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Antithrombotic Drug Therapy in Cardiovascular Disease
376. Chang YS, Munn LL, Hillsley MV et al (2000) Effect of vascular endothelial growth factor on cultured endothelial cell
monolayer transport properties. Microvasc Res 59:265–277
377.
Beekhuizen H, van Furth R (1994) Growth characteristics of cultured human macrovascular venous and arterial and
microvascular endothelial cells. J Vasc Res 31:230–239
378.
Rupnick MA, Carey A, Williams SK (1988) Phenotypic diversity in cultured cerebral microvascular endothelial cells.
In Vitro Cell Dev Biol 24:435–444
379.
Christie PD, Edelberg JM, Picard MH et al (1999) A murine model of myocardial microvascular thrombosis. J Clin
Invest 104:533–539
380.
Edelberg JM, Aird WC, Wu W et al (1998) PDGF mediates cardiac microvascular communication. J Clin Invest
102:837–843
381.
Guillot PV, Liu L, Kuivenhoven JA et al (2000) Targeting of human eNOS promoter to the Hprt locus of mice leads to
tissue-restricted transgene expression. Physiol Genomics 2:77–83
382.
Rosenberg RD, Aird WC (1999) Vascular-bed – specific hemostasis and hypercoagulable states. N Engl J Med
340:1555–1564
383.
Nishida M, Springhorn JP, Kelly RA et al (1993) Cell-cell signaling between adult rat ventricular myocytes and cardiac
microvascular endothelial cells in heterotypic primary culture. J Clin Invest 91:1934–1941
384.
Tabrizi P, Wang L, Seeds N et al (1999) Tissue plasminogen activator (tPA) deficiency exacerbates cerebrovascular
fibrin deposition and brain injury in a murine stroke model: studies in tPA-deficient mice and wild-type mice on a
matched genetic background. Arterioscler Thromb Vasc Biol 19:2801–2806
385.
Koeleman BP, Reitsma PH, Bertina RM (1997) Familial thrombophilia: a complex genetic disorder. Semin Hematol
34:256–264
386.
van Boven HH, Reitsma PH, Rosendaal FR et al (1996) Factor V Leiden (FV R506Q) in families with inherited anti-
thrombin deficiency. Thromb Haemost 75:417–421
387. Seligsohn U, Zivelin A (1997) Thrombophilia as a multigenic disorder. Thromb Haemost 78:297–301
388.
Auro K, Alanne M, Kristiansson K et al (2007) Combined effects of thrombosis pathway gene variants predict cardio-
vascular events. PLoS Genet 3:e120
389. Roldan V, Gonzalez-Conejero R, Marin F et al (2005) Five prothrombotic polymorphisms and the prevalence of pre-
mature myocardial infarction. Haematologica 90:421–423
390. Hudson M, Herr AL, Rauch J et al (2003) The presence of multiple prothrombotic risk factors is associated with a
higher risk of thrombosis in individuals with anticardiolipin antibodies. J Rheumatol 30:2385–2391
391. Potti A, Bild A, Dressman HK et al (2006) Gene-expression patterns predict phenotypes of immune-mediated throm-
bosis. Blood 107:1391–1396
392. Nurden AT (2006) Polymorphisms and platelet genotyping: the shape of things to come. J Thromb Haemost
4:1194–1196
393.
Van Hylckama Vlieg A, Callas PW, Cushman M et al (2003) Inter-relation of coagulation factors and d-dimer levels in
healthy individuals. J Thromb Haemost 1:516–522
394. Nesheim M (2001) Myocardial infarction and the balance between fibrin deposition and removal. Ital Heart J
2:641–645
395.
Vlassara H, Fuh H, Donnelly T et al (1995) Advanced glycation endproducts promote adhesion molecule (VCAM-1,
ICAM-1) expression and atheroma formation in normal rabbits. Mol Med 1:447–456
396. De Cristofaro R, Picozzi M, Morosetti R et al (1996) Effect of sodium on the energetics of thrombin-thrombomodulin
interaction and its relevance for protein C hydrolysis. J Mol Biol 258:190–200
397.
Ginsburg GS, Shah SH, McCarthy JJ (2007) Taking cardiovascular genetic association studies to the next level. J Am
Coll Cardiol 50:930–932
398. Soria JM, Almasy L, Souto JC et al (2002) A quantitative-trait locus in the human factor XII gene influences both
plasma factor XII levels and susceptibility to thrombotic disease. Am J Hum Genet 70:567–574
399. Soria JM, Almasy L, Souto JC et al (2003) A new locus on chromosome 18 that influences normal variation in activated
protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility. Blood
101:163–167
400. Hennis BC, Van Boheemen PA, Koeleman BP et al (1995) A specific allele of the histidine-rich glycoprotein (HRG)
locus is linked with elevated plasma levels of HRG in a Dutch family with thrombosis. Br J Haematol 89:845–852
401. Almasy L, Soria JM, Souto JC et al (2003) A quantitative trait locus influencing free plasma protein S levels on human
chromosome 1q: results from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project. Arterioscler Thromb
Vasc Biol 23:508–511
402. Hixson JE, Blangero J (2000) Genomic searches for genes that influence atherosclerosis and its risk factors. Ann N Y
Acad Sci 902:1–7
112
https://t.me/med1917
The Genetics of Thrombosis
403. Souto JC, Almasy L, Soria JM et al (2003) Genome-wide linkage analysis of von Willebrand factor plasma levels:
results from the GAIT project. Thromb Haemost 89:468–474
404.
Souto JC, Almasy L, Muniz-Diaz E et al (2000) Functional effects of the ABO locus polymorphism on plasma levels
of von Willebrand factor, factor VIII, and activated partial thromboplastin time. Arterioscler Thromb Vasc Biol
20:2024–2028
405.
Buil A, Soria JM, Souto JC et al (2004) Protein C levels are regulated by a quantitative trait locus on chromosome 16:
results from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. Arterioscler Thromb Vasc Biol
24:1321–1325
406.
Berger M, Mattheisen M, Kulle B et al (2005) High factor VIII levels in venous thromboembolism show linkage to
imprinted loci on chromosomes 5 and 11. Blood 105:638–644
407.
Scott BT, Hasstedt SJ, Bovill EG et al (2002) Characterization of the human prostaglandin H synthase 1 gene (PTGS1):
exclusion by genetic linkage analysis as a second modifier gene in familial thrombosis. Blood Coagul Fibrinolysis
13:519–531
408.
Almasy L, Soria JM, Souto JC et al (2005) A locus on chromosome 2 influences levels of tissue factor pathway inhibi-
tor: results from the GAIT study. Arterioscler Thromb Vasc Biol 25:1489–1492
409.
Rey E, Kahn SR, David M et al (2003) Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 361:901–908
410.
Balta G, Altay C, Gurgey A (2002) PAI-1 gene 4G/5G genotype: A risk factor for thrombosis in vessels of internal
organs. Am J Hematol 71:89–93
411. Alessio AM, Hoehr NF, Siqueira LH et al (2007) Association between estrogen receptor alpha and beta gene polymor-
phisms and deep vein thrombosis. Thromb Res 120:639–645
412. Colaizzo D, Amitrano L, Tiscia GL et al (2007) A new JAK2 gene mutation in patients with polycythemia vera and
splanchnic vein thrombosis. Blood 110:2768–2769
413. McMahon C, Abu-Elmagd K, Bontempo FA et al (2007) JAK2 V617F mutation in patients with catastrophic intra-
abdominal thromboses. Am J Clin Pathol 127:736–743
414. Remacha AF, Estivill C, Sarda MP et al (2007) The V617F mutation of JAK2 is very uncommon in patients with throm-
bosis. Haematologica 92:285–286
415. Elbaz A, Poirier O, Canaple S et al (2000) The association between the Val34Leu polymorphism in the factor XIII gene
and brain infarction. Blood 95:586–591
416. Franco RF, Pazin-Filho A, Tavella MH et al (2000) Factor XIII val34leu and the risk of myocardial infarction.
Haematologica 85:67–71
417. Palkimas MP Jr, Skinner HM, Gandhi PJ et al (2003) Polymorphism induced sensitivity to warfarin: a review of the
literature. J Thromb Thrombolysis 15:205–212
418. Honda S, Honda Y, Bauer B et al (1995) The impact of three-dimensional structure on the expression of PlA alloanti-
gens on human integrin beta 3. Blood 86:234–242
419.
Lazo-Langner A, Knoll GA, Wells PS et al (2006) The risk of dialysis access thrombosis is related to the transforming
growth factor-beta1 production haplotype and is modified by polymorphisms in the plasminogen activator inhibitor-
type 1 gene. Blood 108:4052–4058
420.
Saito K, Nakayama T, Sato N et al (2006) Haplotypes of the plasminogen activator gene associated with ischemic
stroke. Thromb Haemost 96:331–336
421. Kelly PJ, Rosand J, Kistler JP et al (2002) Homocysteine, MTHFR 677C→T polymorphism, and risk of ischemic stroke:
results of a meta-analysis. Neurology 59:529–536
422.
Ozben B, Diz-Kucukkaya R, Bilge AK et al (2007) The association of P-selectin glycoprotein ligand-1 VNTR poly-
morphisms with coronary stent restenosis. J Thromb Thrombolysis 23:181–187
423. Humphries SE, Luong LA, Ogg MS et al (2001) The interleukin-6 – 174 G/C promoter polymorphism is associated
with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J 22:2243–2252
424. O’Leary DH, Polak JF, Kronmal RA et al (1999) Carotid-artery intima and media thickness as a risk factor for myocardial
infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340:14–22
425. Pola R, Flex A, Gaetani E et al (2003) Synergistic effect of -174 G/C polymorphism of the interleukin-6 gene promoter
and 469 E/K polymorphism of the intercellular adhesion molecule-1 gene in Italian patients with history of ischemic
stroke. Stroke 34:881–885
426. van der Meer I, Brouwers GJ, Bulk S et al (2004) Genetic variability of von Willebrand factor and risk of coronary heart
disease: the Rotterdam Study. Br J Haematol 124:343–347
427. Durante-Mangoni E, Davies GJ, Ahmed N et al (2002) The prothrombin G20210A polymorphism in patients with
myocardial infarction. Blood Coagul Fibrinolysis 13:603–608
428. Belvis R, Santamaria A, Marti-Fabregas J et al (2006) Diagnostic yield of prothrombotic state studies in cryptogenic
stroke. Acta Neurol Scand 114:250–253
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429. Djousse L, Karamohamed S, Herbert AG et al (2007) Fucosyltransferase 3 polymorphism and atherothrombotic dis-
ease in the Framingham Offspring Study. Am Heart J 153:636–639
430.
Helgadottir A, Manolescu A, Helgason A et al (2006) A variant of the gene encoding leukotriene A4 hydrolase confers
ethnicity-specific risk of myocardial infarction 1. Nat Genet 38:68–74
431.
Kastrati A, Koch W, Gawaz M et al (2000) PlA polymorphism of glycoprotein IIIa and risk of adverse events after coro-
nary stent placement. J Am Coll Cardiol 36:84–89
432.
Bennett JS, Catella-Lawson F, Rut AR et al (2001) Effect of the Pl(A2) alloantigen on the function of beta(3)-integrins
in platelets. Blood 97:3093–3099
433.
Gorchakova O, Koch W, Mehilli J et al (2004) PlA polymorphism of the glycoprotein IIIa and efficacy of reperfusion
therapy in patients with acute myocardial infarction. Thromb Haemost 91:141–145
434.
Chew DP, Bhatt DL, Topol EJ (2001) Oral glycoprotein IIb/IIIa inhibitors: why don’t they work? Am J Cardiovasc
Drugs 1:421–428
435.
Gonzalez-Conejero R, Rivera J, Corral J et al (2005) Biological assessment of aspirin efficacy on healthy individuals:
heterogeneous response or aspirin failure? Stroke 36:276–280
436.
Quinn MJ, Topol EJ (2001) Common variations in platelet glycoproteins: pharmacogenomic implications. Pharma-
cogenomics 2:341–352
437.
Jefferson BK, Foster JH, McCarthy JJ et al (2005) Aspirin resistance and a single gene. Am J Cardiol 95:805–808
438.
Arepally G, McKenzie SE, Jiang XM et al (1997) Fc gamma RIIA H/R 131 polymorphism, subclass-specific IgG
anti-heparin/platelet factor 4 antibodies and clinical course in patients with heparin-induced thrombocytopenia and
thrombosis. Blood 89:370–375
439.
Carlsson LE, Santoso S, Baurichter G et al (1998) Heparin-induced thrombocytopenia: new insights into the impact of
the FcgammaRIIa-R-H131 polymorphism. Blood 92:1526–1531
440. Sacchi E, Tagliabue L, Scoglio R et al (1996) Plasma factor VII levels are influenced by a polymorphism in the pro-
moter region of the FVII gene. Blood Coagul Fibrinolysis 7:114–117
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Part II
Antithrombotic Therapy for Stable Coronary
Atherosclerotic Disease
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5 Aspirin in Primary and Secondary
Prevention of Cardiovascular Disease
Jinesh Kochar and J. Michael Gaziano
Co n t e n t s
History Of Aspirin
Pharmacokinetics
Mechanism Of Action
Aspirin For Cardiovascular Prevention
Adverse Effects Of Low-Dose Aspirin
Aspirin May Not Always Work
Recommendations
References
Ab s t r A c t For over a century, aspirin has been used for different indications, mainly as an antipyretic,
analgesic, and anti-inflammatory agent. However, its cardioprotective properties were discovered only a
few decades ago. Initially employed for its antiplatelet effect in secondary prophylaxis of cardiovascular
(CVD) events, various large-scale trials have established the role of aspirin in primary prevention of CVD
in people at high risk. This chapter summarizes the clinical trial data that demonstrated the efficacy of this
drug in both secondary and primary prevention of cardiovascular disease events, the leading cause of death
in the US. In addition, an account of the historical perspective on aspirin, its mechanism of action, optimal
dose, adverse effects, interaction with other nonsteroidal anti-inflammatory agents, aspirin resistance, and
current recommendations for its use in primary prophylaxis of CVD are presented.
Key words:
Aspirin; Primary prevention; Stable CAD; Efficacy; Atherosclerosis
HISTORY OF ASPIRIN
With more than 35,000 kg of aspirin (ASA) being consumed daily in the US, it is the most commercially
successful synthetic drug in the world (1). From a historical perspective, as early as about 3000 BC, ASA,
in its crude form, was known to the Egyptians, who employed the decoction of salicylate-containing
plants like myrtle or willow leaves for joint pain. Hippocrates of Kos, around 500 BC, recommended
extract of willow bark for pain during childbirth. The first scientific description of the beneficial effects
of willow bark in ague (fever, usually taken to be malaria) was given in 1763 by Reverend Edward Stone
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_5
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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of Oxfordshire, UK. In 1876, Thomas MacLagan, a Scottish physician, carried out the first known clinical
trial of salicin in a patient with acute rheumatism and reported his findings in The Lancet.
The search for the active ingredient in willow bark spanned most of the early and middle 1800s,
and a purified form of salicin was obtained by Buchner in 1828. A series of modification of this
compound, attempted by European scientists, led to the discovery of salicylic acid as an analgesic and
antipyretic agent. Sodium salicylate, the then-commercially available form of this compound had
lower gastric tolerability. A Friedrich Bayer & Co. chemist, Felix Hoffmann, in an attempt to improve
its tolerability, in 1897 is credited for preparing a purified acetylated form of the molecule. The Bayer
Company, on March 6, 1899, first registered the product under the trade name of Aspirin (“a” from
acetyl, “spir” from Spirea ulmania, a plant containing the compound). By circulating the new drug
information to about 30,000 physicians, Bayer is said to have introduced the first mass marketing of
a drug. Aspirin’s acceptance by the laity has been equally impressive; in 1950, aspirin found a place
in the Guinness Book of Records, as the most popular pain killer in the world. In existence for over
100 years, aspirin has been a subject of constant attention for its potential role in the treatment or
prevention of many acute and chronic conditions.
PHARMACOKINETICS
After oral intake, nondissociated acetylsalicylic acid passively diffuses across the gastric and intes-
tinal mucosa. Enteric coating considerably delays absorption time (peak plasma levels in 3–4
h as
compared to 30–40
min for the uncoated aspirin). Once aspirin enters the liver, it is hydrolyzed by
esterases. Aspirin has a half-life of about 15–20
min in the human circulation. The mean lifespan of
human platelets is approximately 10 days; about 10% of circulating platelets are replaced each day,
and 5–6 days following aspirin ingestion, approximately 50% of the platelets function normally.
Aspirin thus exhibits a dissociation of pharmacokinetics and pharmacodynamics.
Cumulative effect of low-dose aspirin: In a study done on 46 healthy adults, cumulative daily doses
of 0.45 mg/kg of aspirin inhibited the T × B
2
(a stable breakdown product of T × A
2
) level to less than
5% by day 7 of therapy
(2). For a 133-pound person, a daily dose of as little as 27 mg of aspirin
reduced T
× B
2
by 36% on day 1, 70% on day 2, 87% on day 3, and 90% on day 4. Greater than 95%
inhibition of platelet T
× B
2
was maintained for the 30-day period of aspirin administration (Fig. 3).
MECHANISM OF ACTION
After rapid absorption from the stomach and upper small intestine, ASA first comes in contact with
platelets in the portal circulation, where it leads to irreversible inactivation of the cyclooxygenase
activity of prostaglandin H synthase 1 and synthase 2, referred to as COX-1 and COX-2, respectively
(Fig. 1). These enzymes catalyze the conversion of arachidonic acid to PGH
2
, which is then converted
to the prostaglandins, prostacyclin, and thromboxane A
2
by tissue-specific isomerases. After diffusing
through the cell membrane, ASA enters the COX channel, ASA first binds to an arginine 120 residue,
and then acetylates the serine 529 residue in COX-1 and serine 516 in COX-2. This prevents access
of arachidonic acid to the COX catalytic site. As the anuclear platelets cannot synthesize new
enzymes, this effect of ASA remains for the rest of their lifespan. In contrast, the inhibition of COX-
2-dependent pathophysiologic processes like hyperalgesia and inflammation, mediated by nucleated
cells, requires larger doses of aspirin and frequent dosing because higher levels of ASA are required
to inhibit COX-2 than to inhibit COX-1. In addition, unlike platelets, nucleated cells can repeatedly
synthesize fresh COX-2, explaining the approximate 100-fold variation in daily doses of aspirin when
it is used for anti-inflammatory rather than antithrombotic purposes (Fig. 1).
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Aspirin in Primary and Secondary Prevention of Cardiovascular Disease
ASPIRIN FOR CARDIOVASCULAR PREVENTION
About 36% of the US adult population, and 80% of those with cardiovascular disease take aspirin
for cardiovascular disease prevention, accounting for consumption of 10–20 billion aspirin tablets for
cardiovascular disease prevention annually (3).
Secondary Prevention
Over 400 trials have been conducted to evaluate the antiplatelet effects of ASA and other
drugs. Aspirin has established benefits in preventing another event in patients with established
cardiovascular disease.
Fig. 1. Mechanism of action of aspirin. Arachidonic acid, a 20-carbon fatty acid containing four double bonds, is
liberated from the sn2 position of membrane phospholipids by several forms of phospholipase A
2
, which are activated
by diverse stimuli. Arachidonic acid is converted by cytosolic prostaglandin H synthases, which have both cyclooxy-
genase and hydroperoxidase (HOX) activity, to the unstable intermediates prostaglandin G
2
and prostaglandin H
2
,
respectively. The synthases are colloquially termed cyclooxygenases and exist in two forms, cyclooxygenase-1 (COX-
1) and cyclooxygenase-2 (COX-2). Low-dose aspirin selectivity inhibits COX-1, whereas high-dose aspirin inhibits
both COX-1 and COX-2. Prostaglandin H
2
is converted by tissue-specific isomerases to multiple prostanoids. These
bioactive lipids activate specific cell-membrane receptors of the superfamily of G-protein-coupled receptors, such as
the thromboxane receptor, the prostaglandin D
2
receptors, the prostaglandin E
2
receptors, the prostaglandin F
2
recep-
tors, and the prostacyclin receptor (Source : Patrono et al. (5)).
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Antithrombotic Drug Therapy in Cardiovascular Disease
Fig. 2. Benefits and risks of low-dose aspirin in primary-prevention trials. The numbers of vascular events
avoided and episodes of major bleeding caused per 1,000 patients treated with aspirin per year plotted from the
results of individual placebo-controlled trials of aspirin in different patient populations characterized by various
degrees of cardiovascular risk, as noted on the abscissa. WHS Women’s Health Study, PHS Physicians’ Health
Study, PPP Primary Prevention Project, HOT Hypertension Optimal Treatment Study, BDT British Doctors Trial,
TPT Thrombosis Prevention Trial, SAPAT Swedish Angina Pectoris Aspirin Trial. (Source: Patrono et al. (5)).
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Aspirin in Primary and Secondary Prevention of Cardiovascular Disease
The Antithrombotic Trialists Collaboration conducted a meta-analysis that reviewed 287 studies
involving 135,000 patients in comparisons of aspirin versus control and 77,000 patients in compari-
sons of different antiplatelet regimens (4). The main outcome measures included nonfatal myocardial
infarction (MI), nonfatal stroke, and vascular death, collectively termed as “serious vascular event.”
Fig. 4. The effect of aspirin alone and of ibuprofen plus aspirin on platelet cyclooxygenase-1. The platelet prostag-
landin G/H synthase-1 (cyclooxygenase-1) is depicted as a dimer. The arachidonic acid substrate gains access to the
catalytic site through a hydrophobic channel that leads into the core of the enzyme (a). Aspirin blocks the access of
arachidonic acid to the catalytic site by irreversibly acetylating a serine residue at position 529 in platelet cyclo
-
oxygenase-1, near but not within the catalytic site (b). Interpolation of the bulky acetyl residue prevents metabolism
of arachidonic acid into the cyclic endoperoxides PGG
2
and PGH
2
for the lifetime of the platelet. Because PGH
2
is
metabolized by thromboxane synthase into thromboxane A
2
, aspirin prevents the formation of thromboxane A
2
by the
platelets until new platelets are generated. Nonsteroidal anti-inflammatory drugs, such as ibuprofen, are reversible, com-
petitive inhibitors of the catalytic site (c) whose use results in the reversible inhibition of thromboxane A
2
formation
during the dosing interval. Prior occupancy of the catalytic site by ibuprofen prevents aspirin from gaining access to
its target serine (Source: Catella-Lawson et
al (33)).
Fig. 3. (Upper) The effect of low dose (0.45 mg/kg) aspirin on platelet TXB
2
. Serum TXB
2
was measured in nine
healthy subjects during seven consecutive days without and with (indicated by arrows) aspirin. Each mark on X-axis
represents a day. (Lower) The long term effects of low dose (0.45 mg/kg per day) aspirin on platelet TXB
2
and renal
PGI
2
synthesis. Serum TXB
2
concentration and urinary excretion of 6-keto-PGF
1
-
a
(a prostacycline metabolite) were
measured in three healthy subjects before, during and after aspirin therapy. Mean values and standard error of mean
are plotted. Arrows indicate duration of aspirin therapy (Source: Patrignari et al. (2)).
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Antithrombotic Drug Therapy in Cardiovascular Disease
Overall, aspirin and other antiplatelet drugs led to a 22% risk reduction in serious vascular events in
patients with MI, stroke, transient ischemic attack (TIA), coronary artery disease, peripheral vascular
disease (PVD), at-risk of pulmonary embolism, or with other high-risk conditions such as diabetes
mellitus, hemodialysis, and carotid disease. Exclusion of acute stroke patients increased this figure to
25%. At different doses, aspirin alone reduced the risk of serious vascular events by 23%. At doses of
500–1,500 mg, aspirin reduced the risk of vascular events by 19%. The corresponding risk reduction
at doses of 160–325
mg, 75–150 mg, and less than 75 mg were 26%, 32%, and 13%, respectively.
It has been suggested that in cardiovascular disease patients with a 4–8% annual risk of a serious
vascular event, aspirin prevents 10–20 fatal and nonfatal vascular events in every 1,000 patients
treated over a period of 1 year
(5). In patients undergoing carotid endarterectomy, risk of stroke, MI,
and death within 30 days and 3 months of endarterectomy were lower in patients taking 81 or 325
mg
of aspirin daily as compared to those taking 650 or 1,300
mg (6).
Various studies have looked into whether the addition of another antiplatelet agent, with another
mechanism of action has additional cardiovascular benefits. The CURE (Clopidogrel in Unstable
angina to prevent Recurrent ischemic Events) study randomized 12,562 patients with acute non-ST
segment elevation coronary syndrome into two groups: a clopidogrel (a loading dose of 300 mg
orally, followed by 75
mg daily) plus aspirin group and a placebo plus aspirin group (75–325 mg)
(7). The clopidogrel and aspirin group had a 20% reduced risk of death from cardiovascular causes,
nonfatal MI, or ischemic stroke. This effect was more pronounced in patients with high TIMI
(Thrombolysis in Myocardial Infarction) risk score (relative risk reduction 45%).
The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and
Avoidance (CHARISMA) study randomized people at high cardiovascular risk, defined as either
those with pre-existing cardiovascular disease or with cardiovascular risk factors (8). A statistically
nonsignificant 8% reduction in nonfatal myocardial infarction, nonfatal ischemic stroke, and mortality
from all cardiovascular causes was observed. In a randomized trial comparing the combination of
aspirin plus ticlopidine to aspirin alone and aspirin plus warfarin in subjects with coronary stents, the
aspirin–ticlopidine combination significantly reduced the incidence of primary endpoints (composite
of death from any cause, revascularization of the target lesion without death, evidence of thrombosis
of the target vessel on repeated angiography without revascularization, or nonfatal myocardial
infarction). The relative risks were 0.15 (p < 0.001) and 0.20 (p = 0.01), respectively. As compared to
aspirin alone, addition of intravenous GP IIb-IIIa antagonist to aspirin was associated with a
statistically significant 19% reduction in serious vascular events, translating into preventing 20
vascular events per 1,000 patients in a month. In the Antithrombotic Trialists Collaboration meta-
analysis, addition of dipyridamole to aspirin showed a statistically nonsignificant 6% reduction in
serious vascular events.
In sum, aspirin reduces the risk of future CVD events, including MI and stroke, in those with CVD.
There is no evidence that dose ranges higher than 75–150 mg daily are more effective. The combination of
ASA with another antiplatelet agent such as clopidogrel should be reserved for those at the highest risk,
including those with acute coronary syndrome and immediately following stent placement.
Primary Prevention
Evaluation of the role of aspirin in primary prevention of cardiovascular events is more complicated,
in part because the absolute risk of these events is lower than in secondary prevention. In contrast
to the hundreds of trials for secondary prevention, only six large-scale trials have explored the role
of aspirin in primary prevention of CVD (Table 1): the British Male Doctors’ Trial (BMD) (9),
the Hypertension Optimal Treatment Trial (HOT) (10), the Thrombosis Prevention Trial (TPT) (11), the
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