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108
CHAPTER 7 Lipid-Modifying Therapy
23. Chapman MJ, Assmann G, Fruchart JC, et al . Raising high-density lipoprotein
cholesterol with reduction of cardiovascular risk: the role of nicotinic acid—a
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24. Gordon DJ, Rifkind BM. High-density lipoprotein—the clinical implications of
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25. Voight BF, Peloso GM, Orho-Melander M, et al . Plasma HDL cholesterol
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27. Sarwar N, Sandhu MS, Ricketts SL, et al . Triglyceride-mediated pathways and coro-
nary disease: Collaborative analysis of 101 studies. Lancet 2010; 375: 1634–1639 .
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32. Campbell SC, Moffatt RJ, Stamford BA . Smoking and smoking cessation—the
relationship between cardiovascular disease and lipoprotein metabolism: A
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33. Gepner AD, Piper ME, Johnson HM, et al . Effects of smoking and smoking ces-
sation on lipids and lipoproteins: outcomes from a randomized clinical trial, Am
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40. Brunzell JD . Clinical practice. Hypertriglyceridemia. N Engl J Med
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111111
Chapter 8
Antithrombotic Therapy
Amy Sarma and Michelle L. O’Donoghue
Platelets are central to the pathogenesis of atherothrombotic diseases. They
adhere to sites of vascular injury through glycoprotein (GP) Ib/V/IX, where
they are subsequently activated by numerous mediators, including adenosine
diphosphate (ADP), thrombin, epinephrine, and thromboxane A
2
.
1
Thrombin,
generated by injured vascular tissue, is a potent platelet activator and promotes
fi brin formation. By cross-linking platelets through the GP IIb/IIIa receptor,
fi brinogen promotes platelet aggregation and thrombus stabilization. Therapies
that inhibit platelet activation and aggregation, as well as the coagulation cas-
cade, are therefore central to the prevention and treatment of atherothrom-
botic diseases.
Antiplatelet agents
Aspirin
To date, aspirin remains the most commonly used antiplatelet drug. Aspirin
irreversibly acetylates the cyclooxygenase (COX)-1 enzyme, thereby blocking
formation of thromboxane A
2
(TXA
2
) and TXA
2
-mediated platelet activation
and aggregation.
2
Since the platelet lacks a nucleus, the effects of aspirin last
throughout the platelet’s 7- to 10-day lifespan.
Aspirin for primary prevention
There is continued interest in the use of aspirin to help reduce the risk of a
fi rst cardiovascular (CV) event in patients without established atherosclerotic
disease. However, the evidence to support the routine use of aspirin in this
patient population remains mixed. In an early open-label trial of aspirin that
enrolled 5,139 healthy male doctors in Britain, prophylactic aspirin (500 mg
daily or enteric-coated 300 mg daily) failed to reduce the risk of CV events dur-
ing a follow-up period of 6 years.
3
In contrast, a benefi cial effect for aspirin was
observed in the Physicians’ Health Study published the subsequent year. The
latter study enrolled 22,071 healthy male physicians in the United States and
randomized them to aspirin (325 mg daily) or placebo in a double-blind design.
4
After a mean treatment duration of 60.2 months, aspirin reduced the risk of
myocardial infarction (MI) by 44 percent (RR 0.56, 95 percent CI 0.45–0.70),
with enhanced benefi t seen in patients over the age of 50 years. However, the
use of aspirin failed to reduce CV mortality (RR 0.96, 95 percent CI 0.50–1.54)
and was associated with a trend toward an increased risk of stroke (RR 2.14,
95 percent CI 0.96–4.77, p = 0.06).
4
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CHAPTER 8 Antithrombotic Therapy
Similar fi ndings were observed nearly a decade later in the Thrombosis
Prevention Trial
5
and Hypertension Optimal Treatment
6
studies. The
Thrombosis Prevention Trial was a randomized double-blind, placebo-con-
trolled trial that enrolled 5,085 men (aged 45 to 69) who were deemed to
be at high risk of vascular disease.
5
Subjects were randomized in a 2 × 2 facto-
rial design to aspirin (75 mg daily) and/or warfarin (target INR 1.5) or match-
ing placebo pills. Irrespective of the use of warfarin, treatment with aspirin
reduced the primary endpoint of CV death or MI by 20 percent (95 percent
CI 1–35 percent, p = 0.04) compared with placebo. The benefi t was driven
by a signifi cant 32 percent reduction in nonfatal MI (95 percent CI 12–48 per-
cent, p = 0.004). However, the use of aspirin in this high-risk primary preven-
tion population failed to confer a mortality benefi t (RR 1.06, 95 percent CI
0.88–1.28).
5
Consistent fi ndings were also seen in the Hypertension Optimal
Treatment trial, a randomized trial of aspirin (75 mg daily) versus placebo in
18,790 patients aged 50 to 80 years with hypertension.
6
Aspirin reduced the
risk of CV death, MI, or stroke by 15 percent compared to placebo. Again this
benefi t appeared to be driven by a signifi cant reduction in the risk of MI (HR
0.64, 95 percent CI 0.49–0.85), and no overall mortality benefi t was observed
(HR 0.93, 95 percent CI 0.79–1.09).
In light of the favorable fi ndings for aspirin from the Hypertension Optimal
Treatment and Thrombosis Prevention Trials, another trial named the Primary
Prevention Project was terminated early for effi cacy.
7
In this open-label trial,
4,495 men and women were randomized to aspirin (100 mg daily) or no treat-
ment. Although patients did not have an established history of atherosclerotic
disease, all subjects were required to have established CV risk factors. After a
mean of 3.6 years, aspirin reduced the primary endpoint of CV death, MI, or
stroke by 22 percent, including a signifi cant 44 percent reduction in CV death.
The Women’s Health Study was one of the fi rst trials to cast doubt on the
routine use of aspirin in women for primary prevention.
8
The trial enrolled
39,876 female health professionals and randomized them to aspirin 75 mg every
other day or placebo. After a mean follow-up period of 10 years, aspirin failed
to reduce the primary endpoint of CV death, MI, or stroke (HR 0.91, 95 per-
cent CI 0.80–1.03) in women.
8
In contrast to prior studies, a signal was observed
toward a reduction in transient ischemic attack (TIA) or stroke with aspirin, but
there was no reduction in CV death or MI. Subgroup analyses suggested a pos-
sible benefi t in women older than 65 years.
8
The Antithrombotic Trialists’ Collaboration (ATC) performed a patient-
level meta-analysis that combined data from across these six published trials
and demonstrated that the use of aspirin reduced the risk of CV events by
12 percent in primary prevention patients and that this benefi t appeared to
be comparable in both men and women and independent of age.
9
However,
since the absolute benefi t of aspirin is small in this low-risk population, the
potential benefi t of aspirin must be carefully weighed against an increased risk
of extracranial hemorrhage (primarily gastrointestinal bleeding), as well as the
small risk of intracranial hemorrhage. Further doubt has been cast on the effi -
cacy of aspirin for routine primary prevention based on randomized trials of
aspirin in diabetic patients that have failed to demonstrate a signifi cant reduc-
tion in CV events despite being a higher-risk population.
10,11
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CHAPTER 8 Antithrombotic Therapy
Aspirin for secondary prevention
Although the net clinical benefi t of aspirin in primary prevention remains
disputed, its role in secondary prevention is well established. The fi rst ran-
domized clinical trial to defi nitively demonstrate the effi cacy of aspirin in
the setting of acute MI was the Second International Study of Infarct Survival
(ISIS-2) study.
12
Using a 2 × 2 factorial design, 17,187 subjects were random-
ized to aspirin (162 mg daily) and/or fi brinolytic therapy versus matching pla-
cebo. Aspirin conferred a 23 percent reduction in the odds of death versus
placebo that was similar in magnitude to those subjects treated with fi brin-
olytic alone. Moreover, the effects of aspirin appeared to be additive such
that there was additional benefi t for those subjects treated with the combi-
nation of fi brinolytic and aspirin.
12
Consistent fi ndings were observed when
data were combined across trials by the ATC trialists, who demonstrated that
aspirin reduced the risk of nonfatal coronary events by 30 percent and vascular
death by 15 percent.
13
Dosing considerations
To date, observational studies that examined the effi cacy of aspirin across
various doses suggested that lower doses of aspirin achieved similar effi cacy
as higher doses of aspirin and with a diminished risk of bleeding.
14
This ques-
tion was then directly addressed in the Clopidogrel and Aspirin Optimal Dose
Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies
in Ischemic Syndromes (CURRENT-OASIS 7) trial, a randomized trial of high-
dose (325-mg loading dose, 300 to 325 mg daily) versus low-dose (325-mg load-
ing dose, 75 to 100 mg daily) aspirin in 25,086 patients with an acute coronary
syndrome (ACS).
15
The risk of CV death, MI, or stroke at 30 days was similar
regardless of aspirin dose (4.4 versus 4.2 percent, respectively). Although the
incidence of major bleeding was similar for both treatment arms, high-dose
aspirin increased the risk of minor bleeding ( p = 0.04) and gastrointestinal (GI)
bleeding ( p = 0.04). In light of these data, updated guidelines support the use of
long-term low-dose aspirin for secondary prevention and after PCI.
16
P2Y12 antagonists
Platelet activation and aggregation may occur in the presence of aspirin
through pathways unrelated to TXA
2
(Fig. 8.1). Therefore, this unmet need
has prompted the development of alternate oral antiplatelet drugs to use in
combination with or as a substitute for aspirin. The P2Y12 receptor is the target
for many established and novel antiplatelet agents, including ticlopidine, clopi-
dogrel, prasugrel, ticagrelor, elinogrel, and cangrelor.
Ticlopidine
Ticlopidine is a fi rst-generation oral thienopyridine that irreversibly blocks
the P2Y12 receptor and thereby prevents platelet activation and aggregation
mediated by ADP signaling pathways.
17
When combined with aspirin, ticlopi-
dine reduces the risk of CV events in patients undergoing coronary stenting, as
compared with aspirin monotherapy or aspirin in combination with warfarin.
17
However, an unfavorable safety profi le (including risk of neutropenia) and slow
onset of action led the way for clopidogrel to emerge shortly thereafter as the
preferred thienopyridine in appropriate settings.
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CHAPTER 8 Antithrombotic Therapy
Clopidogrel
Compared with ticlopidine, clopidogrel has been shown to have similar effi -
cacy, improved tolerability,
17
and faster pharmacodynamic effects following a
loading dose.
18
In a meta-analysis that combined data across 13,995 subjects
treated with ticlopidine or clopidogrel, the use of clopidogrel was associated
with a signifi cant reduction in mortality and recurrent ischemic events as com-
pared to ticlopidine, with fewer side effects.
19
The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE)
trial was the fi rst major randomized clinical trial to assess the effi cacy of dual
antiplatelet therapy with clopidogrel and aspirin in patients with non-ST-
elevation ACS (NSTE-ACS). The trial randomized 12,562 subjects with NSTE-
ACS to clopidogrel (300-mg loading dose, 75 mg daily) versus placebo on a
background of aspirin.
20
After a mean treatment duration of 9 months, clopi-
dogrel signifi cantly reduced the risk of CV death, MI, or stroke by 20 percent
compared with placebo (HR 0.80, 95 percent CI 0.72–0.90). The addition of
clopidogrel increased the risk of major bleeding by 38 percent but did not
increase the risk of fatal bleeding.
20
The effi cacy of clopidogrel has also been demonstrated in patients receiving
fi brinolytic therapy in ST-elevation MI (STEMI). The Clopidogrel as Adjunctive
Reperfusion Therapy (CLARITY-TIMI 28) trial randomized 3,491 patients (aged
18 to 75 years) with STEMI to clopidogrel (300-mg loading dose, 75 mg daily) or
placebo on a background of fi brinolytic therapy.
21
All patients were to undergo
coronary angiography 48 to 192 hours after the start of study medication.
Clopidogrel signifi cantly reduced the odds of a closed infarct-related artery
Thromboxane
Inhibitors:
Aspirin
NCX-4016
Ridogrel
S18886
PAR Antagonists:
Atopaxar
Vorapaxar
ADP Receptor
Antagonists:
Cangrelor
Clopidogrel
Prasugrel
Ticagrelor
Ticlopidine
Glycoprotein
IIb/IIIa Inhibitors:
Abciximab
Eptifibatide
Tirofiban
Adhesion Antagonists:
C1qTNF-related protein-1
DZ-6976
GPIa/lla
GPVI GPIb-IX-V
GPIIb-IIIa
Platelet
ADP
ADP
ADP
P2Y
12
P2Y
1
ADP
Thrombin
Thrombin
TxA
2
TxA
2
TxA
2
Intracellular
Signaling
Activation
Figure 8.1 Platelet agonists, including ADP, TXA
2
, and thrombin, bind to receptors
on the platelet cell surface, leading to an intracellular signaling cascade that culminates
in platelet activation. In activated platelets, a conformational change in the GP IIb/
IIIa receptor allows platelet aggregation to occur through fi brinogen cross-linking.
(Reprinted with permission from Wolters Kluwer Health.)
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115
CHAPTER 8 Antithrombotic Therapy
at angiography by 36 percent (95 percent CI 24–47 percent) compared with
placebo. By 30 days, clopidogrel therapy reduced the odds of CV death, MI, or
recurrent ischemia leading to urgent revascularization by 20 percent (95 per-
cent CI 3–35 percent). The rates of major bleeding and intracranial hemorrhage
were similar in the two groups.
21
The clinical benefi t of clopidogrel in STEMI patients was further demon-
strated in the large-scale Clopidogrel and Metoprolol in Myocardial Infarction
(COMMIT) trial.
22
The COMMIT trial randomized 45,852 patients with STEMI
(of whom 55 percent received a fi brinolytic) to clopidogrel (75 mg daily with-
out loading dose) or placebo. Clopidogrel reduced the risk of death, reinfarc-
tion, or stroke by 9 percent (95 percent CI 3–14 percent) and reduced the risk
of all-cause mortality by 7 percent (95 percent CI 1–13 percent). Clopidogrel
did not increase overall bleeding ( p = 0.59), including in subjects over the age
of 70 years.
22
The benefi t of clopidogrel for reducing CV events in the setting of stable
atherosclerotic disease has been evaluated. The Clopidogrel versus Aspirin in
Patients at Risk of Ischemic Events (CAPRIE) trial assessed the effi cacy of mono-
therapy with clopidogrel (75 mg daily) versus aspirin (325 mg daily) in 19,185
patients with recent MI, stroke, or symptomatic peripheral arterial disease.
23
After a median of 1.91 years, clopidogrel monotherapy signifi cantly reduced
the risk of vascular death, MI, or stroke by 8.7 percent (95 percent CI 0.3–
16.5 percent), with an overall similar safety profi le. The incidence of GI hemor-
rhage was higher for patients on aspirin compared with clopidogrel ( p = 0.05).
23
The effi cacy of clopidogrel on a background of aspirin therapy was sub-
sequently evaluated in the Clopidogrel for High Atherothrombotic Risk and
Ischemic Stabilization (CHARISMA) trial. The CHARISMA trial enrolled 15,603
patients with a history of multiple atherothrombotic risk factors or clinically
evident atherosclerotic disease and randomized them to clopidogrel (75 mg
daily) versus placebo in addition to aspirin (75 to 162 mg daily) for a median
of 28 months.
24
Overall, dual antiplatelet therapy was not superior to aspi-
rin monotherapy in reducing the primary endpoint of CV death, MI, or stroke
(HR 0.93, 95 percent CI 0.83–1.05). However, in patients with symptomatic ath-
erosclerotic disease (including prior MI, prior stroke, or symptomatic peripheral
arterial disease [PAD]), the addition of clopidogrel signifi cantly reduced the risk
of CV death, MI, or stroke by 17 percent (HR 0.83, 95 percent CI 0.72–0.96,
p = 0.01) compared with placebo.
25
Although the results of the CHARISMA trial
do not support the use of dual antiplatelet therapy in all patients with stable
atherosclerotic disease, the trial supported the concept that intensifi cation of
antiplatelet therapy may be of benefi t in higher-risk patients with symptomatic
atherosclerotic disease.
Several trials have also examined the benefi t of clopidogrel and the optimal
timing of loading-dose administration in patients undergoing percutaneous coro-
nary intervention (PCI). In the PCI substudy of the CURE trial, subjects who
were pretreated with clopidogrel prior to PCI and who continued clopidogrel
for up to 1 year had a 31 percent lower risk of CV death or MI compared with
patients who were not pretreated and who were treated for only 4 weeks after
the procedure.
26
Similar early and long-term benefi ts with clopidogrel were dem-
onstrated in the Clopidogrel for the Reduction of Events During Observation
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CHAPTER 8 Antithrombotic Therapy
(CREDO) trial, which randomized patients to a loading dose of clopidogrel 3 to
24 hours prior to PCI and then to continued maintenance therapy beyond the
fi rst month following the procedure.
27
Subjects randomized to early and sus-
tained clopidogrel treatment had a 26.9 percent reduction in the risk of death,
MI, or stroke that appeared to persist throughout the fi rst year.
27
Dosing consideration for clopidogrel and duration of therapy
In the CURRENT-OASIS 7 trial, subjects with ACS were randomized to stan-
dard-dose clopidogrel (300-mg loading dose, 75 mg daily) versus high-dose
clopidogrel (600-mg loading dose, 150 mg daily for 6 days, followed by 75 mg
daily) and followed for 1 month.
15
Overall, doubling the dose of clopidogrel
did not signifi cantly reduce the risk of CV death, MI, or stroke at 30 days (HR
0.94, 95 percent 0.83–1.06), but it increased the risk of major bleeding (HR
1.24, 95 percent CI 1.05–1.46). In the cohort of subjects who underwent PCI
after randomization, double-dose clopidogrel signifi cantly reduced the risk of
CV death, MI, or stroke by 14 percent (95 percent CI 1–26 percent) and stent
thrombosis by 66 percent (95 percent CI 26–61 percent); however, this effi cacy
signal was accompanied by a 41 percent increase in major bleeding (95 percent
CI 9–83 percent).
28
The optimal duration of dual antiplatelet therapy with clopidogrel after
PCI continues to be debated. The Prolonging Dual Antiplatelet Treatment
After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) trial ran-
domized 2,013 patients following PCI to dual antiplatelet therapy for 6 ver-
sus 24 months.
29
The incidence of CV events was similar across treatment
arms (10.1 versus 10.0 percent, p = 0.92), whereas the incidence of bleeding
was higher for patients who continued treatment for 24 months (7.4 versus
3.5 percent, p < 0.001). Similar fi ndings were seen in two trial populations that
included 2,701 subjects in Korea who were randomized to aspirin alone ver-
sus continued dual antiplatelet therapy at 12 months following PCI.
30
Although
underpowered due to a low event rate, more prolonged dual antiplatelet ther-
apy failed to demonstrate any signal toward clinical effi cacy.
30
A similar lack of
effi cacy was demonstrated for dual antiplatelet therapy beyond 6 months in
patients undergoing placement of a drug-eluting stent.
31
The effi cacy and safety
of prolonged dual antiplatelet therapy beyond 12 months is currently undergo-
ing evaluation in the larger Dual Antiplatelet Therapy (DAPT) trial (clinicaltri-
als.gov NCT00977938).
Clopidogrel response variability
It is now well established that there exists signifi cant interpatient variability in
pharmacodynamic response to clopidogrel. Following a 300-mg loading dose,
approximately 30 percent of subjects have an inadequate response to clopi-
dogrel after 24 hours.
32
In a study comparing high-dose (600 mg loading dose,
150 mg/day) to standard-dose clopidogrel (75 mg/day) in 2,214 patients with high
on-treatment platelet reactivity, the Gauging Responsiveness with A VerifyNow
assay (GRAVITAS) trial did not fi nd a difference in the composite endpoint of
CV death, nonfatal MI, or stent thrombosis between the two dosing groups.
33
Similarly, the use of platelet function testing to help guide intensifi cation of
therapy showed no benefi t in the Assessment by a Double Randomization
of a Conventional Antiplatelet Strategy versus a Monitoring-guided Strategy
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CHAPTER 8 Antithrombotic Therapy
for Drug-Eluting Stent Implantation and of Treatment Interruption versus
Continuation One Year after Stenting (ARCTIC) trial.
34
Therefore, the use of
platelet function testing to guide management decisions cannot be endorsed at
this time; however, trials in this area are still ongoing.
Clopidogrel is a pro-drug that requires two-step bio-oxidation through the
cytochrome P450 enzyme system to form its active metabolite. The CYP2C19
enzyme is a key enzyme involved in the biotransformation to clopidogrel’s
active form. It has been identifi ed that high-risk individuals who carry at least
one copy of a reduced-function CYP2C19 allele are at increased risk of CV
events when treated with clopidogrel.
35
In carriers of a reduced-function allele,
a 225-mg daily maintenance dose of clopidogrel is required to achieve a similar
degree of platelet inhibition as wild-type carriers receiving a 75-mg daily main-
tenance dose.
36
However, there is no evidence to date that a strategy of routine
genotyping to help guide therapy will translate into improved outcomes.
Since proton pump inhibitors (PPIs) variably inhibit the CYP2C19 enzyme,
there exists concern that some PPIs may interfere with the biotransformation of
the clopidogrel pro-drug to its active metabolite. These concerns are supported
by data from randomized trials that have demonstrated that some PPIs, such as
omeprazole and esomeprazole, might interfere with the pharmacodynamic effects
of clopidogrel.
37
However, to date, evidence is lacking to indicate that this in vitro
observation translates into an increased risk of adverse outcomes in clopidogrel-
treated patients. In the Trial to Assess Improvement in Therapeutic Outcomes
by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38), the risk of
CV events was similar regardless of background PPI use (including omeprazole
or esomeprazole) in patients treated with clopidogrel.
38
These fi ndings were con-
fi rmed in the Clopidogrel and the Optimization of Gastrointestinal Events Trial
(COGENT) trial that randomized 3,873 subjects to clopidogrel or the combination
of clopidogrel and omeprazole.
39
Although the trial was terminated prematurely,
the combination of clopidogrel and omeprazole reduced the risk of GI events
(including GI bleeding) by 66 percent (HR 0.34, 95 percent CI 0.18–0.63) and did
not increase the risk of CV events (HR 0.99, 95 percent CI 0.68–1.44).
39
Prasugrel
Prasugrel is a third-generation thienopyridine that irreversibly binds to the
P2Y12 receptor. Compared to clopidogrel, prasugrel achieves more rapid,
more potent, and more consistent inhibition of platelet aggregation.
40
Since the
active metabolites of both prasugrel and clopidogrel are believed to be equi-
potent, it is hypothesized that prasugrel achieves greater potency due to more
effi cient metabolism of the pro-drug through the CYP450 isoenzyme system.
The TRITON-TIMI 38 trial randomized 13,608 subjects with ACS undergo-
ing PCI to clopidogrel (300-mg loading dose, 75 mg daily) or prasugrel (60-mg
loading dose, 10 mg daily).
40
After a median of 14.5 months, prasugrel signifi -
cantly reduced the risk of CV death, MI, or stroke by 19 percent compared
with clopidogrel (HR 0.81, 95 percent CI 0.73–0.90). Prasugrel also signifi cantly
reduced the risk of MI (9.7 versus 7.4 percent, p < 0.001) and stent throm-
bosis (2.4 versus 1.1 percent, p < 0.001, Fig. 8.2).
40
Although major bleeding
was infrequent, prasugrel signifi cantly increased the risk of non-CABG-related
TIMI major bleeding by 32 percent (2.4 versus 1.8 percent, p = 0.03, Fig. 8.2),
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