Rates of death and myocardial infarction were assessed for a national sample of acute coronary syndrome patients after stopping clopidogrel. In the first 90 days after stopping treatment, patients experienced a nearly twofold increased risk of adverse events compared with subsequent follow-up intervals for patients treated medically without stents and for patients treated with coronary stents. This suggests a possible clopidogrel rebound effect, but additional studies are needed to support this hypothesis and to identify strategies to reduce early events after clopidogrel cessation.
Clinical trials have established the efficacy of clopidogrel (Plavix) therapy following acute coronary syndrome (ACS) hospitalization for patients treated medically or with percutaneous coronary intervention (PCI).1-3 Current clinical practice guidelines recommend clopidogrel therapy following ACS hospitalization for at least 1 month and, ideally, as long as 1 year for patients treated medically or with bare-metal stents (BMS) and for at least 1 year for patients treated with drug-eluting stents (DES).4
Although clopidogrel is efficacious for ACS patients, we sought to evaluate whether there was a concentration or clustering of thrombotic events shortly after clopidogrel cessation. Several factors raised this hypothesis, including a clustering of adverse events seen in ACS patients after cessation of long-term aspirin and heparin therapy, thought to be related to a hyperthrombotic state after treatment cessation5,6; and reports of thrombotic events after thienopyridine cessation in patients receiving coronary stents, particularly DES, although these events were largely attributed to stent-related mechanisms.7
We assessed the incidence and timing of mortality and/or myocardial infarction (MI) after stopping clopidogrel in a national cohort of ACS patients. Specifically, we evaluated for a clustering of events after stopping clopidogrel among nonstented, medically treated ACS patients. For comparison, we assessed the incidence and timing of death and MI among ACS patients who received PCI.
We included all patients with acute MI or unstable angina (as documented by standard electrocardiographic criteria, elevated troponin levels, or other clinical evidence) discharged with clopidogrel from any of 127 Veterans Affairs medical centers between October 1, 2003, and March 31, 2005, who remained event-free during clopidogrel treatment. Patients who had an adverse event while receiving clopidogrel therapy were excluded, because they had not stopped clopidogrel therapy and the adverse events could not be related to a potential rebound phenomenon.
The duration of clopidogrel therapy encompassed the day of hospital discharge to the last clopidogrel refill date plus the number of days supplied for the last refill according to pharmacy data.8 The primary outcome was the combined end point of all-cause mortality or MI hospitalization following clopidogrel cessation. Vital status information was available after hospital discharge on all patients through January 31, 2007.
Statistical methods. The primary objective of our analysis was to assess the incidence and timing of adverse events among nonstented medically treated ACS patients after they stopped clopidogrel therapy. Poisson regression was used to compare the risk of adverse events associated with the 0- to 90-day interval after stopping clopidogrel versus the 91- to 180-day interval, adjusting for all Table 1 variables, including the duration of clopidogrel treatment. To assess the robustness of our findings, we performed a series of additional analyses that included the following parameters and subgroups: using the MI outcome only; patients who took clopidogrel for 3 months or less following ACS; patients who took clopidogrel for 6 months or less following ACS; patients who took clopidogrel for 9 months or longer following ACS; patients with diabetes; patients without diabetes; and patients without any outpatient or inpatient bleeding and ICD-9 codes following index ACS hospitalization. We also adjusted for statin adherence, because medication adherence could partially explain any association between medication use (per pharmacy refill data) and outcomes, and conducted a matched propensity analysis between those who took clopidogrel 6 months or less and those who took clopidogrel longer than 6 months. Next, we compared the rate of adverse events following index ACS discharge in patients while taking clopidogrel to the rate of adverse events after stopping clopidogrel. Finally, we repeated the analyses, evaluating the incidence and timing of events in PCI-treated ACS patients after they stopped clopidogrel.
Medically treated ACS patients. Baseline characteristics of the medically treated patients (n = 1568) are listed in Table 1. The mean duration of clopidogrel therapy following hospital discharge was 278 ± 169 days. All-cause mortality or MI occurred in 17.1% (n = 268) of patients, with 60.8% of events occurring within 90 days of stopping clopidogrel, 21.3% from 91 to 180 days, and 9.7% from 181 to 270 days (Figure and Table 2). In multivariable analysis, including adjustment for duration of clopidogrel treatment, the 0- to 90-day interval was associated with an increased risk of adverse events after stopping clopidogrel, compared with the 91- to 180-day interval (incidence rate ratio [IRR], 1.98; 95% confidence interval [CI], 1.46-2.69).
An increased risk of adverse events associated with the 0- to 90-day interval was consistent across all subgroups. For the entire cohort of patients taking clopidogrel after hospital discharge, the rate of adverse events was 1.20 per 1000 patient-days in the initial 90 days, which decreased to a “background rate” of approximately 0.50 per 1000 patient-days in the 91- to 360-day interval. In comparison there was a spike in adverse events following clopidogrel cessation (1.31 per 1000 patient-days for 0- to 90-day interval) among patients event free prior to stopping clopidogrel, further supporting our hypothesis associating a clustering of events with clopidogrel cessation.
PCI-treated ACS patients. Table 1 lists baseline characteristics for the PCI-treated patients (n = 1569). Approximately two-thirds of patients (62.7%) received BMS, whereas one-third (37.3%) received DES. The mean duration of clopidogrel therapy following hospital discharge was 302 ± 151 days. The combined end point of all-cause mortality or MI occurred in 7.9% (n = 124) of patients, with 58.9% of events occurring within 90 days of stopping clopidogrel, 23.4% from 91 to 180 days, and 6.5% from 181 to 270 days (Table 2).
In the multivariable analysis, the 0- to 90-day interval after stopping clopidogrel was associated with an increased risk of adverse events compared with the 91- to 180-day interval (IRR, 1.82; 95% CI, 1.17-2.83). A similar trend of increased adverse events (n = 23) was observed in DES patients in the 0- to 90-day interval after stopping clopidogrel, but the smaller number of patients and events (n = 41) precluded multivariable analysis. The finding of an increased risk of adverse events in the 0- to 90-day interval after stopping clopidogrel was consistent for BMS patients (IRR, 2.14; 95% CI, 1.23-3.74).
To our knowledge, this is the first study to evaluate patterns of adverse events in a national cohort of ACS patients after they stopped taking clopidogrel. We found a clustering of death and MI events in the initial 90-day period after clopidogrel cessation, compared with subsequent follow-up intervals. Findings were consistent among subgroups of patients who received shorter or longer durations of clopidogrel therapy, patients with or without diabetes, and ACS patients who underwent PCI. The rate of adverse events in the initial 90-day interval after stopping clopidogrel was higher than the rate of adverse events following hospital discharge while patients were still taking clopidogrel. These findings support the hypothesis of a rebound hyperthrombotic period after clopidogrel cessation. They also highlight the need for additional studies to confirm these findings and to gain a deeper understanding of the pathophysiology of this phenomenon as well as allowing identification of strategies to attenuate this effect.
The results of this study add to the literature supporting the hypothesis of a rebound phenomenon following antiplatelet agent withdrawal. In vitro and physiologic evidence exist that support the notion of a short-term increase in platelet activation and corresponding thrombotic risk immediately after stopping antiplatelet therapy.9-11 Previous studies have shown that discontinuation of aspirin therapy is associated with an increased short-term risk of cerebrovascular and cardiac events compared with continuous aspirin use.12-14
The STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus Eluting Stent versus Abciximab and Bare Metal Stent in Acute Myocardial Infarction) study reported a clustering of death or nonfatal MI within 30 days of stopping thienopyridine therapy among patients treated with DES or BMS for ST-segment elevation MI7; however, a stent-related mechanism was identified as the likely etiology for these events. We observed an increase in the incidence of adverse events in nonstented, medically treated ACS patients following clopidogrel cessation, implicating a mechanism unrelated to stenting.
Our study has several potential implications. First, while the absolute rate of adverse events was low, the relative increase in adverse events seen in the early period after clopidogrel cessation was nearly two-fold higher than in later periods. The absolute number of adverse events attributable to this event clustering is significant when extrapolated to a population level.15 These findings do not necessarily offset the benefits of clopidogrel therapy for patients with ACS. They do indicate, however, that additional studies are urgently needed to confirm event clustering and understand the pathophysiology of this phenomenon. Should these findings be confi rmed, guideline recommendations may need to be reconsidered regarding the duration of clopidogrel therapy and possibly the means of clopidogrel cessation. Possibilities include continuing clopidogrel for an extended period or indefinitely, although before implementing this recommendation, the increased risk of bleeding with prolonged dual antiplatelet therapy and the cost-effectiveness of such a strategy would need to be considered16; tapering clopidogrel therapy; bridging clopidogrel cessation with higher-dose aspirin for a given period; or using alternative antiplatelet regimens. All these approaches would require formal study before making a specific recommendation.
In a national cohort of medically treated and PCI-treated ACS patients, we found a higher incidence of death and MI during the initial 90-day period after clopidogrel cessation. In conjunction with previous physiologic studies, these findings support the hypothesis of possible rebound platelet activation associated with clopidogrel withdrawal.
This study was supported by the Quality Enhancement Research Initiative of the US Department of Veterans Affairs. Dr Ho is supported by a VA HSR&D Career Development Award. Dr Peterson is supported by an R01 from the National Institute on Aging. Dr Peterson has received honoraria and research support from a BMS-Sanofi partnership. However, the views expressed in this article are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs.