By now most people are aware that aspirin and NSAIDs are associated with an increased
risk of upper gastrointestinal bleeding, and the risk with NSAIDs has been carried
before (
Bandolier
52
,
79
). A question still asked though, concerns the risk associated with low dose aspirin
(75 mg up to 300 mg a day) used in the secondary or primary prevention of heart
disease or stroke. A new epidemiological study [1] and meta-analysis [2] may help.
Risk of bleeding with low-dose aspirin
A case-control study was conducted using the UK General Practice Research Database
that contains details of patient demographics, medical histories and diagnoses,
referrals and prescriptions. The UKGPRD is becoming an important research tool, used
frequently by researchers from all over the world. The authors of the aspirin study
were based in Madrid.
The source population were patients aged 40 to 79 years with the same GP for at
least two years. Cases were identified as those with upper gastrointestinal bleeding
or perforation, excluding those with cancer, varices, liver disease, or alcoholism,
or with other obvious reasons why they may have had a propensity for gastrointestinal
bleeding. For inclusion a case had to have a specific site of bleeding located in
stomach or duodenum or a clinical diagnosis of peptic ulcer, and be referred to a
specialist or admitted to hospital. Paper records confirmed the accuracy of the
computer diagnoses. Controls were selected at random and matched for age, sex and
year, and with the same exclusion criteria.
Current users were defined as use within 30 days, recent users between 31 and 180
days, and past users longer than 180 days before the incident date. Exposure to other
drugs was noted and analysed. Results were adjusted for a variety of covariates using
logistic regression to compute a relative risk.
Results
There were 2,105 cases and 11,500 controls. They were well matched for age and sex.
Two-thirds were men older than 60 years. The indication for aspirin use was
predominantly for secondary prevention of coronary or cerebrovascular disease (about
80% of the time) in cases and controls. The most common dose prescribed was 75 mg
(48%), 150 mg (27%) or 300/325 mg (19%). Only in 6% of people was the prescribed dose
more than this.
For current users of low-dose aspirin the relative risk of upper GI bleeding was 2.0
(95% confidence interval 1.7 to 2.3). The risk diminished when aspirin had not been
used for 180 days or more (Figure 1). The risks were the same for fatal or non-fatal
bleeding, for men or women, and for age groups 40-59 years, 60-69 years and 70-79
years. There was no difference for risk associated with site of bleeding.
Figure 1: Upper GI bleed with low-dose aspirin according to recency of use
Formulation
Enteric-coasted aspirin had a similar risk associated with upper GI bleeding or
perforation to plain aspirin (Table 1).
Table 1: Upper GI bleed with low-dose aspirin according to formulation
|
|
|
Adjusted relative risk (95% CI)
|
|
All sites
|
Plain
|
1.9 (1.6 to 2.3)
|
|
|
Coated
|
2.3 (1.6 to 3.2)
|
| Gastric |
Plain |
2.0 (1.5 to 2.5) |
|
|
Coated |
2.2 (1.4 to 3.6) |
| Duodenal |
Plain |
1.6 (1.3 to 2.1) |
|
|
Coated |
2.2 (1.4 to 3.4) |
Dose
There was a hint of a dose-response over a limited dose-range with a higher risk
of upper GI bleeding at doses above 300 mg daily, but this was based on a very
small number. There was no appreciable dose response below 300 mg.
Drug interactions
Using aspirin together with high-dose NSAID increased the risk of upper GI
bleeding substantially, with a relative risk of 13 (9 to 21), beyond the sum of
the independent effects. Interaction were only additive at low or medium doses of
NSAIDs. There was no apparent interaction between aspirin and paracetamol or
aspirin and steroids.
Duration effects
There was an indication that the risk of upper GI bleed with low-dose aspirin
was greater in the first two months of use than with use over a longer time
period (Figure 2).
Figure 2: Upper GI bleed with low-dose aspirin according to duration of
use
|
|
Aspirin for primary prevention
A question frequently asked of
Bandolier
concerns the appropriateness of using low-dose aspirin in the primary prevention
of cardiovascular disease. Which patients are likely to benefit? A new
meta-analysis from Sheffield, with some clever thought behind it, goes most of
the way to telling us.
The problem, simply put is this. Aspirin may reduce the number of heart attacks,
but it can, at the same time, increase the number of bleeds, both
gastrointestinal bleeds and perhaps strokes. Is there some point at which the
benefits outweigh the risks, or vice versa?
|
|
Meta-analysis
The meta-analysis was of randomised trials of aspirin for primary prevention.
Studies had also to give information on total cardiovascular events, myocardial
infarction, stroke, bleeding complications, and all cause mortality.
There were four studies with 48,500 people, 25,000 of whom were given 75-500 mg
aspirin daily. Only one trial included women. Trial duration was 3.8 to 6.8
years.
Results
Table 2 shows the weighted mean results from the four trials for a variety of
outcomes, as the absolute risk per year of the event in the control group, the
absolute benefit or harm, and the odds ratio. Clearly low dose aspirin reduced
cardiovascular events and heart attacks but increased haemorrhage, non-cerebral
bleeds and non-minor bleeds (all non-cerebral bleeds not classed as minor). It
was interesting that the odds ratio for the increase in bleeding events caused by
low dose aspirin in this meta-analysis (odds ratio about 1.7) was similar to the
increase found in the case-control study [1] (relative risk 2.0).
Table 2: Benefit and harm from low dose aspirin in a meta-analysis
|
|
Event
|
Absolute risk in control group (Percent/year)
|
Absolute benefit from aspirin (Percent per year)
|
Odds ratio (95% CI)
|
| Cardiovascular events |
0.92 |
0.13 |
0.85 (0.78 to 0.94) |
| Myocardial infarction |
0.52 |
0.15 |
0.70 (0.62 to 0.79) |
| Strokes |
0.29 |
-0.02 |
1.06 (0.91 to 1.24) |
| All cause mortality |
0.73 |
0.05 |
0.94 (0.85 to 1.04) |
|
|
|
|
|
|
|
Absolute risk in control group (Percent/year)
|
Absolute harm from aspirin (Percent per year)
|
Odds ratio (95% CI)
|
| Best overall estimate of haemorrhage |
0.13 |
0.09 |
1.69 (1.38 to 2.07) |
| Major non-cerebral bleeds |
0.05 |
0.04 |
1.73 (1.14 to 2.63) |
| Non-minor bleeds |
0.22 |
0.18 |
1.77 (1.40 to 2.25) |
|
|
|
|
|
The authors then set out to calculate the
net
benefit by calculating the number of heart attacks prevented net of bleeding
events at different levels of baseline risk for cardiac events. This was done on
the basis of 100 patients treated for five years with low dose aspirin at annual
risk levels of 0.5%, 1% and 1.5% a year. The assumption was that low dose aspirin
reduced the risk of MI by 30%, but that the risk of bleeding was constant. They
also give the number of patients needed to be treated with low dose aspirin over
five years to prevent one event.
These results are in Table 3. At a low risk, 0.5% a year, 133 people have to be
treated with low dose aspirin for five years to prevent one myocardial
infarction. But as we take into account the increased risk of cerebral
haemorrhage, major bleeds and non-minor bleeds, the NNT increases until
eventually it becomes an NNH so that eventually one person is
harmed
for every 500 treated. The results look better with increasing cardiovascular
risk.
Table 3: Benefit and harm from low dose aspirin: overall absolute benefits
and NNTs
|
|
|
CHD event risk
|
|
|
0.5%/ year
|
1.0%/ year
|
1.5%/ year
|
|
Myocardial infarcts prevented
|
Absolute reduction (%/year)
|
NNT
|
Absolute reduction (%/year)
|
NNT
|
Absolute reduction (%/year)
|
NNT
|
| Total |
0.75 |
133 |
1.5 |
67 |
2.25 |
44 |
| Net of 0.19 cerebral haemorrages |
0.56 |
179 |
1.31 |
76 |
2.06 |
49 |
| Net of 0.17 major bleeds |
0.39 |
256 |
1.14 |
88 |
1.89 |
53 |
| Net of 0.76 non-minor bleeds |
-0.20 |
-500 |
0.55 |
182 |
1.3 |
77 |
| Numbers are calculated on basis of treating 100
patients for five years. NNT is the number of patients needed to be treated for
five years to prevent one event. Negative values show number of patients needed
to be treated to harm one patient |
Comment
Together these two papers help us think our way through the problems around the
use of aspirin in primary prevention. We may know that aspirin is a good thing
for preventing heart attacks, but the risk of harm from bleeding is not
negligible, even at the low doses used. The balance tips to benefit over harm
when the annual risk of a cardiovascular event is 1% or above (the authors say
> or = 0.8%), and the Sheffield Tables for Primary Prevention allow the risk
to be calculated.
|
|
Their conclusion was that aspirin for primary prevention is safe and worthwhile
at a coronary risk of 1.5% a year or more, safe but of limited value at a
coronary risk of 1% a year, and unsafe at a coronary risk of 0.5% a year. Those
with Sheffield Tables to hand will know that this means that primary prevention
with aspirin makes no sense unless the patient is "bad enough" to be "on" the
Sheffield tables. We have to remember that aspirin, like all other drugs, is a
poison [3].
References:
- FJ de Abajo, LA García Rogríguez. Risk of upper
gastrointestinal bleeding and perforation associated with low-dose aspirin as
plain and enteric-coated formulations. BMC Clinical Pharmacology 2001 1:1 (
www.biomedcentral.com/1472-6904/1/1
)
- PS Sanmuganathan et al. Aspirin for primary prevention of coronary heart
disease: safety and absolute benefit related to coronary risk derived from
meta-analysis of randomised trials. Heart 2001 85: 265-271).
- Tramèr MR. Aspirin, like all other drugs, is a poison. BMJ 2000 321:
1170-1171.
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