Author + information
- aMazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
- bDuke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
- ↵∗Reprint requests and correspondence:
Dr. Eric D. Peterson, Duke University Hospital, 2400 Pratt Street, Suite 7009, Durham, North Carolina 27705.
Advances in interventional cardiology techniques and stent technology have dramatically expanded the use of percutaneous coronary intervention (PCI), even to those with complex, multivessel coronary artery disease (1). Dual antiplatelet therapy (DAPT) is a mainstay therapy following PCI, helping to prevent downstream stent thrombosis and other coronary events, yet at a cost of increased risk for bleeding. Despite decades of research, the optimal duration of DAPT following PCI remains quite controversial. Randomized clinical trials comparing shorter versus longer durations of DAPT have yielded mixed results (2–9). The key question, however, is whether there is one answer applicable to all PCI patients or whether DAPT duration should be personalized to the particular patient. In this issue of the Journal, Giustino et al. (10) provide compelling evidence that the ideal duration of DAPT most likely varies, depending on procedural complexity and other clinical characteristics.
The data supporting these conclusions came from a rigorously performed, patient-level meta-analysis from 6 randomized trials that compared shorter (3 to 6 months) versus longer (12+ months) duration DAPT following PCI. The investigators specifically set out to evaluate whether patients undergoing more complex PCI procedures required longer-term DAPT. Procedural complexity was prospectively defined by the investigators as those procedures with ≥1 of the following angiographic characteristics: 3 vessels treated; ≥3 stents implanted; ≥3 lesions treated; bifurcation with 2 stents implanted; total stent length >60 mm; or chronic total occlusion (CTO) as the target lesion.
Consistent with prior studies, the investigators found that patients with complex PCI (17.5% of all randomized patients) had significantly higher adverse cardiac events at 1 year than those without, including increased cardiac death (2.0% vs. 1.3%, p = 0.009) and all-cause mortality (3.2% vs. 2.2%, p = 0.01). The investigators also found a significant interaction between procedural complexity and the outcomes of longer versus shorter DAPT. Among complex PCI patients, longer duration DAPT relative to shorter DAPT was associated with significantly lower major adverse cardiac event (MACE) rates (adjusted hazard ratio: 0.56; 95% confidence interval: 0.35 to 0.89). In contrast, among those with noncomplex PCI, MACE outcomes were similar, regardless of the duration of DAPT (adjusted hazard ratio: 1.01; 95% confidence interval: 0.75 to 1.35; pinteraction = 0.01). In addition, the investigators found that the benefits of longer duration DAPT tended to increase sequentially as the number of complex angiographic features increased. However, balancing these benefits of longer duration DAPT was increased bleeding risks. Relative to those receiving shorter DAPT, those receiving longer DAPT had significantly higher major bleeding rates, regardless of procedural complexity.
The study had several strengths. It was based on high-quality data pooled from a large number of trials and patients (n = 9,577). Most of these trials evaluated the use of current-generation drug-eluting stents (85% overall). And, for the most part, the endpoints were similarly defined and well-adjudicated among the trials. The authors also examined the incremental predictive value of PCI complexity on outcomes after adjusting for other clinical risk factors (such as age, disease presentation, and comorbid illness), and examined the impact of complexity on outcomes among important patient subgroups.
The readers should, however, be aware of certain limitations. First and foremost, the study is ultimately a synthesis of retrospective data and thus can only analyze what was collected. Therefore, the investigators definition of “procedural complexity” was constrained to those features collected consistently across each trial. Thus, the investigators did not consider such angiographic risk factors as saphenous vein grafts, small-diameter vessels (stent diameter <3 mm), or final stent apposition. Second, the investigators predefined their complexity definition, rather than prospectively deriving it on the basis of their analysis. As such, CTO was considered a component of “complex PCI,” even though their analysis found that CTO intervention (n = 182) actually had similar MACE risk, regardless of the duration of DAPT (see Online Figure 4 in Giustino et al. ).
Third, the investigators’ definition of risk was ultimately binary, on the basis of procedural risk alone, rather than a clinically integrated risk score. Other studies have provided risk scores that included patient characteristics (PARIS score, n = 4,190), and integrated patient and procedural complexity indicators (DAPT score, n = 11,648) (2,3). Fourth, the optimal duration of DAPT must consider both the downstream risks for MACE and major bleeding. One could debate whether the reductions in MACE gained by longer term DAPT, even among those with complex PCI, were worth it after accounting for their higher risks for major bleeding. This debate is particularly relevant because overall mortality rates were similar regardless of the duration of DAPT among those with complex or noncomplex PCI.
Fifth, the field of intervention continues to evolve, and the generalization of prior studies to contemporary practice is also suspect. Are the risks of stent thrombosis or MACE on the basis of trials using first- and second-generation stents relevant to the latest generation stents (e.g., bioabsorbable, lower profiles)? Similarly, do the benefits (and risks) of DAPT based predominately on clopidogrel generalize to those treated with ticagrelor? Even the choices of DAPT duration are shifting. The investigators only looked at DAPT durations of up to 12 months, yet the recent DAPT trial found that among those tolerating DAPT to that point, continued DAPT therapy beyond 1 year could further reduce MACE risks. On the other end of the spectrum, the strategy of short-term DAPT (1 month) with subsequent prolonged ticagrelor monotherapy is currently being addressed in the Global Leaders study, which may alter these discussions in the future (GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation; NCT01813435).
The current analysis provides further evidence that PCI procedural complexity predicts subsequent adverse clinical events. The investigators’ synthesis also importantly demonstrates that procedural complexity also powerfully influences the benefits of a longer duration of DAPT. On the basis of these data and those from other studies, it seems reasonable to consider shorter duration DAPT in those with low clinical risk (e.g., nonacute coronary syndrome, nondiabetic, de novo lesions) and low angiographic procedural risks. Among those with high risk on the basis of either patient or procedural risk factors, clinicians will need to assess the patient’s long-term bleeding risks on DAPT. Then, they must determine whether the benefits of longer duration DAPT on MACE are worth the slight, but real increased risk for bleeding. Although these decisions may be complex, such individualization appears required to optimize patient outcomes.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Welsh has reported that he has received research grants and honoraria from AstraZeneca, Bristol-Myers Squibb, Pfizer, Bayer, and Janssen. Dr. Peterson has reported that he has received consulting fees and research funds from AstraZeneca and Sanofi.
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