Antiplatelet Therapy after PCI — Different Durations for Different Stents?

Abstract & Commentary

By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study.

Source: Valgimigli M, et al. Should duration of dual antiplatelet therapy depend on the type and/or potency of implanted stent? A pre-specified analysis from the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY). Eur Heart J 2013;34:909-919.

There is considerable debate concerning the optimal duration of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Clearly, there is benefit to DAPT early after PCI. The delayed vascular healing associated with DES is thought to contribute to late (and very late) stent thrombosis. The ACC/AHA guidelines recommend 12 months of DAPT for patients receiving DES, based on data from first-generation DES. The newer-generation DES that elute everolimus or zotarolimus have different potency in preventing neointimal proliferation and have lower rates of stent thrombosis than first-generation DES. European guidelines now allow for shorter duration of DAPT with some of the newer DES. Should the duration of DAPT be tailored to the individual stent type that has been implanted? To address this question, Valgimigli and colleagues present a subgroup analysis of data from the PRODIGY trial.

The PRODIGY trial had a randomized, 4 × 2 factorial design in which patients undergoing PCI were randomized to bare-metal stents (BMS) with thin struts, paclitaxel-eluting stents (PES), everolimus-eluting stents (EES), or zotarolimuseluting stents (ZES). They were also randomized to 6 months or 24 months of DAPT with aspirin and clopidogrel. Patients were recruited if they were undergoing PCI for any indication (i.e., stable coronary artery disease, acute coronary syndromes [ACS], or ST elevation myocardial infarction [MI]). Exclusion criteria were allergy to aspirin or clopidogrel, planned surgery within 24 months of PCI (unless DAPT could be maintained throughout the perioperative period), bleeding diathesis, active bleeding, stroke in the prior 6 months, surgery within the prior 15 days, need for anticoagulation, pregnancy, or limited life-expectancy. This was a prespecified subgroup analysis that analyzed events from 30 days to 24 months post-PCI. The primary endpoint was death, MI, or stroke.

Over a 2-year period at three centers in Italy, 1970 patients were enrolled and randomized to either 6 months or 24 months of DAPT and to one of the four stent types. The baseline characteristics were similar between groups. Mean number of stents implanted was 1.8 per patient, for a mean total stent length of 39 mm, and this did not differ across groups. Comparing 24 months of DAPT to 6 months of DAPT, the primary outcome did not differ in patients receiving BMS (hazard ratio [HR], 0.89; P = 0.64), PES (HR, 0.74; P = 0.26), or EES (HR, 0.63; P = 0.17), whereas it was significantly higher in ZES patients who received 24 months of DAPT [HR, 2.85; P = 0.0018]. The authors then performed a landmark analysis, studying the outcomes from 6 months to 24 months post-PCI, which is when the treatments really differed. There were fewer events in the patients receiving ZES with 6-month DAPT (P = 0.002), and there were fewer definite or probable stent thromboses in PES patients treated with 24-month DAPT (P = 0.049). The authors conclude that optimal duration of DAPT may be stent-specific and it does not support a clear association between stent potency and vulnerability to shorter DAPT therapy.

Commentary

The PRODIGY study showed that 6 months and 24 months of DAPT resulted in similar event rates. Now, in this study, the authors further stratify these data by stent type. Interestingly, the primary outcome was similar between BMS and DES, regardless of DAPT duration, with the exception that patients receiving ZES and shorter DAPT appeared to have fewer clinical events. This study challenges the paradigm that there is a necessary dichotomy between BMS and DES in terms of DAPT duration. It appears that PES may derive benefit in reducing stent thrombosis with longer duration of DAPT, but the newer DES appear to have a similar rate of ischemic outcomes to BMS.

There is a belief in the interventional cardiology community that there is a trade-off between neointima formation (i.e., in-stent restenosis) and stent thrombosis, and that higher rates of restenosis are protective against stent thrombosis. The corollary is that more potent antiproliferative DES should have higher rates of stent thrombosis. Everolimus is the most powerful antiproliferative drug among the stents studied, followed by paclitaxel. Yet, EES had similar event rates to BMS, regardless of DAPT duration. PES, on the other hand, seemed to derive benefit from longer-term DAPT. ZES, which has the least potent antiproliferative drug, appeared to have the lowest event rates with short-term DAPT. The data challenge the paradigm that ischemic events in patients with DES are inversely related to the potency of antiproliferative drugs.

There are several important limitations to this dataset. First, the patients enrolled in this study were heterogeneous with respect to their presenting symptoms. We are not told whether the acuity of presentation had an effect on outcomes. There may be some interaction between ACS presentations and ischemic events, as has been shown in numerous previous trials. Second, it was not powered to detect differences in stent thrombosis. Third, this is a subgroup analysis with the attendant limitations thereof. For these reasons, these data are unlikely to alter guidelines for DAPT duration. However, this study forms part of a growing body of literature that suggest the newer generation of DES do not carry the same risks of late events that dogged the first generation of DES. Clinicians can be reassured that if patients must interrupt their DAPT late in the first year after PCI, the event rates remain reasonably low.