Aspirin benefit/risk

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The risks and benefits of taking aspirin in people having various levels and

types

of cardiovascular and bleeding risks are described in the not yet in Medline

pdf-available article below.

New Engl J Med 353:2373-2383 Dec 1, 2005 # 22

Low-Dose Aspirin for the Prevention of Atherothrombosis

Carlo Patrono, M.D., A. García Rodríguez, M.D., Raffaele Landolfi, M.D.,

and

Colin Baigent, B.M., B.Ch.

Atherosclerosis, the major cause of ischemic coronary artery disease and

cerebrovascular disease, is a chronic inflammatory disorder in which immune

mechanisms interact with metabolic risk factors to initiate, propagate, and

activate

vascular lesions.1 Arterial thrombosis, an acute complication that develops on

the

surface of a ruptured atheromatous plaque or as a consequence of endothelial

erosion,1 may cause myocardial infarction or ischemic stroke. Platelets are key

cellular components of arterial occlusive thrombi and may participate in the

development and progression of atheromatous plaques.2 Platelets are also vital

components of hemostasis, the physiologic process that arrests hemorrhage after

tissue trauma and vascular injury. Although the adhesion and activation of

platelets

can be viewed as a repair-oriented response to sudden fissuring or rupture of an

atheromatous plaque, uncontrolled progression of such a process through a series

of

self-sustaining amplification loops may lead to the intraluminal formation of

thrombus, vascular occlusion, and transient ischemia or infarction. The ability

of

platelets to participate in both normal hemostasis and atherothrombosis depends

on

their adhesive properties and their capacity to become activated very quickly in

response to various stimuli.2

Currently available antiplatelet drugs interfere with certain steps in the

activation process by selectively blocking key platelet enzymes or receptors,

reducing the risk of arterial thrombosis through mechanisms that cannot be

dissociated from an increased risk of bleeding complications.3 In particular,

randomized trials indicate that low-dose aspirin can prevent arterial thrombosis

under various circumstances, including first vascular events among low-risk,

healthy

subjects and recurrent vascular events among patients with known acute or

chronic

occlusive vascular disease.3

The aim of this review is to integrate our current understanding of the

molecular

mechanism of action of aspirin with the results of clinical trials and

epidemiologic

studies of aspirin as an antiplatelet agent, placing special emphasis on the

benefits and risks in various patient populations.

Pharmacokinetics

Aspirin is rapidly absorbed in the stomach and upper small intestine, primarily

by

passive diffusion of nondissociated acetylsalicylic acid across gastrointestinal

membranes. Plasma levels peak 30 to 40 minutes after the ingestion of uncoated

aspirin. In contrast, it can take up to three or four hours for plasma levels to

peak after the administration of enteric-coated formulations; thus, patients

should

chew these preparations if a rapid antiplatelet effect is required. Esterases

hydrolyze aspirin in the gastrointestinal mucosa and the liver, forming

salicylic

acid.4 The oral bioavailability of regular aspirin tablets is approximately 40

to 50

percent over a wide range of doses, but the bioavailability of enteric-coated

tablets and sustained-release, microencapsulated preparations is considerably

lower.4 Aspirin first comes into contact with platelets in the portal

circulation,

and as a consequence, platelets are exposed to substantially higher drug levels

than

are present in the systemic circulation.4 Aspirin has a half-life of 15 to 20

minutes in plasma.

Despite the rapid clearance of aspirin from the circulation, its antiplatelet

effect

lasts for the life of a platelet owing to the permanent inactivation of a key

platelet enzyme, an effect that can be reversed only through the generation of

new

platelets.5 Thus, there is a complete dissociation between the pharmacokinetics

and

pharmacodynamics of aspirin, allowing the use of a once-a-day regimen for

antiplatelet therapy despite the very short half-life of the drug.

Mechanism of Action ...

Functional Consequences of the Expression and Inhibition of Cyclooxygenase

Although newly formed platelets express both COX-1 and COX-2,8 mature platelets

express only COX-1. In contrast, vascular endothelial cells express both COX-1

and

COX-2. The latter is up-regulated in response to physiologic hemodynamics9 and

is

the predominant source of PGI2 in health10 and disease.11,12 Platelets and

vascular

endothelial cells process PGH2 to produce primarily TXA2 and PGI2, respectively.

TXA2 is synthesized and released by platelets in response to a variety of

stimuli

(for example, collagen, thrombin, and adenosine diphosphate) and, in turn,

induces

irreversible platelet aggregation through its interaction with a

G-protein–coupled

receptor, the TXA2 receptor.13,14 Thus, TXA2 provides a mechanism for amplifying

the

responses of platelets to diverse agonists. In addition, TXA2 is a potent

vasoconstrictor,15 induces the proliferation of vascular smooth-muscle cells,

and is

proatherogenic.16 In contrast, PGI2 inhibits platelet aggregation in response to

all

agonists through its interaction with the PGI2 receptor.15 PGI2 also induces

vasodilation,15 inhibits the proliferation of vascular smooth-muscle cells,

protects

the myocardium against oxidant stress, and is antiatherogenic.16 Deletion of the

gene encoding the PGI2 receptor is associated with increased susceptibility to

experimental thrombosis, thus supporting the importance of PGI2 in vascular

thromboresistance.17

Although TXA2 is a prostanoid largely derived from COX-1 (mostly from platelets)

and

its biosynthesis is highly sensitive to inhibition by aspirin,18,19 vascular

PGI2 is

derived predominantly from COX-210,11,12 and is less susceptible to inhibition

by

low doses of aspirin.19 Aspirin induces a long-lasting functional defect in

platelets that can be detected clinically as a prolonged bleeding time.20 In

contrast, low-dose aspirin has no measurable effects on PGI2-dependent vascular

functions; thus, it does not increase blood pressure,21 impair renal function,22

or

interfere with the antihypertensive effects of diuretics and

angiotensin-converting–enzyme (ACE) inhibitors.23

Although other mechanisms have been proposed,3 inhibition of platelet COX-1 is

sufficient to explain the antithrombotic effects of low-dose aspirin. This does

not

necessarily imply that a single mediator, TXA2, is responsible for the one

quarter

of major vascular events that can be prevented by low-dose aspirin in high-risk

patients, because inhibition of platelet activation at sites of vascular injury

may

have indirect consequences, such as reducing the release of inflammatory

cytokines,24 oxygen radicals,25 growth factors,26 and other proteins.27

Moreover,

reduced release of these diverse platelet products may contribute, at least in

part,

to interference with other disease processes in which the efficacy and safety of

low-dose aspirin are currently being investigated. In fact, the efficacy of

once-a-day regimens of low-dose aspirin in preventing the recurrence of

colorectal

adenoma28,29 is consistent with the hypothesis that activated platelets induce

the

up-regulation of COX-2 in one or more types of cells involved in early

intestinal

carcinogenesis.30

Clinical Pharmacology of the Inhibition of Platelet Cyclooxygenase

.... typical regimens of 75 to 100 mg of aspirin per day clearly exceed the

minimal

effective dose required for a full pharmacodynamic effect, thus accommodating

some

degree of interindividual variability in drug response. There is no evidence

that

the pharmacodynamics of platelet inhibition by aspirin is any different in women

than in men.18,31

Because the maximal biosynthetic capacity of human platelets33 (Figure 2A) is

several thousand times as high as the basal rate of TXA2 biosynthesis in healthy

subjects34 (Figure 2B), the relationship between the inhibition of platelet

COX-1

activity and TXA2 biosynthesis in vivo is strikingly nonlinear35 (Figure 2C).

The

inhibition of platelet COX-1 attains functional relevance when the maximal

capacity

to generate TXA2 is reduced by at least 95 percent.35,36

The relative COX-1 selectivity of low-dose aspirin most likely accounts for the

substantial residual COX-2–dependent PGI2 biosynthesis in vivo at daily doses in

the

range of 20 to 80 mg,19 despite transient suppression of COX-1–dependent release

of

PGI2.37 More profound suppression of PGI2 formation by higher doses of aspirin,

as a

function of the dose-dependent inhibition of COX-2, might be expected to

attenuate

the antithrombotic efficacy of the drug. However, there is limited direct

evidence

supporting this possibility.38,39,40

Permanent inactivation of platelet COX-1 by aspirin may lead to bleeding

complications as well as the prevention of arterial thrombosis. At least two

distinct COX-1–dependent mechanisms contribute to the increased risk of upper

gastrointestinal bleeding associated with aspirin therapy: the inhibition of

TXA2-mediated platelet aggregation and the impairment of PGE2- and PGI2-mediated

cytoprotection in the gastrointestinal mucosa.3 Whereas the former effect is

independent of a dose in excess of 30 mg daily, the latter effect is clearly

dose-dependent. Inhibition of platelet function may largely account for the

twofold

increase in the risk of upper gastrointestinal bleeding associated with daily

doses

of aspirin in the range of 75 to 100 mg, inasmuch as a similar relative risk is

associated with other drugs that interfere with primary hemostasis but do not

affect

COX-dependent cytoprotection.41 Dose-dependent inhibition of cytoprotection by

higher doses of aspirin amplifies the risk of bleeding and perforation by

causing

new mucosal lesions or aggravating existing ones and increases the risk by a

factor

of 4 to 10 at analgesic doses. The use of an antisecretory agent (especially a

proton-pump inhibitor) was associated with a reduced risk of upper

gastrointestinal

bleeding in patients taking aspirin in a case–control study,42 but no adequately

sized placebo-controlled, randomized trial has examined the protective effects

of

acid-antisecretory therapy in patients treated with 75 to 100 mg of aspirin

daily.

Drug Interactions ...

Low-dose aspirin therapy can cause upper gastrointestinal bleeding.3 In two

large

trials, subgroup analyses suggested that aspirin may attenuate the

gastrointestinal

safety of selective COX-2 inhibitors, as compared with traditional NSAIDs.52,53

However, this potential interaction needs to be assessed further in studies that

compare selective COX-2 inhibitors with traditional NSAIDs in patients who are

receiving aspirin.

Aspirin Resistance ...

Efficacy and Safety of Low-Dose Aspirin in the Prevention and Treatment of

Atherothrombosis in High-Risk Patients

The efficacy and safety of aspirin have been evaluated in several populations,

ranging from apparently healthy persons at low risk to patients presenting with

an

acute myocardial infarction or an acute ischemic stroke. Among patients with

occlusive vascular disease, both individual studies3 and a meta-analysis of

trials

of antiplatelet therapy38 indicate that aspirin and other antiplatelet drugs

reduce

the risk of a serious vascular event (nonfatal myocardial infarction, nonfatal

stroke, or death from vascular causes) by approximately 25 percent. This figure

represents a composite of a 34 percent reduction in the rate of nonfatal

myocardial

infarction, a 25 percent reduction in the rate of nonfatal stroke, and a

reduction

by one sixth in the rate of death from a vascular or unknown cause.3,38 Since

each

of these proportional reductions applies similarly to all categories of patients

with vascular disease, the absolute benefits of aspirin in individual patients

can

be estimated by reducing the estimated absolute risk of nonfatal myocardial

infarction by one third, the risk of nonfatal stroke by one fourth, and the risk

of

death from vascular causes by one sixth.3,38 Thus, among a wide range of

patients

with vascular disease, in whom the annual risk of a serious vascular event

ranges

from 4 to 8 percent, aspirin typically prevents at least 10 to 20 fatal and

nonfatal

vascular events for every 1000 patients treated for one year (Figure 3).3,38

Observational studies61 and a meta-analysis of randomized clinical trials in

high-risk patients38 have demonstrated that long-term therapy with low-dose

aspirin

approximately doubles the risk of major extracranial (mostly, upper

gastrointestinal) bleeding. In middle-aged patients, this corresponds to an

estimated absolute excess of approximately 1 to 2 major bleeding complications

per

1000 patients treated with low-dose aspirin for one year.3,38,61 Moreover, there

is

an absolute excess of hemorrhagic strokes of 1 to 2 per 10,000 patients.38

Therefore, for most high-risk patients taking low-dose aspirin, the number in

which

a serious vascular event would be avoided clearly outweighs the number with a

major

bleeding episode, unless a given patient has increased susceptibility to

bleeding

owing to advanced age, a history of ulcer, or concomitant treatment with other

drugs

interfering with primary hemostasis or gastrointestinal cytoprotection.

Such a favorable risk–benefit ratio of low-dose aspirin in high-risk patients

has

resulted in level 1 recommendations,60 and the Food and Drug Administration has

approved aspirin for patients at high risk for occlusive vascular disease.

Despite

such a recommendation, aspirin use appears to be less than optimal, according to

cardiovascular registries62,63 and a recent survey.64 A history of adverse

reactions

to aspirin is a common reason for avoiding long-term use in high-risk patients.

In a

double-blind, placebo-controlled, randomized study of 150 patients using

low-dose

(80 mg daily) aspirin with upper gastrointestinal symptoms, treatment with a

proton-pump inhibitor significantly reduced the rate of heartburn, but not other

aspirin-associated symptoms.65 In addition to causing gastrointestinal

intolerance,

aspirin is an infrequent cause of unpredictable hypersensitivity reactions,

often

referred to as " aspirin allergy. " 66 Proper classification of patients who are

allergic to aspirin and early referral of such patients to allergy services for

potential desensitization may allow continued use of this lifesaving drug.66

Thus, aspirin is recommended in all clinical conditions in which antiplatelet

prophylaxis has a favorable risk–benefit profile.3,60 Given the potential of

aspirin

to cause dose-dependent impairment of gastric cytoprotection and endothelial

thromboresistance, physicians are encouraged to use the lowest dose of aspirin

shown

to be effective in each clinical setting67,68,69,70,71,72,73,74 (Table 1). The

available evidence supports the use of daily doses of aspirin in the range of 75

to

100 mg for the long-term prevention of serious vascular events in high-risk

patients. The use of a once-a-day regimen is preferable to the use of an

every-other-day regimen because of interindividual variability in the platelet

turnover rate, which represents an important determinant of the extent and

duration

of platelet inhibition on repeated dosing with low-dose aspirin.31 In clinical

settings in which an immediate antithrombotic effect is required (such as in the

presence of acute coronary syndromes or acute ischemic stroke), a loading dose

of

160 to 200 mg should be given at the time of diagnosis to ensure rapid and

complete

inhibition of thromboxane-dependent platelet aggregation.3

Table 1. High-Risk Disorders for Which Aspirin Has Been Shown to Be Effective

and

Lowest Effective Daily Dose.

=============================

Disorder Lowest effective daily dose*, mg

=============================

Chronic stable angina 75

Polycythemia vera 100

Unstable angina 75

Acute myocardial infarction 160

Transient ischemic attack and ischemic stroke 50

Severe carotid artery stenosis 75

Acute ischemic stroke 160

Atrial fibrillation 325

=============================

* The lowest effective daily dose is the lowest daily aspirin dose for which

direct

randomized evidence of effectiveness is available.

Efficacy and Safety of Low-Dose Aspirin in Low-Risk Subjects

In contrast to the clear benefits of low-dose aspirin on the risk of myocardial

infarction, stroke, and death from vascular causes among high-risk patients with

known occlusive vascular disease, its effects in low-risk persons are less

clear. A

meta-analysis of five primary-prevention trials21,75,76,77,78 indicated that

aspirin

reduces the risk of myocardial infarction by approximately 30 percent (which is

similar to the benefit associated with secondary prevention) but has no

significant

effect on the risk of stroke.79 More recently, the results of the aspirin

component

of the Women's Health Study, which compared 100 mg of aspirin every other day

with

placebo in approximately 40,000 apparently healthy women, were reported.80 The

results were surprising because they appeared to contrast with the results of

earlier trials, in which the majority of participants had been men. Aspirin

reduced

the risk of stroke by 17 percent (95 percent confidence interval, 1 to 31

percent;

P=0.04), but there was no significant reduction in the risk of myocardial

infarction

(relative risk, 1.02; 95 percent confidence interval, 0.84 to 1.25). However, in

secondary-prevention trials, the effects of aspirin on the risk of major

coronary

events and strokes were similar in men and women. ...

Whereas the benefits of aspirin exceed the risks of bleeding in most patients

with

clinically overt arterial disease, the risk–benefit ratio is marginal in

low-risk

populations. As shown in Figure 4, whereas the risk of a vascular event was

almost 4

percent per year among patients with ischemic heart disease in the Swedish

Angina

Pectoris Aspirin Trial,67 the average annual risk was much lower (0.3 to 1.6

percent

per year) in six primary-prevention trials involving mostly asymptomatic

subjects.

The benefit of aspirin did not clearly outweigh the harm within this range of

cardiovascular risk. In these primary-prevention trials, few subjects exceeded

the

threshold for aspirin prophylaxis recommended by the American Heart Association

— a

risk of coronary heart disease of 1 percent per year.83 It is worth remembering

that

these trials included few people older than 70 years of age, in whom the

predicted

risk of coronary heart disease and stroke rises steeply and who are the dominant

demographic group at elevated risk (i.e., the risk exceeds 1 percent per year).

The

lack of randomized trials involving older people makes it difficult to assess

whether any possible benefits of aspirin would exceed the known risks of upper

gastrointestinal bleeding in this age group.84 As illustrated in Figure 5, the

risk

of such complications increases sharply among people 70 years of age or older.

This

risk is further increased by a history of gastrointestinal disturbances (Figure

5)

and by concomitant use of nonsteroidal antiinflammatory drugs (data not shown).

Although there seems to be a general agreement among gastroenterologists that

proton-pump inhibitors should be prescribed to high-risk patients taking

low-dose

aspirin,85 such a strategy has not been widely adopted because of a lack of

definitive evidence to support it.

Future Directions ...

Dr. Patrono reports having received consulting fees from Bayer and Ni and

lecture

fees from Sanofi, Bayer, and Eli Lilly; Dr. García Rodríguez, lecture fees from

Bayer and grant support from Pfizer; Dr. Landolfi, lecture fees from Aventis and

Bayer Italia; and Drs. Baigent and Patrono, grant support from Bayer and Merck.

Al Pater, PhD; email: old542000@...

__________________________________

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