Effect of Prior Aspirin Treatment on Patients With Acute Coronary Syndromes: Insights From the PROSPECT Study
Abstract: Background. Prior aspirin treatment is considered a risk factor for adverse outcomes in acute coronary syndrome (ACS) patients. The relationships between aspirin pretreatment and findings on quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS), as well as clinical outcomes, are not well understood. Methods. In the PROSPECT trial, QCA and triple-vessel IVUS imaging were performed after successful percutaneous coronary intervention (PCI) of the culprit lesion(s) in ACS patients. We compared patients receiving aspirin within 7 days of enrollment to those naive to aspirin. Propensity score matching was performed to adjust for differences in baseline characteristics. Results. Aspirin-pretreated patients (n = 236; 35%) were older and more likely to have known coronary disease than those without pretreatment (P≤.01 for all). Pretreated patients had more untreated non-culprit lesions with angiographic and IVUS characteristics predictive of future events (53.1% vs 38.6%; P<.001). There were no significant differences in overall major adverse cardiac event (MACE) rates at 3 years between the aspirin and no-aspirin groups (23.6% vs 18.8%, respectively; P=.17) in unadjusted or propensity-adjusted analyses. Prior aspirin use was not an independent predictor of MACE at 3 years (hazard ratio, 1.21; 95% confidence interval, 0.73-2.01; P=.45). Conclusion. In the PROSPECT trial, aspirin pretreatment identifies an older population with more advanced coronary disease. Aspirin pretreatment was not an independent predictor of MACE in ACS patients treated with an early invasive strategy. The extent to which aspirin pretreatment is a risk factor for adverse events after PCI in ACS should be revisited.
J INVASIVE CARDIOL 2015;27(12)536-541. Epub 2015 July 15.
Key words: risk factors, adverse events
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Aspirin is increasingly used for primary or secondary vascular protection, particularly in patients with or at risk for coronary artery disease (CAD).1 Aspirin is a mainstay of therapy for acute coronary syndrome (ACS) patients, and is recommended indefinitely after initial treatment.2
The TIMI (Thrombolysis In Myocardial Infarction)-11B trial (n = 3910)3 and the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events) trial (n = 3171)4 compared the utility of low-molecular-weight heparin vs unfractionated heparin in ACS patients. The two studies were combined to derive the widely used TIMI unstable angina risk score for ACS, based on the results of a multivariable model including numerous baseline characteristics.5 Pretreatment with aspirin within 7 days of ACS was an independent predictor of major adverse cardiac events (MACE, defined as all-cause death, myocardial infarction, or severe recurrent ischemia prompting revascularization) through 14 days (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.17-2.59; P=.01). Like the other six predictors in the TIMI unstable angina risk score (age ≥65 years, ≥3 CAD risk factors, severe angina in the previous 48 hours, known CAD, elevated cardiac biomarkers, and ST-segment deviation), aspirin pretreatment is assigned 1 of 7 possible points in this score and confers risk similar to the other components. The C-statistic for this score was 0.65, indicating only moderate discrimination, and these data were obtained more than a decade ago, reflecting the outcomes of ACS patients treated with a predominantly conservative strategy. Whether prior aspirin treatment remains a risk factor in the contemporary percutaneous coronary intervention (PCI) era has not been examined. Moreover, why this aspirin pretreatment paradox may exist has not been well characterized.
We used the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study to investigate the correlates and implications of prior aspirin treatment in a contemporary cohort of ACS patients undergoing revascularization followed by extensive evaluation of the coronary tree with quantitative coronary angiography (QCA), intravascular ultrasound (IVUS), and virtual histology (VH) imaging.6
Methods
The PROSPECT study has been described in detail.6,7 In brief, a total of 697 patients presenting with ACS (ST-segment elevation myocardial infarction [STEMI], non-ST segment elevation myocardial infarction [NSTEMI], or unstable angina with electrocardiographic changes) were enrolled after successful PCI of all lesions believed to be responsible for the clinical presentation and after completion of any other planned interventions (culprit lesions) in ≤2 major epicardial coronary arteries. Three-vessel QCA and VH-IVUS imaging were then performed as previously described.8,9
Patients were followed for a median of 3.4 years. The primary endpoint was the occurrence of MACE, consisting of cardiac death, cardiac arrest, MI, or rehospitalization for unstable or progressive angina as adjudicated by an independent clinical events committee. Each adverse event was assessed as having arisen from either an originally treated culprit lesion vs an untreated non-culprit lesion, or was termed indeterminate in origin if follow-up angiography was not performed at the time of the late event. Stent thrombosis was adjudicated according to Academic Research Consortium (ARC) definitions.10
Quantitative coronary angiography. QCA measurements were performed over the entire length of the coronary tree (including side branches) in any vessel ≥1.5 mm in diameter with the use of proprietary methods modified from QCA-CMS version 7.0 (Medis Medical Imaging Systems BV). The reference vessel diameter, minimal lumen diameter, and diameter stenosis were calculated for each vessel. Analysis of all angiographic lesions with ≥30% visual diameter stenosis was also prespecified in the study protocol.
VH-IVUS analysis. Grayscale and virtual histology (VH)-IVUS of the left main and proximal 6-8 cm of each major epicardial coronary artery was performed using motorized catheter pullback at 0.5 mm/s after PCI. Offline grayscale and VH-IVUS analysis was performed using: (1) QCA-CMS for contouring; (2) pcVH version 2.1 (Volcano Corporation) for contouring and VH data output; and (3) proprietary qVH version 2.5 (developed and validated at the Cardiovascular Research Foundation) for segmental qualitative assessment and data output. Quantitative IVUS measurements included external elastic membrane, lumen, plaque plus media cross-sectional area, and plaque burden (defined as plaque plus media divided by external elastic membrane). An IVUS lesion was defined as a segment with ≥3 consecutive frames with ≥40% plaque burden. VH-IVUS plaque components (fibrofatty, fibrotic, dense calcium, and necrotic core) were reported as cross-sectional area and percentage of total plaque area. Lesions were classified into five main phenotypes: (1) VH thin-cap fibroatheroma; (2) thick-cap fibroatheroma; (3) pathological intimal thickening; (4) fibrotic plaque; and (5) fibrocalcific plaque, as previously described.6
Statistical analysis. Patients with vs without aspirin treatment within the 7 days prior to the index ACS presentation were compared. Continuous variables (presented as median with interquartile range) and categorical variables (presented as proportions) were analyzed with ANOVA and chi-square tests, respectively. Kaplan-Meier time-to-event estimates were compared with the log-rank test. Propensity matching of patients was performed to balance baseline characteristics. The variables used for matching were age, diabetes mellitus, hypertension, hyperlipidemia, prior myocardial infarction, prior PCI, known CAD, and prior angina. Cox regression analysis was performed to evaluate the independent correlation of aspirin pretreatment for 3-year MACE. Besides aspirin pretreatment and the propensity score for aspirin pretreatment, the model included worst non-culprit lesion by QCA (diameter stenosis >70%, 50%-70%, or <50%); any lesion with MLA <4 mm2, plaque burden >70%, or VH thin-cap fibroatheroma; diabetes mellitus (DM); age; chronic kidney disease (creatinine clearance <60 mL/min); and prior MI. All analyses were performed with SAS version 9.2 (SAS Institute). A 2-sided P-value <.05 was considered significant.
Results
Baseline features. Aspirin pretreatment was present in 236 of the 675 patients (35.0%) in whom aspirin status prior to enrollment was known. As shown in Table 1, aspirin-pretreated patients were significantly older (by 5 years), had more CAD risk factors, and were more likely to have known CAD, be treated with a statin, and have prior revascularization, prior MI, and prior angina. The incidence of DM was similar among the groups. Presentation with NSTEMI was more common in the pretreated patients. High-sensitivity C-reactive protein levels were significantly lower among aspirin-pretreated patients.
Angiography revealed similar findings in the two groups, with some differences. There were more patients with two-vessel CAD in the aspirin-pretreated group (37.2% vs 26.9%; P=.01) and fewer with three-vessel CAD (9.4% vs 18.7%; P=.01) than in the no-aspirin group. By IVUS, untreated plaque ruptures in non-culprit lesions were more common in aspirin-pretreated patients vs no-aspirin patients (17.7% vs 11.8%; P=.04). The total volume of necrotic plaque was also higher in aspirin-pretreated patients (38.91 mm3 [range, 16.50-74.24 mm3] vs 32.63 mm3 in the no-aspirin group [range, 15.38-58.20 mm3]; P=.04). There were no other major differences between the groups with respect to VH-IVUS parameters.
Clinical outcomes. At 30 days, a time point more likely to be affected by pretreatment, MACE occurred in 1.7% of the aspirin-pretreated group and 1.2% of the no-aspirin group (P=.56). The incidence of MACE at 3 years is shown in Table 2 and Figure 1. There were no significant differences between the two groups in overall or culprit-lesion MACE. However, at 3 years, non-culprit lesion-related MACE was more common in the aspirin-pretreated group (15.3% vs 9.6% in the no-aspirin group; P=.04).
Because of significant differences in baseline characteristics between the groups, we performed propensity score matching and were able to match 147 patients in each group (62% of the pretreatment group). The matched groups were much better balanced for baseline characteristics, with the exception of ACS presentation, with 
more NSTEMI in the aspirin-pretreated group (P=.01). The incidence of MACE at 3 years in the matched cohort is shown in Table 3. Non-culprit MACE occurred in 13.7% in the aspirin-pretreated group and 8.1% of the no-aspirin group (P=.14). By multivariable analysis, prior aspirin use was not an independent predictor of MACE at 3 years (hazard ratio, 1.21; 95% CI, 0.73-2.01; P=.45). The only independent predictors of MACE were the presence of untreated lesions with MLA <4 mm2 (P=.03) or plaque burden >70% (P=.01), and diabetes mellitus (P=.04).
Discussion
The main findings of this post hoc analysis from the PROSPECT study can be summarized as follows: (1) one-third of patients with ACS were already on aspirin before presenting with ACS; (2) patients with prior aspirin treatment were older, more often treated with statins, and had more adverse baseline characteristics than patients with no prior aspirin treatment; (3) MACE rate, early on and at 3 years, was not significantly different between the two groups before and after propensity matching; and (4) prior aspirin treatment was not an independent predictor of MACE.
Because of the differential ability of vascular endothelial cells and platelets to regenerate cyclooxygenase (prostaglandin H-synthase or COX) 1 and 2, aspirin’s predominant effect is to prevent thrombosis.11 These enzymes facilitate the first committed step of arachidonic acid metabolism – its conversion to PGH2, a precursor of at least 5 prostanoids, such as prostacyclin (PGI2), thromboxane (TXA2), and others.12 Mature platelets express only COX-1. Larger doses of aspirin are needed to inhibit COX-2 than COX-1.13 TXA2 is released by platelets in response to stimuli such as collagen, thrombin, and adenosine diphosphate and works as an amplifier of platelet aggregation by other stimulants. It also causes vasoconstriction.14 When released, TXA2 aggregates platelets via a G-protein coupled receptor.15 Aspirin irreversibly acetylates COX and prevents the access of PGH2 to COX, and thus prevents TXA2 formation. In order to be effective as an antiplatelet agent, aspirin needs to inhibit ~95% of the synthetic ability of platelets to generate TXA2.16 For patients with known vascular disease, chronic aspirin therapy considerably improves event-free survival. In a meta-analysis of 65 randomized clinical trials, aspirin resulted in a 23% lower rate of ischemic events (vascular death, myocardial infarction, or stroke) compared with placebo (12.9% vs 16.0%, respectively; P<.001).17
In the TIMI unstable angina risk score, prior aspirin therapy in ACS was identified as an independent predictor for adverse events (representing patients who have “failed aspirin”) in an era in which conservative management was the standard of care.5 In this regard, some experimental data suggest that aspirin pretreatment may aggravate the consequences of an acute MI. In anesthetized dogs subjected to coronary occlusion and reperfusion, specific thromboxane synthase inhibitors reduced infarct size. After aspirin pretreatment, their effect is attenuated because the prostaglandins PGG2 and PGH2 can be transformed into protective compounds – PGD2 (plasma) and PGI2 (endothelium) – but are suppressed by aspirin inhibition of the entire prostaglandin pathway.18
In contrast, in our study of patients with ACS treated with contemporary PCI technologies with adjunct pharmacotherapy (including high rates of secondary prevention with statins, beta-blockers, and angiotensin-converting enzyme inhibitors), although prior aspirin treatment identified a group of patients with more adverse baseline characteristics, prior aspirin treatment per se was neither protective nor conferred short-term or late risk. It may be that any increased risk of having failed aspirin therapy is overcome by effective revascularization in ACS, as in our study patients. The higher volume of necrotic plaque observed in pretreated patients confirms, for the first time, the fact that ASA pretreatment identifies not only a higher-risk group of patients based on clinical and demographic parameters, but also a cohort with more advanced CAD. This increased burden of atherosclerosis, rather than being caused by ASA pretreatment, may explain the higher rate of non-culprit MACE at follow-up. Indeed, some clinical and experimental reports have supported the notion that chronic aspirin therapy is beneficial when ACS occurs. Kennon et al19 reported that among 304 patients presenting with NSTEMI, C-reactive protein and troponin elevation were lower in patients with vs without aspirin pretreatment. Portnay et al20 reported that 33.2% of 118,992 Medicare recipients presenting with acute myocardial infarction were taking aspirin before admission, similar to our findings. Mortality rates at 1 month and 6 months were significantly lower in those pretreated with aspirin (16.1% vs 19.0% and 24.7% vs 27.5%, respectively; P<.001 for both). By multivariable analysis, aspirin pretreatment was an independent predictor of lower mortality at both time periods. In an experimental model of diagonal branch ligation in baboons, myocardial blood flow in both the subendocardial and the epicardial zones was higher in aspirin-pretreated animals than in controls.21 In a more recent analysis of 66,443 ACS patients from various TIMI trials, prior aspirin use was associated with older age, more CAD risk factors, and less severe ACS presentation (all P<.001), similar to our results.22 After adjusting for differences in baseline characteristics, there was no difference in mortality between those with pretreatment vs those without pretreatment, but prior aspirin use was associated with a slightly higher rate of recurrent MI (odds ratio, 1.26; P<.05).
Study limitations. The sample size of PROSPECT was not sufficient to exclude a moderate degree of benefit or harm from aspirin pretreatment. We did not have complete data on what prompted aspirin pretreatment in all patients. We also did not assess the duration or dosage of and compliance with previous aspirin therapy. Furthermore, there was no assessment of platelet function on admission to corroborate aspirin pretreatment or possible aspirin resistance. PROSPECT was also a study of ACS patients, including those with STEMI, undergoing PCI, and thus we cannot make any statements regarding the impact of aspirin pretreatment in patients treated medically or with coronary artery bypass graft surgery following angiography.
Conclusion
Despite these limitations, we conclude that aspirin pretreatment does not appear to be a major risk factor for clinical outcomes in patients with ACS treated with modern medical therapy and contemporary PCI. A large prospective observational study of national cardiovascular registries may be useful in confirming or refuting these findings, which might prompt a reassessment of aspirin pretreatment as a component of risk stratification scores for ACS.
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From 1New York Methodist Hospital, Brooklyn, New York; 2Cardiovascular Research Foundation, New York, New York; 3Columbia University Medical Center, New York, New York; 4Shaare Zedek Medical Center, Jerusalem, Israel; 5Cardiovascular Center, OLV Hospital, Aalst, Belgium; and 6Erasmus University Medical Center, Thoraxcenter, Rotterdam, The Netherlands.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Brener reports personal fees from AstraZeneca and Eli Lilly, outside the submitted work. Dr Maehara reports a research grant from Boston Scientific Corporation; speaker fees from St. Jude Medical. Dr Stone reports grants from Volcano and Abbott Vascular during the conduct of the study; and personal fees from InfraReDx and Boston Scientific outside the submitted work. The remaining authors have no disclosures regarding the content herein.
Manuscript submitted March 10, 2015 and accepted March 15, 2015.
Address for correspondence: Sorin J. Brener MD, FACC, Professor of Medicine, Director, Cardiac Catheterization Laboratory, New York Methodist Hospital, 506 6th Street, KP-2, Brooklyn, NY 11215. Email: sjb9005@nyp.org
