Aspirin reduces stroke in women?

[Guest guest]

Hi All,

The below commentary introduces the topic that stroke, especially ischemic

stroke,

can be prevented by aspirin in women, as well as men.

It was not harmful for hemorrhagic stroke, but whether it would be not harmful

in

CRers with reduced blood clotting potential remains to be seen.

The below and its described references are pdf-available.

Freek WA Verheugt and Sidney C

JAMA 366, Iss 9492 , 1-7 Oct 2005-7.

The lady aspirin for cardiovascular disease

Since the 1980s, it has become clear that aspirin is a highly cost-effective and

fairly safe component of the acute treatment and secondary prevention of various

cardiovascular diseases.1 However, aspirin in the primary prevention of

cardiovascular disease remains controversial. Although four of the five large

randomised trials show a reduction in myocardial infarctions, none detected a

reduction in cardiovascular mortality or stroke.2 There is even a suggestion of

increased haemorrhagic stroke by the use of prophylactic aspirin in healthy

individuals. Moreover, most of the trials included only men or mostly men, and

there

has been little evidence of the beneficial effect of prophylactic aspirin in

women.

Women face the first events of cardiovascular disease later in life than men,

with a

break-even point occurring at about 65 years of age. Clinical trials in

cardiovascular medicine have mainly focused on men because of this age

difference in

risk. Yet the consequences of cardiovascular events in women seem worse than in

men.3 Therefore it is not clear why there have been so few trials on prevention

and

treatment of cardiovascular disease which included women, let alone in women

exclusively. Specific female conditions, such as menopause, have been studied

for

prevention of cardiovascular disease, but such research has only dealt with

hormone

treatment.4 and 5 Although potential benefits have been suggested by many

observational and mechanistic studies, postponing menopause with hormone therapy

in

randomised trials does not reduce the risk of cardiovascular disease in women.

Therefore the recently published Womens' Health Study (WHS) of low-dose aspirin

in

the primary prevention of cardiovascular disease in women over the age of 45 is

welcome.6 It is not only the largest trial with aspirin so far, it is also the

first

done in women exclusively. The results have been commented on in the lay press,7

as

well as in an accompanying editorial8 and are somewhat surprising, because this

is

the first primary prevention trial with aspirin, that showed a significant

reduction

in stroke numbers (table). Myocardial infarction, which has been consistently

lowered in the primary prevention observations in men, was not reduced (1·0% in

both

groups), until after the age of 65 (2·0% for aspirin and 3·0% for placebo,

relative

risk ratio 0·66 [0·44–0·97], p=0·04). No differences were seen in total (3·1%)

or

cardiovascular (0·6%) mortality. The overall risk of a cardiovascular event was

less

than 0·25% a year and strokes were more frequent than myocardial infarction in

the

women in WHS. For each four myocardial infarctions, five strokes occurred,

whereas

in the Physicians' Health Study (PHS), which included men only, for each four

myocardial infarctions there were only two strokes.9 Therefore, the chance of

seeing

an effect on stroke in WHS was much larger than in PHS.

Table. Incidence of stroke in the Womens' Health Study

==========

Aspirin (n=19 934) Placebo (n=19 942) Relative risk (95% CI) p

==========

Total stroke 221 (1·1%) 266 (1·3%) 0·83 (0·69–0·99) 0·040

Ischaemic stroke 170 (0·9%) 221 (1·1%) 0·76 (0·63–0·93) 0·009

Haemorrhagic stroke 51 (0·3%) 41 (0·2%) 1·24 (0·82–1·87) 0·310

Fatal stroke 23 (0·1%) 22 (0·1%) 1·04 (0·58–1·86) 0·900

Non-fatal stroke 198 (1·0%) 244 (1·2%) 0·81 (0·67–0·97) 0·020

Data does not equal total number because some cases not classifable.

It is unclear what underlying mechanisms might contribute to the observed sex

differences in rates of stroke and myocardial infarction between WHS and PHS.

Women

tend to have a higher frequency of hypertension, whereas smoking is more common

in

men. Hypertension is a very substantial risk factor for stroke,10 although

smoking

carries a stronger risk for myocardial infarction. In WHS and PHS, which were 16

years apart, hypertension was probably treated better in WHS. Similarly,

knowledge

about treatment of cardiovascular risk factors in these health-care

professionals,

which was the study population in WHS, must have been higher than in the male

PHS.

For instance, statins and angiotensin-converting-enzyme inhibitors, both

effective

agents against the development and progression of atherosclerosis and with it

myocardial infarction, were hardly available in the time of PHS, but would have

been

used in WHS.

However, the most important risk modifier, of course, is age. Both in PHS and

WHS,

age is the strongest modulator of the effect of aspirin. In the low-risk women

under

the age of 65 enrolled in WHS there is no effect of low-dose aspirin on

myocardial

infarction and the benefit on stroke increases with age. In PHS the same

gradient of

the aspirin effect was seen with age, but only for myocardial infarction.

Thus women not only present a first cardiovascular event later in life, they

also

have a higher risk of stroke than myocardial infarction. Because aspirin tends

to

prevent strokes in women with hypertension,11 the higher rates of strokes than

heart

attacks in young women might account for the main the results of WHS, wherein a

benefit was seen for stroke, but not myocardial infarction in younger women

taking

aspirin.

Clearly, the major risk of aspirin is bleeding, even when used in low doses.

Thromboxane A2 production is almost completely inhibited in doses as low as that

used in WHS. Low doses of aspirin promote gastric bleeding in existing

gastrointestinal ulceration. The most serious fear of bleeding is cerebral

bleeding

because of aspirin. However, even in the large WHS enrolment including nearly

400

000 person-years, it has not been proven that aspirin causes cerebral bleeding.

By

contrast, in no previous aspirin study has the risk-benefit ratio of aspirin for

gastrointestinal bleeding been so clearly shown. For each stroke prevented,

three

gastrointestinal bleedings occur. For those needing transfusion, this figure is

less

than one per stroke prevented. However, stroke is a catastrophical

cardiovascular

complication and devastating for the patient, family, and society, whereas

gastrointestinal bleeding usually can be effectively treated. In this setting,

hospitalisation and blood transfusion might be psychologically difficult for a

healthy woman taking prophylactic aspirin. Importantly, in WHS there were no

fatal

excess bleedings because of aspirin use.

There have been only a few trials involving aspirin with daily doses lower than

75

mg. WHS is by far the largest trial testing a dose of 100 mg every other day or

50

mg daily. It is unlikely that the somewhat disappointing results on the

prevention

of myocardial infarction are a result of dosing, as correctly pointed out by the

WHS

authors. The 25% increased risk of gastrointestinal bleeding and 40% of minor

bleeding observed in WHS clearly indicates a strong effect of very-low-dose

aspirin

on platelet function. Also, in the few studies comparing directly two different

doses of aspirin, there was no significant evidence that a dose lower than 75 mg

is

less effective than higher doses as used in PHS.12 50 mg daily is even lower

than

the widely used European dose of 80 mg daily, which has been derived from the

anti-inflammatory dose used in sick children (known as baby aspirin). The dose

used

in WHS is even lower (termed lady aspirin) and now proven effective for

preventing

stroke in low-risk women.

Thus the WHS adds greatly to current knowledge about primary prevention of

cardiovascular disease with antiplatelet agents: a clear reduction in myocardial

infarction in women over the age of 65 of nearly the same magnitude for men in

PHS.

For the first time, WHS shows that aspirin can prevent strokes in healthy

individuals. The sex differences in the aspirin effects can be attributable to

the

age gradient for the first manifestations of cardiovascular disease, occurring

10

years earlier in men, and by the fact that women are more likely to develop

stroke

more frequently than myocardial infarction in the young low-risk age groups in

WHS.

Since many events in WHS occurred in women over the age of 65 years,

prophylactic

aspirin in women younger than 65 years should be mainly based on risk

stratification. In women at low cardiovascular risk (<1% a year), which

consisted of

97% of the WHS population, there was no benefit of aspirin in reducing

myocardial

infarction. In women younger than the age of 65 years with risk factors,

especially

hypertension,10 prophylactic aspirin should be considered, when high blood

pressure

is well treated.11

FWAV has received departmental research funds and consultancy and speaker's fees

from the manufacturers of the mentioned compounds, but declares no conflict with

the

above trials. SCS has received speaker's honoraria, travel, and accommodation

expenses from the manufacturers of the mentioned compounds

6 PM Ridker, NR Cook and IM Lee et al., A randomized trial of low-dose aspirin

in

the primary prevention of cardiovascular disease in women, N Engl J Med 352

(2005),

pp. 1293–1304. Full Text via CrossRef

8 RI Levin, Aspirin and the puzzle of sex, N Engl J Med 352 (2005), pp.

1366–1368.

Abstract-EMBASE | Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE

|

$Order Document | Full Text via CrossRef

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

__________________________________

- PC Magazine Editors' Choice 2005

http://mail.