British Columbia Medical Journal - Jul-Aug 2010 - Does an Aspirin a day keep the doctor away? Acetylsalicylic acid for the primary prevention of cardiovascular disease

Michael Bayliss, MD, FRCPC, Andrew Ignaszewski, MD, FRCPC

Does an Aspirin a day keep the
doctor away? Acetylsalicylic
acid for the primary prevention
of cardiovascular disease
More evidence is needed before ASA can be recommended for
routine use to reduce the risk of CV disease, especially in women
and diabetic patients.

he Greek physician Hippo - ment and prevention of cardiovascu-

T
ABSTRACT: Acetylsalicylic acid was
introduced to the pharmaceutical crates was first to describe the lar (CV) disease.
market just over 100 years ago. analgesic effects of bark from Dr Lawrence Craven, a general
Although it was originally intended the willow tree, a salicylate-containing practitioner from Glendale, Califor-
for use as an analgesic, physicians plant. Although the mechanism through nia, first proposed that ASA could pre-
quickly realized it provided many which willow bark relieved pain was vent myocardial infarctions after he
other therapeutic benefits. Dr Law- not understood, it was used as an noted increased bleeding rates in chil-
rence Craven first suggested ASA effective herbal remedy for over 2000 dren who chewed ASA gum after ton-
could prevent cardiovascular events years. In 1826, two Italian researchers, sillectomy and tooth extractions.3,4 In
with his publication of a large case Brugnatelli and Fontana, successfully 1950, he published a case series of 400
series in 1950. Since then, several isolated the active compound, salicin.1 patients prescribed ASA.5 After 2 years
large randomized controlled trials Unfortunately, because of its signifi- of follow-up, none of these patients
involving more than 100 000 patients cant gastrointestinal side effects, the had experienced a CV event.
have investigated the role of ASA compound’s clinical utility was limited. Evidence for ASA continued to
for primary prevention of cardiovas- In 1894, German chemist Felix build in the 1960s and 1970s, al-
cular events. These trials suggest Hoffman joined the Bayer Pharma- though research was largely confined
that ASA provides modest protection ceutical Company. In search of a com- to the secondary prevention popula-
at the expense of a small but real pound to relieve his father’s arthritis tion. Studies suggested that ASA pre-
increase in bleeding. Based on these pain, he looked again at Brugnatelli vented 10 to 20 reinfarctions for every
findings, several governing bodies and Fontana’s salacin, which had been 1000 patients treated and had a small
have recommended using ASA for further refined by chemists to produce but significant effect on mortality.6
primary prevention. However, in light pure salicylic acid. By adding a buffer However, ASA use was also associat-
of recent studies, particularly in sev- to the salicylic acid to create acetyl- ed with a small increase in nonfatal
eral selected subgroups, there con- salicylic acid (ASA), Hoffman devel- bleeding. Given the lower CV risk in
tinues to be debate regarding the oped a compound that was better tol- the primary prevention population,
use of ASA for preventing cardiovas- erated and had fewer gastrointestinal researchers questioned whether the
cular events. side effects.2 In 1899, acetylsalicylic benefits of ASA in this group would
acid was released on the market and
sold as “Aspirin.” Although Bayer ini- Dr Bayliss is a cardiology resident at the
tially maintained that their compound University of British Columbia. Dr Ignas-
had no effect on the heart, ASA would zewski is head of Providence Healthcare
eventually become one of the most and the UBC Division of Cardiology at St.
widely used medications for the treat- Paul’s Hospital.

298 BC MEDICAL JOURNAL VOL. 52 NO. 6, JULY/AUGUST 2010 www.bcmj.org

Does an Aspirin a day keep the doctor away? Acetylsalicylic acid for the primary prevention of cardiovascular disease

be significant enough to outweigh its American Heart European Society of
US Preventive Services Task Force
Association Cardiology
adverse effects.
Recommends use Recommends use of Recommends use of ASA when the potential
of ASA when 10- ASA when there is benefit of MIs prevented (men) and strokes pre-
Early primary year risk of cardio- markedly increased vented (women) outweighs the potential harm of
prevention trials vascular event 10-year risk of car- increased GI hemorrhage
In the early 1980s, investigators from exceeds 10% diovascular disease
mortality and con- Risk level at which benefit exceeds harm
Harvard’s Brigham and Women’s Hos- trolled blood pres-
pital in Boston designed the Physi- sure Men: 10-year coronary heart disease risk
cians’ Health Study, the first random- age 45–59 years > 4%
ized controlled trial to investigate age 60–69 years > 9%
ASA for the primary prevention of CV age 70–79 years > 12%
events.7 Over 260 000 American male Women: 10-year stroke risk
physicians aged 40 to 84 were screen- age 55–59 years > 3%
ed, with 22 071 subjects eventually age 60–69 years > 8%
assigned to ASA (325 mg daily) or age 70–79 years > 11%
placebo arms. This study was stopped
early at 60 months because of a sig-
nificant 44% relative risk reduction Table. Recommendations for ASA use to prevent cardiovascular disease.
(RRR) in MI. Although there was a
32% increase in risk of bleeding, this mended that the US Food and Drug Finally, the Primary Prevention
increase was mostly attributed to easy Administration approve professional Project recruited 4495 patients with
bruising. labeling of ASA to reduce the risk of a one or more cardiac risk factors from
At approximately the same time first MI. However, the FDA did not a general practitioner’s clinic and as-
that the Physicians’ Health Study was follow this recommendation because signed them to ASA (100 mg daily) or
underway, a group from Oxford Uni- the two trials were interpreted to have placebo.13 This trial was stopped early
versity in England was conducting a divergent results.10 because of a 23% RRR in CV events
large randomized trial, the British Doc- The Thrombosis Prevention Trial and a 44% reduction in cardiac death.
tors’ Trial.8 Over 20 000 invitations was a two-by-two factorial trial that As in other studies, there was a small
were mailed to healthy male doctors randomly assigned subjects to war- increase in bleeding complications
who had previously responded to a farin (goal INR 1.3–1.8), ASA (75 mg over the 3.6 years of follow-up
smoking questionnaire. Ultimately, daily), or a combination of the two.11 (absolute risk increase 0.7%), mainly
5139 subjects were randomly assign- Acetylsalicylic acid and warfarin in- driven by an increase in GI bleeds.
ed to this open-label trial and asked to dividually showed a 20% RRR in is- These five landmark trials found
take ASA (500 mg daily) or to avoid chemic heart disease, mostly driven that using ASA was associated with a
ASA. The results of this study failed by a reduction in nonfatal MI. Although 15% to 44% RRR of a first major CV
to show any significant difference in the combination of ASA and warfarin event. Although bleeding rates were
the incidence of nonfatal MI, stroke, had a 34% RRR in MI, it was also mildly increased, the events were
or mortality. associated with a threefold increase in mostly small and nonfatal. Based on
Although the results from the bleeding complications. these results and subsequent meta-
British Doctors’ Trial conflicted with The Hypertension Optimal Treat- analyses, the American College of
those of the Physicians’ Health Study, ment (HOT) study was designed to Cardiology (ACC) recommended the
it is important to note that the British assess the safety and efficacy of ASA use of ASA for the prevention of CV
trial was open-labeled and had an in patients with hypertension, particu- events in patients who had a 10-year
event rate 3 times lower, consequent- larly in terms of ASA’s effect on bleed- risk exceeding 10%.14 The US Preven-
ly making it significantly underpow- ing and hemorrhagic stroke.12 Acetyl- tive Services Task Force and the Euro-
ered. An overview of these two trials salicylic acid demonstrated a 15% pean Society of Cardiology (ESC)
did suggest an overall 33% reduction RRR in major CV events. While a small have made similar recommendations,
in the incidence of a first MI.9 Based increase in nonfatal major and minor endorsing ASA for primary preven-
on this evidence, the Cardio-Renal bleeding was observed, there was no tion in an intermediate- to high-risk
Drugs Advisory Committee recom- difference in fatal major bleeding. population ( Table ).15,16 However, the

www.bcmj.org VOL. 52 NO. 6, JULY/AUGUST 2010 BC MEDICAL JOURNAL 299


FDA has yet to approve professional a potential benefit in older women. deemed ASA of uncertain value for
labeling of ASA for this indication Furthermore, only 24% of subjects primary prevention and stated that the
because of ongoing uncertainties had more than one CV risk factor. The potential benefits with ASA needed to
and the need for more evidence, espe- yearly major CV event rate was 0.26%, be carefully weighed against the risk
cially regarding women and diabetic indicating that this was a low-risk of major bleeding.
patients. group of patients. Finally, the dose of The recently published Aspirin for
ASA used in this study was lower than Asymptomatic Atherosclerosis Trial
ASA in women in previous studies, suggesting a high- found no evidence supporting the effi-
Cardiovascular disease is the largest er dose might have been more effec- cacy of ASA for primary prevention.21
single cause of death among women.17 tive. Despite the lack of any substan- This study involved 3350 subjects
Despite this fact, only two of the five tial evidence suggesting a benefit in aged 50 to 80 with an ankle brachial
trials reviewed above enrolled women women, the ACC guidelines still rec- index of less than 0.95, an accepted
(HOT and the Primary Prevention ommend ASA for all intermediate- to surrogate for vascular disease. After
Project). Subgroup analysis from these high-risk individuals regardless of 8.2 years of follow-up there was no
trials suggests that ASA did not pro- sex. difference in the composite outcome
vide women with protection from CV of fatal and nonfatal coronary event,
events. Some have postulated that Emerging evidence stroke, or revascularization. However,
ASA may be ineffective in women The Antithrombotic Trialists’ Collab- as observed with the Antithrom -
because of male-female differences in oration performed a meta-analysis botic Trialists’ Collaboration, the
salicylate metabolism or interactions using all of the individual participant yearly rate of major bleeding was
with hormones.18 However, only 180 data from the primary prevention tri- approximately 0.1%. Re search ers
of the 2402 CV events from all five of als reviewed above. The results of this hope the results of two ongoing stud-
the primary prevention trials occurred study were published recently in The ies, ASPREE (ASPirin in Reducing
in women, making it difficult to draw Lancet and included over 95 000 indi- Events in the Elderly) and ARRIVE
any firm conclusions. viduals with a total of 330 000 person- (Aspirin to Reduce the Risk of Vascu-
The Women’s Health Study set out years of follow-up.20 The absolute risk lar Events) will provide some further
to definitively answer questions of of a serious vascular event per year insight.
effectiveness of ASA in women.19 In was 0.51% in the ASA group compar-
1992, 1.7 million invitations were sent ed with 0.57% in the placebo group. ASA in diabetes
to female health professionals. Eligi- This equates to a statistically signifi- Patients with diabetes are known to
ble subjects had to be older than 45 cant but clinically modest absolute be at increased risk for CV events,
and have no history of CV disease. risk reduction (ARR) of 0.06% and a having a twofold to fivefold increase
After the completion of a 3-week run- relative risk reduction of 12%. Thus, in risk of MI and stroke over the gen-
in phase, a total of 39 876 women were 1666 patients would need to be treat- eral population.6,22 Both the American
assigned to ASA (100 mg on alternate ed with ASA for a year to prevent one National Cholesterol Education pro-
days) or placebo. After a follow-up of serious CV event. Although the relative gram and the ESC guidelines consid-
10 years, there was no significant dif- risk reduction of CV events is similar er diabetes to be a “coronary equiva-
ference in the incidence of MI or mor- for both primary and secondary pre- lent,” consequently placing all diabetic
tality. However, a significant 24% vention studies, the absolute risk patients into the high-risk category.23,24
RRR in ischemic stroke was observed. reduction is much smaller in the pri- Diabetic patients are also known
Although these results raise ques- mary prevention population (ARR to have abnormal platelet function,
tions regarding the efficacy of ASA in 0.06% vs. 1.49%). A small increase in in cluding alterations in platelet
women, there are important details hemorrhagic stroke was seen in the turnover, enhanced aggregation, and
that should be highlighted. Women in ASA arm (0.04% vs. 0.03%), which augmented thromboxane A2 synthe-
this study were generally younger was counterbalanced by a small re- sis ( Figure ).25 Antiplatelet agents are
than the male subjects enrolled in pre- duction in ischemic stroke. There was therefore a seemingly logical choice
vious trials. Only 10% of the partici- also a small absolute increase in major for reducing CV events. Disappoint-
pants were older than 65. In this small bleeding of 0.03%. In response to ingly, subgroup analysis from the pri-
subgroup there was a significant 26% these disappointing results, the Anti- mary prevention trials and the Anti-
RRR in major CV events, suggesting thrombotic Trialists’ Collaboration thrombotic Trialists’ Collaboration



have failed to show a benefit in this
population.20,26
There have been two large random- Endothelial
ized trials investigating the effective- dysfunction
ness of ASA in the diabetic popula-
tion. The JPAD trial was a multicentre Lipid rich Increased
randomized trial at 163 institutions atheroma platelet
activation
throughout Japan.27 Because Japanese
law prohibits the administration of a
Increased
placebo in clinical trials, this was an coronary heart
open-label trial. In addition to dia- disease
betes, 60% of subjects had a history of
smoking, 60% had hypertension, and Increased
55% had a history of dyslipidemia. platelet Reduced
aggregation fibrinolysis
Despite this seemingly high-risk pop-
ulation, there was no significant
difference in CV events after just over Increased
fibrinogen
4 years of follow-up. However, the
event rate was 3 times lower than ex-
pected, which indicates that this group
was not as high-risk as expected, des-
pite the presence of significant CV Figure. Factors contributing to accelerated coronary heart disease in diabetic patients.
risk factors.
The POPADAD trial was conduct-
ed by the Scotland Diabetic Registry outcome. Patients may have also been questionable clinical benefit. Further-
Group.28 This study randomly assign- “better treated,” limiting ASA’s ability more, there has been no evidence to
ed diabetic patients with an ankle to reduce CV risk any further. Finally, date suggesting that ASA is of benefit
brachial index of less than 0.99 to ASA diabetic patients may require higher in either female or diabetic subgroups.
(100 mg daily) or placebo. Patients doses of ASA because of an increased The current guidelines continue to
enrolled in this trial also had a signif- turnover rate of thromboxane A2. endorse ASA for primary prevention
icant burden of traditional CV risk fac- Despite the lack of evidence, many in those at moderate to high risk of
tors. Unfortunately, low enrollment governing bodies continue to recom- cardiovascular disease. Researchers
and funding issues led to premature mend ASA for diabetic patients.29 The hope that the results of several ongo-
termination of the study before a tar- ASCEND and ACCEPT D trials are ing trials will provide us with more
get sample size of 1600 was reached. currently enrolling patients and aim to insight into several unanswered ques-
After nearly 7 years of follow-up further investigate the effectiveness tions and help further define the
POPADAD failed to demonstrate a of ASA in the diabetic population. patient population in which ASA
benefit in composite CV outcomes. should be used.
As in the JPAD trial, CV event rates Conclusions
were threefold lower than originally Acetylsalicylic acid is one of the most Competing interests
predicted, again a surprising finding widely used preventive medications None declared.
given the seemingly high-risk popula- in the era of modern medicine. Since
tion. Dr Craven proposed that the anti- References
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both underpowered for their primary tion of a first CV event, which is of cause for secondary post-tonsilectomy

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British Columbia Medical Journal - Jul-Aug 2010 - Does an Aspirin a day keep the doctor away? Acetylsalicylic acid for the primary prevention of cardiovascular disease

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British Columbia Medical Journal - Jul-Aug 2010 - Does an Aspirin a day keep the doctor away? Acetylsalicylic acid for the primary prevention of cardiovascular disease