Aspirin For Elderly Woman

new england
The
journal of medicine
established in 1812 march 31 , 2005 vol. 352 no. 13
A Randomized Trial of Low-Dose Aspirin

in the Primary Prevention of Cardiovascular Disease in Women
Paul M Ridker, M.D., Nancy R. Cook, Sc.D., I-Min Lee, M.B., B.S., David Gordon, M.A.,
J. Michael Gaziano, M.D., JoAnn E. Manson, M.D., Charles H. Hennekens, M.D., and Julie E. Buring, Sc.D.
abstract
background
Randomized trials have shown that low-dose aspirin decreases the risk of a first myo- From the Divisions of Preventive Medicine
cardial infarction in men, with little effect on the risk of ischemic stroke. There are few (P.MR., N.R.C., I-M.L., D.G., J.M.G., J.E.M.,
J.E.B.), Cardiovascular Medicine (P.MR.,
similar data in women. J.M.G.), and Aging (J.M.G., J.E.B.), Depart-
ment of Medicine, Brigham and Women's
methods Hospital, Harvard Medical School; the De-
We randomly assigned 39,876 initially healthy women 45 years of age or older to re- partment of Epidemiology, Harvard School
of Public Health (P.MR., N.R.C., I-M.L.,
ceive 100 mg of aspirin on alternate days or placebo and then monitored them for 10 J.E.M., J.E.B.); Veterans Affairs Boston
years for a first major cardiovascular event (i.e., nonfatal myocardial infarction, non- Healthcare System (J.M.G.); and the De-
fatal stroke, or death from cardiovascular causes). partment of Ambulatory Care and Preven-
tion, Harvard Medical School (J.E.B.) all
results in Boston; and the Departments of Medi-
cine and Epidemiology and Public Health,
During follow-up, 477 major cardiovascular events were confirmed in the aspirin group, University of Miami School of Medicine,
as compared with 522 in the placebo group, for a nonsignificant reduction in risk with and the Department of Biomedical Sci-
aspirin of 9 percent (relative risk, 0.91; 95 percent confidence interval, 0.80 to 1.03; ence, Center of Excellence, Florida Atlan-
tic University, Miami (C.H.H.). Address
P=0.13). With regard to individual end points, there was a 17 percent reduction in the reprint requests to Dr. Buring at the
risk of stroke in the aspirin group, as compared with the placebo group (relative risk, Division of Preventive Medicine, Brigham
0.83; 95 percent confidence interval, 0.69 to 0.99; P=0.04), owing to a 24 percent re- and Womens Hospital, 900 Common-
wealth Ave. East, Boston, MA 02215, or at
duction in the risk of ischemic stroke (relative risk, 0.76; 95 percent confidence inter- jburing@rics.bwh.harvard.edu.
val, 0.63 to 0.93; P=0.009) and a nonsignificant increase in the risk of hemorrhagic
stroke (relative risk, 1.24; 95 percent confidence interval, 0.82 to 1.87; P=0.31). As This article was published at www.nejm.org
on March 7, 2005.
compared with placebo, aspirin had no significant effect on the risk of fatal or nonfatal
myocardial infarction (relative risk, 1.02; 95 percent confidence interval, 0.84 to 1.25; N Engl J Med 2005;352:1293-304.
P=0.83) or death from cardiovascular causes (relative risk, 0.95; 95 percent confidence Copyright 2005 Massachusetts Medical Society.
interval, 0.74 to 1.22; P=0.68). Gastrointestinal bleeding requiring transfusion was

more frequent in the aspirin group than in the placebo group (relative risk, 1.40; 95
percent confidence interval, 1.07 to 1.83; P=0.02). Subgroup analyses showed that as-
pirin significantly reduced the risk of major cardiovascular events, ischemic stroke,
and myocardial infarction among women 65 years of age or older.
conclusions
In this large, primary-prevention trial among women, aspirin lowered the risk of stroke
without affecting the risk of myocardial infarction or death from cardiovascular causes,
leading to a nonsignificant finding with respect to the primary end point.
n engl j med 352;13 www.nejm.org march 31, 2005 1293
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Copyright 2005 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine
tective effect, while minimizing gastrointestinal
a lthough aspirin is effective in

the treatment of acute myocardial infarc-
tion and in the secondary prevention of
cardiovascular disease among both men and wom-
en,1 its use in primary prevention remains contro-
side effects through the use of a low dose and al-
ternate-day administration. The design of the study
has previously been described in detail.14,15 In brief,
between September 1992 and May 1995, letters of
versial. To date, five randomized trials involving invitation were mailed to more than 1.7 million fe-
55,580 participants have evaluated aspirin in the male health professionals. A total of 453,787 com-
primary prevention of cardiovascular disease.2-6 In pleted the questionnaires, with 65,169 initially will-
aggregate, these trials indicate that, as compared ing and eligible to enroll. Women were eligible if
with placebo, aspirin therapy was associated with a they were 45 years of age or older; had no history
significant, 32 percent reduction in the risk of my- of coronary heart disease, cerebrovascular disease,
ocardial infarction, but the data on the risk of stroke cancer (except nonmelanoma skin cancer), or other
and death from cardiovascular disease remain in- major chronic illness; had no history of side effects
conclusive.7 Moreover, three of these trials evaluat- to any of the study medications; were not taking as-
ed men exclusively, and fewer than 180 of the 2402 pirin or nonsteroidal antiinflammatory medications
vascular events occurred in women. Thus, at this (NSAIDs) more than once a week (or were willing
time, the current recommendations for the use of to forego their use during the trial); were not taking
aspirin in primary prevention in women are based anticoagulants or corticosteroids; and were not tak-
on limited direct data from women.8-10 ing individual supplements of vitamin A, E, or beta
Direct evidence regarding the effects of aspirin carotene more than once a week. For the purposes
in women is necessary because cardiovascular dis- of this study, inhibitors of cyclooxygenase, wheth-
ease is the leading cause of death among both wom- er selective or nonselective, were considered to be
en and men. Direct evidence is also relevant be- NSAIDs.
cause of the potential for sex-based differences in Eligible women were enrolled in a three-month
salicylate metabolism11 and continuing uncertain- run-in period of placebo administration to identify
ty regarding the cardiovascular effects of hormone- a group likely to be compliant with long-term treat-
replacement therapy.12 Moreover, in addition to a ment. A total of 39,876 women were willing, eligi-
paucity of data on women, the prophylactic use of ble, and compliant during the run-in period and un-
aspirin in both sexes has prompted concern owing derwent randomization: 19,934 were assigned to
to the potentially increased risk of hemorrhagic receive aspirin and 19,942 to receive placebo. Writ-
stroke.13 This issue is particularly complex, since ten informed consent was obtained from all partic-
the relative proportion of stroke to myocardial in- ipants. The trial was approved by the institutional
farction differs between women and men. review board of Brigham and Womens Hospital,
We addressed these questions in the Womens Boston, and was monitored by an external data and
Health Study, a large randomized, double-blind, pla- safety monitoring board.
cebo-controlled trial of low-dose aspirin in the pri- Every 12 months, the women were sent a years
mary prevention of cardiovascular disease among supply of monthly calendar packs containing ac-
39,876 apparently healthy women followed for a tive agents or placebo as well as questionnaires on
mean of 10 years for the major cardiovascular events compliance, side effects, the occurrence of relevant
of myocardial infarction, stroke, and death from car- clinical end points, and risk factors. Study medica-
diovascular causes. tions and end-point ascertainment were continued
in a blinded fashion through the scheduled end of
methods the trial (March 31, 2004). Follow-up and validation
of reported end points were completed in February
study design 2005. Rates of follow-up with respect to morbidity
The Womens Health Study is a two-by-two facto- and mortality were 97.2 percent complete and 99.4
rial trial evaluating the balance of risks and bene- percent complete, respectively.
fits of low-dose aspirin (100 mg every other day; All the women were followed for myocardial in-
Bayer HealthCare) and vitamin E (600 IU every farction, stroke, or death from cardiovascular caus-
other day; Natural Source Vitamin E Association), es. Medical records were obtained for all women in
in the primary prevention of cardiovascular disease whom a cardiovascular end point was reported to
and cancer. The trial was designed to evaluate the occur and were reviewed in a blinded fashion by
lowest dose of aspirin that would have a cardiopro- an end-points committee of physicians. Myocardial
1294 n engl j med 352;13 www.nejm.org march 31 , 2005
low-dose aspirin and cardiovascular disease in women
infarction was confirmed if symptoms met World and other randomized treatment assignments (vi-
Health Organization criteria and if the event was as- tamin E and beta carotene, which was a component
sociated with abnormal levels of cardiac enzymes or of the trial for a median of 2.1 years17). Prespecified
diagnostic electrocardiograms. A confirmed stroke subgroup analyses were performed according to
was defined as a new neurologic deficit of sudden the presence or absence of major cardiovascular
onset that persisted for at least 24 hours. Clinical in- risk factors. Modification of the effect of aspirin
formation, computed tomographic scans, and mag- by the risk factors was assessed with the use of in-
netic resonance images were used to distinguish teraction terms between subgroup indicators and
hemorrhagic from ischemic events.16 Death was aspirin assignment, with tests for trend performed
confirmed to be from cardiovascular causes on the when subgroup categories were ordinal. To exam-
basis of an examination of autopsy reports, death ine effects among women who were compliant,
certificates, medical records, and information ob- we performed a sensitivity analysis in which fol-
tained from the next of kin or other family mem- low-up data were censored at the time a woman re-
bers. The use of coronary revascularization (bypass ported having taken less than two thirds of the
surgery or percutaneous coronary angioplasty) was study medication during the previous year. In ad-
confirmed by a review of the medical records. A con- ditional analyses, data were censored on women
firmed transient ischemic attack was defined as a if and when they started taking NSAIDs more than
neurologic deficit of sudden onset that lasted for three times a month.
less than 24 hours. Death from any cause was con-
firmed by the end-points committee or on the basis results
of a death certificate. Only confirmed end points
were included in this analysis. For women with a primary analyses
reported myocardial infarction, the most common As shown in Table 1, the aspirin and placebo groups
diagnoses among those in whom the diagnosis was were similar with respect to baseline characteris-
not confirmed were stable or unstable angina or tics. The average duration of follow-up from ran-
chest pain without evidence of infarction. For wom- domization to the end of the trial was 10.1 years
en with a reported stroke, the most common alter- (range, 8.2 to 10.9). At the completion of the trial,
native diagnosis was transient cerebral ischemia. 999 women had had a first major cardiovascular
event (Table 2), for an absolute event rate of 253 per
statistical analysis 100,000 person-years. Of these women, 477 were
All primary analyses were performed on an inten- in the aspirin group and 522 were in the placebo
tion-to-treat basis. The primary end point was a group, indicating that there was a nonsignificant
combination of major cardiovascular events, in- reduction in risk of 9 percent (relative risk, 0.91; 95
cluding nonfatal myocardial infarction, nonfatal percent confidence interval, 0.80 to 1.03; P=0.13).
stroke, and death from cardiovascular causes, and Regarding individual end points, women in the
the trial was initially designed to have a statistical aspirin group had a 17 percent reduction in the risk
power of 86 percent to detect a 25 percent reduc- of stroke (relative risk, 0.83; 95 percent confidence
tion in this end point. Secondary end points includ- interval, 0.69 to 0.99; P=0.04), as compared with
ed the individual end points of fatal or nonfatal myo- women in the placebo group; a 24 percent reduction
cardial infarction, fatal or nonfatal stroke, ischemic in the risk of ischemic stroke (relative risk, 0.76; 95
stroke, hemorrhagic stroke, and death from cardio- percent confidence interval, 0.63 to 0.93; P=0.009);
vascular causes. Additional analyses included the and a nonsignificant increase in the risk of hem-
incidence of death from any cause, transient ische- orrhagic stroke (relative risk, 1.24; 95 percent con-
mic attack, and the need for coronary revascular- fidence interval, 0.82 to 1.87; P=0.31) (Table 2).
ization. If more than one end point occurred in a There was no significant difference between the
given woman, only the first event within each cate- groups in the risk of fatal stroke (relative risk in the
gory was counted; for the primary combined end aspirin group, 1.04; 95 percent confidence interval,
point, the first event in each woman was counted. 0.58 to 1.86; P=0.90), but the aspirin group had a
Cox proportional-hazards models were used to decreased risk of nonfatal strokes (relative risk,
calculate relative risks and 95 percent confidence 0.81; 95 percent confidence interval, 0.67 to 0.97;
intervals for the comparison of event rates in the as- P=0.02), as compared with the placebo group.
pirin and placebo groups after adjustment for age There was no evidence that, as compared with
Table 1. Baseline Characteristics of the Women.
Characteristic Aspirin (N=19,934) Placebo (N=19,942) Total (N=39,876)

Age
Mean SD (yr) 54.67.0 54.67.0 54.67.0
4554 yr (%) 60.2 60.2 60.2
5564 yr (%) 29.5 29.5 29.5
65 yr (%) 10.3 10.3 10.3
Smoking status (%)
Current 13.0 13.3 13.1
Past or never 87.0 86.7 86.9
Body-mass index*
Mean SD 26.15.1 26.05.0 26.05.1
<25.0 (%) 50.8 50.8 50.8
25.0 to 29.9 (%) 30.9 31.0 30.9
30.0 (%) 18.3 18.2 18.2
Menopausal status and use of HRT(%)
Premenopausal 27.5 27.6 27.6
Uncertain 17.7 18.2 18.0
Postmenopausal and current HRT 30.4 29.7 30.0
Postmenopausal and no HRT 24.4 24.4 24.4
Hypertension (%)
Yes 26.0 25.7 25.9
No 74.0 74.3 74.1
Blood pressure (%)
<120/<75 mm Hg 32.2 32.9 32.6
120129/7584 mm Hg 32.2 31.8 32.0
130139/8589 mm Hg 19.5 19.3 19.4
140/90 mm Hg 16.1 15.9 16.0
placebo, aspirin reduced the overall risk of myocar- myocardial infarction, ischemic stroke, and hem-
dial infarction (relative risk, 1.02; 95 percent con- orrhagic stroke according to the year of follow-up.
fidence interval, 0.84 to 1.25; P=0.83), fatal myo- Because it has been suggested that the ability of as-
cardial infarction (relative risk, 1.16; 95 percent pirin to inhibit platelet function diminishes over
confidence interval, 0.54 to 2.51; P=0.70), nonfa- time,18 we also evaluated incidence rates according
tal myocardial infarction (relative risk, 1.01; 95 per- to the length of follow-up. A beneficial effect of as-
cent confidence interval, 0.83 to 1.24; P=0.90), or pirin on stroke was observed early in the trial and
death from cardiovascular causes (relative risk, persisted throughout the trial, with no apparent ben-
0.95; 95 percent confidence interval, 0.74 to 1.22; efit of aspirin on myocardial infarction at any point
P=0.68). However, aspirin therapy was associated during follow-up.
with a 22 percent reduction in the risk of transient Neither treatment with vitamin E nor treatment
ischemic attack (relative risk, 0.78; 95 percent con- with beta carotene significantly modified the effect
fidence interval, 0.64 to 0.94; P=0.01), with no sig- of aspirin on the primary or secondary end points.
nificant effects on the risk of coronary revascular-
ization (relative risk, 1.04; 95 percent confidence subgroup analyses
interval, 0.90 to 1.20; P=0.61) or death from any There was no evidence that any of the cardiovas-
cause (relative risk, 0.95; 95 percent confidence in- cular risk factors considered, except smoking sta-
terval, 0.85 to 1.06; P=0.32). tus and age, modified the effect of aspirin on the
Figures 1 and 2 present the cumulative inci- primary end point of major cardiovascular events
dence rates of major cardiovascular events, stroke, (Table 3). We observed a greater benefit of aspirin
Table 1. (Continued.)
Characteristic Aspirin (N=19,934) Placebo (N=19,942) Total (N=39,876)
Hyperlipidemia (%)
Yes 29.9 29.1 29.5
No 70.1 70.9 70.5
Diabetes (%)
Yes 2.7 2.5 2.6
No 97.3 97.5 97.4
Parental history of myocardial infarction
before 60 yr of age (%)
Yes 13.0 12.9 12.9
No 87.0 87.1 87.1
10-yr risk of coronary heart disease (%)
<5.0% 84.4 84.6 84.5
5.0 to 9.9% 11.8 11.3 11.5
10.0% 3.9 4.1 4.0
No. of risk factors (%)
0 41.8 42.4 42.1
1 34.1 34.1 34.1
2 18.0 17.2 17.6
3 6.2 6.3 6.2
* The body-mass index is the weight in kilograms divided by the square of the height in meters.
HRT denotes hormone-replacement therapy.
Hypertension was defined as a systolic blood pressure of at least 140 mm Hg, a diastolic blood pressure of at least
90 mm Hg, or self-reported physician-diagnosed hypertension.
Hyperlipidemia was defined as a total cholesterol level of at least 240 mg per deciliter (6.2 mmol per liter) or self-report-
ed physician-diagnosed high cholesterol levels.
This variable was calculated with the Framingham risk score for those with blood specimens.
Risk factors were smoking, hypertension, hyperlipidemia, diabetes, and obesity.
Table 2. Incidence and Relative Risk of Confirmed Cardiovascular End Points.

Aspirin Placebo Relative Risk
End Point (N=19,934) (N=19,942) (95% CI)* P Value
no. of events
Major cardiovascular event 477 522 0.91 (0.801.03) 0.13
Stroke 221 266 0.83 (0.690.99) 0.04
Ischemic 170 221 0.76 (0.630.93) 0.009
Hemorrhagic 51 41 1.24 (0.821.87) 0.31
Fatal 23 22 1.04 (0.581.86) 0.90
Nonfatal 198 244 0.81 (0.670.97) 0.02
Myocardial infarction 198 193 1.02 (0.841.25) 0.83
Fatal 14 12 1.16 (0.542.51) 0.70
Nonfatal 184 181 1.01 (0.831.24) 0.90
Death from cardiovascular causes 120 126 0.95 (0.741.22) 0.68
Transient ischemic attack 186 238 0.78 (0.640.94) 0.01
Coronary revascularization 389 374 1.04 (0.901.20) 0.61
Death from any cause 609 642 0.95 (0.851.06) 0.32
* CI denotes confidence interval.

A major cardiovascular event was defined as a nonfatal myocardial infarction, a nonfatal stroke, or death from cardiovas-
cular causes.
sis in which follow-up data were censored at the

0.03 time a woman reported having taken less than two
Cumulative Incidence of Major Cardiovascular Events
thirds of the study medication during the preced-

Placebo ing year. In this analysis, aspirin, as compared with
placebo, reduced the risk of major cardiovascular
events by 13 percent, reduced the risk of stroke by
0.02 Aspirin 26 percent, reduced the risk of ischemic stroke by
33 percent, and had no significant effect on the risk
of myocardial infarction (relative risk, 1.03; 95 per-
cent confidence interval, 0.81 to 1.32; P=0.79).
Some women started taking NSAIDs during the
0.01
trial a potentially important issue with respect to
the risk of thrombotic events, since certain NSAIDs
P=0.13 can compete with aspirin for receptors on plate-
lets.19 According to our data, however, the lack of
an effect of aspirin therapy on the risk of myocar-
0.00
0 2 4 6 8 10 dial infarction was not explained by concomitant
Years of Follow-up use of NSAIDs.20
Figure 1. Cumulative Incidence Rates of the Primary End Point of Major Car- side effects
diovascular Events. Reports of gastrointestinal bleeding and peptic
A major cardiovascular event was defined as a nonfatal myocardial infarction, ulcer were confirmed by means of follow-up ques-
a nonfatal stroke, or death from cardiovascular causes. tionnaires. These side effects were significantly
more common among women in the aspirin group
than among women in the placebo group (Table 4).
There were 127 episodes of gastrointestinal bleed-
on the risk of major cardiovascular events among ing requiring transfusion in the aspirin group, as
former smokers and those who had never smoked, compared with 91 in the placebo group (relative risk,
with an apparent increased risk among current 1.40; 95 percent confidence interval, 1.07 to 1.83;
smokers (P for interaction <0.001), although it is P=0.02). Self-reported hematuria, easy bruising,
important to interpret this information in the con- and epistaxis were frequent among women in both
text of multiple comparisons. In addition, age sig- groups, with small but significant excesses among
nificantly modified the effect of aspirin on the risk those in the aspirin group. The percentage of wom-
of both major cardiovascular events and myocar- en reporting any symptoms suggestive of gastric up-
dial infarction (P for interaction=0.05 and 0.03, re- set was virtually identical in the two groups. There
spectively). The most consistent benefit of aspirin were five fatal gastrointestinal hemorrhages, two in
was observed among the subgroup of women 65 the aspirin group and three in the placebo group.
years of age or older at study entry; in this sub-
group, the risk of major cardiovascular events was discussion
reduced by 26 percent among those who took aspi-
rin as compared with those who took placebo (rel- In this large, placebo-controlled, primary-preven-
ative risk, 0.74; 95 percent confidence interval, 0.59 tion trial involving 39,876 initially healthy wom-
to 0.92; P=0.008), and the risk of ischemic stroke en, prophylactic aspirin at a dose of 100 mg every
was reduced by 30 percent (relative risk, 0.70; 95 other day was associated with a nonsignificant re-
percent confidence interval, 0.49 to 1.00; P=0.05). duction in the risk of major cardiovascular events,
This was also the only subgroup in which aspirin, a reduced risk of total stroke and of ischemic stroke,
as compared with placebo, significantly reduced a nonsignificant increase in the risk of hemorrhagic
the risk of myocardial infarction (relative risk, stroke, and no significant effect on the risk of my-
0.66; 95 percent confidence interval, 0.44 to 0.97; ocardial infarction or death from cardiovascular
P=0.04). causes. With respect to the primary end point of
To address whether compliance may have af- major cardiovascular events as well as the individ-
fected our results, we performed a sensitivity analy- ual end points of fatal or nonfatal stroke and my-
0.02 0.02
of Myocardial Infarction
Cumulative Incidence
Placebo
of Stroke
0.01 Aspirin Aspirin

0.01
Placebo
P=0.04 P=0.83
0.00 0.00
0 2 4 6 8 10 0 2 4 6 8 10
Years of Follow-up Years of Follow-up
0.02 0.02
of Hemorrhagic Stroke
of Ischemic Stroke
0.01 Placebo 0.01

Aspirin
P=0.31
Aspirin
P=0.009
Placebo
0.00 0.00
0 2 4 6 8 10 0 2 4 6 8 10
Years of Follow-up Years of Follow-up
Figure 2. Cumulative Incidence Rates of Stroke, Myocardial Infarction, Ischemic Stroke, and Hemorrhagic Stroke.
ocardial infarction, consistent benefits of aspirin (relative risk, 0.76; 95 percent confidence inter-
were observed among the subgroup of women val, 0.62 to 0.95; P=0.01) but had no significant
who were 65 years of age or older. We found no ev- effect on the risk of stroke (relative risk, 0.97; 95
idence that menopausal status, the use or nonuse percent confidence interval, 0.83 to 1.13; P=0.69).
of hormone-replacement therapy after menopause, In analyses stratified according to sex (Fig. 3), com-
or global cardiovascular-risk status modified the bined data on women from the Womens Health
effect of aspirin. As expected, the frequency of side Study, the Hypertension Optimal Treatment (HOT)
effects related to bleeding and ulcers was increased study,5,21 and the Primary Prevention Project6 (and
among women who received aspirin. Roncaglioni MC: personal communication) indi-
Our findings must be interpreted in the context cate that aspirin therapy was associated with a sig-
of those of other completed, randomized trials of nificant, 19 percent reduction in the risk of stroke
aspirin in the primary and secondary prevention of (relative risk, 0.81; 95 percent confidence interval,
cardiovascular disease. In secondary prevention, the 0.69 to 0.96; P=0.01), with no reduction in the risk
Antithrombotic Trialists Collaboration showed that of myocardial infarction (relative risk, 0.99; 95
aspirin clearly reduced the risk of cardiovascular percent confidence interval, 0.83 to 1.19; P=0.95).
events, myocardial infarction, and ischemic stroke By contrast, the aggregate data on men from the
in both men and women.1 To address the effects Physicians Health Study,2 the British Doctors
of aspirin in primary prevention, we performed a Trial,3 the Thrombosis Prevention Trial,4 the HOT
random-effects meta-analysis that included current study,5,21 and the Primary Prevention Project6 indi-
data from the Womens Health Study, as well as cate that aspirin therapy was associated with a sig-
data from five prior trials involving 55,580 partici- nificant, 32 percent reduction in the risk of myo-
pants with no history of heart disease.2-6,21 Over- cardial infarction (relative risk, 0.68; 95 percent
all, as compared with placebo, aspirin therapy sig- confidence interval, 0.54 to 0.86; P=0.001) and a
nificantly reduced the risk of myocardial infarction nonsignificant increase in the risk of stroke (rela-
Table 3. Incidence and Relative Risk of Cardiovascular Events, According to Baseline Characteristics.*
1300
Group Total No. Major CV Event Stroke Ischemic Stroke Myocardial Infarction
RR P RR P RR P RR P
Asp Pla (95% CI) Value Asp Pla (95% CI) Value Asp Pla (95% CI) Value Asp Pla (95% CI) Value
no. no. no. no.
Age
4554 yr 24,025 163 161 1.01 (0.811.26) 0.92 77 90 0.85 (0.631.16) 0.31 57 71 0.80 (0.571.14) 0.21 69 56 1.23 (0.871.75) 0.25
5564 yr 11,754 183 186 0.98 (0.801.20) 0.84 76 90 0.84 (0.621.14) 0.26 60 75 0.80 (0.571.12) 0.19 88 75 1.17 (0.861.59) 0.32
65 yr 4,097 131 175 0.74 (0.590.92) 0.008 68 86 0.78 (0.571.08) 0.13 53 75 0.70 (0.491.00) 0.05 41 62 0.66 (0.440.97) 0.04
Smoking status
Current 5,235 157 127 1.30 (1.031.64) 0.03 63 58 1.14 (0.801.63) 0.48 50 46 1.14 (0.761.70) 0.52 76 53 1.50 (1.062.13) 0.02
Past or never 34,605 319 392 0.80 (0.690.93) 0.003 157 207 0.75 (0.610.92) 0.006 119 174 0.67 (0.530.85) 0.001 122 139 0.87 (0.681.10) 0.25
Body-mass index
<25.0 19,849 184 223 0.82 (0.681.00) 0.05 95 126 0.75 (0.580.98) 0.04 67 97 0.69 (0.500.94) 0.02 67 73 0.92 (0.661.28) 0.63
The
25.0 to 29.9 12,081 158 175 0.89 (0.721.11) 0.31 70 84 0.83 (0.601.13) 0.24 57 72 0.78 (0.551.11) 0.16 76 68 1.11 (0.801.54) 0.52
30.0 7,126 116 111 1.05 (0.811.36) 0.72 50 53 0.96 (0.651.41) 0.81 41 49 0.85 (0.561.29) 0.44 45 46 0.98 (0.651.47) 0.91
Menopause and HRT
Premenopausal 10,973 55 63 0.88 (0.611.26) 0.47 30 31 0.97 (0.591.60) 0.91 23 23 1.01 (0.561.79) 0.98 18 26 0.69 (0.381.26) 0.23
n engl j med 352;13

Uncertain 7,149 67 75 0.91 (0.661.27) 0.59 24 43 0.57 (0.350.94) 0.03 16 35 0.47 (0.260.85) 0.01 38 26 1.49 (0.912.46) 0.11
Postmenopausal, 11,948 150 149 0.98 (0.781.23) 0.85 79 78 0.98 (0.721.34) 0.92 60 65 0.9 (0.631.27) 0.54 58 51 1.12 (0.771.63) 0.57
current HRT
Postmenopausal, 9,704 201 234 0.86 (0.711.03) 0.11 86 113 0.76 (0.571.00) 0.05 69 97 0.71 (0.520.96) 0.03 81 90 0.9 (0.671.21) 0.49
no HRT
new england journal
www.nejm.org
Hypertension
of
Yes 10,317 235 270 0.84 (0.711.00) 0.05 109 138 0.76 (0.590.98) 0.04 91 120 0.73 (0.560.96) 0.02 98 101 0.95 (0.721.25) 0.69
No 29,550 241 252 0.96 (0.8111.15) 0.69 111 128 0.88 (0.681.13) 0.31 78 101 0.78 (0.581.05) 0.10 100 92 1.10 (0.831.46) 0.52
Blood pressure
medicine
<120/<75 12,799 72 70 1.04 (0.751.45) 0.81 40 43 0.94 (0.611.45) 0.79 27 35 0.78 (0.471.29) 0.34 24 19 1.28 (0.702.34) 0.42
march 31 , 2005
mm Hg

120129/7584 12,581 107 113 0.94 (0.721.22) 0.63 51 57 0.89 (0.611.30) 0.54 37 45 0.82 (0.531.26) 0.36 43 42 1.02 (0.661.56) 0.94
mm Hg
130139/8589 7,642 131 138 0.94 (0.741.20) 0.62 47 62 0.75 (0.511.09) 0.13 36 48 0.74 (0.481.15) 0.18 66 59 1.11 (0.781.58) 0.55
mm Hg
140/90 6,295 158 190 0.81 (0.651.00) 0.05 76 101 0.73 (0.540.98) 0.04 65 90 0.7 (0.510.96) 0.03 64 68 0.92 (0.661.30) 0.65
mm Hg
Hyperlipidemia
Yes 11,745 183 227 0.80 (0.660.97) 0.02 75 119 0.62 (0.470.83) 0.001 67 98 0.68 (0.500.93) 0.01 92 88 1.03 (0.771.39) 0.82
No 28,115 294 295 0.98 (0.841.16) 0.84 146 147 0.99 (0.781.24) 0.9 103 123 0.83 (0.641.08) 0.16 106 105 1.00 (0.771.31) 0.99
Diabetes
Yes 1,027 58 62 0.9 (0.631.29) 0.57 15 31 0.46 (0.250.85) 0.01 13 29 0.42 (0.220.82) 0.01 36 24 1.48 (0.882.49) 0.14
No 38,825 418 460 0.9 (0.791.03) 0.13 206 235 0.87 (0.721.05) 0.15 157 192 0.81 (0.661.00) 0.05 162 169 0.96 (0.771.18) 0.68
Parental history of myocardial in-
farction before 60 yr of age
Yes 4,633 61 74 0.86 (0.611.21) 0.39 23 32 0.74 (0.431.26) 0.27 19 27 0.73 (0.411.31) 0.29 31 37 0.89 (0.551.43) 0.62
No 31,210 355 388 0.90 (0.781.04) 0.16 170 206 0.82 (0.671.00) 0.05 130 170 0.75 (0.600.95) 0.02 141 136 1.03 (0.811.30) 0.82
10-yr risk of CHD
<5.0% 23,331 152 175 0.86 (0.691.07) 0.17 78 97 0.80 (0.591.07) 0.13 54 76 0.70 (0.501.00) 0.05 59 59 0.99 (0.691.42) 0.94
5.0 to 9.9% 3,186 96 97 0.96 (0.721.27) 0.76 48 42 1.11 (0.741.68) 0.61 35 37 0.92 (0.581.46) 0.72 36 45 0.78 (0.501.20) 0.26
n engl j med 352;13

10.0% 1,100 61 60 1.06 (0.741.52) 0.74 17 32 0.54 (0.300.98) 0.04 16 29 0.57 (0.311.04) 0.07 32 23 1.48 (0.862.53) 0.15
No. of risk factors
0 16,399 81 95 0.86 (0.641.15) 0.31 45 53 0.86 (0.581.28) 0.46 31 41 0.76 (0.481.22) 0.26 26 29 0.90 (0.531.53) 0.70
1 13,291 151 162 0.92 (0.731.14) 0.44 75 84 0.88 (0.641.20) 0.42 50 70 0.70 (0.491.01) 0.06 58 61 0.94 (0.651.34) 0.73
www.nejm.org
2 6,860 128 156 0.80 (0.631.01) 0.06 57 79 0.70 (0.500.98) 0.04 49 65 0.73 (0.501.06) 0.10 54 56 0.94 (0.641.36) 0.73
3 2,428 96 93 1.07 (0.801.42) 0.66 37 46 0.83 (0.541.28) 0.40 34 41 0.86 (0.541.35) 0.51 50 40 1.30 (0.861.98) 0.21
* A major cardiovascular (CV) event was defined as a nonfatal myocardial infarction, a nonfatal stroke, or death from cardiovascular causes. The total number of cardiovascular events may
not sum to 39,876 owing to missing data for some variables. Asp denotes aspirin, Pla placebo, no. number of women, RR relative risk, CI confidence interval, HRT hormone-replacement
march 31, 2005

therapy, and CHD coronary heart disease.
The body-mass index is the weight in kilograms divided by the square of the height in meters.
Hypertension was defined as a systolic blood pressure of at least 140 mm Hg, a diastolic blood pressure of at least 90 mm Hg, or as self-reported physician-diagnosed hypertension.
Hyperlipidemia was defined as a total cholesterol level of at least 240 mg per deciliter or as self-reported physician-diagnosed high cholesterol levels.
This variable was calculated with the Framingham risk score for those with blood specimens (28,345 women).
Risk factors were smoking, hypertension, hyperlipidemia, diabetes, and obesity.

1301
Table 4. Incidence and Relative Risk of Side Effects.*

Aspirin Placebo Relative Risk
Side Effect (N=19,934) (N=19,942) (95% CI) P Value
no. of events (%)
Gastrointestinal bleeding
Any 910 (4.6) 751 (3.8) 1.22 (1.101.34) <0.001
Requiring transfusion 127 (0.6) 91 (0.5) 1.40 (1.071.83) 0.02
Peptic ulcer 542 (2.7) 413 (2.1) 1.32 (1.161.50) <0.001
Hematuria 3,039 (15.2) 2,879 (14.4) 1.06 (1.011.12) 0.02
Easy bruising 10,561 (53.0) 8,494 (42.6) 1.40 (1.371.45) <0.001
Epistaxis 3,801 (19.1) 3,321 (16.7) 1.16 (1.111.22) <0.001
Any report of gastric upset 11,856 (59.5) 11,915 (59.7) 0.99 (0.971.02) 0.59
* The presence of gastrointestinal bleeding or peptic ulcer was confirmed by a specific follow-up questionnaire. CI denotes
confidence interval.
tive risk, 1.13; 95 percent confidence interval, 0.96 also believe it unlikely that a reduction in the effica-
to 1.33; P=0.15). The differences between men cy of aspirin over time is a viable explanation, since
and women were significant at the P=0.01 level for the cumulative incidence data presented in Figures
myocardial infarction and at the P=0.005 level for 1 and 2 offer no support for this hypothesis. Fur-
stroke. thermore, suboptimal compliance is an unlikely ex-
The reasons for any sex-based differences in the planation, since aspirin did not decrease the risk
efficacy of aspirin for primary prevention are un- of myocardial infarction among women with high
clear and require further exploration. Although the rates of compliance an observation again in con-
observed reductions in the risk of stroke could be trast to data on stroke among the same women.
due to chance, the reduced risk of transient ische- With regard to daily clinical practice, our data
mic attack associated with aspirin therapy adds demonstrate that aspirin therapy was associated
support to the possibility of a causal interpretation. with a net reduction in the risk of stroke among
We cannot rule out the possibility that our null find- women, with a reduction in the risk of the far more
ing for the risk of myocardial infarction in women common ischemic stroke and an increase in the risk
was due to an insufficient dose of aspirin or to the of hemorrhagic stroke. This observation is partic-
alternate-day regimen. However, we believe these ularly relevant, since as compared with men, wom-
explanations to be unlikely for three reasons. en have a relatively greater proportion of strokes
First, we have previously shown that the dose than of myocardial infarctions. Among women in
of 100 mg every other day used in the Womens the placebo group, there were more strokes than
Health Study reduces thromboxane levels by 93 per- myocardial infarctions (266 vs. 193), and thus, the
cent and prostacyclin levels by 85 percent and that ratio of incident strokes to incident myocardial in-
these effects are similar in men and women.22 Sec- farctions was 1.4:1, as compared with the ratio of
ond, in the HOT study, a 75-mg daily dose of aspi- 0.4:1 among men in the Physicians Health Study.2
rin significantly lowered the risk of myocardial in- From a policy perspective, our findings clearly dem-
farction overall, with a 42 percent reduction in the onstrate the importance of studying women as well
risk among men but a far smaller and nonsignifi- as men in major cardiovascular clinical trials.
cant reduction among women.21 Third, since the An interesting finding in our subgroup analyses
dose and alternate-day regimen of aspirin used in was that the most consistent benefit of aspirin was
our study were adequate to lower the risk of stroke, observed among women 65 years of age or older.
it is unlikely that any hypothesized sex-based dif- This group of 4097 women composed 10 percent
ferences in the resistance to aspirin were at play of the study population yet had almost one third
overall. However, resistance to aspirin may be more of the cardiovascular events. In this group, aspirin
prevalent among smokers,23 and this resistance use, as compared with placebo use, led to 44 few-
may have played some role in the increased risk er myocardial infarctions, strokes, or deaths from
with aspirin observed among current smokers. We cardiovascular causes (P=0.008) but to 16 more
Trial Relative Risk of Myocardial Infarction Trial Relative Risk of Stroke among Men
among Men
BDT, 1988 BDT, 1988
PHS, 1989 PHS, 1989
TPT, 1998 TPT, 1998
HOT, 1998 HOT, 1998
PPP, 2001 PPP, 2001

RR=0.68 (0.540.86) RR=1.13 (0.961.33)
P=0.001 P=0.15
Combined Combined
0.2 0.5 1.0 2.0 5.0 0.2 0.5 1.0 2.0 5.0
Aspirin Better Placebo Better Aspirin Better Placebo Better
Trial Relative Risk of Myocardial Infarction Trial Relative Risk of Stroke among Women
among Women
HOT, 1998 HOT, 1998
PPP, 2001 PPP, 2001
WHS, 2005 WHS, 2005
RR=0.99 (0.831.19) RR=0.81 (0.690.96)

P=0.95 P=0.01
Combined Combined
0.2 0.5 1.0 2.0 5.0 0.2 0.5 1.0 2.0 5.0
Aspirin Better Placebo Better Aspirin Better Placebo Better
Figure 3. Aspirin in the Primary Prevention of Myocardial Infarction and Stroke among Men and Women.
The results of a sex-specific random-effects meta-analysis of data from six trials are shown: the British Doctors Trial
(BDT), the Physicians Health Study (PHS), the Thrombosis Prevention Trial (TPT), the Hypertension Optimal Treatment
(HOT) study, the Primary Prevention Project (PPP), and the current Womens Health Study (WHS). The relative risk (RR)
and 95 percent confidence interval (in parentheses) are shown for each trial (indicated by the box and horizontal line
through each box, respectively), and the relative risk is shown for the combined results (indicated by the diamond and
the dashed line in each graph). For the relative risk of myocardial infarction among women, the dashed line is coincident
with the solid line at 1.00. The size of the box is proportional to the amount of information in the corresponding trial.
gastrointestinal hemorrhages requiring transfu- woman consults her physician or health care pro-
sion (P=0.05), emphasizing, as with any agent, the vider, so that the net absolute benefits and risks for
importance of balancing benefits and risks. This the individual patient can be ascertained.
age-based difference deserves further investigation. Supported by grants (HL-43851 and CA-47988) from the Nation-
With respect to guidelines in primary preven- al Heart, Lung, and Blood Institute and the National Cancer Insti-
tute, Bethesda, Md. Aspirin and aspirin placebo were provided by
tion, in 2002, the Preventive Services Task Force24 Bayer HealthCare. Vitamin E and vitamin E placebo were provided
and the American Heart Association9 recommend- by the Natural Source Vitamin E Association.
ed aspirin for adults whose 10-year risks of a first Dr. Ridker reports having received grant support from Bayer. Dr.
Cook reports having served as a consultant to Bayer. Dr. Gaziano re-
coronary-heart-disease event were at least 6 percent ports having served as a consultant to, and receiving grant support
and 10 percent, respectively. However, this may be from, Bayer and McNeil. Dr. Hennekens reports having served as a
complex for women, since in our study overall, as- consultant to Bayer and McNeil and receiving grant support from
Bayer.
pirin lowered the risk of stroke without affecting We are indebted to the 39,876 participants in the Womens Health
the risk of myocardial infarction or death from car- Study for their dedicated and conscientious collaboration; to the en-
diovascular causes. Thus, as with men, any decision tire staff of the Womens Health Study, under the leadership of Da-
vid Gordon, Maria Andrade, Susan Burt, Mary Breen, Marilyn Chown,
about the use of aspirin in primary prevention Lisa Fields-Johnson, Georgina Friedenberg, Inge Judge, Jean Mac-
among women must ultimately be made after a Fadyen, Geneva McNair, Laura Pestana, David Potter, Philomena
Quinn, Claire Ridge, Fred Schwerin, and Harriet Samuelson; to Pradhan, Kathryn Rexrode, Bernard Rosner, and H. Jacqueline Suk
Christine Albert, Michelle Albert, Gavin Blake, Claudia Chae, Wendy for their assistance in the design and conduct of the trial; and espe-
Chen, Richard Doll, Carlos Kase, Tobias Kurth, Richard Peto, Aruna cially to James Taylor for chairing the end-points committee.
appendix
Members of the data and safety monitoring board included L. Cohen, R. Collins, T. Colton, D. DeMets, I.C. Henderson, A. La Croix, R. Pren-
tice, and N. Wenger (chair) and M.F. Cotch, F. Ferris, L. Friedman, P. Greenwald, N. Kurinij, M. Perloff, E. Schron, and A. Zonderman (ex of-
ficio members).
references
1. Antithrombotic Trialists Collaboration. cardiovascular events: a summary of the evi- tation and incidence of cancer and cardio-
Collaborative meta-analysis of randomised dence for the U.S. Preventive Services Task vascular disease: the Womens Health Study.
trials of antiplatelet therapy for prevention Force. Ann Intern Med 2002;136:161-72. J Natl Cancer Inst 1999;91:2102-6.
of death, myocardial infarction, and stroke 9. Pearson TA, Blair SN, Daniels SR, et al. 18. Pulcinelli FM, Pignatelli P, Celestini A,
in high risk patients. BMJ 2002;324:71-86. AHA guidelines for primary prevention of Riondino S, Gazzaniga PP, Violi F. Inhibi-
[Erratum, BMJ 2002;324:141.] cardiovascular disease and stroke: 2002 up- tion of platelet aggregation by aspirin pro-
2. Steering Committee of the Physicians date: consensus panel guide to comprehen- gressively decreases in long-term treated pa-
Health Study Research Group. Final report sive risk reduction for adult patients without tients. J Am Coll Cardiol 2004;43:979-84.
on the aspirin component of the ongoing coronary or other atherosclerotic vascular 19. Catella-Lawson F, Reilly MP, Kapoor SC,
Physicians Health Study. N Engl J Med 1989; diseases. Circulation 2002;106:388-91. et al. Cyclooxygenase inhibitors and the an-
321:129-35. 10. Mosca L, Appel LJ, Benjamin EJ, et al. tiplatelet effects of aspirin. N Engl J Med
3. Peto R, Gray R, Collins R, et al. Ran- Evidence-based guidelines for cardiovascu- 2001;345:1809-17.
domised trial of prophylactic daily aspirin in lar disease prevention in women. Circulation 20. Kurth T, Glynn RJ, Walker AM, et al. In-
British male doctors. Br Med J (Clin Res Ed) 2004;109:672-93. hibition of clinical benefits of aspirin on
1988;296:313-6. 11. Montgomery PR, Berger LG, Mitenko first myocardial infarction by nonsteroidal
4. The Medical Research Councils Gener- PA, Sitar DS. Salicylate metabolism: effects antiinflammatory drugs. Circulation 2003;
al Practice Research Framework. Thrombo- of age and sex in adults. Clin Pharmacol Ther 108:1191-5.
sis prevention trial: randomised trial of low- 1986;39:571-6. 21. Kjeldsen SE, Kolloch RE, Leonetti G, et
intensity oral anticoagulation with warfarin 12. Manson JE, Hsia J, Johnson KC, et al. Es- al. Influence of gender and age on prevent-
and low-dose aspirin in the primary preven- trogen plus progestin and the risk of coro- ing cardiovascular disease by antihyperten-
tion of ischaemic heart disease in men at in- nary heart disease. N Engl J Med 2003;349: sive treatment and acetylsalicylic acid: the
creased risk. Lancet 1998;351:233-41. 523-34. HOT study. J Hypertens 2000;18:629-42.
5. Hansson L, Zanchetti A, Carruthers SG, 13. Rodondi N, Bauer DC. Assessing the risk/ 22. Ridker PM, Hennekens CH, Tofler GH,
et al. Effects of intensive blood-pressure low- benefit profile before recommending aspi- Lipinska I, Buring JE. Anti-platelet effects of
ering and low-dose aspirin in patients with rin for the primary prevention of cardiovas- 100 mg alternate day oral aspirin: a random-
hypertension: principal results of the Hyper- cular events. Am J Med 2004;117:528-30. ized, double-blind, placebo-controlled trial
tension Optimal Treatment (HOT) random- 14. Buring JE, Hennekens CH. The Wom- of regular and enteric coated formulations
ised trial. Lancet 1998;351:1755-62. ens Health Study: summary of the study de- in men and women. J Cardiovasc Risk 1996;
6. Collaborative Group of the Primary Pre- sign. J Myocardial Ischemia 1992;4:27-9. 3:209-12.
vention Project. Low-dose aspirin and vita- 15. Rexrode KM, Lee IM, Cook NR, Henne- 23. Sanderson S, Emery J, Baglin T, Kin-
min E in people at cardiovascular risk: kens CH, Buring JE. Baseline characteristics month A-L. Narrative review: aspirin resis-
a randomised trial in general practice. Lan- of participants in the Womens Health Study. tance and its clinical implications. Ann In-
cet 2001;357:89-95. [Erratum, Lancet 2001; J Womens Health Gend Based Med 2000;9: tern Med 2005;142:370-80.
357:1134.] 19-27. 24. Preventive Services Task Force. Aspirin
7. Eidelman RS, Hebert PR, Weisman SE, 16. Atiya M, Kurth T, Berger K, Buring JE, for the primary prevention of cardiovascular
Hennekens CH. An update on aspirin in the Kase CS. Interobserver agreement in the clas- events: recommendation and rationale. Ann
primary prevention of cardiovascular dis- sification of stroke in the Womens Health Intern Med 2002;136:157-60.
ease. Arch Intern Med 2003;163:2006-10. Study. Stroke 2003;34:565-7. Copyright 2005 Massachusetts Medical Society.
8. Hayden M, Pignone M, Phillips C, Mul- 17. Lee I-M, Cook NR, Manson JE, Buring
row C. Aspirin for the primary prevention of JE, Hennekens CH. b-Carotene supplemen-
clinical problem-solving series

The Journal welcomes submissions of manuscripts for the Clinical Problem-Solving
series. This regular feature considers the step-by-step process of clinical decision
making. For more information, please see http://authors.nejm.org.
- 6 - PL Journal Club April 2005 PL Journal Club April 2005 - 7 -
The following succinct analysis appeared in Prescribers Letter. Analysis of new study
CARDIOLOGY 3. What type of study was this and how were patients selected?
New research suggests that aspirin has different effects in women Randomized, double-blind, placebo-controlled trial.
than in men for preventing first MIs and strokes. Patients received aspirin 100 mg every OTHER day or placebo for an average follow-up of ten years.
In men, aspirin reduces the risk of a first MI...but is less Patients selected were female health professionals who responded to mailed questionnaires. Women
effective for preventing ischemic stroke. were eligible if they were at least 45 years of age, and had no history of cardiovascular disease, cancer,
The opposite seems to be true for women. or other chronic illness. They also could not have sensitivity to aspirin.
In women, aspirin reduces the risk of ischemic stroke...but only
A 3-month run-in period allowed the investigators to determine which patients would be compliant
women 65 and older seem to benefit from fewer MIs.
But its not clear why a gender difference is seen. with the study protocol. Each year, patients received a years supply of medication in blister packs.
Its probably because healthy women under age 65 have a low The blinded endpoints committee adjudicated all cases of myocardial infarction, stroke, or death from
cardiac risk already. They may not need aspirins cardiac benefits. cardiovascular causes. Medical records were evaluated to confirm these cases.
Use aspirin for patients with a 10% or greater Framingham risk of The primary endpoint included non-fatal myocardial infarction, non-fatal stroke, and death from
cardiovascular disease. You can calculate risk based on age, gender, cardiovascular causes.
cholesterol, BP, and smoking status. Secondary endpoints included these same individual endpoints as well as hemorrhagic stroke, transient
Go to our Detail-Document for a link to a risk calculator. ischemic attack, the need for coronary revascularization, and total mortality. Adverse event rates were
Also continue to give aspirin to patients who have already had an also collected, and included gastrointestinal hemorrhage, hematuria, epistaxis, and easy bruising.
MI or stroke. Aspirin is beneficial for secondary prevention in both
men and women. 4. How were the study groups defined?
The Heart Assoc recommends 75 mg to 162 mg aspirin per day. If you
give 81 mg/day youll be using the same dose as mostexperts.
39,876 women were randomized.
(For more on this topic see Detail-Document #210409 at www.prescribersletter.com.)
60% were between the ages of 45 and 54 years, 29% were between 55 and 64 years, and 10% were
Primary Reference Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention greater than 65 at baseline.
of cardiovascular disease in women. N Engl J Med Published online 03/07/05; doi:10.1056/NEJMoa050613. 13% were current smokers; half the patients had a body mass index less than 25 kg/m2. 26% had
hypertension at baseline, and 27% were pre-menopausal. It should be noted that only about 2.5% of the
Discussion Questions patients were diabetic at baseline, 13% had a parental history of premature CHD, and 84% had a 10-
year risk of heart disease of less than 5%.
Overview of current therapy
Table 1 provides additional demographic and subgroup characteristics within the study cohort. Because
1. Why is low-dose aspirin recommended less often for reducing cardiovascular risk in of the considerable size of the trial, the baseline characteristics were very evenly matched between the
study groups.
women?
The U.S. Preventive Services Task Force and American Heart Association recommend low-dose aspirin for 5. What are the strengths of this trial?
adults who have a 10-year risk of coronary heart disease of at least 6% and 10%, respectively. However, of
the 5 large-scale PRIMARY prevention trials that have been done, 3 involved ONLY men. Fewer than 10% This trial was well-designed to examine aspirin for PRIMARY prevention of cardiovascular disease.
of the total number of vascular events that occurred in these trials were in women. It is clear that more data Cardiovascular events were well-defined and adjudicated by chart review.
are needed on the use of aspirin for PRIMARY prevention of cardiovascular disease in women. The primary analysis was done by the intention-to-treat principle.
The rates of follow-up with regard to morbidity and mortality were extremely high (>97%).
2. What factors may influence the efficacy of aspirin in women? A sensitivity analysis was performed to investigate whether compliance with the medication regimen
affected the results.
From large amounts of epidemiological data, we know that:
Women have a lower risk of cardiovascular disease than men. 6. How did the drugs work in this trial?
Pre-menopausal women have a substantially lower rate of cardiovascular disease than post-menopausal
women. After an average of 10.1 years of follow-up, 999 women had a cardiovascular event. This translates to
Other factors that influence cardiovascular disease include the presence of hypertension, obesity, an absolute event rate of 253 per 100,000 person years.
dyslipidemia, diabetes, family history of cardiovascular disease, and smoking status. The event rate in the placebo group (a good indicator of how sick the patient population was) over the
10-year study was 2.6%. There was a 9% reduction in the risk of this composite endpoint (95%
Because women have lower rates of cardiovascular disease than men, PRIMARY prevention studies need to confidence interval 0.80-1.03; p=0.13).
be very large and must have a long duration of follow-up. Large studies allow for detailed analysis of For secondary endpoints in the aspirin group, there was a 17% reduction in the risk of stroke (NNT =
demographic characteristics and other population sub-groups. 500), and a 24% reduction in the risk of ischemic stroke (NNT = 404, both p<0.05). There was no
significant difference in the number of fatal strokes; however, the aspirin group had fewer non-fatal
strokes (RR=0.81; 95% confidence interval 0.67 to 0.97; p=0.02). There was no difference in the risk
of total myocardial infarctions or death from cardiovascular causes. Aspirin did reduce the risk of
LEADER NOTES LEADER NOTES

The following succinct analysis appeared in Prescribers Letter. Analysis of new study
CARDIOLOGY 3. What type of study was this and how were patients selected?
New research suggests that aspirin has different effects in women Randomized, double-blind, placebo-controlled trial.
than in men for preventing first MIs and strokes. Patients received aspirin 100 mg every OTHER day or placebo for an average follow-up of ten years.
In men, aspirin reduces the risk of a first MI...but is less Patients selected were female health professionals who responded to mailed questionnaires. Women
effective for preventing ischemic stroke. were eligible if they were at least 45 years of age, and had no history of cardiovascular disease, cancer,
The opposite seems to be true for women. or other chronic illness. They also could not have sensitivity to aspirin.
In women, aspirin reduces the risk of ischemic stroke...but only
A 3-month run-in period allowed the investigators to determine which patients would be compliant
women 65 and older seem to benefit from fewer MIs.
But its not clear why a gender difference is seen. with the study protocol. Each year, patients received a years supply of medication in blister packs.
Its probably because healthy women under age 65 have a low The blinded endpoints committee adjudicated all cases of myocardial infarction, stroke, or death from
cardiac risk already. They may not need aspirins cardiac benefits. cardiovascular causes. Medical records were evaluated to confirm these cases.
Use aspirin for patients with a 10% or greater Framingham risk of The primary endpoint included non-fatal myocardial infarction, non-fatal stroke, and death from
cardiovascular disease. You can calculate risk based on age, gender, cardiovascular causes.
cholesterol, BP, and smoking status. Secondary endpoints included these same individual endpoints as well as hemorrhagic stroke, transient
Go to our Detail-Document for a link to a risk calculator. ischemic attack, the need for coronary revascularization, and total mortality. Adverse event rates were
Also continue to give aspirin to patients who have already had an also collected, and included gastrointestinal hemorrhage, hematuria, epistaxis, and easy bruising.
MI or stroke. Aspirin is beneficial for secondary prevention in both
men and women. 4. How were the study groups defined?
The Heart Assoc recommends 75 mg to 162 mg aspirin per day. If you
give 81 mg/day youll be using the same dose as mostexperts.
39,876 women were randomized.
(For more on this topic see Detail-Document #210409 at www.prescribersletter.com.)
60% were between the ages of 45 and 54 years, 29% were between 55 and 64 years, and 10% were
Primary Reference Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention greater than 65 at baseline.
of cardiovascular disease in women. N Engl J Med Published online 03/07/05; doi:10.1056/NEJMoa050613. 13% were current smokers; half the patients had a body mass index less than 25 kg/m2. 26% had
hypertension at baseline, and 27% were pre-menopausal. It should be noted that only about 2.5% of the
Discussion Questions patients were diabetic at baseline, 13% had a parental history of premature CHD, and 84% had a 10-
year risk of heart disease of less than 5%.
Overview of current therapy
Table 1 provides additional demographic and subgroup characteristics within the study cohort. Because
1. Why is low-dose aspirin recommended less often for reducing cardiovascular risk in of the considerable size of the trial, the baseline characteristics were very evenly matched between the
study groups.
women?
The U.S. Preventive Services Task Force and American Heart Association recommend low-dose aspirin for 5. What are the strengths of this trial?
adults who have a 10-year risk of coronary heart disease of at least 6% and 10%, respectively. However, of
the 5 large-scale PRIMARY prevention trials that have been done, 3 involved ONLY men. Fewer than 10% This trial was well-designed to examine aspirin for PRIMARY prevention of cardiovascular disease.
of the total number of vascular events that occurred in these trials were in women. It is clear that more data Cardiovascular events were well-defined and adjudicated by chart review.
are needed on the use of aspirin for PRIMARY prevention of cardiovascular disease in women. The primary analysis was done by the intention-to-treat principle.
The rates of follow-up with regard to morbidity and mortality were extremely high (>97%).
2. What factors may influence the efficacy of aspirin in women? A sensitivity analysis was performed to investigate whether compliance with the medication regimen
affected the results.
From large amounts of epidemiological data, we know that:
Women have a lower risk of cardiovascular disease than men. 6. How did the drugs work in this trial?
Pre-menopausal women have a substantially lower rate of cardiovascular disease than post-menopausal
women. After an average of 10.1 years of follow-up, 999 women had a cardiovascular event. This translates to
Other factors that influence cardiovascular disease include the presence of hypertension, obesity, an absolute event rate of 253 per 100,000 person years.
dyslipidemia, diabetes, family history of cardiovascular disease, and smoking status. The event rate in the placebo group (a good indicator of how sick the patient population was) over the
10-year study was 2.6%. There was a 9% reduction in the risk of this composite endpoint (95%
Because women have lower rates of cardiovascular disease than men, PRIMARY prevention studies need to confidence interval 0.80-1.03; p=0.13).
be very large and must have a long duration of follow-up. Large studies allow for detailed analysis of For secondary endpoints in the aspirin group, there was a 17% reduction in the risk of stroke (NNT =
demographic characteristics and other population sub-groups. 500), and a 24% reduction in the risk of ischemic stroke (NNT = 404, both p<0.05). There was no
significant difference in the number of fatal strokes; however, the aspirin group had fewer non-fatal
strokes (RR=0.81; 95% confidence interval 0.67 to 0.97; p=0.02). There was no difference in the risk
of total myocardial infarctions or death from cardiovascular causes. Aspirin did reduce the risk of

transient ischemic attack by 22% (p=0.01). Aspirin did not affect the risk of coronary revascularization,
Apply the new findings to the following case
nor did it impact total mortality.
You get back positive results for chlamydia or gonorrhea on an almost weekly basis, and are frustrated that
7. Were there any interesting results in the subgroup analyses? many of the patients whom you treat quickly get re-infected. You ask your patients to tell all their sexual
contacts to come in for a check-up and treatment if necessary, but theres not enough time to track down each
Only smoking status and age influenced the primary endpoint. Aspirin appeared to provide a greater partner. At a recent staff meeting one of your colleagues suggested the clinic try a new approach, called
benefit to patients who had never smoked and former smokers in comparison to current smokers. It PDPT, and give patients extra antibiotic doses to give directly to all their partners.
appears that aspirin was actually detrimental among women who currently smoked. However, since this
was a subgroup analysis, it can only be used to derive a hypothesis. To accept this association, another 12. How great is the disease burden for Chlamydia trachomatis and Neisseria gonorrhoeae?
study would be required (e.g., randomize smokers to aspirin therapy or no aspirin therapy).
With regard to age, women who were greater than 65 had a more substantial benefit across the board Each year approximately 3 million Americans are infected with chlamydia. Chlamydia is the most
with aspirin therapy. In this sub-group there was a significant 34% reduction in risk of myocardial common bacterial STD in the U.S.
infarction, a 30% reduction in ischemic stroke, and a 26% reduction in the composite endpoint of Women are frequently re-infected if their sex partners are not treated. In adolescent girls the prevalence
major cardiovascular events. may approach 15%.
Among women with hypertension (n=10,317), aspirin use was associated with a 16% reduction in Infections can be asymptomatic. Up to 40% of women with untreated chlamydia will develop pelvic
major cardiovascular events. Aspirin also appeared to reduce the risk of major cardiovascular events in inflammatory disease (PID), which in turn can lead to chronic pelvic pain, infertility, an increased risk
women with hyperlipidemia at baseline. of ectopic pregnancies, and increased risk of HIV infection if exposed.
There was no influence of aspirin therapy on the risk of cardiovascular disease when women were Gonorrhea affects an estimated 650,000 patients annually in the U.S., second only to chlamydia. The
stratified by their 10-year risk of coronary heart disease. It should be noted, however, that the number number of reported cases has declined over past decades, especially among older, white populations.
of patients with a 10-year risk of CHD greater than 5% was relatively small in this trial. Adolescents and minority populations have the highest infection rates.
Untreated gonorrhea can lead to cervicitis, urethritis, proctitis, and PID.
8. Were there any design issues that might create bias or influence results?
Annual screenings are recommended for:
The study was conducted in relatively YOUNG patients with NO history of cardiovascular disease. For All sexually active women age 25 years and younger
example, the placebo event rate for myocardial infarction was less than 1% and the combined endpoint Older women with risk factors (new or multiple sex partners, previous STD, inconsistent use of barrier
of major cardiovascular events was approximately 2.6% over the 10-year period. This raises the point contraceptives
of spectrum bias. These were healthy patients with a low prior risk and thus not likely to benefit from All pregnant women
medication. Giving aspirin to patients on the other side of the spectrum (those with a 10 year risk
greater than 10%) would likely have shown a benefit. Spectrum bias is an element of external validity. 13. Are there legal risks to PDPT?
Just as with any bias, it should be examined before determining external validity.
The study was conducted in HEALTH PROFESSIONALS. These patients may be more likely to be Yes. Many states have laws requiring a provider see a patient before prescribing medications, or to have seen
more concerned about their health, eat right, and exercise compared to the general population. the patient sometime in the past. These laws were in part motivated to limit internet prescribing, but they may
In the past, it has been thought that aspirins ability to provide antiplatelet activity may decrease over also apply to PDPT. Some states, such as California, Washington, and Tennessee, have passed laws that
time. This study debunked this issue to some extent by demonstrating that the beneficial effects of allow for PDPT and provide some protection for providers. However, there is little case law. Even with such
aspirin on stroke occurred EARLY on and CONTINUED through the study, per the investigators. state laws, providers have legal exposure for adverse outcomes resulting from PDPT. NOTE: Please check
The aspirin DOSE utilized in this study was atypical. Most clinicians prescribe low-dose daily aspirin with your state health department to find out if PDPT has been addressed.
(81 mg/day) in either PRIMARY or SECONDARY prevention. Theoretically, there is a concern that a
100 mg dose every OTHER day was too low to positively influence the myocardial infarction endpoint. 14. Are there any guidelines on the use of PDPT?
However, as the authors state, 100 mg has been shown to have significant antiplatelet affects.
Yes. CDC suggests that PDPT has the potential to considerably expand the role of practitioners in the
9. Were the results expressed in terms we can understand and can explain to patients? control of STDs. CDC is meeting this month (April 2005) and hopes to update guidelines for 2006.
AMA House of Delegates passed a resolution in support of PDPT.
Yes. In women over the age of 45 with no prior history of cardiovascular disease, we can expect that American College of Preventive Medicine has a policy statement in support of PDPT.
for every 500 patients treated with aspirin for 10 years we would prevent one stroke. This is a relatively See Prescribers Letter Detail-Document #210404 for examples from California and Tennessee. We
small impact. Aspirin therapy would not be expected to influence the development of myocardial have also created a patient handout for you to give to patients to take to their partners along with the
infarction, coronary revascularization, or death from any cause. It would reduce the risk of TIA. medication. It explains the risks, benefits, and importance of taking the medication.
Subgroup analyses may help to better define the patients that we would expect to get a greater benefit
from aspirin. This includes those with pre-existing hypertension (NNT for major CV event = 166). In 15. Would you use PDPT in selected patients? How many would NEVER use it? Are the
those patients with hyperlipidemia, the NNT for preventing one new cardiovascular event over a 10- potential benefits worth the medical and legal risks?
year period is approximately 125. The number needed to harm for a major GI bleed (i.e., one requiring
transfusion) is approximately 1000 over a 10-year period.
For women over 65, aspirins benefit was more consistent. This is primarily because this age group is
For more content and to see comments from other PL Journal Clubs on this topic go to
at greater risk for cardiovascular disease. As the investigators point out, women over 65 made up only
10% of the study population, yet about 30% of the cardiovascular events occurred in this subgroup. www.prescribersletter.com - click on PL Journal Club - click on DISCUSSION FORUM.
Older women also appear to be at greater risk for GI bleeding. Youll be able to pose your questions to the study author, Dr. Matthew Golden.

intercourse after initial treatment, 3% of patients with gonorrhea and 8% of patients with chlamydia had How should the new findings change current therapy?
persistent infections at follow-up. These treatment failures were limited to women. No males tested positive
at follow-up. An increased risk of persistent or recurrent STD was associated with 1) a greater number of sex 10. Are the patients studied similar to those you see in clinic?
partners since treatment and 2) re-exposure to a sex partner believed to have other partners.
The patients were similar to those you might see in primary care. However, it should be noted that the women
7. What adverse effects were reported? included in the womens health study were all health professionals and may be more motivated to a healthy
lifestyle than the typical patients seen in primary care. This might minimize aspirins benefit.
No drug-related adverse effects were reported. Previous studies have also demonstrated no adverse drug
reactions with similar regimens. However, because the partners were never evaluated or followed-up, the 11. Do the results force you to change your practice? How?
actual adverse event rate is unknown. In addition, nearly 1/3 of the index cases were not followed-up. This
reduces the ability to detect uncommon or rare adverse events. Perhaps. Low-dose aspirin would be expected to provide a small but statistically significant reduction in the
risk of ischemic stroke in women over the age of 45. The magnitude of this benefit is small. In women over
8. Were there any other study design issues that might create bias or influence results? the age of 65, aspirin administered at 100 mg every OTHER day is associated with a more significant
reduction in the risk of myocardial infarction, ischemic stroke, and other related cardiovascular disease.
The study was done in a very select population. Only about 1/3 of presenting STD patients were Patients should be monitored for GI hemorrhage, hematuria, and epistaxis.
enrolled in the trial. This limits the external validity, and thus generalizability, of the findings.
However, the subjects are still quite representative of the population as a whole. Apply the new findings to the following case
About 32% of subjects were lost to follow-up. But, the number of patients completing the study was
very similar in the two groups. With this many patients lost to follow-up there is a chance that rare JB is a generally healthy, 57 year-old female who scheduled an appointment with you to discuss a newspaper
adverse events or complications may go undetected. We should note, however, that even with the loss article she recently read in USA Today entitled Aspirin lessens womens strokes. JB states that her husband
to follow-up, there were enough patients in each group to demonstrate a difference in the two groups if takes aspirin 81 mg daily to prevent heart attacks, and asks if she should be taking it too. JB asks if you read
it existed; the study still had adequate power to find a difference. USA Today because the publication often has good health information in it. The article is also online.
Its not known what STDs were present in partners of the index cases. The drug efficacy in these
partners is also unknown. Clearly, these patients had multiple partners before, and likely after, 12. Is there a difference between mass media reports of scientific meetings and research
treatment. This broad exposure may complicate the efficacy data. In addition, up to 3 partners were publications?
treated; if index cases had more than 3 partners, how might this influence the data?
PDPT results in a lost opportunity to educate partners and evaluate them for other STDs (HIV, syphilis, Yes. Research presented at scientific meetings may be preliminary, lack peer review, and not be widely
etc). PDPT may leave providers open to legal consequences because they are treating partners, but accepted. A JAMA article published in 2002 found that, of 147 selected research abstracts reported in 252
never actually examining them. From a public health perspective, it makes sense to treat all of the news stories, 25% were not published during the three years after the meeting in which they were presented.
possible contacts of an index case. However, PDPT is not covered by legal or administrative rulings in This may because they were based on questionable design and science. Of those published, a third were
most states. published in low-impact journals.
By design, most mass media reports are intended to capture readers attention. Thus medical reports often
9. Were the results expressed in terms we can understand?
describe dramatic findings, major advances, or issues of immediate or significant public danger. The nature
Yes. Persistent or recurrent gonorrhea or chlamydia occurred in 13% of the usual care group and in and time constraints of mass media can constrict complex issues to inaccurate tidbits. Negative studies are
10% of the PDPT group. This is an absolute risk reduction of 3%, and an NNT of 33. less interesting and one rarely sees follow-up articles to expand, or correct, initial reports.
PDPT was effective in patients with gonorrhea or chlamydia. It was significantly associated with a This news article relates the findings of research presented at the American College of Cardiology meeting
reduced risk of persistent or recurrent infection when adjusted for many different co-founders. that is NOT preliminary. This particular research had undergone peer review and been accepted for
The PDPT group was significantly less likely to report having sex with an untreated partner. publication in the New England Journal of Medicine.
How should the new findings change current therapy? 13. Should you tell JB to take aspirin 81 mg daily like her husband?
10. Are the patients studied similar to those you see in clinic? No. Based on this article JB should not take aspirin solely for the primary prevention of heart attacks. This
report found a significant risk reduction for heart attack only among women 65 and over. JB is 57. If JB had a
The patients are similar to those seen in primary care (Health Department, STD Clinic, Student Health Clinic, higher baseline risk for cardiovascular disease, such as being a smoker with hyperlipidemia, a stronger case
etc). But, it should be noted that in this trial only about 10% of patients with STDs were randomized. for taking aspirin could be made. This study did show that aspirin benefited women greater than age 45 in
Appropriate selection of these patients in clinic may be difficult and therefore the efficacy observed may not reducing their risk of stroke, and for that reason JB may wish to take aspirin. Note that this study investigated
be generalizable to all settings. Alternatively, since this was a high-risk population, outcomes may actually be an aspirin dosing of 100 mg every OTHER day, not 81 mg daily. Aspirin use is associated with a higher risk
better in your patient population. of bleeding events. Aspirin IS indicated in men and women who have had a prior MI or stroke.
11. Do the results force you to change your practice? How?
For more content and to see comments from other PL Journal Clubs on this topic go to
www.prescribersletter.com - click on PL Journal Club - click on DISCUSSION FORUM.
Youll be able to pose your questions to the study author, Dr. Julie Buring.

References 2. What treatments are currently recommended for chlamydia and gonorrhea?
Get our chart on the CDCs latest STD guidelines, Detail-Document #180603.
INFECTIOUS DISEASES
Chlamydia
Fortenberry JD, Brizendine EJ, Katz BP, Orr DP. The role of self-efficacy and relationship quality in partner notification by adolescents azithromycin 1 gm PO, single dose, directly observed
with sexually transmitted infections. Arch Pediatr Adolesc Med 2002;156:1133-7. doxycycline 100 mg PO BID for 7 days
Gonorrhea (uncomplicated urogenital)*
Golden MR, Whittington WL, Handsfield HH, et al. Partner management for gonococcal and chlamydial infection: expansion of public
health services to the private sector and expedited sex partner treatment through a partnership with commercial pharmacies. Sex cefixime 400 mg PO, single dose (currently unavailable in the U.S., expected fall 2005)
Transm Dis 2001;28:658-65. ceftriaxone 125 mg IM, single dose
ciprofloxacin 500 mg PO, single dose
Golden MR, Hogben M, Handsfield HH, et al. Partner notification for HIV and STD in the United States: low coverage for gonorrhea, ofloxacin 400 mg PO, single dose
chlamydial infection, and HIV. Sex Transm Dis 2003;30:490-6. levofloxacin 250 mg PO, single dose
spectinomycin 2 gm IM, single dose (if cephalosporin-allergic and quinolones can not be used)
Golden MR, Whittington WL, Handsfield HH, et al. Effect of expedited treatment of sex partners on recurrent or persistent gonorrhea
or chlamydial infection. N Engl J Med 2005;352:676-85. *CDC continues to recommend that patients with gonorrhea be empirically treated for chlamydia as well.
NOTE: Quinolone-resistant strains of gonorrhea have developed in Southeast Asia, Hawaii, and California.
Niccolai LM, Winston DM. Physicians opinions on partner management for nonviral sexually transmitted infections. Am J Prev Med These patients should be treated with an antibiotic other than a quinolone.
2005;28:229-33.
Analysis of new study
Stekler J, Bachmann L, Erbelding E, et al. Concurrent STI morbidity in sexual contact to persons with bacterial STIs: implications for
patient-delivered partner therapy. Abstract (DO1B) presented at National STI Prevention Conference, Philadelphia, 2004. 3. What type of study was this and how were patients selected?
Additional Prescribers Letter Resources available at www.prescribersletter.com Randomized-controlled trial. Patients received either PDPT or usual care.
Usual care group received advice for their partners to seek care. This care was available free.
Patient-Delivered Partner Therapy for Gonorrhea and Chlamydia. Pharmacists Letter/Prescribers Letter PDPT group received cefixime 400 mg and/or a dose of 1 gram of azithromycin, depending on
2005;21(4):210404. diagnosis. Patients also received information about the medications, their adverse affects and
instructions for use, condoms, and an STD prevention brochure.
Increases in Fluoroquinolone-Resistant Neisseria gonorrhoeae Among Men Who Have Sex with Men. Pharmacists The primary outcome was persistent or recurrent gonorrhea or chlamydia in the index patients. All patients
Letter/Prescribers Letter 2004;20(6):200607.
were reassessed 21-133 days after their initial treatment.
Summary Chart of 2002 CDC Treatment Guidelines for STDs. Pharmacists Letter/Prescribers Letter 2002;18(6):180603.
4. How were the study groups defined?
CARDIOLOGY 26,656 patients presented with gonorrhea or chlamydia. Many were excluded.
7,723 patients were asked to participate. 5,252 were interviewed. 2,501 of these patients already had
Campion EW. Medical research and the news media. N Engl J Med 2004;351:2436-7.
their partners treated.
Grilli R, Ramsay C, Minozzi S. Mass media interventions: effects on health services utilisation. Cochrane Database Syst Rev 2,751 patients were randomized.
2002:CD000389. Over the course of the trial, 32% of patients were lost to follow-up, leaving approximately 930 patients
in each arm of the trial.
Kovach B, Rosenstiel T, Mitchell A. A first step to change: a commentary on the findings. Committee of Concerned Journalists and About 23% of the patients were male. The mean age was 23 years. 78% had chlamydia only. 17% had
Pew Research Center for the People and the Press. Available at: http://people- gonorrhea only. 5% had both STDs.
press.org/reports/display.php3?PageID=616on22December2003 (Accessed March 21, 2005).
About half of the patients were white and just over 1/3 were black; the remainder represented several
other ethnic groups. Patients averaged 1.5 sex partners in the 60 days prior to diagnosis.
Moynihan R, Soumerai S, Fletcher R, et al. Tipsheet--for reporting on drugs, devices, and medical technologies. Available at:
http://www.cmwf.org/publications/publications_show.htm?doc_id=239323 (Accessed on March 21, 2005). Table 1 provides demographic characteristics of the study cohort. Overall, these baseline
characteristics were evenly matched between the two study groups.
Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in
women. N Engl J Med 2005;352 [Epub ahead of print]. 5. What are the strengths of this trial?
Schwartz LM, Woloshin S, Baczek L. Media coverage of scientific meetings: too much, too soon? JAMA 2002;287:2859-63. Trial was randomized, but NOT blinded. It would be extremely difficult to maintain blinding in this type of
study design and would complicate the logistics of the trial. Follow-up in this study was approximately 68%.
Additional Prescribers Letter Resources available at www.prescribersletter.com This low rate of follow-up may compromise the validity of the trial slightly, but in this patient population,
adequate follow-up is difficult.
Primary Prevention of Cardiovascular Disease in Women. Pharmacists Letter/Prescribers Letter 2005;21(4):210409.
6. How did the intervention work in this trial?
Aspirin For The Primary Prevention of Cardiovascular Events. Pharmacists Letter/Prescribers Letter 2002;18(3):180302.
PDPT group had significantly less gonorrhea or chlamydia at follow-up than the usual care group (relative
risk =0.76; 95% confidence interval = 0.59 to 0.98). PDPT appeared to be more effective in reducing the
recurrence rate of gonorrhea as compared with chlamydia. Among the patients reporting NO sexual

The following succinct analysis appeared in Prescribers Letter. Welcome to PL Journal Club
PL Journal Club gives you insights and guides you to the discoveries that Prescribers Letter researchers and editors uncover. Each
INFECTIOUS DISEASES month we analyze many new studies and help you discover the answers to the hard questions. What are the real advantages and
disadvantages of new therapies? How do they compare with other options? What do prescribers and pharmacists need to know?
We look beyond the headlines and promotional materials to interpret the clinical studies and data. Sometimes the marketing spin
Should patients being treated for sexually transmitted diseases doesnt stand up to scrutiny. Sometimes studies do not really prove what they are reported to prove. PL Journal Club helps guide you
get extra antibiotics for their partner? to the truth and how to apply new findings to patient care.
Treating the patient is only half the battle.
PL Journal Club builds on Prescribers Letter to provide you with background for your own journal club discussions. We wont bring
All partners within the past 60 days should also be treated to up every possible question, but you canin your own journal club. If a question comes up, go to www.prescribersletter.com to find
prevent reinfection. more background. As a PL Journal Club participant, you get access to all of Prescribers Letter and you get access to the special PL
These partners SHOULD be seen by a provider first...but many Journal Club online tools. Youll be able to communicate with other PL Journal Club participants in many other locations. Plus,
partners are reluctant to come in. youre able to send questions and comments to the author of the published study that is discussed in PL Journal Club. And all PL
In this situation, some prescribers write for more Journal Club participants will benefit from seeing the responses from the study author. To see this, go to www.prescribersletter.com,
antibiotics...or a separate Rx with or without a name...for the click PL JOURNAL CLUB, then click DISCUSSION FORUM. Feel free to call or email us with suggestions or if we can be of
patient to give to their partner(s). assistance 209-472-2240 or PLJournalClub@pletter.com.
This approach concerns many prescribers. They worry about legal
Instructions
exposure when giving a prescription without seeing the partner. Go to www.prescribersletter.com to get materials and use the PL Journal Club tools. PL Journal Club leaders can use the tools to
However youll see more of this in the future. invite participantssend remindersget attendance rostersdownload interpretations and analyses of studiesetc. Participants can
A few states...California, Tennessee, Washington...already have use the tools to get discussion materials...get advance notice of discussion questions...reference citationsetc. Youll also get great
rules allowing this for chlamydia treatment. background materials, including Prescribers Letter and Prescribers Letter Detail-Documents. PL Journal Club functions like a
The AMA supports this type of treatment in states that allow it. typical journal club meeting, except that it is pre-organized for you and you get the expert analysis of important new studies done by
The CDC will be coming out with a letter...and is likely to the large Prescribers Letter research and editorial staff. Let the questions serve as a springboard for your discussions. Let your own
endorse this as a way to protect public health. Keep in mind that your patient cases shape the discussion. Each month PL Journal Club gives you two topics that are also covered in Prescribers Letter.
Your group might discuss only one or both topics. Youll also find a library of previous PL Journal Clubs online for your use. And
malpractice insurance may NOT cover problems with patients you have the discussion forum lets you share your thoughts, observations, questions, etc with other PL Journal Club participants online.
not seen. Fortunately, experts say theyre not aware of lawsuits
arising from this. PL Journal Club Contributing Editors:
Emphasize to all patients treated for an STD that their partners Rex W. Force, Pharm.D., FCCP, BCPS Mark Graber, M.D. Brian C. Harrington, M.D., MPH, FAAFP
must be checked. Be sure to document this discussion AND give the Professor, Department of Family Medicine Research Director, Past Program Director,
patient educational material for their partner. Associate Professor, Department of Division of Emergency Medicine Darnall Family Medicine Residency Program
We have a patient handout to make this much easier. Get it from Pharmacy Practice Associate Professor of Clinical Fort Hood, TX
www.prescribersletter.com anytime you need it. Director of Research, Grants and Surgery and Family Medicine Current Teaching Faculty
Information Systems Univ. of Iowa Hospitals and Southern Colorado Family Medicine Residency Program
Consider writing the diagnosis and drug sensitivity on the Family Medicine Clinical Research Center Clinics Assistant Clinical Professor
page. Tell the patient to take it to their partner(s)...and encourage Idaho State Univ. Univ. of Colorado Health Sciences Center
the partner to get seen.
(For more on this topic see Detail-Documents #210404 and #180603 at www.prescribersletter.com.) Prescribers Letter Editorial Staff: Editor: Jeff M. Jellin, Pharm.D.; Senior Associate Editor: Karen Davidson, Pharm.D.; Assistant Editors: Kim
Palacioz, Pharm.D., Tanveer Khan, Pharm.D., Joseph A. Woelfel, Ph.D., FASCP, R.Ph., Melissa Murfin, PA-C, Pharm.D., Kayla Dotson, Pharm.D.,
Primary Reference Golden MR, Whittington WL, Handsfield HH, et al. Effect of expedited treatment of sex partners on Crystal Amos, Pharm.D.; Assistant Editor and Director of Continuing Education: Tony Martin, Pharm.D., MBA; Associate Clinical Editor: Mark
recurrent or persistent gonorrhea or chlamydial infection. N Engl J Med 2005;352:676-85. Graber, M.D.; Editorial Project Manager: Timothy Swaim; Editorial Liaison: Karen Wilson; Editorial Assistant: Tyler Nagata; Database
Coordinator: Stephanie Feilzer-Pate; Drug Information Consultants: Neeta OMara, Pharm.D., BCPS, Jill E. Allen, Pharm.D., BCPS; Research and
Review: Kwabena O.M. Adubofour, M.D., FACP, Thomas Barringer, M.D., FAAFP, Robert T. Browne, M.D., FAAFP, Matthew Cline, M.D.,
Discussion Questions FAAFP, Sandra Harley Counts, Pharm.D., Rex Force, Pharm.D., BCPS, Joseph Guglielmo, Pharm.D., Marcia Isakari, M.D., Sheela Kapre, M.D.,
Adam Kaye, Pharm.D., FASCP, William Kehoe, Pharm.D., MA, FCCP, BCPS, Ted Lee, M.D., Stanley Leong, Pharm.D., Guey Mark, M.D., John
Overview of current therapy Morozumi, M.D., Kay Niegel, R.Ph., Mike Pastrick, R.Ph., Allen Shaughnessy, Pharm.D., Tom Simpson, Pharm.D., FCSHP, Sharm Steadman,
Pharm.D.
1. How commonly is treatment offered to partners of patients with STDs without an exam? Prescribers Letter Editorial Advisory Board: Jan Basile, M.D., Professor of Medicine, Medical Univ. of South Carolina; Robert E. Bickerton,
M.D., FACP, Private Practice; David B. Brushwood, J.D., Law Professor, University of Florida; Narinder Duggal, M.D., BSc (Pharm) CDE, CGP,
FRCPC, Univ. of Washington; COL John D. Grabenstein, R.Ph., Ph.D., Deputy Director for Clinical Operations, US Army Medical Command; Mark
Not often at all. Although patient-delivered partner therapy (PDPT) is attractive for a variety of reasons, it is A. Graber, M.D., Research Director, Div of Emergency Medicine, Associate Professor of Clinical Surgery and Family Medicine, University of Iowa
not a widely implemented treatment strategy among primary care providers or public health facilities. PDPT Hospitals and Clinics; Arthur Hull Hayes, Jr., M.D., President, MediScience Associates, Inc., former Commissioner of the FDA; Mark Hess, M.D.,
may offer several potential advantages from a public health perspective: FACP, Wright State University; Peter Jacobsen, Ph.D., D.D.S., Professor of Oral Medicine, University of the Pacific, School of Dentistry; Evan L.
Lipkis, M.D., Medical Director, Advanced Center for Total Health Care, Glenbrook Hospital; Stephen L. McKernan, BS.Pharm., N.D., D.O., FAAFP,
Patients can identify partners without a potentially embarrassing clinic visit. Director, Conroe Family Practice Residency Program; Robert W. Patterson, M.D., FABFP, FAAFP, Family Practice; David E. Rosenthal, M.D.,
Improved patient compliance (due to single dose oral regimens available for chlamydia and gonorrhea) FACP, Abington Memorial Hospital; David Stadtner, M.D., Private Practice; Kathryn Taubert, Ph.D., American Heart Assoc National Center; Walter
Way, M.D., University of Cal at San Francisco; C. Wayne Weart, Pharm.D., BCPS, Professor and Chair, Medical University of South Carolina;
Expedited treatment (Partners dont need to interrupt their schedules for a clinic visit.) Charles, F. Weiss, M.D., Clinical Professor of Pediatrics, University of South Florida; Craig Williams, Pharm.D., Purdue University.
Reduced risk of re-infection (because partners get treated)
Cost-effective way to reduce the prevalence of chlamydia and gonorrhea (because partners get treated.) DISCLOSURE:
Therapeutic Research Center/Prescribers Letter does not receive any commercial support and does not accept any advertising. It is completely
independent and is supported entirely by subscriptions. It is our policy that all editors refrain from having any ties with any organization that could
influence the editorial objectivity of Prescribers Letter or PL Journal Club. Prescribers Letter and PL Journal Club focus on delivering completely
objective, unbiased drug information and advice for the benefit of subscribers.

- 12 - PL Journal Club April 2005 ISSN #1555-0109 (print)
AFTER the meeting PL JOURNAL CLUB

Go to www.prescribersletter.com and click on PL Journal Club to:
Enter participant names so the site can keep your attendance rosters
BRINGING CLINICIANS TOGETHER TO DISCUSS CURRENT DRUG THERAPY
Enter date and location for the next PL Journal Club meeting
Based on content from Prescribers Letter, Vol. 12, No. 4, April 2005
Send email invitations and reminders to participants
April 2005
Invite new members Checklist Vol. 2, No. 4
Take advantage of PL Journal Club BONUS features
Suggest topics for PL Journal Club
Communicate with other PL Journal Club participants online including
comments sent to and from the author of the published study Manage your journal club at www.prescribersletter.com
NOTES BEFORE the meeting
Invite participants Go to www.prescribersletter.com and click on PL Journal Club
Reserve a location
Use www.prescribersletter.com to:

Enter the meeting time and location
Send email invitations and reminders to participants
Print your attendance sheet
Print PL Journal Club LEADER NOTES for yourself
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The most practical knowledge in the least time...
3120 West March Lane, P.O. Box 8190, Stockton, CA 95208 Discuss any changes in practice based on the last journal club
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www.prescribersletter.com ~ www.pharmacistsletter.com Use your LEADER NOTES to facilitate PL Journal Club discussion
Reproduction or reuse is prohibited by law. The contents are copyrighted. Copyrighted 2005 by Therapeutic Research Center.

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new england

A Randomized Trial of Low-Dose Aspirin

interval, 0.74 to 1.22; P=0.68). Gastrointestinal bleeding requiring transfusion was

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tective effect, while minimizing gastrointestinal

a lthough aspirin is effective in

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Table 1. Baseline Characteristics of the Women.

Characteristic Aspirin (N=19,934) Placebo (N=19,942) Total (N=39,876)

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Table 2. Incidence and Relative Risk of Confirmed Cardiovascular End Points.

* CI denotes confidence interval.

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sis in which follow-up data were censored at the

thirds of the study medication during the preced-

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0.01 Aspirin Aspirin

0.01 Placebo 0.01

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n engl j med 352;13

Copyright 2005 Massachusetts Medical Society. All rights reserved.

n engl j med 352;13

march 31, 2005

Copyright 2005 Massachusetts Medical Society. All rights reserved.

Table 4. Incidence and Relative Risk of Side Effects.*

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BDT, 1988 BDT, 1988

PHS, 1989 PHS, 1989

TPT, 1998 TPT, 1998

HOT, 1998 HOT, 1998

PPP, 2001 PPP, 2001

HOT, 1998 HOT, 1998

PPP, 2001 PPP, 2001

WHS, 2005 WHS, 2005

RR=0.99 (0.831.19) RR=0.81 (0.690.96)

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clinical problem-solving series

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