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The Aspirin as a Protective Factor During
Hospital Evolution of the Acute Ischemic
Syndrome Without Persistent
ST-Segment Elevation

Bono, Julio O; Fernández Cid, Gerardo; Ramos, Hugo; and Investigators of the Multicenter Study (TROTESATI)

Coronary Care Committee of the Intensive Unit Care Argentine Society,
Buenos Aires, Argentina

SUMMARY
Introduction: According to world literature published, the risk of patients with Acute Ischemic Syndromes(AIS) without persistent ST-segment elevation who were taking aspirin (AAS) before the event is controversial.
Objective: To establish if patients that developed AIS taking AAS previously, had less risk of presenting intrahospital events (IE).
Material and method: It is a prospective study of 405 patients admitted to the multicentric study Tropt Sensitive in patients with AIS from 1/12/1999 to 1/2/2001. The combined result of two TropT Sensitive (TT) was used. The IE considered were: Pump Failure, mortality, refractory angina, acute MI Q and not Q. The groups were divided according to previous consumption of AAS: A (with AAS) and NA (without AAS). A versus NA was compared in baseline variables. The relative Risk(RR) was estimated with CI 95% of IE according to AAS and the risk was stratified to two confounders: (age and TT) by stratified analysis of Mantel and Haenszel (MH).
Results: In Group A: 164 patients ( 41.3%) and 233 in Group NA (58.7%). In A, 6 years average more of age (P<0,001). In A the incidence of acute MI Q and not Q was less than in patients NA (14 % versus 21.9%, P= 0.048). The RR of IE in A was 0.64 (CI 95% 0.33-1.03), that is to say, 36% less. RR pondered of MH controlled by age: 0.58 (CI 95% 0.36-0.93), RR=0.39in patients <60 years and RR=0.68 en > RR pondered of MH controlled by TT: 0.67 (CI 95% 0.45-0.98), RR= 0.59 when TT positive and RR =1.04 when negative.
Conclusion: The background of AAS in patients with AIS with persistent ST- depression, would appear as a protector factor against the intrahospital development of acute MI Q and not Q- MI. This phenomenon was more evident in high risk patients (TT positive) and not in sexagenarian ones.

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INTRODUCTION
   For three decades, Aspirin (ASA) was considered the platelet antiaggregation agent best well known in the management of patients with AMI and after it in a secondary prevention of the recurrent cardiovascular events (1-4). The therapeutically effect of ASA in the evolution of patients with unstable angina (UA) is included among these benefits (1,7-9 ).

   Some studies have suggested that in spite of a chronic or previous use of ASA, an episode of UA and /or ACS without ST elevation is associated to a higher rate of cardiovascular events during intrahospital evolution, and then previous ASA would be an independent indicator of a bad prognosis in these patients (8-15). This phenomenon that presumes the recurrence of ACS in spite of the prevention with ASA and followed by a bad prognostic evolution suggests an unappropiate inhibition of the platelet activation that might be called "aspirin failure" and/or "aspirin resistance" (16-20); but it could also be attributed to a clinical slant due to the patients' characteristics (21-25 ).

   Our aim was to determine the relation between previous administration of ASA and the development of ischemic events during the intrahospital evolution in patients admitted with UA. Besides, we tried to analyze if the prognostic effect of the previous ASA showed interaction with the evidence of myocardial injury evaluated with Troponin T.

MATERIAL AND METHODS
   397 out of 406 patients with UA were selected from our data of patients enrolled for the multicenter trial TROTESATI (8/16/1999 to 3/30/ 2001). We evaluated the predictive value of a qualitative quick cardiac Troponin test (TROP® Roche) in patients with UA. 21 national hospitals; 2 Coronary Care Units (CCU) (n=204) and 19 Intensive Care Units (ICU) (n= 201) took part in the study.

   We included patients with UA and with changes T/ST in EKG at admission and UA without changes T/ST in EKG at admission with prior coronary disease.

   The patients were classified according to the background of prolonged antiplatelet therapy with ASA (more than 7 days before admission) in prior ASA and non ASA according to positive or negative data.

   The fatal and non fatal IE considered were: cardiovascular mortality, AMI Q and non Q, recurrent or refractory angina. We did not include as IE the mortality due to other cause, stroke or peripheral vascular disease. In all the cases, the cause of death and the rest of IE were verified by cardiologists and clinical professionals without any relation to the trial and they were disguised so as to ignore the TROPT result.

   Prior admission variables were included in the baseline, such as demographic variables (age and sex), diagnostic at admission (UA with or without EKG changes), type of angor (already started, prolonged, progressive, post-infarction), its duration, EKG professional's interpretation (with ischemic changes, normal or non conclusive, objective EKG changes (ST segment and T-wave), functional type, FC, TAS/TAD, CK, troponin T (TROPT®) and angiographic lesions. Therapeutically variables after admission like the medicine given, anticoagulation and surgical approach were also included.

   As baselines measures, the value of EKG within the first 12 hours of pain was considered; also, CK/CK-MB and TROPT in the first 6 hours of symptoms, or the earliest time possible if the patient is admitted after the 6 hours of the beginning of symptoms. CK/CK_MB and Trop Test were always repeated if the first was negative, at exactly 6 hours after the first measurement.

STATISTICAL ANALYSIS
   Baseline variables were compared between prior ASA and non ASA groups with Chi square Test, Student Test (symmetric distributions) and Mann-Whitney (asymmetric distributions) two tailed test.

   The association of AMI and prior ASA as a protective factor was analyzed by a contingency table 2x2 with x2 and stratified analysis of Mantel and Haenszel (MH) to evaluate effects of confusion and /or interaction with variables that are not balanced in the baseline.

RESULTS
   Of the 397 patients studied, 164 (41.3%) were admitted with prior prolonged use of Aspirin as platelet antiaggregation meanwhile 233 patients (58.7%) hadn't had that background.

   Table 1 shows the baseline of patients with continuous previous use of ASA and of those without use of ASA. The former group is an average of 6 years older (P<0.001) meanwhile the others are younger and they are admitted more frequently with UA of a new onset (P<0.001). Besides, patients with prior use of ASA were given (while in hospital) in less proportion Beta- blockers (P<0.05) and in a larger frequency Calcium-channel blockers (P<0.001), but in the others therapeutically variables both groups were equally treated.

   Nevertheless, in a multiple logistic regression analysis neither the unbalanced medicines nor the new onset of UA were significantly associated to the results of IE in an independent way. Only the age factor remained as a significative prognostic one, thus its effect of covariability with ASA and AMI should be controlled in its appropiate moment in order to avoid confusion.

   Both groups were balanced in the baseline with similar coronary lesion degree to CCA, similar proportion of patients with ischemic changes in EKG, patients with more than 30 minutes'angor, similar functional type, similar level of serum markers and in the rest of the cardiovascular examination.

   Out of 397 patients, 130 had one or more combined Ischemic Events (IE) during the intrahospital follow-up (32.7%); 32.3% of the patients with prior ASA and 33% without ASA (n=53 and 77 respectively; P= 0.88). Also, 74 patients showed AMI Q (4.5%) and non Q (14.1%) during evolution that represent the 56.9% of all the patients with IE and a 18.6% incidence of this complication on the 397 patients evaluated with UA.

   The rate of AMI Q and non Q with prior ASA (14%, n=23) was significantly less than the rate of patients without ASA (21.9%) n=51; P= 0.048), and the Relative Risk (RR) of incidence of these events with ASA was only 0.64 (CI 95% 0.33-1.03), that is to say, an incidence of 36% less with the previous use of aspirin.

  Since the age turned out to be an important prognostic factor in the multivariate analysis and it is related to the prior use of ASA, the result of the association between ASA and stratified IE for two age groups (<60 years old and >60 years old) is shown in Table 2 and figure 1.

   The incidence of AMI Q and non Q in patients younger than 60 years old was 8.2% and 21% in patients with and without prior ASA (P=0.048) and in the >60 years old group, it was15.7% and 23.3% respectively (P=0.16). The RR of each group was 0.39 and 0.68 for <60 and >60 years old respectively, so it was evident that there was an interaction between ASA and age on the final incidence of AMI. After adjusting the effect of prior ASA for the age in an stratified analysis of Mantel-Haenszel, the result was a ponderate RR of 0.58 (CI 95% 0.36-0.93; P<0.05)

   The incidence of AMI Q and non Q when the patient had positive TROPT was 38.6% and 65.2% if he took previous ASA or not respectively (P<0.01; RR = 0.59 CI 95% 0.39-0.90, Table 2; Figure 1; thus, a 41% less risk, meanwhile if at admission the TROPT was negative the incidence was 5% and 4.8% with and without ASA respectively (P= 0.94 RR= 1.04; Table 2)

DISCUSSION
   There is no agreement on the prognosis of those patients that develop Acute Coronary Syndrome (ACS) when they are under antiplatelet prophylaxis with ASA.

   Some studies support the idea of a probable failure or resistance to the aspirin because the prior use of aspirin in these patients was shown as an independent risk factor in the development of clinical ischemic events or mortality during the evolution and this was reflected by the multivariate analysis after the adjustment of baseline or therapeuticals differences between patients with or without previous ASA.(8-15) In addition, regarding the evidence of platelet aggregation in 8%-12% of the times after the estimulation with different techniques on cardiovascular patients with ASA (16) and that it allowed to identify different degrees of antiplatelet results in patients with coronary background being treated with a low dose of ASA, it was suggested then, the need of an individualized dosage in order to avoid insensibility to aspirin.(17)

   Another explanation to this phenomenon would be the presence of a possible clinical slant (21) due to baseline or therapeutical characteristics that points out a difference between patients treated with ASA and those that never got ASA.

   Some examples of those who support the idea of a probable failure or resistance, are reported in large multicenter trials and they used patients in a secondary study to analyze the independent risk factors for clinical events or mortality, such as data base of ENAI (9), ECLA 3 (8), ESSENCE (12), TIMI studies (13,14), PURSUIT (15) and in others (10,11). In all of them, the previous use of ASA was associated independently to a higher rate of combined and/or isolated final points (mortality, AMI, recurrent ischemia, urgent revascularization)

   Aspirin would have failed in preventing the unstable angina in these patients at first instance, indicating a more severe evolution and thus, the treatment with aspirin would not add benefit during it (21). Consequently, there would be conditions in which aspirin would fail in providing a complete antitrombotic beneficial effect.

   Multiple stimulus may activate the platelets through different mechanisms that may lead to a thrombosis in spite of the aspirin treatment (26). Perhaps these mechanisms could be the explanation in why these patients' resistance to ASA makes it possible to get a benefit with the new antiplatelet agents IIb / IIIa (11,12,13,21) or with the combined antiplatelet treatment (27), or by early catheterization- revascularization (14).

   Also, the UA would be associated with an elevated peroxidation of lipids and with a reduction of antioxidant defenses. A failure of the aspirin was reported in the elimination of an increase in the thromboxane biosynthesis present in a subgroup of patients with episodes of platelet activation (18). These investigators suggest that "in vivo" formation of PG-F-2alfa, an active product of the peroxidation of the araquidonic acid is increased in the UA meanwhile there is an inverted correlation with the serum concentration of vitamin E, thus helping the insensibility of the aspirin with the tromboxane biosynthesis. It allowed to infer the existence of an association between the increase of the oxidative stress and the insensibility of the aspirin to the increase in the thromboxane biosynthesis in patients with UA.

   Those studies that support the idea of a clinical slant identify previous ASA as an univariate risk factor, but that association disappears when the baseline differences between patients with ASA and non ASA are adjusted (21,24) due to confusion variables such as, age, worse basal EKG, previous use of beta-blockers, diabetes, more backgrounds of clinical coronary diseases, etc. The possibility of a clinical slant is reinforced with studies showing that previous ASA does not modify the prognosis or otherwise it achieves a straight beneficial effect when it is correlated to a reduction in the rate of events after a relapsed in a Acute Coronary Syndrome (ACS) (22,23,25,28,29). In coincidence with these, we could also observe in our study a reduction in the risk of AMI (mainly Q and also non Q), though we didn't establish the prognostic on cardiovascular mortality, CHF and recurrent angor.

   Besides, since there is evidence of a gradient of thrombosis that goes from AMI Q to the AMI non Q and unestable angina UA (22) we may infer that the use of the aspirin causes a decrease in the severity of the acute coronary disease (22,23,30). This observation would widen the well known rol of the aspirin in the primary and secondary prevention since, besides reducing the incidence of AMI (1), it would also turn the 50% of potentials AMI into UA and the 20% of AMI Q in non Q(22). Due to the increase of aspirin use in prevention, these observations help to understand the recent tendency of a higher proportion of UA and less AMI in the Coronary Units31, and it could also contribute to continue decreasing the cardiovascular mortality rate in some countries.

   Therefore, we may accept that patients with prior ASA and with larger cardiovascular background (23) when they suffer a new episode of Acute Coronary Syndrome, it would probably be an UA (22,28) and during evolution it would turn into recurrent angor or AMI non Q instead of AMI Q (22). So, ASA is a previous cardiovascular disease marker and not a significant independent factor of prognosis in patients with UA. The aspirin seems to reduce the clinical manifestations and the development of ACS with aspirin is not necessarily a "failure" of the treatment or an "aspirin resistance" indicator (24).

   In this study we observed that the patients admitted with UA and who had a prior use of ASA were elderly, and it was less frequent an angina of new onset and they were given beta-blockers more frequently than patients without previous ASA. In a multivariate analysis the angor type or the treatment with beta-blockers did not modify the prognosis, but the age >60 years old did it. Therefore, age could be a confusing factor. The principal confusing factors (in relation to previous ASA and prognosis) described in the bibliography were age, basal EKG, beta-blockers use, comorbility and a larger frequency of clinical coronary disease background (example: previous AMI, angioplastía, etc) (6,9,21,25,28,32).

   Since in our case age turns out to be covariable, we did a stratified analysis and we observed that the chronic use of this drug was particularly beneficial in non sexagenarian patients with a reduction of 60% in the probability of AMI, meanwhile, in sexagenarian the reduction was 30%; or a reduction of 42% average when the effect of age (ponderate RR of MH) was eliminated.

   The frequency of an elevated qualitative Troponin T was independent of the prior use of ASA, but we could observe that in our serie the negative patients did not benefit with ASA, and the benefit in the positive ones that used ASA was a reduction of 40% in the risk of AMI. This interaction is not described in the bibliography, but it is known the benefit of prior ASA in patients with elevated Reactive C Protein (RCP) in the admission of patients with ACS (21,33).

CONCLUSION
  The background on the continuous prophylaxis with Aspirin in patients that suffer an episode of unstable angina would show as a protective factor with intrahospital ischemic events (AMI). This benefit is evident in patients with a high risk of ischemia marked by the presence of an abnormal elevated Troponin T and with a larger effect on non sexagenarian patients

We thank to:
English Teacher : Miss Olga Bonetti
Statistical analysis: Daniel Senestrari MD
Assistant Reachers: Miss Mariella Focaccia

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
Scientific Committee
President
Dr. Armando Pacher
Technical Committee - CETIFAC
President
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