The Influence of Low (81 mg) versus High (325 mg) Doses of
ASA on the Incidence of Sirolimus-Eluting Stent Thrombosis

Conflicting opinions exist regarding the optimal dose of acetyl salicylic acid (ASA) to be given after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy suggested a daily dose of 75–100 mg of ASA with concomitant clopidogrel, without differentiating between bare-metal and DES.¹ Recent PCI guidelines state that patients without ASA allergy, resistance or increased risk of bleeding should receive a daily dose of 325 mg for 3 to 6 months depending on the type of DES implanted.² However, higher doses of ASA in combination with clopidogrel are proven to increase the risk of bleeding.³ Hence, despite the recent PCI guidelines,² the optimal dose of ASA at the time of discharge is still a matter of debate. ASA is rapidly absorbed after ingestion,⁴ with platelet inhibition occurring within 30–40 minutes and lasting for the lifespan of the platelet (7–10 days).^5,6 Low-dose ASA (75–100 mg/day) is sufficient for providing maintenance of chronic platelet inhibition by suppression of thromboxane A2 (TXA2) production.⁷ Since ASA does not prevent restenosis,⁸ its clinical benefits are derived in the prevention of stent thrombosis and long-term secondary prevention of cardiovascular events. Low-dose ASA has been proven efficacious in this latter regard, and it is thus the regimen of choice for long-term use.^9,10 From a pharmacodynamic point of view, no reason exists to believe that a higher dose of ASA is necessary to confer sufficient antiplatelet effect after implantation of a DES. The purpose of the current study is to evaluate the influence of ASA dose on the incidence of unexplained subacute and late stent thrombosis in the era of DES.

Methods

The incidence of subacute and late stent thrombosis was retrospectively reviewed in our patient population over a 2- year period (January 2004 to December 2005). At our institution, and prior to the 2005 PCI guidelines,¹ the discharge dose of ASA was at the discretion of the interventional cardiologist. The medical records of all patients who underwent PCI over the study period were reviewed. After initial review, the chronic daily dose of ASA was confirmed by telephone contact. The analysis was limited to patients having received at least 1 Cypher^™ sirolimus-eluting stent (SES) (Cordis Corp., Miami, Florida) and who were discharged and maintained on a daily ASA dose of either 81 mg or 325 mg. Patients with stent thrombosis due to poor angiographic results were excluded, as it is a known possible explanation for thrombosis.11 We defined poor angiographic result as presence of persistent dissection on initial angiogram, significant residual stenosis or gross stent underdeployment documented on intravascular ultrasound. We excluded patients with thrombosis who had discontinued clopidogrel before the recommended duration post-SES implantation. During the study period, the duration of clopidogrel use post-SES was 3 months based on practice guidelines. Subacute stent thrombosis was defined as stent thrombosis within 4 weeks of stent implantation. Late stent thrombosis was defined as stent thrombosis occurring later than 4 weeks and up to 1 year post-implantation. Acute stent thrombosis (within first 24 hours) was excluded from the analysis, as it is most often explained by technical factors and not ASA dose.Screening for subacute or late stent thrombosis was performed by review of medical records and telephone contact with the entire study population. Repeat angiographic films from our hospital were reviewed in cases of suspected stent thrombosis. If a patient returned to the hospital with an acute ST-elevation myocardial infarction (STEMI) within 1 year of DES implantation and did not undergo a repeat coronary angiogram, stent thrombosis was assumed. Similarly, if a patient presented to an outside hospital with an acute STEMI during the same period, stent thrombosis was assumed. In patients who died suddenly without a clear noncardiac cause of death within 1 year, stent thrombosis was also assumed. Once late stent thrombosis was assumed, the thrombosis was further classified as definite, probable or possible based on the new Academic Research Consortium (ARC) standardized definitions. Definite stent thrombosis refers to an acute coronary syndrome and either angiographic confirmation of thrombus or occlusion, or pathologic confirmation of thrombosis. Probable stent thrombosis refers to unexplained death within 30 days or target vessel myocardial infarction (MI) without angiographic confirmation of thrombosis or other identified culprit lesion. Possible stent thrombosis refers to unexplained death after 30 days. The study was approved by the institutional review board at Loyola University Medical Center. For statistical purpose, the definition of stent thrombosis used was the ARC “all definitions”. Statistical analysis was performed as follows: student’s t-tests were used to analyze differences between groups for all relevant continuous variables. Comparison betweenthe groups relative to the proportion of patients with thrombosis was performed using both chi-square and Z-tests of column proportions. Statistical significance was defined as p < 0.05. All statistical analyses were conducted using SPSS, version 13.0 (SPSS, Inc., Chicago, Illinois).

Results

During the study period, 1,093 patients had at least 1 SES implantation and were discharged on a daily ASA dose of either 81 or 325 mg. Baseline characteristics are summarized in Table 1. The groups are well matched except for a slightly older population in the 81 mg group versus the 325 mg group (65.96 ± 11.7 vs. 64.39 ± 11.9 years; p = 0.027). A total of 583 patients (53.4%) took 81 mg of ASA and 510 patients (46.7%) took 325 mg of ASA. Twelve unexplained stent thromboses occurred during the study period (1.1% of 1,102 patients). Six were subacute and 6 were late thromboses. Seven patients with thrombosis were excluded because of either poor initial angiographic results or clopidogrel discontinuation within the minimum 3 months’ duration post-SES implantation. No significant difference in the incidence of stent thrombosis was observed between the two ASA dose groups. Seven patients had stent thrombosis in the 81 mg group (1.2% of 583 patients), while 5 had thrombosis in the 325 mg group (1% of 510 patients); p = 0.7727. A description of the baseline and procedural characteristics of the patients who had thrombosis is provided in Table 2. Also, further classification of definite, probable and possible stent thrombosis based on the ARC definitions is included in Table 2. In patients with thrombosis, the mean stent length, vessel size and number of SES implanted were 22.7 mm, 3.0 mm and 1.3, respectively. When considering the total number of individual PCIs (1,807 PCIs) performed on the study population during the study period, the incidence of subacute or late stent thrombosis was 0.7%.

Discussion

The data concerning the benefit of ASA during PCI antedates the stent era. Extremely high doses of ASA (990 mg/day) were previously used, resulting in significant reductions in periprocedural Q-wave MI.⁸ Although ASA was initially used in combination with dypyridamole, the elimination of the latter did not increase acute periprocedural complication rates.¹² Much smaller doses of ASA are now routinely used in clinical practice, but comparative data of those doses in the literature are limited. To our knowledge, only one unpublished study comparing 80 mg versus 1,500 mg of ASA prior to percutaneous transluminal coronary angioplasty (PTCA) has addressed the issue; it demonstrated no difference between the incidence of MI and emergency coronary artery bypass graft surgery (CABG).¹³ Whether this can be extrapolated with the use of DES has never been tested. Irrespective of the dose, the effects of ASA during PCI are on periprocedural MI, stent thrombosis and bleeding.Restenosis, on the other hand, is mainly a matter of intimal hyperplasia and it is not reduced by chronic ASA therapy.⁸ The gastrointestinal side effects of ASA are, however, doserelated.¹ In a post hoc analysis of the CURE study, the incidence of major bleeding increased as a function of the ASA dose.³ In comparing patients with ASA regimen of < 100 mg, 101–199 mg and > 200 mg, the incidence of major bleeding increased with increasing ASA dose (3.0%, 3.4% and 4.9%, respectively).³ For patients taking clopidogrel and ASA, the adjusted hazard ratio for major bleeding for the highest versus the lowest dose of ASA was 1.6 (95% CI 1.19 to 2.23).³ The increased risk of bleeding is explained by permanent inactivation of platelet COX-1 by ASA, leading to the inhibition of both TXA2-mediated platelet aggregation and prostaglandin (PG) E2 and PGI2-mediated gastrointestinal cytoprotection.¹⁴ As opposed to the effect on platelet aggregation, the impairment on gastrointestinal mucosa is dosedependent, explaining the higher incidence of bleeding with higher doses.¹⁴ Despite this established fact, recent PCI guidelines have presumed an increased effectiveness of higher dose of ASA and have advocated 325 mg as a minimal dose post- PCI.² These recommendations are likely due to protocols employing a daily ASA dose of 325 mg in recent DES studies.^15,16 However, other DES studies either used at least 100 mg17 or did not mention the ASA dose.¹⁸ The daily dose of ASA needed for suppression of platelet TXA2 production is approximately 30 mg.^7,19 Thus the usual dosage in clinical practice of at least 75 mg exceeds the minimal effective dose for full pharmacodynamic effect.¹⁹ Since ASA exerts its effect for the lifespan of a platelet, discontinuation of even low-dose ASA may take up to 7 days for full platelet recovery. This benefit of low-dose ASA has been seen in clinical practice for the primary prevention of atherothrombosis in high-risk patients and for secondary preventions of MI after a cardiovascular event.^9,19 In this study, we found no significant difference on the incidence of stent thrombosis between 81 mg and 325 mg of ASA. The incidence of stent thrombosis in our study occurred in 1.1% of patients at 1 year, which is comparable to recent registries addressing the issue.^20–22 The rate of stent thrombosis in our study is similar to previous data on baremetal stents thrombosis.²³ However, we did not compare our current study population with historical controls and conclusions regarding this important issue cannot be drawn from this study. Since low-dose aspirin is better tolerated and is often preferred by patients, it may be the dose of choice, especially in patients at higher risk of bleeding and in patients requiring chronic oral anticoagulation. Regardless, in view of the fear of the prolonged de-endothelialization or possible endothelial dysfunction observed post-DES implantation, it is recommended that patients maintain a prolonged uninterrupted dual antiplatelet regimen. Endothelial cell recoverage does in fact occur to a similar extent in animal models,²⁴ but the functional status of the endothelial cells remains to be fullyassessed.²⁵ Furthermore, antiplatelet resistance may also play an important role in DES thrombosis. Whether any of the assumed thrombosis was related to ASA or clopidogrel resistance was not tested in this study. Although the overall incidence of stent thrombosis in our patient population was low, we do not believe our results are due to chance alone. Despite a large number of separate PCI procedures in our catheterization laboratory over a 2-year period, we did not find a significant difference in the incidence of thrombosis between the two ASA regimens. If, however, a difference between groups exists, a considerably larger number of patients than our study population would be needed in order to achieve statistical significance. For example, if a 1% difference were to be confirmed, one would need 4,638 patients to achieve 80% power using a two-sided chi-square test without continuity correction and with a significance level (p) of 0.05. Whether this would translate into clinical significance is debatable but needs to be proven by a largescale, randomized, controlled trial.

Conclusion

In conclusion, we found no significant difference in the incidence of unexplained subacute or late stent thrombosis with the use of a low (81 mg) versus high (325 mg) dose of ASA in our patient population. Although subject to inherent biases from its retrospective nature, we believe this study provides previously lacking evidence on the safety and efficacy of low-dose ASA post-implantation of SES.

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