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Aspirin in Primary and Secondary Prevention of Cardiovascular Disease
Table 1
Characteristics of the six major trials of aspirin for primary prevention of cardiovascular disease
Variable BDT PHS TPT HOT PPP WHS
Year 1988 1989 1998 1998 2001 2005
N 5,139 22,071 5,085 18,790 4,495 39,876
% of Women 0 0 0 47 58 100
Aspirin dose 500 mg per day 325 mg every
other day
75 mg per day 75 mg per day 100 mg per day 100 mg every other day
Age (years) <60 (47%)
60–69 (39%)
70–79 (14%)
Mean: 53 Mean: 57.5 Mean: 61.5 <60 (29%)
60–69 (45%)
70–79 (24%)
45–64 (60%)
55–64 (30%)
65 and up (10%)
Additional drug None b-carotene Warfarin Felodipine
± ACE
inhibitor ± b-blocker
Vitamin E Vitamin E
Study population Apparently
healthy male
physicians
Apparently
healthy male
physicians
Men at high
risk of CAD
Men and women with
hypertension
Men and women
with ³1 major
CVD risk factor
Apparently healthy
female health
professionals
Mean follow up
(years)
6 5 6.4 4 3.6 10.1
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Antithrombotic Drug Therapy in Cardiovascular Disease
Primary Prevention Project (PPP) (12), the U.S. Physicians’ Health Study (PHS) (13), and the Women’s
Health Study (WHS)
(14) (Fig. 2).
The BMD was one of the first large-scale trials to examine the role of aspirin in the primary prevention
of CVD. No significant difference was noted in risk of nonfatal MI in the aspirin or placebo groups.
The PHS was a randomized, double-blind, placebo-controlled trial to determine if 325
mg of aspirin
every other day decreased cardiovascular mortality and whether beta carotene decreased the incidence
of cancer in 22,071 healthy US male physicians. With a statistically significant 44% decrease in the
risk of first MI, it was the first of the primary prevention trials reporting the benefits of aspirin in
primary prevention of MI. An 18% risk reduction in the composite outcome of MI, stroke, and CVD
death was observed (RR: 0.82, 95% CI: 0.70–0.96). However, the small number of strokes and total
cardiovascular deaths yielded inconclusive results for aspirin’s effect on these outcomes.
The TPT assessed the effects of aspirin and placebo warfarin, placebo aspirin and warfarin, aspirin
and warfarin, and placebo aspirin and placebo warfarin. Aspirin was associated with a statistically
significant reduction in the incidence of nonfatal stroke, total ischemic heart disease, and nonfatal
ischemic heart disease. The HOT study revealed a 36% reduction in fatal and nonfatal MI in hyper-
tensive patients taking aspirin. In people with hypertension, hypercholesterolemia, diabetes, obesity,
family history of MI and in the elderly, the PPP demonstrated that 100
mg per day of aspirin reduced
the risk of total cardiovascular deaths by 23%, and of cardiovascular mortality by 44%. To date, the
largest study of primary prevention of CVD by aspirin is the WHS. This trial, comprising about
40,000 women, did not show a significant difference in the risk of fatal or nonfatal MI and CVD
mortality between the aspirin and placebo groups. However, a 24% reduction in the risk of ischemic
stroke and a 22% reduction in the risk of TIA were observed. In women 65 and older, aspirin had
beneficial effects on major CVD (nonfatal MI, nonfatal stroke and CVD death, MI and ischemic
stroke). Age modified the effect of aspirin on major CVD and MI; in women 65 and older, aspirin
showed a significant 26% reduction in the risk of major CVD and 30% in the risk of ischemic stroke.
Additionally, this was the only age group in which aspirin significantly reduced the risk of MI.
Various meta-analyses have analyzed the primary prevention trials to summarize the overall effec-
tiveness of primary prophylaxis with aspirin (15–19). A recent meta-analysis of data from all six
primary prevention trials has shown that aspirin reduces the risk of nonfatal MI by 25%, total coronary
heart disease by 23%, and total cardiovascular events by 15%. No statistically significant decrease in
stroke, fatal coronary heart disease, and all-cause mortality was noted with aspirin
(15). Similar results
have been reported by other meta-analyses
(16–18). It is interesting to note that although statistically
not significant, the addition of WHS data to the other five trials in the meta-analysis by Bartolucci et
al.
showed that aspirin was better than placebo for decreasing the risk of stroke and all-cause mortality
(15). More studies are required to clarify the exact role of aspirin for these outcomes.
Thus, aspirin reduces the risk of first nonfatal MI and CHD. Overall, aspirin has clear benefits in
preventing CVD events in men and women.
ADVERSE EFFECTS OF LOW-DOSE ASPIRIN
In a sex-specific meta-analysis of the six primary prevention trials, aspirin use was associated with
a 70% increased risk of major bleeding events in men and women; this translated into causing one
major bleeding event per 400 women and per 303 men over 6.4 years of aspirin use (19).
Gastrointestinal tract perforation, ulceration, and bleeding are expected adverse effects in that they
are, at least in part, explained by inhibition of prostaglandin synthesis produced by aspirin.
Gastrointestinal bleeding risk is dose dependent; higher doses are associated with higher rates of
bleeding (20,21). A case-control study has suggested that proton pump inhibitors are more effective
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Aspirin in Primary and Secondary Prevention of Cardiovascular Disease
than H
2
receptor antagonists in preventing upper GI bleeds associated with aspirin use (22). At least
five randomized controlled trials of healthy volunteers have suggested that enteric-coated aspirin is
associated with endoscopically documented decreased risk of gastric mucosal injury
(23). Aspirin
hypersensitivity is an uncommon adverse effect, and desensitization therapy may be helpful in permit-
ting the continued use of aspirin.
ASPIRIN MAY NOT ALWAYS WORK
While aspirin can reduce the risk of primary or secondary events, some patients may not get the
maximal benefit. Many factors may underlie such a reduction in the effect of aspirin (Table
2), including
but not limited to noncompliance, cigarette smoking, drug–drug interactions, drug–disease interactions,
and biochemical aspirin resistance. Noncompliance with aspirin can be related to habitual noncompliance
to medications, or its adverse effects, chiefly gastric. Cigarette smoking has been shown to interfere
with the antiplatelet activity of aspirin. The WHS has demonstrated a reduction in risk of CVD events
among nonsmokers but not among smokers. Smoking may interfere with aspirin’s effect on platelets
by increasing F
2
isoprostanes, which have prothrombotic and vasoconstrictor effects (24).
Certain NSAIDs, including ibuprofen and indomethacin, have been shown to antagonize the
antiplatelet effects of aspirin. These drugs may interfere with access of aspirin to the COX-1 binding
site (Fig. 4). Whether or not this interaction translates into clinically important events remains to be
Table 2
Possible causes of recurrent ischemic vascular events among patients taking aspirin
(Adapted from Hankey et al. (34))
Nonatherothrombotic causes
• Embolismfromtheheart(red,fibrinthrombi;vegetations;calcium;tumor;prostheses)
• Arteritis
Poor aspirin bioavailability
• Poorcompliance
• Inadequatedose
• Concurrentintakeofcertainnonsteroidalanti-inflammatorydrugs(forexampleibuprofen,indomethacin),
possibly preventing the access of aspirin to cyclooxygenase-1 binding site
Alternative mechanisms of platelet activation
• Platelet
activationbypathwaysthatarenotblockedbyaspirin(forexample,redcell-inducedplatelet
activation: stimulation of collagen, adenosine diphosphate, epinephrine, and thrombin receptors on platelets)
• Increasedplateletsensitivitytocollagenandadenosinediphosphate
• Biosynthesisofthromboxanebypathwaysthatarenotblockedbyaspirin(forexample,by
cyclooxygenase-2 in monocytes and macrophages, and vascular endothelial cells)
High platelet turnover
• Increasedproductionofplateletsbythebonemarrowinresponsetostress(forexample,aftercoronary
artery bypass surgery), introducing into blood stream newly formed platelets unexposed to aspirin during the
24-h dose interval (aspirin is given once daily and has only a 20 min half-life)
Genetic polymorphisms
• PolymorphismsinvolvingplateletglycoproteinIa/IIa,Ib/V/IX,andIib/IIIareceptors,andcollagenandvon
Willebrand factor receptors
• Polymorphismsofcyclooxygenase-1,cyclooxygenase-2,thromboxaneA
2
-synthase, or other arachidonate
metabolism enzymes
• FactorXIIIVal34Leupolymorphism,leadingtovariableinhibitionoffactorXIIIactivationby
low-dose aspirin
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Antithrombotic Drug Therapy in Cardiovascular Disease
more clearly defined with few, observational studies available. In one study of 7,107 patients dis-
charged on low-dose aspirin (<325
mg/day) after their first hospital admission for CV disease, patients
taking aspirin plus ibuprofen had an increased risk of all-cause mortality (adjusted hazard ratio: 1.93,
95% CI: 1.30–2.87, p
= 0.0011) and cardiovascular mortality (1.73, 1.05–2.84, p = 0.0305) compared
with those taking aspirin alone
(25). More recent data lend some doubt to the adverse interaction
between ibuprofen and aspirin
(26,27). Among 70,316 patients discharged after admission for an MI
a similar risk of death was seen in patients discharged on aspirin alone, aspirin and ibuprofen, or on
aspirin and another NSAID
(26). A recent nested case-control study further supports the lack of an
adverse interaction between ibuprofen, other NSAIDs, and aspirin
(27). Due to over-the-counter avail-
ability of these drugs and frequent coexistence of painful conditions such as arthritis in those who may
use aspirin, it is important to look for such interactions.
The term “aspirin resistance” suffers from a lack of consensus definition and validity. It has been
varyingly defined as recurrence of coronary heart disease, stroke, and peripheral vascular disease
despite prescription of a regular therapeutic dose of aspirin (“clinical aspirin resistance”), or persistent
ex vivo platelet activation, measured by platelet function tests, despite aspirin use (“biochemical” or
“laboratory aspirin resistance”). A recent meta-analysis showed that patients with laboratory aspirin
resistance have higher risk of clinical aspirin resistance (28). Laboratory tests to investigate platelet
function include optical platelet aggregation tests, PFA-100, P-selectin flow cytometry, urinary
thromboxane excretion analysis, etc. No study has shown a clear benefit from routine screening for
aspirin resistance. There is some indication that genetic factors like polymorphism PLA1/A2 of the
gene encoding for glycoprotein IIIa might be associated with altered platelet function and increased
risk of cardiovascular events. Although unclear from current research, clopidogrel or ticlopidine
might be effective alternatives for clinical failure of aspirin.
Overall, aspirin remains the most cost-effective drug for secondary prevention of atherothrombotic
disease; factors like cigarette smoking, compliance, and interactions with NSAIDs should be identified
and addressed.
RECOMMENDATIONS
Aspirin decreases the incidence of a first CVD event in adults at an increased risk of heart disease.
The absolute risk reduction is lower than that seen in secondary prevention; however, the incidence
of gastric side effects is comparable. There are various guidelines for decision making in prescribing
aspirin for primary prevention of CVD.
Aspirin is clearly indicated for secondary prevention among those with any form of cardiovas-
cular disease. In this setting, it is safe and highly cost effective. For primary prevention, the use
of aspirin requires a risk assessment. The U.S. Preventive Services Task Force (USPSTF) recom-
mends that overall risk assessment be done before initiating primary prophylaxis with aspirin.
These risk factors are age, sex, diabetes, elevated total cholesterol, low HDL cholesterol, elevated
blood pressure, family history of CAD, and smoking (29). Men older than 40 years of age, post-
menopausal women, and younger adults at high risk of CAD might benefit from aspirin therapy;
the estimated 5-year magnitude of which is shown in Table
3. It is recommended that the risks and
benefits of aspirin therapy be discussed with the patient at least every 5 years in middle age and
older people or when other cardiovascular risk factors are detected. According to the USPSTF
2009 guidelines, there is a grade A recommendation for use of aspirin to prevent MI in men age
45–79, and ischemic stroke in women age 55–79. There is insufficient evidence to recommend
aspirin in other age groups.
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Aspirin in Primary and Secondary Prevention of Cardiovascular Disease
The American Heart Association (AHA) guidelines for Primary Prevention of Cardiovascular Diseases
and Stroke suggest low-dose aspirin (75–160
mg/day) for persons with a 10-year CAD risk of more than
or equal to 10% (instead of >6% 10-year risk of CAD suggested by USPSTF)
(30). The underlying
rationale for this difference is to improve the risk-benefit ratio. It is also recommended that persons with
diabetes or with a 10-year CAD risk >20% be considered equivalent to persons with established CAD.
Similar recommendations have been made by the American Diabetes Association. Low-dose aspirin
(75–162 mg) has been recommended to men and women with type 1 or type 2 diabetes at increased
cardiovascular risk, including those over 40 years of age or who have additional risk factors (family
history of CVD, hypertension, smoking, dyslipidemia, albuminuria) (31). Aspirin therapy is not associated
with an increased risk for retinal or vitreous hemorrhage.
The European Society of Cardiology recommends aspirin prophylaxis in high-risk individuals, such
as treated hypertensive patients whose blood pressure is well controlled and men at “particularly high”
CHD risk
(32). The Society does not recommend such therapy in all high-risk individuals. The definition
of “particularly high” risk is not clearly described.
To sum up, we recommend aspirin for primary prophylaxis of CAD in high-risk individuals, as
defined by USPSTF, after individual evaluation of the patient.
ACKNOWLEDGMENTS
Dr. Gaziano has received a research grant from McNeil Consumer Products and honoraria from
Bayer. He is a consultant for Bayer and for McNeil Consumer Products.
REFERENCES
1. Jack DB (1997) One hundred years of aspirin. Lancet 350(9075):437–439
2. Patrignani P, Filabozzi P, Patrono C (1982) Selective cumulative inhibition of platelet thromboxane production by low-
dose aspirin in healthy subjects. J Clin Invest 69(6):1366–1372
3. Ajani UA, Ford ES, Greenland KJ, Giles WH, Mokdad AH (2006) Aspirin use among U.S. adults: Behavioral Risk
Factor Surveillance System. Am J Prev Med 30(1):74–77
4. Antithrombotic Trialists’ Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy
for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324(7329):71–86
5. Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C (2005) Low-dose aspirin for the prevention of atherothrombosis.
N Engl J Med 353(22):2373–2383
Table 3
The USPSTF estimates of benefits and harms of aspirin for primary prophylaxis
(5 years of therapy to 1,000 individuals) (Adapted from Hayden et al. (18))
Benefits and harms
Baseline risk of coronary heart disease over 5 years
1% 3% 5%
Total mortality No effect No effect No effect
CHD events avoided 1–4 4–12 6–20
Hemorrhagic strokes caused 0–2 0–2 0–2
Major GI bleeding events caused 2–4 2–4 2–4
To estimate the 10-year risks, double the baseline risks; i.e., 5-year risk of 1% = 10-year risk of 2%, and so on
These estimates are based on a 28% risk reduction in coronary heart disease events in aspirin-treated subjects
Major GI bleeding events may be 2–3 times higher in people older than 70 years
127
https://t.me/med1917
Antithrombotic Drug Therapy in Cardiovascular Disease
6. Taylor DW, Barnett HJ, Haynes RB et al (1999) Low-dose and high-dose acetylsalicylic acid for patients undergoing
carotid endarterectomy: a randomised controlled trial. ASA and Carotid Endarterectomy (ACE) Trial Collaborators.
Lancet 353(9171):2179–2184
7. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (2001) Effects of clopidogrel in addition to aspirin in
patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345(7):494–502
8. Bhatt DL, Fox KA, Hacke W et al (2006) Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrom-
botic events. N Engl J Med 354(16):1706–1717
9. Peto R, Gray R, Collins R et al (1988) Randomised trial of prophylactic daily aspirin in British male doctors. Br Med
J (Clin Res Ed) 296(6618):313–316
10.
Hansson L, Zanchetti A, Carruthers SG et al (1998) Effects of intensive blood-pressure lowering and low-dose aspirin
in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT
Study Group. Lancet 351(9118):1755–1762
11.
(1998) Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose
aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s
General Practice Research Framework. Lancet 351(9098):233–241.
12.
de Gaetano G, Collaborative Group of the Primary Prevention Project (2001) Low-dose aspirin and vitamin E in people
at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project.
Lancet 357(9250):89–95
13.
(1989) Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the
Physicians’ Health Study Research Group. N Engl J Med 321(3):129–135.
14. Ridker PM, Cook NR, Lee IM et al (2005) A randomized trial of low-dose aspirin in the primary prevention of cardio-
vascular disease in women. N Engl J Med 352(13):1293–1304
15. Bartolucci AA, Howard G (2006) Meta-analysis of data from the six primary prevention trials of cardiovascular events
using aspirin. Am J Cardiol 98(6):746–750
16. Eidelman RS, Hebert PR, Weisman SM, Hennekens CH (2003) An update on aspirin in the primary prevention of car-
diovascular disease. Arch Intern Med 163(17):2006–2010
17. Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE (2001) Aspirin for primary prevention of coronary
heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart
85(3):265–271
18.
Hayden M, Pignone M, Phillips C, Mulrow C (2002) Aspirin for the primary prevention of cardiovascular events: a
summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 136(2):161–172
19. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL (2006) Aspirin for the primary prevention of cardio-
vascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 295(3):306–313
20. Farrell B, Godwin J, Richards S, Warlow C (1991) The United Kingdom transient ischaemic attack (UK-TIA) aspirin
trial: final results. J Neurol Neurosurg Psychiatry 54(12):1044–1054
21. The Dutch TIA Trial Study Group (1991) A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a
transient ischemic attack or minor ischemic stroke. The Dutch TIA Trial Study Group. N Engl J Med 325(18):1261–1266
22. Lanas A, Garcia-Rodriguez LA, Arroyo MT et al (2007) Effect of antisecretory drugs and nitrates on the risk of ulcer
bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am J Gastroenterol
102(3):507–515
23. Walker J, Robinson J, Stewart J, Jacob S (2007) Does enteric-coated aspirin result in a lower incidence of gastrointestinal
complications compared to normal aspirin? Interact Cardiovasc Thorac Surg 6(4):519–522
24.
Morrow JD, Frei B, Longmire AW et al (1995) Increase in circulating products of lipid peroxidation (F2-isoprostanes)
in smokers. Smoking as a cause of oxidative damage. N Engl J Med 332(18):1198–1203
25. MacDonald TM, Wei L (2003) Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 361(9357):573–574
26. Curtis JP, Wang Y, Portnay EL, Masoudi FA, Havranek EP, Krumholz HM (2003) Aspirin, ibuprofen, and mortality after
myocardial infarction: retrospective cohort study. BMJ 327(7427):1322–1323
27. Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, Gonzalez-Perez A (2004) Nonsteroidal antiinflammatory drugs
and the risk of myocardial infarction in the general population. Circulation 109(24):3000–3006
28. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Huisman MV (2007) Association of laboratory-defined aspirin
resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med
167(15):1593–1599
29. Aspirin for the primary prevention of cardiovascular events (2002) recommendation and rationale. Ann Intern Med
136(2):157–160
128
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30. Pearson TA, Blair SN, Daniels SR et al (2002) AHA Guidelines for Primary Prevention of Cardiovascular Disease and
Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary
or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating
Committee. Circulation 106(3):388–391
31. Colwell JA (2004) Aspirin therapy in diabetes. Diabetes Care 27(Suppl 1):S72–S73
32.
Prevention of coronary heart disease in clinical practice (1998) Recommendations of the Second Joint Task Force of
European and other Societies on coronary prevention. Eur Heart J 19(10):1434–1503
33.
Catella-Lawson F, Reilly MP, Kapoor SC et al (2001) Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.
N Engl J Med 345(25):1809–1817
34.
Hankey GJ, Eikelboom JW (2004) Aspirin resistance. BMJ 328(7438):477–479
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6 Thienopyridines in Stable Coronary Disease
Marcus D. Flather and Dipak Kotecha
Co n t e n t s
Introduction
Thienopyridines
Brief Review Of Thienopyridine Trials
The Charisma Trial
Pooled Analysis Of Large Trials Of Clopidogrel Plus Aspirin
Additional Analyses From Charisma
Thienopyridines In Stable Coronary Artery Disease
Should Dual Antiplatelet Treatment Be Started In Stable Patients?
Discussion
References
Ab s t r A c t Antiplatelet agents including aspirin and clopidogrel have an established role in reducing the risk
of death, stroke and myocardial infarction, and other complications of cardiovascular disease. Aspirin is
the standard acute and long-term antiplatelet agent, although clopidogrel alone is slightly more effective
than aspirin alone. Several randomized trials have tested the effects of clopidogrel added to aspirin com-
pared to aspirin alone and beneficial effects in the region of 10–20% proportional reductions in risk have
been observed in acute coronary syndromes (ST-elevation and non-ST-elevation) and percutaneous coronary
intervention. In the chronic setting, where there are far more patients who could potentially benefit, there
has been no proven effect of adding clopidogrel to aspirin compared to aspirin alone. In the CHARISMA
trial there were trends to benefit in subgroups with pre-existing vascular disease or a prior vascular event.
The combination of clopidogrel plus aspirin compared to aspirin alone increases the risk of major bleeding
by about 30%. A simple pooling of published data suggests that the overall benefit of adding clopidogrel
to aspirin in patients with acute or chronic vascular disease decreases the risk of cardiovascular death,
myocardial infarction, and stroke by a proportional 10% and an absolute 1% (with greater effects in higher-
risk patients) which is clinically worthwhile. Further work is needed to test the effects of clopidogrel when
added to aspirin in patients with a prior stroke, myocardial infarction, or peripheral arterial disease as there
may be worthwhile benefits that were not apparent in the CHARISMA trial.
Key words: Clopidogrel; Ticlopidine; CHARISMA trial; Stable CAD; Atherosclerosis
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_6
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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INTRODUCTION
Prevention of vascular events such as death, myocardial infarction (MI), and stroke is a key part of
the management of cardiovascular disease both among patients with a prior history of vascular disease,
and apparently healthy individuals with cardiovascular risk factors. Emphasis on a healthy lifestyle
including appropriate eating habits, regular exercise, and avoidance of cigarette smoking is a standard
approach to prevention of cardiovascular disease, but this approach is time consuming and proving
efficacy has been difficult (1,2). Thus for patients with established vascular disease there is an emphasis
on pharmacological therapies with proven benefits including statins, antiplatelet agents, angiotensin-
converting enzyme inhibitors, and beta blockers
(3). In addition the careful management of important risk
factors such as hypertension, diabetes, and hyperlipidemia through pharmacological and nonpharma-
cological methods is essential
(4).
Aspirin has clinically useful antiplatelet effects by inhibiting the enzyme cyclooxygenase and
reducing thromboxane A2 which is involved in platelet activity. Numerous studies have established
aspirin as a key long-term antithrombotic agent that is well tolerated and effective. In high-risk patients
it reduces the risk of nonfatal myocardial infarction by 30%, nonfatal stroke by 25% and overall vascular
death by around 15% (5). Unfortunately, a considerable number of patients suffer a further event despite
aspirin treatment
(6).
The search for new antithrombotic therapies that augment the protective effects of aspirin (or substitute
in patients with intolerance) has identified several promising agents. These include oral anticoagulants
(warfarin and the direct thrombin inhibitors), oral glycoprotein IIb/IIIa receptor antagonists (which were
found to have an adverse effect in spite of good biological rationale) (7), and more recently the oral
thienopyridine clopidogrel. The latter is slightly more effective than aspirin alone, and in combination
with aspirin has additional benefits in patients with acute coronary syndromes (ACS).
In this chapter we review data from the larger clinical trials about the potential benefits and risks of
longer-term thienopyridine treatment in patients with coronary, cerebral, and peripheral vascular disease.
THIENOPYRIDINES
The two main thienopyridines are clopidogrel and prasugrel, but newer agents including short-
acting intravenous compounds are under investigation
(8,9). Prasugrel is relatively new and has been
investigated in patients with ACS with evidence of efficacy and will be discussed in other chapters.
Both act on the P2Y12 (ADP) receptor on the platelet, decrease platelet reactivity, and provide irre-
versible platelet inhibition. Clopidogrel is a prodrug which is converted to an active metabolite with
a short half-life in the liver before exerting its antiplatelet effect, whereas prasugrel is immediately
effective resulting in a quicker onset of action. Clopidogrel is one of the most carefully studied anti-
thrombotic agents, and it is estimated that more than 100,000 patients have been enrolled in randomized
trials involving clopidogrel.
BRIEF REVIEW OF THIENOPYRIDINE TRIALS
Thienopyridines, mainly clopidogrel, have been studied in several disease areas including
chronic vascular disease (CAD, cerebrovascular, and PAD either separately or in combination),
ACS, percutaneous coronary intervention (PCI), and atrial fibrillation (Table 1). The first study to
show the safety and efficacy of clopidogrel was the CAPRIE trial which randomized 19,185
patients with a history of prior stroke, prior MI, or PAD to either clopidogrel 75 mg or aspirin
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Table 1
Results from the major randomized trials of clopidogrel plus aspirin
Trial name Patients studied Treatment group Control group
vascular
outcome
Months of
follow up
Treatment N
(%)
Control N
(%)
HR (95%CI)
P-value
Major bleeds
HR (95% CI)
P-value
Acute coronary syndromes
CURE Non-ST elevation
ACS
Clopidogrel 300mg loading
then 75mg daily
Aspirin 75–325mg
Placebo
clopidogrel + aspirin
CV death,
stroke, MI
9 582/6,259
(9.3%)
719/6,303
(11.4%)
0.80
(0.72–0.90)
P < 0.001
1.38
(1.13–1.67)
P = 0.001
CLARITY ST elevation ACS
(fibrinolysis)
Clopidogrel 300mg
load followed by
75mg + aspirin
150–325mg load then
75–162mg daily
Placebo
clopidogrel + aspirin
CV death, MI 30 days
(treatment
up to 8
days)
89/1,752
a
(5.1%)
100/1,739
a
(5.8%)
0.89
P = NS
1.26
P = 0.24
(TIMI
major or
minor)
COMMIT ST elevation or
bundle branch
block ACS (50%
fibrinolysis)
Clopidogrel 75mg
Aspirin 162mg
Placebo clopidogrel
plus aspirin
Death, MI,
stroke
Up to 1 month
Mean 16
days
2,125/22,958
(9.3%)
2311/22,891
(10.1%)
0.91
(0.86–0.97)
P = 0.002
1.1
PCI, stable vascular disease and risk factors
CREDO PCI Clopidogrel 300mg loading
then 75mg daily
Aspirin 325mg
Placebo loading, active
clopidogrel for 28
days post PCI, then
placebo + aspirin
throughout
Death, stroke,
MI
12 89/1,053
(8.5%)
122/1,063
(11.5%)
0.73
(0.56–0.96)
P = 0.02
1.31
P = 0.07
CHARISMA CAD, CVD, PAD or
combination of
risk factors
Clopidogrel 75mg
Aspirin 75–162mg
Placebo clopidogrel
plus aspirin
CV death, MI,
stroke
Median 28
months
534/7,802
(6.8%)
573/7,801
(7.3%)
0.93
(0.83–1.05)
P = 0.22
1.25
(0.97–1.61)
P = 0.09
Cerebrovascular disease
MATCH Prior stroke or TIA Clopidogrel 75mg
Aspirin 75mg
Clopidogrel 75mg
Placebo aspirin
Vascular death,
ischemic
stroke, MI
18 445/3,797
(11.7%)
473/3,802
(12.4%)
0.94
(0.83–1.07)
P = 0.36
1.36
(0.86–1.86)
P < 0.001
Atrial fibrillation
ACTIVE-W Atrial fibrillation
with high-risk
features
Clopidogrel 75mg
Aspirin 75–100mg
Warfarin or other
oral anticoagulant
(OAC)
CV death, MI,
stroke
15 months 234/3,335
(7.0%)
OAC
165/3,371
(4.9%)
1.44
(1.18–1.76)
P = 0.0003
1.10
(0.83–1.45)
P = 0.53
ACTIVE-A Atrial fibrillation
with high-risk
features
Clopidogrel 75mg
Aspirin 75–100mg
Placebo clopidogrel
plus aspirin
CV death, MI,
stroke
36 months
a
Estimated from published data where information is not exactly as required for the table. ACS Acute coronary syndrome, CAD Coronary artery disease, CVD Cerebrovascular disease, HR Hazard ratio, 95% CI 95%
Confidence intervals, OAC Oral anticoagulation, PAD Peripheral arterial disease, PCI Percutaneous coronary intervention, TIA Transient ischemic attack
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