Methods

The study population consisted of patients enrolled in the Dual Antiplatelet Therapy (DAPT) Study, an international, multicenter, randomized, controlled trial investigating duration of thienopyridine therapy in combination with ASA after PCI with stent implantation. The trial design and study protocol have been published previously. The DAPT Study enrolled 26,194 adult patients who underwent elective or urgent PCI with bare-metal stent or drug-eluting stent (DES) deployment and who were eligible for long-term dual antiplatelet therapy. Enrollment from 444 sites in 11 countries occurred from August 2009 to July 2011. Randomization to a total of 12 versus 30 months of clopidogrel or prasugrel occurred 12 months after index PCI procedure. ASA was mandatory, but the dose (75 to 325 mg/day) was left to physician’s discretion, although the lowest acceptable dose was recommended. The DAPT Study is still in follow-up for the coprimary end points of all-cause death, myocardial infarction, and stroke; definite or probable stent thrombosis; and the safety end point of major bleeding. Enrollment data collected during index admission were used for this analysis (database accessed in October 2012). All patients provided written consent to participate in the DAPT Study. The study was approved by the local ethics committee at each enrolling center.

The primary outcome for this analysis was receiving a prescription of LD ASA at discharge after the index procedure. The threshold for LD ASA was defined as any prescription of ≤100 mg/day based on the previous definition of LD ASA. Information on ASA dose at discharge was available for 26,006 subjects in the DAPT Study (99.3%).

Baseline characteristics that were examined as possible factors influencing ASA dose included demographic factors (age, gender, and race [for US subjects only]), risk factors for coronary artery disease (hypertension, diabetes, smoking status, weight, and body mass index), cardiovascular and noncardiovascular co-morbidities (prior PCI, coronary artery bypass surgery, stroke, peripheral artery disease, atrial fibrillation, heart failure, left ventricular ejection fraction <30%, cancer, bleeding event in the past, and chronic renal failure), clinical presentation (ST-segment elevation myocardial infarction and non–ST-segment elevation acute coronary syndrome), angiographic factors (in-stent restenosis, PCI in >2 vessels, unprotected left main intervention, >2 lesions per vessel, lesion length ≥30 mm, bifurcation lesion, vein bypass graft, and thrombus-containing lesion), type of stent implanted (DES or bare-metal stent), and type of thienopyridine given for dual antiplatelet therapy (clopidogrel or prasugrel). A summary variable classifying subjects at increased risk of stent thrombosis was also included if any of the following characteristics were present: ST-segment elevation myocardial infarction or non–ST-segment elevation acute coronary syndrome presentation, chronic kidney disease, left ventricular ejection fraction <30%, and/or any angiographic factors listed previously.

Baseline characteristics of patients are presented separately for US and non-US subjects. Continuous data are expressed as mean ± SD, and categorical and/or binary data are expressed as proportions. Baseline characteristics between US and non-US patients were compared with Student t test and chi-square test for continuous and categorical and/or binary data, respectively. Because the goal of this study was to assess the use of ASA in the US and a large discrepancy is known to occur in the prescription pattern of ASA after PCI in the US compared with the rest of the world, analyses were made separately for US and non-US subjects. Generalized linear mixed models with binomial distribution and logit link were used to identify predictors of LD ASA use, accounting for clustering within sites and countries, with random intercept for sites for the US subset and random intercept for sites and countries for the non-US subset. Laplace integral approximation was used to compute effect estimates of predictors of LD ASA. For each subset of the DAPT Study population, univariate predictors of LD ASA were identified and multivariate models were built with a backward selection procedure and a p value criterion of ≤0.05 to stay in the model.

Variance explained by individual-level predictors and proportion of residual variance at each level of the generalized linear mixed models were evaluated using a method described by Snijders and Bosker. To assess the importance of clustering factors compared with individual-level characteristics in explaining variation in LD ASA use in each population, median odds ratios (MORs) were calculated using the cluster variance, in which the cluster unit was the site for the US subset and site and country for the non-US subset. A secondary analysis was also performed in the US subset with the introduction of a second level of clustering by state. MOR represents the variation at the level of the clustering factor by comparing 2 subjects chosen randomly from 2 different clusters for their propensity to receive LD ASA. An MOR of 1 would indicate no variability between the cluster units, and an MOR >1 would represent the median increase in odds ratio of receiving LD ASA if a patient was changing from one site to another. The larger the difference between sites for LD ASA prescription, the larger the MOR will be. As the MOR is reported on the odds ratio scale, it can be directly compared with odds ratio of individual variables.

Sensitivity analyses were performed using conventional logistic regression and backward selection of covariates with an identical p value criterion of ≤0.05. To take into consideration clustering of data, each site was dummy coded and forced into the multivariate models (370 US sites and 74 non-US sites). C-statistic from models with sites and clinical predictors identified in the primary analyses was compared with C-statistic from models with sites only and models with clinical predictors only. The primary analysis with generalized linear mixed model was also repeated using forward selection of covariates to evaluate the robustness of the original model. As the CURRENT-OASIS 7 trial was published during the enrollment phase of the DAPT Study, rates of LD ASA use before and after the publication were compared, and its impact was assessed on the primary model by adding a binary covariate representing the 2 time periods. All analyses were performed using SAS 9.2 (SAS Institute, Cary, North Carolina). Statistical significance was defined as p value <0.05 for all analyses.

Results

ASA dose was available in 99.3% of patients (26,012 of 26,194) at discharge. The rate of LD ASA use after PCI was 28.0% (6,525 of 23,336) among patients treated in the US and 94.3% (2,523 of 2,676) among patients treated in non-US countries. The proportion of LD ASA use per site showed greater variability within the US—with close to 60% of sites discharging <30% of their patients on LD ASA ( Figure 1 ) and less variability in the non-US sites—with 80% of sites discharging at least 90% of their patients on LD ASA ( Figure 1 ). Sites from the US enrolled more subjects per site with a median of 40 (interquartile range 16 to 91) compared with a median of 26 (interquartile range 12 to 48) for non-US sites. Characteristics of patients enrolled in the US and outside the US are listed in Table 1 . In the US, patients were slightly older, had more risk factors and co-morbidities, and presented less often with ST-segment elevation myocardial infarction compared with non-US patients.

Distribution of site-specific overall use of LD ASA at discharge after PCI during index hospitalization among US sites (A) and non-US sites (B) .

In the US subset, 19 univariate factors were associated with the use of LD ASA at discharge after PCI ( Table 2 ), and of these, 13 were found to be independent predictors in multivariate generalized linear models ( Table 3 ). The MOR for site, which estimated the overall impact of site as a predictor of the odds of receiving LD ASA, was 5.05 (95% confidence interval [CI] 4.29 to 5.85), which was stronger in magnitude than any patient-level clinical factor ( Table 3 ). Overall, the clinical covariates together explained only 1.6% of total variability in the prediction of ASA dose at discharge. Of the remaining unexplained variability, 45.9% was at the site level and 52.5% was at the patient level. Outside the US, fewer factors were associated with LD ASA ( Table 2 ) and only 1 factor remained independently associated in multivariate analysis. The MOR for site was 7.42 (95% CI 3.45 to 12.80) and the MOR for country was 4.41 (95% CI 1.00 to 10.76; Table 3 ). Again, site had a stronger impact than any clinical predictor. The major portion of unexplained variability was at the site level (41.1%), with clinical characteristics explaining only 5.6% of total variability.

Table 2

Univariate predictors of low-dose aspirin

Covariate	US Subset			Non-US Subset
	Odds Ratio	95% CI	p Value	Odds Ratio	95% CI	p Value
Age, per 10 yrs	1.19	1.15–1.23	<0.001	1.10	0.89–1.35	0.385
Race				NA	NA	NA
White	Reference	Reference
Black	0.93	0.81–1.07	0.293
Latino	1.00	0.83–1.21	0.993
Other	1.14	0.90–1.44	0.277
Weight, per 10 kg	0.97	0.95–0.99	<0.001	0.92	0.80–1.06	0.245
BMI, per kg/m 2	1.00	0.99–1.00	0.202	0.98	0.93–1.03	0.363
Men	0.80	0.74–0.86	<0.001	0.99	0.58–1.68	0.967
Diabetes mellitus	1.14	1.06–1.23	<0.001	1.18	0.68–2.05	0.557
Hypertension	1.33	1.22–1.45	<0.001	1.15	0.73–1.80	0.545
Smoker	0.74	0.69–0.81	<0.001	0.89	0.55–1.43	0.619
Prior PCI	0.99	0.92–1.07	0.851	1.47	0.81–2.67	0.206
Prior coronary artery bypass graft surgery	1.08	0.98–1.19	0.137	0.82	0.31–2.17	0.695
Congestive heart failure	1.22	1.07–1.40	0.003	4.78	0.48–47.21	0.181
Left ventricular ejection fraction <30%	0.93	0.72–1.19	0.572	0.98	0.17–5.60	0.984
Previous stroke	1.15	0.93–1.42	0.191	0.71	0.19–2.66	0.613
Peripheral artery disease	1.27	1.11–1.44	<0.001	2.04	0.56–7.41	0.280
Atrial fibrillation	1.45	1.24–1.71	<0.001	0.92	0.25–3.42	0.904
Cancer history	1.14	1.02–1.27	0.025	0.77	0.31–1.91	0.570
Bleeding history	1.57	1.12–2.19	0.009	NA	NA	NA
Renal failure	1.25	1.08–1.44	0.003	4.37	0.45–42.11	0.202
ST-segment elevation myocardial infarction	0.55	0.48–0.63	<0.001	0.29	0.17–0.50	<0.001
Non–ST-segment elevation acute coronary syndrome	0.70	0.64–0.76	<0.001	0.72	0.37–1.39	0.332
Drug-eluting in-stent restenosis	0.81	0.68–0.96	0.017	6.67	0.37–120.74	0.199
>2 vessel intervention	0.81	0.50–1.33	0.406	NA	NA	NA
Coronary anatomy
Left main intervention	0.73	0.43–1.23	0.237	5.07	0.66–38.80	0.118
>2 Lesions per vessel	0.85	0.68–1.07	0.162	0.29	0.06–1.39	0.121
Lesion length ≥30 mm	0.84	0.75–0.95	0.005	0.65	0.33–1.28	0.212
Bifurcation	0.93	0.80–1.09	0.379	1.23	0.50–3.03	0.657
Saphenous vein graft	1.01	0.83–1.22	0.954	3.33	0.14–80.34	0.459
Thrombus	0.68	0.60–0.77	<0.001	0.63	0.36–1.12	0.116
≥1 stent thrombosis risk factor	0.73	0.68–0.78	<0.001	0.39	0.22–0.66	<0.001
Drug-eluting stent used	1.30	1.13–1.50	<0.001	1.89	1.04–3.44	0.037
Thienopyridine used
Clopidogrel	Reference	Reference		Reference	Reference
Prasugrel	1.01	0.96–1.06	0.797	1.14	0.66–1.95	0.644
Missing	0.84	0.51–1.38	0.501	0.11	0.01–1.45	0.093

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