Background, Incidence, and Predictors of Antiplatelet Therapy Discontinuation During the First Year After Drug-Eluting Stent Implantation
Background— Predictors of antiplatelet therapy discontinuation (ATD) during the first year after drug-eluting stent implantation are poorly known.
Methods and Results— This was a prospective study with 3-, 6-, 9-, and 12-month follow-up of patients receiving at least 1 drug-eluting stent between January and April 2008 in 29 hospitals. Individual- and hospital-level predictors of ATD were assessed by hierarchical-multinomial regression analysis. ATD could be assessed in 1622 candidates for follow-up (82.5%). A total of 234 patients (14.4%) interrupted at least 1 antiplatelet therapy drug, predominantly clopidogrel (n=182, 11.8%). Bleeding events or invasive procedures led to ATD in 109 patients. This was predicted by renal impairment (odds ratio [OR] 2.81, 95% confidence interval [CI] 1.48 to 5.34), prior major hemorrhage (OR 3.77, 95% CI 1.41 to 10.03), and peripheral arterial disease (OR 1.78, 95% CI 1.01 to 3.15). Medical decisions led to ATD in 70 patients; this was predicted by long-term use of anticoagulant therapy (OR 3.88, 95% CI 1.26 to 11.98), undergoing the procedure in a private hospital (OR 13.3, 95% CI 1.69 to 105), and not receiving instructions about medication (OR 2.8, 95% CI 1.23 to 6.36). Thirty-nine patients interrupted ATD on their own initiative, mainly immigrants (OR 3.78, 95% CI 1.2 to 11.98) and consumers of psychotropic drugs (OR 2.58, 95% CI 1.3 to 5.12).
Conclusions— ATD during the first year after drug-eluting stent implantation is based mainly on patient decision or a medical decision not associated with major bleeding events or major surgical procedures. Individual- and hospital-level variables are important to predict ATD.
Received January 20, 2010; accepted June 14, 2010.
Drug-eluting stents (DES) are recognized to reduce revascularization rates compared with bare-metal stents.1 Because DES use conveys a higher stent thrombosis risk during the first months after implantation,2 clinical guidelines recommend at least 1 year of double-antiplatelet therapy.3 Several studies have shown that premature thienopyridine discontinuation is a strong risk factor for stent thrombosis after DES implantation.2,4–6
Editorial see p 946
Clinical Perspective on p 1025
Antiplatelet therapy discontinuation (ATD) during the first year after DES implantation may occur in different scenarios (for instance, life-threatening hemorrhage, lack of adherence/compliance, or errors in medical prescription). Two studies have shown that medical, psychosocial, and care process variables may determine the risk for ATD.2,7 Although these were hypothesis-generating rather than confirmatory studies, adequate assessment of this complex issue in a real-life setting poses major methodological difficulties with regard to outcomes definition and categorization and the analytic approach to be chosen.
The present prospective multicenter study addresses the background, incidence, and potential predictors of at least 1 ATD during the first year after DES implantation. Because ATD is defined simply as discontinuation and thus may involve different scenarios, a model to predict ATD should contain domains of medical, psychosocial, and healthcare process factors. Causal paths may link some of the specific factors within and across domains, thus making it difficult to establish causal inferences. Therefore, in the present study, we explored the data to examine major factors in these pathways, but we make no assertions about causality.
Study Design and Participants
The ACDC study (Adherence to Treatment of Coronary Patients After a Catheterization With DES Implantation) is a prospective study that was undertaken in 29 participating hospitals in Spain. All patients who received at least 1 DES between January 28 and April 28, 2008, were recruited by clinical investigators at each center. Local investigators were trained and actively participated in the draft of the study protocol. Data were entered into a specifically designed database with restricted access through the Internet.
Study variables included data related to coronary angiography, cardiovascular risk factors, cardiovascular history, complications during admission, and medications at discharge. Those patients who signed informed consent documents were interviewed to record social class, educational level, and a depression screen score (Patient Health Questionnaire 915).8 All variables were defined in the study protocol. Because ATD might be influenced by center, several hospital characteristics were recorded: Number of beds, teaching status, type of funding, catheterization laboratory activity (number of patients receiving stents during the study period), proportion of patients receiving DES, and whether a booklet about the importance of antiplatelet therapy (AT) maintenance was routinely given to patients before discharge. A quality control was performed in 2 ways: (1) To ensure consecutive inclusion, investigators were asked to provide a list of all implanted DES during the study period, which was subsequently checked against hospital records; (2) to ensure quality of data collection, the records of 10% to 15% of the included patients were randomly selected and externally audited. All clinical records from centers with 5 or more discrepancies were reviewed, and mistakes were corrected retrospectively.
All patients who provided written informed consent were interviewed by phone by trained researchers at 3, 6, 9, and 12 months using a questionnaire to ascertain (1) vital status, (2) current medications (patients were asked to collect all their current medications and to read out every brand name), (3) medications temporarily or permanently interrupted since the previous phone call, (4) reason for temporary or permanent discontinuation (medical advice, patient initiative, or “unknown reasons”), and (5) hospital readmissions. In case of readmission, clinical records were reviewed at the corresponding center to establish readmission reason and medications used during hospitalization and at discharge. In case of ATD during admission, the reasons for ATD (ie, hemorrhagic complication, ATD in the context of invasive medical procedure, or “unknown” reason) were recorded.
Classification of First Detected ATD
Patients had either no ATD event during follow-up or 1 or more ATD events. The outcome was the first detected ATD event. The use of this outcome recognizes that some nonrespondents may have had ATD events.
ATD was conventionally defined as a minimum of 5 consecutive days without clopidogrel, aspirin, or both. For each patient, information was recorded about the interrupted drug (aspirin, clopidogrel, or both), whether the discontinuation was permanent or temporary, and the number of days of discontinuation. In the few patients who temporarily interrupted their use of AT more than once (n=22), we recorded the data from the first episode of ATD for the sake of simplicity.
From the phone call interview and review of clinical records in the case of rehospitalization, 3 scenarios for ATD were identified: ATD in the context of hemorrhagic episode or invasive procedures (eg, surgical operation), ATD due to physician decision without the occurrence of hemorrhagic or invasive procedures, and ATD due to patient initiative. These scenarios convey a definitely clinical meaning, and for this reason, we classified the variable ATD into 4 categories: ATD for bleeding event or procedure, ATD due to medical decision not related to bleeding event or procedure, ATD due to patient initiative, and no ATD.
Descriptive data are presented as means (SDs) or proportions for individual characteristics and medians (interquartile intervals) or proportions for hospital characteristics. Bivariate and multivariate analyses were based on the dependent variable, grouped into 4 categories. For the bivariate approach, we first performed a global test for each variable to detect statistically significant differences in patient characteristics across the 4 categories (χ2 or Fisher test for discrete variables and 1-way ANOVA for continuous variables). In those variables with statistically significant differences, we then performed several subtests between categories to detect which category differed from the rest.
To assess the determinants of each ATD category, we used multinomial logistic regression modeling. The 3 multivariable model logits of interest corresponded to the categories “ATD for bleeding event or procedure,” “ATD associated with medical decision,” and “ATD due to patient initiative,” with the category “no ATD” as the reference. ATD might also be explained by differences between hospitals (eg, different therapeutic habits). Thus, we developed a model that distinguished individual- from hospital-level factors using a multilevel approach to reflect the hierarchy of patients within a hospital.
Because the number of events was small for some categories, we selected statistically significant variables in the bivariate associations and those identified a priori as potentially relevant on the basis of clinical experience and the previous literature. Candidate individual-level variables were sociodemographic and risk factors (immigrant status, defined as any person who had come to Spain to take up permanent residence; age, sex, and diabetes mellitus), cardiovascular history (peripheral arterial disease, valvular prosthesis, atrial fibrillation, previous acute myocardial infarction, stroke, and previous percutaneous revascularization), other diseases (chronic obstructive pulmonary disease, renal impairment, prior major hemorrhage, prior major surgery, peptic ulcer, other chronic conditions, surgical procedure scheduled for the following year, oral anticoagulant therapy at discharge, and psychotropic drug consumption), admission features (diagnosis, worst Killip class, and mean hemoglobin), and psychosocial characteristics (educational level, professional situation, health insurance type, and Patient Health Questionnaire score). Candidate hospital-level variables were status as a university hospital, provision of written recommendations about AT, and mean number of patients treated with DES during the study period.
The modeling process began with the individual-level variables and involved forward and backward stepwise methods with a threshold set at P>0.10 for exiting and P<0.10 for entering. The aim was a parsimonious model with the minimum number of variables per logit explaining the greatest amount of variability. Coefficients were constrained to be zero for the explanatory variables without a potential relationship with the logit of interest. Candidate hospital-level variables were then assessed by a multilevel (ie, hierarchical) analysis in 3 steps: First, we built an “empty” model that only included a random intercept to measure the amount of variability of ATD between hospitals. Second, we included the selected individual variables. Finally, candidate hospital variables were added to investigate how each category of interest for ATD was associated with hospital characteristics. We estimated odds ratios (ORs) in each outcome category for both individual and hospital characteristics. The Hosmer-Lemeshow test for model calibration and c statistic were computed for each logit. Change between hospital variability at each step was calculated by the percent change in hospital-level variance of the more complex model compared with the “empty” model. Hospital-level variance was measured by estimating the intraclass correlation coefficient and the median OR for each model.
Methods to compute indexes of interhospital variability and different measures of clustering were obtained from Merlo et al.9 Multilevel models were estimated assuming independent covariances. Algorithms to estimate model coefficients were those implemented in the statistical package MLwiN (version 2.11; Centre for Multilevel Modelling, University of Bristol, Bristol, England). The Markov chain Monte Carlo method with 5000 iterative steps was used as a robust method to estimate the coefficients of the model.10 Finally, and only for descriptive purposes, we compared the rate of deaths or rehospitalizations for acute coronary syndrome between patients with or without ATD during the first 3 months after the index episode.
The study was approved by the Vall d'Hebron institutional review committee. The subjects provided informed consent.
ATD could be assessed in 1622 (82.5%) of 1965 candidates for follow-up (Figure 1 In 1536 patients (94.7%), follow-up could be obtained for the 4 time points. In the rest, only 2 or 3 follow-up time points were available. A total of 234 (14.4%) of 1622 patients interrupted at least 1 AT, most of them clopidogrel (n=182, 11.8%). In 111 cases (6.8%), ATD was permanent, and in 123 (7.6%), it was temporary (average 9.5 days; median 7 days; interquartile range 5 to 10 days). The incidence rate of ATD was very similar across time intervals (3% to 3.5% per interval; Figure 2). A total of 83 (5.1%) of 1622 patients died or were hospitalized for acute coronary syndrome during the first year of follow-up. This rate was significantly higher among the 50 patients who discontinued AT during the first 3 months (n=6, 12%) than among the 1572 patients who did not (n=77, 4.9%; OR 2.65, 95% confidence interval [CI] 1.09 to 6.4, P=0.031). In 5 of 6 patients who interrupted AT during the first 3 months and had an event, the interruption had been permanent.
The circumstance associated with ATD could be assessed in 218 patients (93%). The most frequent circumstance was a bleeding event or invasive procedure (n=109); however, only 56 (51.4%) of these 109 cases that led to ATD were major bleeding events or major surgical procedures that required hospitalization (Table 1). Most other cases were minor surgical procedures (n=48, 44%) or hemorrhages (n=3, 2.7%). ATD was strongly correlated with the number of readmissions: The higher the number of readmissions, the greater the rate of ATD (P<0.001; Figure 3).
Table 2⇓ shows differences in individual and hospital variables between the 4 categories of patients. Table 3 shows differences in psychosocial characteristics. Patients with ATD associated with a bleeding event or medical procedure had more peripheral arterial disease, more chronic renal impairment, more previous major hemorrhage, and more frequent peptic ulcer. There were no significant differences in the other individual variables, hospital-level variables, or psychosocial determinants. Patients who interrupted AT because of medical advice more frequently had valvular prostheses than did the other 3 groups. In this subgroup, the diagnosis at admission was more often non–ST-segment elevation acute coronary syndrome. These patients had been hospitalized less often in centers in which written instructions emphasizing the importance of AT maintenance were given before discharge. There were no relevant differences from the other groups in psychosocial determinants. Finally, in patients who interrupted AT on their own initiative, the only individual variable associated with discontinuation was use of psychotropic drugs. Neither hospital-level variables nor psychosocial determinants differed significantly from the other groups, although moderate to severe depression assessed by Patient Health Questionnaire test was more prevalent.
ATD: Multivariable Approach
Table 4 shows the results of the final hierarchical multinomial model. Individual variables associated with ATD due to a bleeding event or medical procedure were chronic renal impairment, peripheral arterial disease, and especially previous major hemorrhage (OR 3.77, 95% CI 1.41 to 10.03). By contrast, previous acute myocardial infarction was associated with lower risk (OR 0.46, 95% CI 0.26 to 0.8). In ATD due to medical recommendation, the only individual-level variable that predicted a higher risk for ATD was oral anticoagulant therapy at discharge (OR 3.88, 95% CI 1.26 to 11.98). Being an immigrant, psychotropic drug consumption, and unemployment predicted a higher risk of ATD due to patient initiative, although the latter did not reach statistical significance. No hospital-level variable predicted ATD due to bleeding event/procedure or due to patient initiative; however, undergoing the procedure in publicly funded hospitals, in hospitals that provided written information on the importance of AT maintenance, and in more active hospitals (with more patients receiving stents) predicted lower risk for ATD due to a medical decision not associated with bleeding events or procedures.
The performance of the model (C statistic) before the inclusion of the hospital-level variables and random effects (ie, interhospital variability) was 0.63 (95% CI 0.57 to 0.7) for hemorrhage/procedure ATD, 0.67 (95% CI 0.61 to 0.73) for medical-decision ATD, and 0.71 (95% CI 0.62 to 0.79) for patient-initiative ATD. After their inclusion, it was 0.63 (95% CI 0.57 to 0.7), 0.75 (95% CI 0.7 to 0.82), and 0.7 (95% CI 0.62 to 0.8), respectively. Model calibrations, tested by Hosmer-Lemeshow test, were 0.91, 0.95, and 0.47, respectively, before inclusion of hospital-level variables and random effects and 0.3, 0.8, and 0.42 after their inclusion.
Measures of between-hospital variation indicated that the center where the patient underwent the procedure was not associated with ATD for bleeding event/procedure. By contrast, the hospital where the index procedure was performed was important in the explanation of risk for ATD due to patient initiative and especially of risk for ATD due to a medical decision (median ORs 1.33 and 2.64, respectively). Variability between hospitals relative to these outcomes was reduced importantly when the individual and hospital variables were introduced (−70.8% and −32.2%, respectively).
In this multicenter study, 14% of patients receiving DES interrupted at least 1 antiplatelet drug for at least 5 consecutive days during the first year after implantation. Although in some cases, ATD could be justified by the occurrence of major hemorrhage or surgical procedure, these events were more often not present. The scenarios that were actually associated with ATD involved minor hemorrhages/procedures, medical decisions without any bleeding or bleeding-risk event, and patient initiative. Individual characteristics that conferred high risk for hemorrhage/procedure ATD, either major or minor, were chronic renal impairment, previous major hemorrhage, and peripheral arterial disease. By contrast, social features (immigration, unemployment, or psychotropic drug use) were the individual variables associated with patient-initiative ATD. Long-term use of anticoagulant therapy predicted ATD on the basis of medical decision, whereas undergoing the procedure in a high-activity publicly funded center and in centers that routinely gave written instructions about AT maintenance conferred a low risk of ATD due to medical recommendation.
Few studies have addressed the rate of ATD after DES implantation and its determinants.2,7 These were rather small studies, either in a single context for DES implantation, such as the first month after acute myocardial infarction,2 or in a single institution.7 Nevertheless, they showed that social factors such as not completing high school2 or living alone7 and medical factors such as bleeding events may be associated with ATD.
These studies also pointed out that a lack of discharge instructions2 or medical recommendation by general practitioners7 might be related to ATD. These findings are not surprising: In a recent survey of 2515 French physicians about AT management, up to 22% of interviewed physicians would have interrupted double AT in a clinical scenario of low risk for bleeding events.11 Moreover, ATD in patients who required invasive procedures depended on the type of physician consulted (specialists versus general practitioners) and on the physician’s age and practice type (rural/private versus urban/hospital). These findings illustrate the complexity of assessing the background of ATD.
The incidence rate of ATD was similar across time intervals, being slightly higher from month 6 to 12 (8.4%) than from discharge to month 6 (6%). This may illustrate the impression among general physicians of lesser risk associated with clopidogrel interruption beyond the sixth month after DES implantation. In fact, 62.3% of all ATDs due to medical decision not associated with bleeding or procedures occurred after the sixth month (data not shown).
A multinomial hierarchical (ie, multilevel) analysis was used to depict factors associated with ATD. This methodology has been used in social epidemiology, where it helps with interpretation of measures of variation with aggregate data to assess a potential contextual phenomenon.12 Using this approach, we can partially answer some of the questions that arose from the results of previous studies. Thus, in the study by Spertus et al,2 although the only variable independently associated with early ATD was “not completing high school,” other factors emerged as hypothetically associated with ATD. Perhaps the most important one was “not given discharge medication instructions,” because this is a modifiable factor. In the present study, a simple intervention that consisted of giving discharge instructions about the importance of maintaining AT was independently associated with a lower risk for ATD. Surprisingly, this intervention prevented ATD advised by a general practitioner but was not associated with lower ATD as a result patient initiative. This suggests that such a strategy did not contribute to patient education, although it might have made the general practitioners more aware of the importance of AT maintenance.
Individual determinants of ATD due to hemorrhage/medical procedure were not surprising, because they depict a frail patient profile more prone to hemorrhagic complications; however, patients with previous acute myocardial infarction were at lower risk for hemorrhage/procedure ATD, perhaps because these patients usually are on long-term AT before the event occurs, and thus, physicians, patients, or both may be more aware of its importance. The poor discriminatory capacity of the model for this outcome is worth noting (C=0.63, 95% CI 0.57 to 0.7). This may be because it actually expresses heterogeneity of clinical scenarios, which range from severe events that clearly imply a high risk (eg, intracranial hemorrhage) to less severe clinical scenarios (eg, dental procedures) in which the decision for ATD could be arguable.
Long-term anticoagulant therapy was strongly associated with ATD due to medical advice. This may reflect physicians’ reluctance to combine anticoagulant and double-antiplatelet therapy in the medium to long term because of a perception of high bleeding risk. By contrast, the risk of ATD due to medical advice was lower when patients underwent the procedure in a publicly funded and highly active center, which suggests that general practitioners caring for these patients are more familiar with AT protocols or that these patients are initially seen by hospital cardiologists, who presumably are more willing to avoid ATD.
Finally, although individual determinants of ATD due to patient initiative were not surprising, one finding deserves consideration: The empty model showed a considerable interhospital variability (0.31), which was extremely reduced after adjustment for the individual variables. This indicates that patients with poorer adherence to AT (ie, immigrants, unemployed patients, and psychotropic drug consumers) were concentrated in some centers.
Study Limitations and Strengths
The conventional definition of ATD may be open to question. We selected 5 days on the basis of recommendations for perioperative management of patients receiving antiplatelet therapy.13 Clopidogrel should be interrupted at least 5 days before surgery because it takes approximately that many days to replace the platelet pool. Therefore, we assumed that the highest risk for stent thrombosis would start beyond the fourth day after clopidogrel discontinuation. However, this is only an assumption, and risk can vary among patients regardless of the length of ATD.
The percentage of candidates for follow-up (n=1965) in whom AT compliance could not be assessed was 17.4% (n=343). Although there were no important differences in the majority of clinical, demographic, and psychosocial variables, the cohorts differed in some characteristics (online-only Data Supplement). This could introduce selection bias, although it is unlikely that the results relative to the main objectives of the study would have changed substantially if those patients had been included in the analyses. In any case, we cannot absolutely rule out that data are not missing at random. The 23 patients in whom AT compliance could not be assessed because they died before the first contact deserve special mention. Stent thrombosis cannot be ruled out as the ultimate cause of death. To the best of our knowledge, none of these patients had undergone invasive procedures or hospitalization for hemorrhagic complications before death; however, ATD because of patient initiative could have occurred. In any case, this potential bias would mainly involve estimation of the association between ATD and cardiovascular events, which was not the objective of the present study.
To simplify the assessment of ATD determinants, arguable assumptions were made, such as the categorization of the dependent variable into 4 independent categories. Such categorization, driven by the findings of prior studies and our own data, introduced us to multinomial-multilevel modelization. Although this view of the determinants of ATD probably cannot be achieved with other analytical tools, assumptions about the nature of the dependent variable and the analytical approach may not wholly reflect the underlying mechanisms of ATD. Moreover, the classification of ATD events into 4 types may certainly have limitations. In any case, the relatively small number of determinants obtained may indicate that the present model is the simplest version of a much more complex reality.
Finally, although most patients were phoned 4 times, a recall bias is still plausible. In addition, the multilevel analysis of potential predictors of ATD did not account for when an ATD event occurred but merely recorded whether an ATD event occurred.
ATD after DES implantation is not unusual, even during the first 3 months of AT, when ATD has a greater impact on adverse cardiovascular outcomes. The risk of many such untoward consequences can be identified in part beforehand, which emphasizes the need for careful patient selection. In addition, because ATD may also depend on the less predictable compliance of patients, proper patient education is mandatory. Medical patterns of care of patients with DES should be better defined, particularly with regard to the maintenance of AT during procedures. Finally, although many factors associated with ATD are not easily modifiable, the simple fact of giving written instructions about the importance of antiplatelet maintenance may avoid some cases of unjustified ATD.
ATD is not unusual during the first year after DES implantation, occurring in different scenarios. Most commonly, ATD depends on a patient decision or medical decision not associated with major bleeding events or major surgical procedures. Determinants of ATD depend on the specific scenarios, with both individual- and hospital-level variables being important to explain them.
We would like to thank Projecta’m and the ACDC investigators (Appendix of online-only Data Supplement) for their excellent work during the study.
Sources of Funding
The present study was funded with grants from the Fondo de Investigación Sanitaria (PI07/90031) and an unrestricted grant from Bristol-Myers Squibb. The funding sources had no role in the study design; the collection, analysis, and interpretation of data; or the writing of the report.
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All guidelines agree on the need for at least 1 year of double-antiplatelet therapy after drug-eluting stent implantation. Our study, conducted in 29 hospitals, shows that 14.4% of 1622 patients receiving drug-eluting stents interrupted at least 1 antiplatelet drug for at least 5 consecutive days during the first year after implantation. Although antiplatelet therapy discontinuation (ATD) can be justified by the occurrence of major hemorrhage or surgical procedure, these events occurred in only 25.7% of ATD cases. The most common scenarios for ATD were minor hemorrhages/procedures, medical decisions without any bleeding or bleeding-risk event, and patient initiative. Several patient characteristics predicted higher risk for ATD; some were associated with future bleeding events or the need for invasive procedures, whereas others were associated with ATD due to patient initiative. Although these determinants are not modifiable, they emphasize the need for careful patient selection. Other determinants were related to the process of care. Thus, long-term use of anticoagulants predicted ATD due to medical decision, whereas simple provision of written instructions about the importance of antiplatelet maintenance may avoid some cases of unjustified ATD. These results highlight that medical patterns of care of patients with drug-eluting stents should be better defined, particularly relative to the maintenance of antiplatelet therapy during procedures. In addition, they illustrate a common dilemma in contemporary medicine as a whole, not just in cardiology: Patients who are cared for by their general practitioners may pose formidable dilemmas to such practitioners because of the subtleties of the therapeutic technology used by different specialists.
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The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.110.938290/DC1.