Twelve Versus Six Months of Clopidogrel to Reduce Major Cardiac Events in Patients Undergoing γ-Radiation Therapy for In-Stent Restenosis
Washington Radiation for In-Stent restenosis Trial (WRIST) 12 Versus WRIST PLUS
Background— Intracoronary γ-radiation reduces recurrent in-stent restenosis (ISR). Late thrombosis was attenuated with 6 months of aspirin and clopidogrel. We aimed to find out whether 12 months of aspirin plus clopidogrel is superior to a strategy of 6 months after radiation therapy for patients with ISR.
Methods and Results— One hundred twenty consecutive patients with diffuse ISR in native coronaries and vein grafts with lesions <80 mm in length underwent PTCA, laser ablation, or rotational atherectomy. Additional stents were placed in 39 patients (33%). After the intervention, a ribbon with different trains of radioactive 192Ir seeds was positioned to cover the treated site, and a dose of 14 Gy to 2 mm was prescribed. Patients were discharged with clopidogrel and aspirin for 12 months and followed up clinically. The cardiac clinical event rates at 15 months were compared with the γ-treated (n=120) patients of the WRIST PLUS study (only 6 months of antiplatelet therapy). Whereas the late thrombosis rates were similar (3.3% for the group given 12 months of antiplatelet therapy versus 4.2% for the group given 6 months, P=0.72), the group treated with 12 months of antiplatelet therapy had a rate of 21% for major adverse cardiac events and 20% for target-lesion revascularization compared with 36% (P=0.01) and 35% (P=0.009), respectively, in patients who were treated with only 6 months of clopidogrel.
Conclusions— Twelve months of clopidogrel is superior to 6 months in reducing overall major cardiac events and revascularization rates at 15 months for patients with ISR treated with γ-radiation. At least 12 months of clopidogrel therapy should be recommended for patients undergoing radiation therapy for ISR.
Received May 29, 2002; revision received June 24, 2002; accepted June 24, 2002.
Treatment of in-stent restenosis (ISR) with vascular brachytherapy has become the standard of care based on 5 randomized studies of intracoronary radiation therapy (IRT). These trials used both γ- and β-emitters and demonstrated a reduction in restenosis and need for target-lesion revascularization (TLR) and target-vessel revascularization (TVR) compared with control.1–4⇓⇓⇓ However, the overall rate of major cardiovascular events reported at 6 to 9 months remained >20%. These events included late total occlusion (>30 days after intervention and radiation) and repeat TVR, with reported rates ranging from 6% to 15% and from 20% to 30%, respectively.5–7⇓⇓
Prolonged antiplatelet therapy with aspirin and clopidogrel for 12 months demonstrated beneficial effects in patients with acute coronary syndromes without ST-segment elevation and was associated with reduction in cardiovascular events in patients undergoing percutaneous coronary intervention.8 Additional supportive evidence of the benefits of clopidogrel is highlighted in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events) and PCI-CURE (Clopidogrel in Unstable angina to prevent Recurrent ischemic Events in patients undergoing Percutaneous Coronary Intervention) analyses.9,10⇓
Late thrombosis after IRT was controlled in part with the administration of at least 60 days of antiplatelet therapy. The WRIST PLUS study demonstrated that 6 months of clopidogrel and aspirin was associated with reduction of the late thrombosis and total occlusion rates after IRT for the treatment of ISR with γ-radiation.11
The optimal duration of antiplatelet therapy for patients undergoing brachytherapy is unknown. In the present study, we (1) report a prospective registry examining the efficacy of clopidogrel 75 mg and aspirin for 12 months in reducing the incidence of major clinical cardiac events after catheter-based γ-IRT for patients with ISR and (2) compare the results with those for 6 months of clopidogrel treatment from the WRIST PLUS study at 15-month follow-up.
This clinical trial involved an Investigational Device Exemption granted by the Food and Drug Administration and was approved with informed consent by the Institutional Review Board. The study was designed as a prospective registry of 120 consecutive patients who presented with symptoms of angina with ISR in a native coronary artery or vein graft and who were enrolled from March 20, 2000, to August 7, 2000. The 15-month clinical outcomes were compared with 120 patients (WRIST PLUS) who were enrolled from August 9, 1999, to February 18, 2000, with the same inclusion and exclusion criteria and who were treated with the same radiation system and dose, except that postprocedural antiplatelet therapy was limited to 6 months.
Entry criteria for both studies included vessels 2.5 to 4.0 mm in diameter and lesion length <80 mm with successful primary treatment (<30% residual stenosis without complications). Major exclusion criteria included recent (<72 hours) acute myocardial infarction (MI), left ventricular ejection fraction <20%, angiographic thrombus, and/or allergy to antiplatelet therapy. Patients underwent intervention with balloon, laser ablation, or rotational atherectomy. Additional stenting was discouraged, yet 39% of patients in WRIST 12 and 28% in WRIST PLUS were restented because of edge dissections or a suboptimal angiographic result.
Patients in both studies were loaded with clopidogrel 300 mg before the intervention and received 75 mg/d for 12 months in WRIST 12 and for 6 months in WRIST PLUS. Only 27 patients from the WRIST PLUS registry continued to take clopidogrel for various medical indications. All patients received lifelong treatment with aspirin (325 mg/d).
Radiation System and Dosimetry
After the intervention, a closed-end lumen catheter (Cordis Checkmate) was introduced into the artery, and a ribbon with different trains of radioactive 192Ir seeds (6, 10, 14, 17, 19, and 23 seeds) was delivered and positioned to cover the treated site. The prescribed radiation dose was 14 Gy to a 2-mm radial distance.
Study End Points and Data Analysis
The primary clinical end points were late thrombosis and the composite major adverse clinical events of death, MI, and TLR at 6 and 12 months. Late thrombosis was defined as angiographic evidence of thrombus or presence of MI related to the treated vessel >30 days after radiation treatment. An independent committee adjudicated all events. Continuous variables were expressed as mean±SD and categorical data as percentages. The Student t test was used to compare continuous variables, and χ2 statistics were used to compare categorical values. Kaplan-Meier curves of event-free survival (death, Q-wave MI, or TVR) at 12 months were calculated.
One hundred twenty patients (69% males, aged 63±11 years) with recurrent ISR were enrolled in WRIST 12. Clinical characteristics included diabetes (49%), hypertension (73%), hyperlipidemia (83%), prior MI (57%), and current smoking habit (8%), all similar to rates in the WRIST PLUS group. Procedural details and the angiographic baseline and postprocedure results are shown in Table 1. Compared with WRIST PLUS, patients in WRIST 12 had fewer right coronary artery ISR lesions (18% versus 33%, P=0.005), less use of the excimer laser (15% versus 37%, P<0.001), and a trend toward more restenting (39% versus 28%, P=0.08).
WRIST 12 patients had a reduced incidence of early creatine kinase release (<30 days after intervention), with similar low rates of death and Q-wave MI at 15 months compared with WRIST PLUS (Table 2). Major cardiac events at 15 months occurred in 25 patients (21%) in WRIST 12 compared with 43 patients (36%, P=0.01) in WRIST PLUS. This was driven by a reduction in TLR (20% versus 35%, P=0.009) and TVR (23% versus 39%, P=0.005) with 12 months of clopidogrel therapy. Divergence of the Kaplan-Meier curves for event-free survival between 6 and 15 months suggests that the additional clopidogrel had a favorable effect on clinical outcomes (Figure). At 12-months, WRIST 12 patients had a nonsignificant reduction in late thrombosis (2.5% versus 4.2%, P=0.72) and late total occlusion (8.6% versus 10.3%, P=0.67).
In WRIST 12, recorded events between 12 and 15 months included 7 patients (5.9%) who required TLR and 9 (7.6%) who required TVR (9 major adverse cardiac events). There were no additional late thrombotic events, deaths, or Q-wave MIs.
The rates of significant bleeding were low and not different between the 2 groups. WRIST 12 patients had equivalent rates of transfusion (2.5% versus 3.3%, P=0.70) and femoral artery hematomas that required treatment (2.5% versus 1.7%, P=0.65) compared with WRIST PLUS patients during hospitalization. No intracranial or retroperitoneal hemorrhages were recorded. Angiographic analysis at 15 months in 95 patients (79%) in WRIST 12 revealed an angiographic binary restenosis rate of 43% and late loss of 0.55±0.78 mm (total analyzed segment).
Clinical trials utilizing IRT with the administration of antiplatelet therapy for <2 months have reported high rates of late total occlusion and late thrombosis that vary from 6% to 14%.6–8⇓⇓ The current recommendations for antiplatelet therapy for the approved radiation systems is at least 60 days with the use of the Beta Cath system (Novoste), 6 months for the Galileo system of Guidant, and 6 months without a stent and 12 months with a new stent for the Checkmate system (Cordis).
The present trial indicates that prolonged antiplatelet therapy (12 months) after γ-IRT for patients treated for ISR reduces the rate of TLR and overall major adverse clinical events, with maintenance of even lower rates of late thrombosis despite a restenting rate of nearly 40% in the WRIST 12 cohort. The late thrombosis that occurred a few weeks after cessation of clopidogrel in the WRIST PLUS study raised the question of whether this resulted from absence of the drug or a rebound phenomenon. Because late thrombosis was not seen in the WRIST 12 groups who stopped the clopidogrel at 12 months, it appears that late thrombosis after discontinuation of clopidogrel was related to lack of healing without protection of antiplatelet therapy. Nevertheless, prolonged antiplatelet therapy does not eliminate late thrombosis. One patient in WRIST PLUS and 3 in WRIST 12 presented with late thrombosis despite taking clopidogrel at the time of the event.
Of interest is the unexpected reduction in major adverse clinical events (TLR) in WRIST 12 compared with WRIST PLUS that occurred after cessation of clopidogrel at 6 months (Figure). It is speculative whether clopidogrel exerted its protective action by reducing fibrin and platelet aggregation, which may have contributed to a reduction of neointimal proliferation and restenosis. Whether 12 months of clopidogrel therapy reduces recurrent ischemic events and exhibits antirestenotic properties will be learned in the Clopidogrel for Reduction of Events During Observation (CREDO) trial. The PCI-CURE trial confirmed a clinical benefit of clopidogrel treatment continued for up to 1 year (mean of 9 months), reported a reduced rate of revascularization (reduced rates of repeated percutaneous coronary intervention), and showed consistent reduction in cardiovascular death or MI when clopidogrel was continued beyond the usual 30 days.9
Although the present study was not randomized, the treated groups had similar baseline characteristics and the same radiation technique and dosage. Although the data in the present study support the use of clopidogrel after IRT for ISR for a minimum of 12 months, additional studies will be required to address the question of whether longer administration of antiplatelet therapy would further reduce the rate of clinical events after IRT.
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