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Previous Aspirin Use and TIMI Score: What Are the Current Treatment Implications? OVERVIEW The
TIMI trials are a group of studies that
started in 1984
in which the first was designed to compare the efficacy of tPA to SK in achieving
coronary reperfusion. Since then, there have been roughly 40
trials comparing multiple drugs in patients with ACS. Risk
stratification of patients with chest
pain is an integral part in the management of potential
ACS. The TIMI risk score is a seven item tool that does not
rely on presentation specific details and was originally derived in
patients with non-ST segment THEORIES While
the exact reason for this increased short term mortality is yet to be
explained fully, there are many theories
as to its correct etiology. Aspirin "Resistance" or "Failure" has been
described in previous aspirin users (PASA). It is believed
that there
is an association with different clot Another interesting finding was that PASA users presenting with ACS had more benign presentations than NASA users. PASA users were more commonly showing up with Unstable Angina while the NASA presenting more often with NSTEMI. Those results on top of the fact that PASA users had a higher 30 day mortality has created a term known as the "Aspirin Paradox." While some forms of aspirin resistance can be mearsured using beside aggregometer to prove someone is in fact apirin "resistant," other forms of resistance can't be measured and aren't taken into effect in the trials such as TIMI and PURSUIT-PLUS. Other factors such as concurrent use of NSAIDS, malabsorption, smoking and increased catecholamine levels may stimulate platlet aggregation and overwhelm the effects of aspirin. On top of all this lies the confounding patient population that take aspirin compared to patients who don't. Most of the PASA users are higher risk patients because of multiple risk factors such as smoking, older age, and non-compliance. Other postulated forms of resistance could be related to decreased prostacyclin production by endothelium or to erythrocyte promotion of platlet reactivity. It could also be possible that platlets upregulate other proteins and pathways to aggregation such as GPIIb-IIIa receptors and ADP receptors which might explain the added benefit of a combination attack of clopidogrel, integrellin and other anti-platlet therapies. STUDIES Consistenly the use of alternatives to UFH alone has shown to be far superior and plays to one of the theories of aspirin changing the composition of subsequent clot formation. LMWH is now favored to UFH in unstable angina and NSTEMI patients because of the ESSENCE trial that showed LMWH superior to UFH by 22% in PASA, and the TIMI 11b trial, which also showed similar results. PRISM-PLUS showed us that GP IIb-IIIa + UFH is supererior to UFH alone in PASA users and PURSUIT showed us that integrillin + UFH is superior to that of UFH alone in PASA users. The CURE trial enrolled a population of 66% that were PASA users and found that clopidogrel + ASA was synergistic in both PASA users and NASA users. The most interesting take home point from all of this is shown that in the NASA group in all of these studies showed no difference in outcomes between paients treated with UFH and those treated with LMWH or the addition of a GP IIb-IIIa inhibitor.
The studies that show this "aspirin paradox" evaluated the relationship of PASA users with non-ST elevation in ACS. It was found that the PASA users were more likely to have death or MI at 30 days versus patients that weren't on ASA. As stated earlier the patients in this trial were mostly older, more were men, and they higher baseline risk factors than the patients not taking ASA. CLINICAL PRACTICE DECISIONS While the 2007 guidelines have focused on a few different strategies as far as the management of UA and NSTEMI. They have yet to address recommendations for treating patients based on their previous use of ASA or addressing STEMI as it pertains to PASA users, which there are currently no post-hoc analysis to date. The only suggestion is that the use of LMWH, GP IIA-IIIB inhibitors or clopidogrel be used is high risk patients as assessed by the TIMI risk score. It has been concluded by some authors that patients with UA or NSTEMI and are PASA users to be considered for LMWH, GP IIb-IIIa inhibitors or both. Taking this a step further one might conclude that being a PASA user makes you automatically high risk. The
questions raised here are those of the definitions of ASA "resistance"
and ASA " failure." It is hard to say whether or not PASA
users have worse outcomes because the failure or resistance of
inhibiting thrombaxane A2 or whether its
because the presence of ASA creates an enviroment for a different
composition of clot. If somebody was resistant It can be concluded that PASA users have been shown to improve outcomes with multiple anti-platlet therapy vs NASA users with the same anti-platlet therapy. What isn't known is why recommendations for PASA users doesn't include that of multiple anti-platlet agents even when they are low risk per the TIMI score. Maybe it is assumed that people presenting with chest pain and PASA will ultimately have a higher TIMI score and therefore qualify them for additional therapy anyways. Judging from the studies to date one should be safe in saying that any PASA user presenting with ACS should be treated with multiple anti-platlet therapies.
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ACS to predict 14 day outcomes. It has
been validated for use in the emergency department (ED) to predict 30
day likelihood of death, acute myocardial infarction (AMI),
or revascularisation in a broad based ED patient population. One of the
risk factors is that of recent aspirin (ASA) use in the past seven
days. It
is a little confusing at first glance to imagine why this would be
considered a risk factor
seeing how many clinical trials have demonstrated a prophylactic role
for aspirin in myocardial infarction and in unstable angina.
A
randomized trial of low-dose aspirin in the primary prevention of
cardiovascular disease in women analyses showed that aspirin
significantly reduced the risk of major cardiovascular events, ischemic
stroke, and myocardial infarction among women 65 years of age or older.
In
a very wide range of patients who have survived a prior occlusive
vascular event aspirin prevents about 25% of serious vascular
events. It is also said that treatment of 100 patients with acute
coronary syndrome
(unstable angina pectoris or acute myocardial infarction) for 2 years
may hinder the development of 3-4 fatal and 4 non-fatal vascular events.
formation and clot composition
which is more resistant to current treatment options.
These
reasonings are backed by analysis in four major studies (ESSENCE, TIMI
11B, PRISM-PLUS, PURSIUT) that shows patients previosly treated with
ASA
show a higher near term mortality than patients not previously treated with
ASA. While ASA failure and resistance has been proven in
laboratory studies it is estimated that up to 35% of the population
have ASA resistance with a percentage representing gene polymorphisms.
The clinical value of testing is very low
considering the testing is variable and laborious. It was
studied
however, and ASA resistance was shown in 40% of patients with ACS while
pts with stable CAD showed a lower frequency of 27%. 
Another
study that looked at clot compositon
at angioscopy in the setting of ACS showed that pts with
NSTEMI and
unstable angina (UA) had different clots than those with STEMI.
Those patients
with STEMI had more fibrin, erythrocyte rich clots vs the platlet rich
white clots of the NSTEMI, UA patients. These results echo
their different
treatment strategies in using fibrinolytics in STEMI vs heparin and
LMWH and
other anti platelet agents in NSTEMI and UA.
to
the anti-platlet
effects of ASA, one would postulate that they would run the same risk
for MI and death at 30 days as NASA users, negating the term aspirin
"resistance" and would lean more towards addressing this as the aspirin
"paradox" because of the probable underlying mechanism. This
reason of
"resistance" to the effects of ASA doesn't seem to account for the
end-points that were concluded in these studies and its reason for
being considered a TIMI risk factor. This term points towards
the
mechanism of someone being a non responder to the known pharmokinetics
of inhibiting the formation thromboxane A2 and not towards altered clot
formation and upregulation of various other platlet function.