Association of Aspirin Dosage to Clinical Outcomes after PCI: Observations from the Ottawa Heart Institute PCI Registry

From the University of Ottawa Heart Institute, Ottawa, Ontario and ^*Harvard School of Public Health, Boston, Massachusetts. Disclosures: Michel Le May has received speaker honoraria from and is a consultant to Sanofi and has received research grants from Schering. Derek So has received speaker honoraria from Sanofi-Aventis and travel grants from Astra-Zeneca. Manuscript submitted July 15, 2008, provisional acceptance given August 19, 2008, manuscript accepted November 10, 2008. Address for correspondence: Derek So, MD, FRCPC, University of Ottawa Heart Institute, Cardiology, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada. E-mail: dso@ottawaheart.ca

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ABSTRACT: Background. Dual antiplatelet therapy, with aspirin and a thienopyridine, is the accepted treatment after percutaneous coronary intervention (PCI). No clear evidence exists regarding the ideal dosage of aspirin. Recent guidelines recommend higher-dose aspirin because of the possible decrease in stent thrombosis. The purpose of this study was to test the hypothesis that high-dose aspirin of 325 mg decreases death and myocardial infarction (MI) compared to a lower dose of 81 mg in patients undergoing PCI. Methods. An observational cohort study of 1,840 consecutive patients who underwent PCI was conducted. Patients who did not survive to discharge were excluded. The primary endpoint was a composite of all-cause mortality and MI at 1 year. Results. Nine-hundred and thirty patients (50.5%) were discharged on 325 mg of aspirin and 910 (49.5%) were discharged on 81 mg. The risk of all-cause mortality or MI was not significantly different between patients: low-dose 5.49% (50/910) vs. high-dose 4.19% (39/930); adjusted odds ratio [OR], 1.16; 95% confidence interval [CI], 0.73–1.85). In a multivariable analysis, the Charlson comorbidity score (OR, 1.37; 95% CI, 1.18–1.58) and urgent PCI (OR, 1.75; 95% CI, 1.03–3.00) were associated with increased death or MI. Among patients with drug-eluting stents, the use of low-dose aspirin did not predispose them to death or MI (adjusted OR, 1.12, 95% CI, 0.53–2.34). Conclusions. In this large contemporary analysis of PCI patients, no differences in death or MI were observed at 1 year between patients discharged on low-dose aspirin 81 mg compared to patients on a higher dose.

J INVASIVE CARDIOL 2009;21:121–127

Key words: aspirin dosage, percutaneous coronary intervention

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Percutaneous coronary intervention (PCI) is the most common revascularization procedure, with over 1 million performed each year worldwide.¹ Despite advances in PCI technology, it is well recognized that the utilization of appropriate adjunctive pharmacotherapy is imperative to long-term success after PCI.² Antiplatelet therapy is the cornerstone in adjunctive PCI pharmacotherapy, with clinical efficacy proven from the peri-PCI period and extending to 1 year.^3,4 Aspirin has been universally accepted as therapy in PCI. Its use was first demonstrated in the balloon angioplasty era, where it was shown to reduce acute ischemic outcomes.^5,6 Although aspirin has been universally accepted as essential therapy for patients undergoing PCI, its optimal dosing has not been extensively studied in this setting. Prior studies of aspirin dosing in various cardiovascular disorders revealed benefits of low-dose aspirin of 75–160 mg in preventing adverse clinical outcomes.^7–10 Low doses may be advantageous in decreasing side effects such as gastrointestinal bleeding.¹¹ None of these studies were based on patients after PCI. Many contemporary studies have focused on the dosing and timing of the antiplatelet drug clopidogrel, an adenosine diphosphate (ADP)-receptor antagonist. These studies have demonstrated the important impact of clopidogrel on clinical outcomes in patients undergoing PCI.^3,4,12,13 Recently, the American College of Cardiology (ACC)/American Heart Association (AHA) released an update on guidelines for patients undergoing PCI, which emphasized the importance of at least 162–325 mg of aspirin for 1 month in patients receiving bare-metal stents (BMS), instead of the often prescribed lower doses.¹⁴ The guidelines further suggested 3 months and 6 months of higher-dose aspirin therapy for those receiving drug-eluting stents (DES) coated with sirolimus and paclitaxel, respectively. The evidence for recommendation was based on the dosage and duration of therapy of aspirin in several large DES trials^15,16 and not on specific studies looking at dosage and duration of antiplatelet treatment. In fact, several smaller DES trials did use lower doses of ≥ 75 mg, but this did not alter the recommendations of the guidelines.^17–21 Concerns of an increased risk of subacute stent thrombosis because of the delayed endothelialization may have prompted these recommendations.^22,23 Although concurrent ADP-receptor antagonist use has been suggested to be the more important factor in preventing stent thrombosis, the dosage of aspirin may also play an integral role. In our analysis, 1,840 patients were followed for a 1-year period after the index PCI procedure to document the occurrence of death, myocardial infarction (MI) and repeat target vessel revascularization. We hypothesized that patients who received a low dose (81 mg/day) of aspirin would have more cardiac adverse events compared to those receiving a higher dose of 325 mg.

Methods

Setting and design. The Ottawa Heart Institute PCI Registry is a prospective registry of all patients undergoing PCI at the University of Ottawa Heart Institute, a tertiary cardiac center with a referral base of 30 peripheral hospitals servicing a population of over 1 million. The present analysis included patients who underwent PCI from December 1, 2003 to November 30, 2004. Patients were identified retrospectively from the registry and were then followed prospectively over a 1-year period. The study was approved by the Human Research Ethics Review Board of the University of Ottawa Heart Institute (Ottawa, Ontario, Canada). Data collection. Trained cardiac registered nurses collected data from hospital charts of patients who underwent PCI during the study period. One year after the index PCI procedure, a telephone interview was conducted. If admission to the hospital for cardiac symptomatology occurred within 1 year of PCI, the records from the admitting hospital were obtained if consent was given. For patients with repeat angiography or PCI, subsequent procedural reports and in-hospital charts were evaluated for the presence of outcomes. For patients with > 1 PCI in the study period, the first procedure was counted as the entry date into the study. Explicit definitions for data elements were predetermined. Recurrent MI was defined as ischemic symptoms with recurrent elevation of ST-segments in ≥ 2 contiguous leads or the elevation of cardiac biomarkers to > 2 times the upper limit of normal. Target vessel revascularization (TVR) was defined as unplanned repeat coronary revascularization by PCI or coronary artery bypass graft surgery (CABG) involving the artery of the index PCI procedure. The Charlson score, a validated measure of comorbidity, was calculated for each patient.²⁴ Urgent PCI was defined as any PCI performed on in-hospital patients. Stent thrombosis included cases confirmed by angiography and autopsy up to 1 year after the index PCI procedure (ARC-definite). The dose of aspirin prescribed was at the operator’s discretion post PCI. Patients were divided into two groups based on dosage of aspirin at the time of hospital discharge. Those with a dose of ≥ 325 mg per day of aspirin were deemed to be in the high-dose group, while those with 1 MI or repeat revascularization, only the first event was counted as an endpoint. Planned staged PCI procedures were not considered as repeat revascularization. Statistical analysis. Statistical analysis for the study was conducted using SAS software, version 9.1 (SAS Institute, Inc., Cary, North Carolina). The primary hypothesis that those with low-dose aspirin would have a higher event rate for the primary outcome compared to those with high-dose aspirin was tested using Fisher’s exact test with adjusted odds ratios (OR). All p-values were reported as two-tailed with an accepted significance of ≤ 0.05. Odds ratios were reported with 95% confidence intervals. Characteristics between the 81 mg and 325 mg groups were compared using the Fisher’s exact test for binary variables and x2 test for other categorical variables. For continuous variables, the student’s t-test was used for normally distributed variables and the Wilcoxon’s Rank Sum test for non-normal data. A logistic regression model to determine predictors for the primary outcome was created. Covariates included in the model were: dosage of aspirin, age, gender, diabetes mellitus, hypercholesterolemia, hypertension, smoking, family history of premature coronary artery disease, history of MI, previous PCI, history of CHF, history of transient ischemic accident or stroke, nonelective PCI, acute coronary syndromes, concurrent lipid-lowering therapy, use of DES, multivessel coronary disease and the Charlson comorbidity score. Multiple separate logistic regression models were constructed using the above variables to determine the impact of low-dose aspirin in several subgroups of interest. An additional analysis was conducted by the creation of a propensity score to predict the probability of receiving a low aspirin dose (a propensity score) from a logistic regression model as a function of the clinical variables in the original logistic model. This analysis approach allows comparisons of treatment groups in observational studies where selection bias may exist, which predisposes patient allocation into one treatment group over another. Conditioning on the propensity score in an adjusted analysis provides an alternative mechanism for controlling confounding variables. A stratified analysis using the Mantel-Haenszel weighted formula was performed with subjects assigned to strata defined by subranges of the propensity score.

Results

Baseline characteristics. During the study period, the OHI-PCI registry contained 2,294 PCI procedures. Review of procedural records revealed 84 to be either failed PCI or cases where PCI was not performed or where patients suffered an in-hospital death. Two hundred and twenty-six procedures were for repeat PCI within the 1-year period. Ninety-nine patients (5.0%) were lost to follow up and were not included in the present analysis. Forty-five patients were further excluded from analysis because of aspirin allergy or absence of aspirin at discharge. One thousand eight hundred and forty patients fulfilled inclusion and exclusion criteria (Figure 1). Among this cohort, 910 patients (49.5%) received Clinical outcomes. The primary outcome of all-cause mortality and MI was similar between the two groups with no benefit observed in the 325 mg users. Among patients with 81 mg of aspirin, 50 (5.5%) suffered the primary endpoint of death or MI. In the high-dose aspirin group, 39 (4.2%) died or had an MI at 1-year follow up. The unadjusted and adjusted odds ratios (OR) for all clinical outcomes are shown in Table 3a. Adjustments for covariates did not significantly alter this result. A stratified analysis using the propensity score confirmed the associations in the main analysis above. The adjusted OR accounting for the propensity score of 81mg of aspirin on the primary outcome was 1.07 (95% CI 0.71–1.61). Predictors for the primary outcome are shown in Figure 2. The dosage of aspirin was not predictive of outcomes. Patients undergoing urgent PCI or who had higher Charlson comorbidity scores were more likely to die or suffer a MI. Patients with hypercholesterolemia had less adverse events. Subgroup analysis (Figure 3) among several high-risk groups did not demonstrate a clear advantage of higher-dose compared to low-dose aspirin. However, there was a trend toward increased death and MI in patients with multivessel disease discharged on 81 mg of aspirin (p = 0.07). Irrespective of whether a BMS or DES was implanted, there was no increase in death or MI between aspirin dosage groups (Table 4). Six of the 910 patients (0.6%) in the low-dose group had stent thrombosis compared to 7/930 (0.7%) in the high-dose group (p = 1.00). There was also no significant difference in death or MI among the patients who started on 81 mg of aspirin and remained on this dosage at 1 year (5.1%) compared to those who started and remained on 325 mg of aspirin (3.3%), p = 0.14 (Table 3b).

Discussion

Our study has shown that in a general cohort of patients undergoing PCI, low-dose aspirin of 81 mg was not associated with an increase in death or MI at 1 year compared to a higher dose of 325 mg. Analysis using a propensity score supported these conclusions. Among subgroups of interest, patients on 325 mg of aspirin did not demonstrate a significant reduction in death or MI. In particular, the theoretical concern of increased subacute stent thrombosis among patients who received a DES was not observed in our study. Event rates in those receiving DES were similar between those with high-dose aspirin versus those with low-dose aspirin. Similarly, observations in a previous study of a cohort of patients with sirolimus-eluting stents noted no differences in subacute and late stent thrombosis.²⁵ In our patients with multivessel coronary artery disease, a trend towards increased death and MI was present among those on low-dose aspirin. This will require further validation before support can be given for routine high-dose aspirin in this subgroup. Some discrepancies were observed among subgroups in our cohort in the choice of aspirin dosing. As this was documented retrospectively and not at the time of PCI, the true reason for the choice of aspirin dosing cannot be elucidated. In our study, those with multivessel disease did have a greater usage of high-dose aspirin. The choice of 325 mg of aspirin may be related to the operator’s concern for stent thrombosis or future ischemic outcomes. Conversely, the usage of 81 mg of aspirin may be more common in patients with a perceived risk of bleeding or in those in whom the operator may not be acquainted with the patient’s medical history. Accordingly, patients with STEMI and shock at presentation in our study had a greater usage of 81 mg of aspirin. Concerns for the utilization of aspirin in patients with CHF have previously been suggested.26 This may, in part, account for the higher usage of low-dose aspirin in CHF patients in our study. A true understanding of the reasoning behind dosage choice would require a prospective analysis of a cohort of patients at the time of PCI. Recently, the updated ACC/AHA guidelines for PCI suggested, as a Class I recommendation, the use of higher-dose aspirin (162–325 mg) in the initial period post PCI. The guidelines were specific for a longer duration of high-dose aspirin in patients receiving DES. Dosing of aspirin after PCI, while topical, has not been studied in a randomized, controlled trial. Previously, the use of lower-dose aspirin has been studied in patients with acute coronary syndromes in an era before the use of DES.²⁷ Joyal et al further studied a cohort, all of whom underwent PCI with sirolimus-eluting stents and demonstrated no differences with low-dose versus high-dose aspirin. To our knowledge, our study is the largest one to evaluate the impact of aspirin dosing in a cohort of general PCI patients in a contemporary setting. Our study, which also included patients with BMS, complements the existing knowledge and supports the often-used dosage of 81 mg as probably being as safe as 325 mg. Despite several recent clinical trials examining the role of other antiplatelet or antithrombotic regimens in PCI, funding for a prospective, randomized trial on aspirin dosing alone would be unlikely. Based on the primary outcome event rates in our study, with an alpha of 0.05 and a power of 0.90, a trial of over 11,000 patients would be required to show a benefit of high-dose aspirin over low-dose aspirin in all-comers undergoing PCI. The ongoing CURRENT/OASIS 7 (Clopidogrel optimal loading dose Usage to Reduce Recurrent eventNTs/Optimal Antiplatelet Strategy for InterventionS) trial studying clopidogrel and aspirin dosing in patients with non-ST-elevation acute coronary syndromes undergoing PCI may provide insights into the role of aspirin dosage in that group of patients.²⁸ The use of combination antiplatelet therapy with aspirin and a thienopyridine after coronary stenting was demonstrated to reduce outcomes compared to conventional approaches where aspirin was used alone or in combination with warfarin.^29–32 The efficacy of this dual-antiplatelet combination has not been extensively studied compared to a treatment of a thienopyridine alone for patients post PCI. A recent study compared the antiplatelet profile with the use of 81 mg versus 325 mg of aspirin before and during treatment with clopidogrel.³³ Using multiple parameters to assess platelet activation, it was consistent that better platelet inhibition was achieved with the higher dose. However, repeat measurements after clopidogrel loading showed no differences in antiplatelet action. Based on these results, the authors concluded that 81 mg may be the better dose when using dual-antiplatelet therapy, in light of decreased bleeding risks.³³ The increased adoption of DES in clinical practice has raised concerns of subacute stent thrombosis.^22,23 Although the actual risk is controversial,^34,35 it has become the impetus for the dosing recommendations of aspirin in the updated ACC/AHA guidelines for PCI. Data on increased events > 1 year after PCI have recently been published in the BASKET-LATE (BAsel Stent Kosten Effektivitats Trial LAte Thrombotic Events) study,³⁶ where all patients were treated with 6 months of clopidogrel. As clopidogrel is often stopped ≤ 1 year, this would suggest that the failure may be due to the premature stopping of clopidogrel rather than aspirin dosing. The extended use of clopidogrel has been associated with a reduction in death and MI in an observational setting, but his concept requires further investigations with large-scale randomized studies.³⁷ Physiologically, the mechanism of aspirin in the prevention of thrombotic events occurs via the inhibition of thromboxane A2 and its subsequent effects on platelet aggregation.³⁸ The inhibition of thromboxane A2 has been shown to be as effective for low-dose aspirin at 75 mg compared to higher doses.³⁹ Consequently, from a mechanistic point of view, an increase in aspirin dosage should not decrease the incidence of thrombotic events. Emerging knowledge on aspirin resistance offers a separate mechanism in which dosage may play a factor. In studies with doses of ≤ 100 mg of aspirin, the prevalence rate of aspirin resistance was higher than those with a dosage ≥ 300 mg.⁴⁰ With the assumption of aspirin resistance being a correlate to increased cardiovascular events, it would be expected that trials of low-dose aspirin are inferior to those with higher dosages. This has not been demonstrated clinically, as previous studies of different populations with cardiovascular diseases have supported an equivalence of low-dose versus high-dose aspirin.^7–9 The event rates for our registry were low. Previous data have shown that adherence to guideline-recommended medications prevents death and MI after PCI. This was more prominent in patients with ≤ 2 classes of recommended drugs.² The use of these medications in our registry was high and may account for the lack of events. This would endorse the idea that adherence to evidence-based medication is imperative, especially if low-dose aspirin is used. Study limitations. Our study is the largest contemporary analysis evaluating the optimal dosage of aspirin in a general PCI population. Although it was a retrospective, nonrandomized study, concurrent patients were enrolled and followed prospectively for 1 year. Our study had few exclusion criteria and would be generalizable to a broad spectrum of patients undergoing PCI. The volume of procedures in our center, as well as the rate of DES use, are comparable to many tertiary centers worldwide. However, our numbers are underpowered in terms of drawing definitive conclusions on stent thrombosis. Our analysis was based on discharge aspirin dosage. The “crossover” of patients from one dose to another after discharge may be a confounding factor. As follow up was conducted at 1 year after PCI, recall bias would preclude a reliable analysis of the aspirin dosage at time intervals before the follow up. Our analysis attempted to account for possible covariates that may affect clinical outcomes. The results of the propensity analysis further support the absence of significant risk in using a lower dose of aspirin in this population. Despite these statistical methods, unknown variables relating to the choice in dosing may exist and may not be accounted for in this study. Lastly, we are unable to confirm that patients were actually taking the actual dosage of aspirin throughout the study period.

Conclusion

The results of the present study suggest no detrimental effects of an 81 mg dose of aspirin compared to a higher dose of 325 mg aspirin post PCI. The conclusions drawn from this analysis should reassure many clinicians that their current practice of low-dose aspirin use after PCI is safe.

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