Influence of Low‐Dose Aspirin (81 mg) on the Incidence of Definite Stent Thrombosis in Patients Receiving Bare‐Metal and Drug‐Eluting Stents

Abstract

Background:

Dual antiplatelet therapy with aspirin plus clopidogrel is the mainstay of therapy in patients undergoing percutaneous coronary intervention (PCI). However, the optimal dose of aspirin following PCI has not been established.

Hypothesis:

There is no difference for definite stent thrombosis in patients taking low dose versus standard aspirin.

Methods:

Low‐dose (81 mg) aspirin was used as part of a standard dual antiplatelet therapy in patients receiving bare‐metal stents (BMS) or drug‐eluting stents (DES) at a large tertiary medical center. We retrospectively analyzed 5368 consecutive cases treated with stent placement and dual antiplatelet therapy. The incidence of definite stent thrombosis (DST) at our institution was compared to DST as reported in a large, published cohort of 24 trials and 12973 patients. We stratified DST events into early (<30 days) and late (>30 days) timing and also stratified by stent type. The effect of aspirin dosing was evaluated using χ ², Cochran‐Mantel‐Haenszel, and homogeneity testing.

Results:

A total of 5187 patients underwent 7604 stent implantations during the study period. The cumulative incidence of DST was 0.60% (95% confidence interval [CI], 0.42%–0.84%) at 30 days and 0.76% (95% CI, 0.56%–1.03%) at 1 year. The overall incidence of DST during the study period was not different based on type of stent (0.53% for DES and 0.75% for BMS, P = 0.36). Compared to the historic, standard‐dose aspirin (162–325 mg) cohort, DST in our low‐dose aspirin (81 mg) cohort was not significantly different at either 30 days (0.72% vs 0.60%, P = 0.39) or at 1 year (1.08% vs 0.76%, P = 0.07). There was no appreciable interaction of aspirin dose on the incidence of DST, controlling for stent type, or timing of the event.

Conclusions:

Low‐dose aspirin therapy in combination with clopidogrel following implantation of either BMS or DES in our cohort does not appear to increase the risk of DST compared to a higher‐dose aspirin regimen. © 2011 Wiley Periodicals, Inc.

The authors have no funding, financial relationships, or conflicts of interest to disclose.

Introduction

The introduction of dual antiplatelet therapy with aspirin and a thienopyridine has resulted in substantial improvements in reducing stent thrombosis (ST) compared with aspirin and an oral anticoagulant in patients receiving coronary stents.1, 2 As such, dual antiplatelet therapy has become a cornerstone of the medical regimen for prevention of ischemic events in patients undergoing percutaneous coronary intervention (PCI) with stent placement. There are conflicting opinions regarding the optimal dose of aspirin to be given to patients after receiving PCI with either drug‐eluting (DES) or bare‐metal stents (BMS). Experimentally, a single oral 100‐mg dose of aspirin is sufficient to completely block the synthesis of thromboxane A₂ in healthy individuals, the predominant pathway by which aspirin inhibits platelet aggregation.3, 4 Most recent PCI guidelines have recommended 300 to 325 mg of aspirin before PCI, and 162 mg to 325 mg of aspirin daily to be given after PCI in patients without allergy or increased risk of bleeding for at least 1 month after BMS implantation, 3 months after sirolimus‐eluting stent implantation, and 6 months after paclitaxel‐eluting stent implantation.5 In a retrospective analysis from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, the benefit from clopidogrel was independent of aspirin dose, and a high aspirin dose (≥200 mg/day) was no more beneficial than a lower dose. More importantly, the bleeding risks appear to increase with the higher aspirin dose.6 Other clinical studies have demonstrated that the lower dose of aspirin is associated with lower incidence of gastrointestinal bleeding7 and equal efficacy.8

The purpose of the current study was to evaluate the influence of low‐dose (81 mg) aspirin on the incidence of definite stent thrombosis (DST) in patients receiving either a BMS or DES at a large tertiary medical center. The incidence of DST in our cohort is compared to that in the network meta‐analysis.9

Methods

The study patient population consisted of consecutive patients who received at least 1 stent implantation during the 3‐year study period from January 1, 2005 to December 31, 2008 and followed during the hospital stay. By state regulation, data must be collected on all patients undergoing PCI and reported to the state using the American College of Cardiology's National Cardiovascular Data Registry instrument. This study was approved by the institutional review board.

All commercially available coronary stent types were included in the analysis. The DES included mostly the Cypher sirolimus‐eluting stent (SES) (Cordis Corp., Miami Lakes, FL) and the Taxus paclitaxel‐eluting stent (PES) (Boston Scientific Corp., Natick, MA). There was a small number of second‐generation DES used during 2008. The incidence of DST was retrospectively reviewed in our patient population.

DST is defined based on the Academic Research Consortium (ARC) classification (U.S. Food and Drug Administration, Circulatory System Devices Panel Meeting, 2006). DST refers to angiographic or pathological confirmation of occlusive or nonocclusive thrombus that originates in the stent or in the segment 5 mm proximal to or distal to the stent, and the presence of at least 1 of the following: (1) acute onset of ischemic symptoms, (2) new ischemic electrocardiogram changes, or (3) typical rise and fall of cardiac biomarkers. The timing of the stent thrombosis was categorized into acute (0–24 hours), subacute (24 hours–30 days), late (30 days–1 year), and very late (>1 year after stent implantation).

At our institution, a large tertiary medical center, aspirin naïve patients are loaded with 324 mg aspirin preprocedure and then 81 mg daily thereafter as part of the dual antiplatelet regimen along with 75 mg of clopidogrel. All patients were prescribed clopidogrel (loading dose, 300 or 600 mg) along with aspirin before or during PCI. After the procedure, 81 mg of aspirin was given daily to all patients during their index hospital stay and was then continued indefinitely. The duration of clopidogrel use following stent implantation was as per practice guidelines: at least 1 month for BMS, 3 months for SES10 and 6 months for PES.11 After the 2006 revision of the guidelines, the duration of clopidogrel was increased to 1 year in patients receiving DES.5

As the only referral center within the region, patients in need of repeat procedures return to our facility and are recorded prospectively in our database. All patients who returned to Baystate for repeat PCI, either due to recurrent myocardial infarction (MI) or other indications, such as recurrent ischemic symptoms or abnormal stress tests, were identified through our catheterization laboratory database. All coronary angiograms on repeat PCI patients were reviewed, and cases of DST were identified using the ARC definition. Medical records of all patients who underwent repeat PCIs were systemically reviewed to confirm the use and dosage of aspirin and clopidogrel.

The cohort to which we compared our data was a published collaborative network meta‐analysis of all randomized controlled trials that compared either DES with BMS or the 2 DES (SES vs PES head to head).8 In this large cohort, trial data using standardized definitions of outcomes from 38 trials (18023 patients) were collected from a collaborative group of investigators/trialists. Twenty‐four trials totaling 12973 patients, on whom ARC‐defined DST was analyzed and included in the final analysis, were used as our comparators.9

Statistical Analysis

Categorical variables are expressed as percentages. Continuous variable are expressed as the mean ± standard deviation. Continuous variables were compared with the Student t test when variables were normally distributed and with the Wilcoxon rank sum test when variables were not normally distributed. Binary variables were compared with χ ² test with normal approximation or Fisher exact test when appropriate. A 2‐tailed P value <0.05 was considered statistically significant. The incidence of DST is expressed as a percentage with 95% confidence intervals (CI). We evaluated the overall incidence of DST in our low‐dose aspirin cohort compared to the network meta‐analysis as the control. Stratification of DST by the type of stent (DES vs BMS) as well as by the timing (acute vs late) of DST in both groups was determined. A χ ² test was calculated for each stratum. The Cochran‐Mantel‐Haenszel test was used to test for differences in DST across these strata.12 The Mantel‐Haenszel test for homogeneity was then used to evaluate for effect modification by aspirin dose on the incidence of DST with respect to stent type or timing of the event.

Results

Baseline patient characteristics of the study are listed in Table 1. During the study period, a total of 5187 patients underwent 5368 PCIs with successful implantation of at least 1 coronary stent. A total of 7604 stents were implanted during the study period, among which 5517 were DES (2045 SES, 2845 PES, and 627 second‐generation DES). Overall, 221 patients had repeat PCI performed during the study period because of recurrent MI or other ischemic symptoms/indications. Among these cases, 59 DSTs were identified, including 6 acute thrombosis (<24 hours), 26 subacute thrombosis (1 day–30 days), 9 late thrombosis (30 days–1 year), and 18 very late thrombosis (>1 year). The incidences of DST according to stent type and time interval are listed in Table 2. The incidence of DST in our cohort was 0.60% (95% CI, 0.42%–0.84%) at 30 days and 0.76% (95% CI, 0.56%–1.03%) at 1 year. During the study period, there was no significant difference in DST between SES and PES (17 vs 19; P = 0.62, respectively). When all DES together were compared to BMS, there was no significant difference in DST either within 30 days (0.34% vs 0.62%) or overall (0.72% vs 0.91%; P = 0.50, respectively). However, first‐generation DES (SES and PES) had a higher incidence of very late (>1 year) DST than BMS (0.35% vs 0.05%; P = 0.045, respectively).

Table 1.

Baseline Patient Characteristic Comparison

	Present Study		Network Meta‐Analysis		P
	No.	%	No.	%
Total	5187		15 068
Age, y	62.6		63.32		0.45
Sex
Male	3579	68.9	11 238	74.58	0.34
Female	1608	31.0	3830	25.53	NA
DM	1517	29.2	4086	25.42	0.22
Hypertension	3663	70.6	NA	NA	NA
Hyperlipidemia	3867	74.5	NA	NA	NA
Smoker	1725	33.3	NA	NA	NA
LVEF	51% (10%–85%)	NA	NA	NA	NA

Abbreviations: DM, diabetes mellitus; LVEF, left ventricular ejection fraction; NA, not applicable.

Table 2.

Cumulative Incidence of Academic Research Consortium‐Defined Definite Stent Thrombosis According to Stent Type and Time Interval

	Acute <1 Day	Subacute 1–30 Days	Late 30 Days–1 Year	Very Late >1 Year	Overall
Sirolimus stent (n = 2045)
Incidence (n)	0.05% (1)	0.15% (3)	0.2% (4)	0.44% (9)	0.83% (17)
95% CI	0.01%–0.27%	0.05%–0.43%	0.08%–0.50%	0.23%–0.83%	0.52%–1.33%
Paclitaxel stent (n = 2845)
Incidence (n)	0.11% (3)	0.28% (8)	0% (0)	0.28% (8)	0.67% (19)
95% CI	0.04%–0.31%	0.14%–0.55%	NA	0.14%–0.55%	0.43%–1.04%
2nd generation DES (n = 627)
Incidence (n)	0% (0)	0.64% (4)	0% (0)	0% (0)	0.64% (4)
95% CI	NA	0.26%–1.62%	NA	NA	0.26%–1.62%
BMS (n = 2087)
Incidence (n)	0.10% (2)	0.53% (11)	0.24% (5)	0.05% (1)	0.91% (19)
95% CI	0.03%–0.35%	0.30%–0.94%	0.10%–0.56%	0.01%–0.23%	0.59%–0.41%
Total cases (n = 5368)
Incidence (n)	0.11% (6)	0.48% (26)	0.17% (9)	0.33 (18)	1.10% (59)
95% CI	0.05%–0.24%	0.33%–0.71%	0.09%–0.32%	0.23%–0.55%	0.85%–1.42%

Abbreviations: BMS, bare metal stent; CI, confidence interval; DES, drug‐eluting stent; NA, not applicable.

2nd generation DES include 244 Endeavor stent, 201 Xience stent, and 182 Promus stent. The discrepancy between the case numbers in Table 2 and patient numbers in Table 1 is due to some patients having repeated percutaneous coronary interventions.

The overall incidence of DST in our low‐dose aspirin (81 mg) cohort compared to the historic controls with standard‐dose aspirin (162 mg–325 mg per day)9 was not significantly different at 30 days (0.60% vs 0.72%, P = 0.39). At 1 year there was a trend toward lower DST in our low‐dose aspirin group compared to the historical control cohort (0.76% vs 1.08%, P = 0.07). DST was significantly lower at 30 days for patients who received a DES in our low‐dose aspirin cohort compared to those who received a DES in the network meta‐analysis (0.34% vs 0.74%, P = 0.01). However, this difference was no longer evident for DST beyond 30 days (0.38% vs 0.36%, P = 0.89). There were no significant differences in DST for patients who received a BMS between our low dose cohort and the controls at either 30 days (P = 0.87) or after 30 days (P = 0.81) (Table 3). The homogeneity test for effect modification did not demonstrate a significant effect on DST with regard to stent type (P = 0.42) or time to event (P = 0.09) from aspirin dose.

Table 3.

Incidence of Academic Research Consortium‐Defined Definite Stent Thrombosis Drug Eluting Stents vs Bare Metal Stents

Stent Type	Acute (95% CI)a			Late (95% CI)b
	Cohort Analysis	Network Analysis	P	Cohort Analysis	Network Analysis	P
DES	0.34% (0.21%–0.54%)	0.74% (0.57%–0.94%)	0.01	0.38% (0.24%–0.59%)	0.36% (0.25%–0.51%)	0.89
BMS	0.62% (0.33%–1.07%)	0.70% (0.47%–1.02%)	0.87	0.29% (0.11%–0.63%)	0.35% (0.2%–0.6%)	0.81

Abbreviations: CI, confidence interval; BMS, bare metal stent; DES, drug‐eluting stent.

^a<30 days.

^b>30 days.

Discussion

The incidence and timing of ST after PCI are available from both randomized trials and real‐word registries from numerous studies.9, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 The collaborative network meta‐analysis9 was thus far the most comprehensive analysis on outcomes associated with both DES and BMS implantation, including 38 randomized clinical trials (18 023 patients) with follow‐up of up to 4 years for patients with DST. The incidence of ARC‐defined DST was found to be 0.7% at 30 days and 1.1% at 1 year. Further confirmation of these data comes from a recently published, large Spanish registry, with over 23 000 patients after DES implantation in which the incidence of DST was 0.6% at 1 month and 1.2% at 1 year.15 In the present study, low‐dose (81 mg) aspirin therapy in combination with clopidogrel following implantation of either BMS or DES did not increase the risk of DST when compared to the higher‐dose aspirin regimen used in historic cohorts. The lack of a significant impact on DST using low‐dose aspirin was further upheld regardless of the stent type and timing of the DST. Well‐designed randomized trials have shown that aspirin is an effective antithrombotic agent when used in doses ranging between 50 and 100 mg per day, and there has been a suggestion that the daily dose of aspirin needed for suppression of platelet TXA2 production is approximately 30 mg per day.4 As the antiplatelet/anticoagulant cocktail therapy is intensified in our effort to reduce ischemic events in patients undergoing PCI, bleeding risk has become a primary concern. In the CRUSADE trial, more than 10% of the acute coronary syndrome (ACS) patients receiving antiplatelet therapy experienced major bleeding events.24, 25 In both CURE and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trials, significant bleeding was detected in the combination clopidogrel/aspirin group when compared to patients on aspirin alone.6, 26 More importantly, in the CURE trial, patients with acute coronary syndromes receiving a dose of aspirin ≤100 mg daily had the lowest rate of major or life‐threatening bleeding complications both in the placebo (1.9%) and clopidogrel (3%) arms of the trial. Bleeding risk increased with increasing aspirin dose, with or without clopidogrel, without change in efficacy.25

Aspirin is effective at doses ranging from 50 mg to 1500 mg per day.27, 28 A wide range of aspirin doses (75–325 mg per day) have been used in practice in patients receiving coronary stents. The CHARISMA study has suggested aspirin doses of 100 mg or greater are not associated with benefit, and may cause harm compared with lower doses in patients taking clopidogrel due to increase bleeding.21 Small registry studies have suggested no difference in the incidence of unexplained subacute or late ST with low (81 mg) vs high (325 mg) doses of aspirin in patients receiving SES.29 Recently, the result of the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions‐7 (CURRENT/OASIS‐7) trial was published.30 The trial randomized 25087 patients with non‐ST elevation or ST elevation ACS who were undergoing angiography with intent of PCI. The patients were then randomized in a 2 × 2 factorial fashion to either high‐dose (600 mg loading followed by 150 mg daily) or standard dose (300 mg loading followed by 75 mg daily) clopidogrel. Comparing the high‐dose aspirin vs the low‐dose aspirin groups, there was no difference in cardiovascular death/MI/stroke between the 2 groups. There was also no difference in DST (0.6% vs 0.7%, P = 0.46) between high‐dose (300–325 mg) and low‐dose (75–100 mg once daily) aspirin groups at 30 days. Despite no difference in overall bleeding complications, there was a trend toward lower gastrointestinal bleeding in the lower‐dose aspirin group (0.24% vs 0.38%, P = 0.051).

Limitations

There were several limitations with our study. First, the current study is observational in nature, which may include unmeasured confounding and bias due to lack of blinding. Second, baseline lesion and vessel parameters and other quantitative angiographic features, which may be predictive factors for DST, were not available for all patients analyzed. Third, DST was the only ARC category analyzed and is very specific. The results may have been different if DST plus probable stent thrombosis were used. Fourth, all patients were discharged with dual antiplatelet therapy; however, patients' adherence to medication could not be adequately assessed. Although unbiased, the use DST may miss some true events of stent thrombosis by requiring angiographic or autopsy confirmation despite a clinical scenario consistent with stent thrombosis. The collaborative network meta‐analysis only documented DST, and the only baseline characteristics analyzed were age, sex, and diabetes mellitus. Our study, which analyzed a large cohort of patients, demonstrated our rates are comparable to the collaborative network meta‐analysis and recently published single‐center observational study.31

Conclusion

In this study, low‐dose (81 mg per day) aspirin therapy in combination with clopidogrel following implantation of either BMS or DES does not appear to increase the risk of DST compared to a higher‐dose aspirin regimen as used in an historical control cohort. We found no interaction of aspirin dose on the incidence of DST controlling for stent type or timing of the event. Given the known increased risk of bleeding with higher doses of aspirin, lower‐dose aspirin should be considered for patients after PCI until more definitive evidence is available. As more potent antiplatelet and anticoagulant drugs (eg, prasugrel, ticagrelor, factor Xa inhibitors, and thrombin receptor antagonists) are added to the pharmacologic cocktail for the treatment of ACS, striking the fine balance of reducing ischemia and minimizing bleeding will be increasingly important. These data add to the growing body of knowledge of comprehensive cardiovascular care to help guide patient management.