerald C. Koenig and Hitinder S. Gurm
Co n t e n t s
Introduction
Background
Definition
Prevalence
Mechanisms
Testing
Clinical Confounders
Clinical Significance
Significance of Anti-Platelet Failure
Treatment
Conclusions
References
Ab s t r A c t Platelet activation and aggregation are central events in arterial thrombosis underlying acute
coronary syndromes and progression of atherosclerotic vascular disease, and constitute complex processes
involving multiple interdependent pathways. Aspirin remains the most well-studied antiplatelet agent and
the backbone of therapy for patients with atherothrombosis. The thienopyridines (i.e., clopidogrel) have
emerged as important additions for the management of patients with atherothrombotic diseases including
those with acute coronary syndromes, those undergoing percutaneous coronary intervention, and selected
patients with known vascular disease. Despite the use of these agents alone or in combination, a proportion of
patients will continue to experience recurrent events. Some of these patients may be considered “resistant”
to the currently available antiplatelet agents. Once thought of as simply a laboratory phenomenon, antiplatelet
resistance has more recently been associated with adverse clinical events. Therefore, an understanding of
the mechanism(s) behind treatment failure and therapeutic regimens needed to remedy them remain an
area of essential research and of significant clinical importance.
Key words:
Clopidogrel; Aspirin; Resistance; Outcomes; Assessment; Platelet function
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_24
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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Antithrombotic Drug Therapy in Cardiovascular Disease
INTRODUCTION
Platelets play an integral role in the pathogenesis of atherothrombotic disorders. While the clinical
benefits of antiplatelet drugs are well recognized, there has been growing awareness of resistance to
these agents. This chapter aims to highlight the definitions, mechanisms, and significance of resistance
to antiplatelet drugs.
BACKGROUND
Platelet activation and aggregation are central events in arterial thrombosis underlying acute coro-
nary syndromes and progression of atherosclerotic vascular disease, and constitute complex processes
involving multiple interdependent pathways. In the acute coronary syndromes, atherosclerotic plaque
rupture exposes collagen, von Willebrand factor, and other adhesive proteins within the subendothe-
lium and intima to circulating platelets. Adhered platelets undergo conformational changes via the
action of extrinsic activators, such as collagen, thrombin, and epinephrine. Upon activation platelets
then release additional factors from their dense- and alpha-granules, including thromboxane A
2
,
adenosine diphosphate (ADP), and pro-inflammatory and pro-thrombotic factors. The activated and
degranulated platelets expose glycoprotein IIb/IIIa receptors on their surface resulting in fibrinogen
binding and platelet aggregation.
Aspirin, or acetylsalicylic acid, was first developed in 1897 by Felix Hoffman of Friedrich Bayer
& Company in a stable, commercially available form (1). However, the potential benefits of salicin,
or salicylic acid, an extract of willow bark, had been known centuries prior and can be dated back to
the Egyptians for its analgesic and anti-inflammatory activity (2). Aspirin has now become essential
therapy in cardiovascular medicine based on several clinical trials documenting primary and secondary
prevention of myocardial infarction, stroke, and cardiovascular mortality. Aspirin serves as an
irreversible inhibitor of platelet cyclooxygenase and platelet thromboxane A
2
production. However,
aspirin does not prevent platelet aggregation due to thrombin, epinephrine, or serotonin, which are
alternative pathways of platelet activation and aggregation.
Clopidogrel and ticlopidine are thienopyridine derivatives which exert their antiplatelet effects
by inhibiting adenosine diphosphate (ADP)-mediated platelet activation. Use of clopidogrel, in combination
with aspirin therapy, has shown significant risk reduction in myocardial infarction, stroke, and
cardiovascular mortality in patients with both stable and unstable coronary artery disease [(CAPRIE
(3), CURE (4), CREDO (5), CLARITY-TIMI-28 (6), COMMIT (7)] (Fig. 1).
However, despite millions of patients worldwide taking monotherapy or combination antiplatelet
therapy, many continue to have cardiovascular events. Further laboratory evaluation of platelet func-
tion has revealed widespread variation in the degree of platelet inhibition in response to these agents.
The understanding of the mechanism(s) behind treatment failure and therapeutic regimens needed to
remedy them remain an area of essential research and of significant clinical importance.
DEFINITION
A true definition of aspirin and clopidogrel resistance has yet to be established. In the litera-
ture, it has been defined in both clinical and pharmacodynamic terms. Predicting clinical events
has been difficult, and there exists a significant inter-assay discordance. Additionally, resistance
may be more of a continuum than a binary determination and the occurrence of thrombotic events
is a culmination of multiple signaling pathways encompassing complex platelet biology and
function (Fig. 2).
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Resistance to Antiplatelet Drugs
Clinical Failure
By strictest terms, the clinical definition of aspirin or clopidogrel failure is the occurrence of a
vascular event despite treatment with aspirin and clopidogrel for thromboprophylaxis. Per the
Antithrombotic Trialists’ Collaboration (8), the frequency of aspirin failure can be estimated to range
from 10.9% to 17.3%, depending on the aspirin dose. There has been no clear relationship between
dosage and clinical failure rate, but several studies have suggested a dose response and time-dependent
variability to both aspirin and clopidogrel treatment. However, because of the complex pathophysiology
of ischemic heart disease, multiple factors potentially contribute to these events including inflammation,
vascular biology, thrombosis, and hemodynamics. Recurrent events may also be mediated by non-
platelet factors. Therefore, treatment failure is not synonymous with pharmacodynamic resistance and
should not be used interchangeably.
Activated
Platelet
Activated
Platelet
ADP
ADP Receptor
P2Y
1
Dense Granules
Arachidonic
Acid
Thromboxane A
2
TxA
2
Receptor
COX-1
Aspirin
Thienopyridines
(Clopidogrel)
CYP450
Fibrinogen
Gp IIbIIIa Inhibitors
(Eptifibatide, Abciximab)
Gp IIb/IIIa
Receptor
P2Y
12
Ca
2+
Fig. 1. Mechanism of platelet activation and regulation by aspirin and clopidogrel.
Fig. 2. Chemical structure of aspirin (a) and clopidogrel (b).
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Antithrombotic Drug Therapy in Cardiovascular Disease
Pharmacodynamic or Laboratory Resistance
The pharmacodynamic definition is the inability of antiplatelet therapy to inhibit the target of its
action, that is, reduce platelet aggregation, using various assay systems. The frequency of aspirin
resistance can be estimated to range from 5.5% to 60%, depending on the assay used.
PREVALENCE
Aspirin resistance has been reported in patients with coronary artery disease, cerebrovascular
disease, peripheral artery disease, chronic heart failure, and atrial fibrillation. The frequency of
reported cases has ranged from 5.5% in patients with stable cardiovascular disease and abnormal
pharmacodynamics to 60% in patients with claudication symptoms on aspirin therapy
(8–19).
Clopidogrel resistance has been reported to have a prevalence between 4% and 30% 24
h after
administration, depending on the assay utilized and baseline platelet reactivity
(20–24).
MECHANISMS
Aspirin
The action of acetylsalicylic acid, or aspirin, on platelet activity has been previously well characterized
(25). Aspirin acts by irreversibly acetylating platelet cyclooxygenase (COX)-1 at serine residue 530
to exert its anti-platelet effect
(26–28). The enzyme COX-1 is then permanently inhibited from
converting arachadonic acid to several eicosanoids, such as leukotrienes, prostaglandins, thromboxane
A
2
(TXA
2
), and prostacyclin (PGI
2
). Thromboxane A
2
is a potent vasoconstrictor and platelet agonist
found in the alpha-granules of platelets. Prostacyclin is a vasodilator and platelet inhibitor produced
by platelets and vascular endothelium. When COX-1 is inhibited by aspirin, platelet thromboxane A
2
production is eliminated for the life span of the anucleated platelet, but prostacyclin synthesis continues
via the vascular endothelium which is able to replenish enzyme levels (28,29). In addition, PGI
2
is
produced by the enzymatic activity of COX-2 which is dramatically less affected by aspirin binding
(30).
Despite this well-characterized and clearly defined mechanism of action, the antiplatelet effects of
aspirin are not uniform in all patients and the inhibition of platelet aggregation is highly variable.
Several theories have been postulated on its mechanism of action and can be generally categorized
into clinical, cellular, and genetic factors. Among the more evaluated mechanisms are platelet hyper-
sensitivity to collagen (31), increased COX-2 activity or over-expression (30), and platelet alloantigen
2 (PLA2) polymorphism of platelet glycoprotein IIIa (32,33). Additional mechanisms include poor
patient compliance (34), poor gastrointestinal absorption (35), interactions with other medications
(36–38), tachyphylaxis (39), increased isoprostane activity (40), CD40–CD40 ligand interaction (41),
thromboxane production by non-platelet cells (42), exercise and catecholamine levels (43), and
COX-1 polymorphism (44). While the theories all appear plausible, the complex nature of platelet
physiology and redundancy of multiple platelet agonists argue for numerous factors being involved.
Clopidogrel
Unlike aspirin, clopidogrel is a prodrug that effects platelet activation and aggregation by a secondary
active hepatic metabolite converted by cytochrome P450 3A4 (CYP3A4) (45). The thiol metabolite, in
turn, acts by blocking adenosine diphosphate (ADP)-mediated platelet activation via irreversible inhibi-
tion of one of three platelet ADP receptors (P2Y
12
) via disulfide bond bridging (46,47). P2Y
12
receptor
binding liberates G
i
protein subunits, which leads to the inhibition of cAMP-mediated phosphorylation
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