DR. COLOMBO: It is my opinion that it will be difficult to randomize many of the patients with high-risk lesions in studies such as Fractional Flow Reserve Guided Percutaneous Coronary Intervention Plus Optimal Medical Treatment Verses Optimal Medical Treatment (FAME II).2 A referring cardiologist dealing with a patient, with a proximal LAD lesion with positive fractional flow reserve, will feel uncomfortable to suggest medical therapy and wait for more dramatic symptoms.
DR. STONE: You make an important point because it is very difficult to enroll adequate numbers of truly high-risk patients in clinical trials. For example, if you look at the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial,3 you will note very low mortality rates and a low level of ischemia in most of the patients who were enrolled. Even though these patients had numerous cardiac risk factors, they were still a low risk cohort.
DR. COLOMBO: If I may interrupt, Dr. Stone. The results of those trials are important, but they don’t give a complete picture of the reality. Many of the patients we just described will have difficulties entering those trials.
DR. STONE: Dr. Kereiakes, do you have complementary or differing views? Do you believe that we are reducing death and/or MI in select patients with stable coronary disease and a certain type of coronary anatomy? This is a critical question because we have to take care of these patients today without the benefit of the perfect clinical trial for every scenario.
DR. KEREIAKES: Over time, in populations, ischemia relief causes reductions in death and MI. If you look at Leslie Shaw’s nuclear substudy of COURAGE,4 there’s a direct linear relationship between ischemia, even at quantitatively low levels, and death or MI over a follow-up period of 5 years. So, I really believe that a drug-eluting stent is an improvement over a bare-metal stent, as shown in both the BAsel Stent Kosten Effektivitäts Trial (BASKET) Nuclear Substudy5 and in the Occluded Artery Trial (OAT),6 and provides more durable relief of ischemia than do bare-metal stents or medical therapy.
DR. STONE: The antirestenotic benefits of drug-eluting stents (due to inhibition of smooth muscle cell proliferation) are concurrent with increased inhibition of endothelial cells and thus stent strut coverage. Everyone is aware of the grave concerns regarding increased rates of stent thrombosis in patients with first-generation, drug-eluting stents, especially the increased rates of very-late stent thrombosis after 1 year, leading to increased requirements for prolonged dual antiplatelet therapy (DAPT), ie, aspirin and an adenosine diphosphate receptor inhibitor. Dr. Kirtane, can you talk to us about the evolution from first-generation, drug-eluting stents to current generation devices and the risk of stent thrombosis compared to bare-metal stents.
DR. KIRTANE: I think that was the real caveat. As physicians, we will opt to treat patients with an effective therapy, provided it has no downside, and one of the limiting factors restricting the more widespread use of drug-eluting stents compared to bare-metal stents was a concern over stent thrombosis. One thing that has been clear is when you look at the randomized trial data with drug-eluting stents and bare-metal stents—and we have good follow-up of 5 years now—there appears to be no difference in the overall stent thrombosis rates over time. We can argue about definitions of stent thrombosis, but that’s beyond the scope of this discussion. I think it’s clear that there’s no excess. The issue, though, is that there appears to be a late accrual of events, particularly with first-generation drug-eluting stents. Moving into the present with the types of stents we have currently, we see a flattening of the event curves beyond 1 year not only with durable polymer designs but also with bioabsorbable polymer designs. There are new data suggesting that there may be a stent thrombosis advantage with certain current generation platforms compared with first-generation platforms and even bare-metal stents. We don’t know if extended DAPT duration makes a difference (Dr. Kereiakes and others are studying this extensively), but stent thrombosis is probably lesser of an issue than we thought in 2006.
DR. STONE: Dr. Colombo, you were the first person who clearly demonstrated that we are able to reduce both stent thrombosis and restenosis using excellent technique. Your work in this regard was initially with bare-metal stents, but the same holds true (perhaps, even more so) with drug-eluting stents. Technique and drug-eluting stent technology continue to improve over time, and stent thrombosis rates are declining. So, what is your current practice with DAPT? How long is DAPT required, and do you treat different types differently in this regard?
DR. COLOMBO: Provided that we currently use only second- or, maybe in Europe, third-generation drug-eluting stents, I would prescribe a minimum of 6 months of DAPT, and I don’t make a strong effort to prolong DAPT over 6 months. Nevertheless, I routinely prescribe DAPT for 1 year. If the patient asks me to stop DAPT after 6 months, I do not disagree. The only exceptions are in the cases of diabetics; very long stents; and unprotected left main, complex bifurcations. In these settings, I usually try to extend DAPT over 1 year. Of course, all of this is done on a personal basis. The bottom line is that 6 months is probably acceptable, and over 6 months is probably useful in some situations. Unfortunately the words “probably” and “acceptable” are used too frequently.
But let me ask you a question, Dr. Stone. Recently, I had a debate with a cardiac surgeon regarding first- and second-generation stents: the issue of stent thrombosis has been raised. There is no question that recent data show that second-generation drug-eluting stents have a lower thrombosis rate than do first-generation stents. I was surprised that the surgeon had an opposing view.
DR. STONE: Yes, that’s true. In general, the major differences that we’ve seen between first- and second-generation, drug-eluting stents have been (1) improved deliverability and user friendliness due to thinner struts and enhanced stent and delivery system designs; (2) some reduction in restenosis; and (3) a clear reduction in stent thrombosis, especially with the durable fluoropolymer-based, everolimus-eluting stents (EES). We have not seen observable differences in death or cardiac death in any randomized or registry studies. Of course, the causes of death are multi-factorial, and the frequency of stent-related cardiac death is low, so it may be hard to delineate such a difference in studies, if indeed one exists. Dr. Kirtane, would you like comment on this issue?
DR. KIRTANE: I think the hard endpoints are obviously very important, and some of these data can be used to generate a hypothesis because they are derived from studies in different eras. I think it’s nice that we now have some head-to-head data from adequately powered studies. For instance, at the European Society of Cardiology (ESC) Congress, we had data from the Patient Related OuTcomes With Endeavor Versus Cypher Stenting Trial (PROTECT),7 which aimed to examine stent thrombosis between first- and second-generation, drug-eluting stents.
DR. STONE: It is worth stating, however, that data from large network meta-analyses, such as the recently published work by Bangalore and colleagues,8,9 suggest that there may actually be a reduction in hard endpoints such as MI with certain current-generation, drug-eluting stents. This is also consistent with the meta-analysis by Palmerini10 showing a clear reduction in stent thrombosis. Although network meta-analyses are not definitive and don’t provide the same level of evidence as a definitive, large-scale, randomized trial, accumulating evidence indicates that patient event-free survival is improving over time with improvements in our devices, drugs, and technique.
DR. STONE: Dr. Kereiakes, you are the coprincipal investigator of the large-scale DAPT trial, which is examining the benefits of 1 year vs 2.5 years of DAPT after drug-eluting stent implantation. Other trials have studied shorter-term DAPT (less than 1 year), and 3 of these have already been published—the Restoration of Chronotropic Competence in Heart Failure Patients with Normal Ejection Fraction (RESET) trial,11 the Prolonging Dual Antiplatelet Treatment after Grading Stent-induced Intimal Hyperplasia Study (PRODIGY),12 and the Efficacy of Xience/Promus Versus Cypher in rEducing Late Loss After stENTing (EXCELLENT) trial13—all of which have suggested that 3 to 6 months of clopidogrel therapy may be more acceptable than 12 months of this therapy. Additionally, most of these studies involved first-generation, drug-eluting stents; early DAPT discontinuation is more likely to be safe with second-generation, drug-eluting stents. So, what are your views on the current evidence base regarding the duration of DAPT treatment for patients with current-generation, drug-eluting stents, and what do you tell your patients?
DR. KEREIAKES: What I would say about Correlation of Clopidogrel Therapy Discontinuation in Real-World Patients Treated with Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events (REAL-LATE)/Evaluation of the Long-Term Safety after Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or Paclitaxel-Eluting Stent Implantation for Coronary Lesions—Late Coronary Arterial Thrombotic Events (ZEST-LATE), PRODIGY, and EXCELLENT, the studies you have referenced, is that (1) they’re underpowered, (2) they’re not blinded, and (3) they’re somewhat confused by factorial design and multiple tiered randomizations. I believe that smaller trials are best when they focus on and answer a single question, rather than multiple questions.
That being said, none of those trials show a difference in ischemic endpoints—either the primary or key secondary ischemic endpoints— stratified by duration of therapy. In fact, REAL-LATE / ZEST-LATE shows a trend in the opposite direction for increased ischemic events with longer duration DAPT. However, less than 25% of the patients enrolled into this trial reached the 2-year time point for evaluation. If the trial is underpowered at 2700 patients, it is extremely underpowered at 600, which is exactly how many patients were counted at 2 years. There are also other methodological flaws in this trial, including the fact that approximately 12% of the subjects were not even randomized until 18-24 months after their PCI procedure. Recall that the hypothesis being tested was 1 vs 2 years of DAPT. In addition, TIMI major bleeding was observed in only 0.1% of subjects at 1 year and 0.2% at 2 years in stark contrast to the 0.6% at 1 year in EXCELLENT and 1.6% at 2 years in PRODIGY. This raises serious question as to the accuracy of endpoint assessment as a quality measure in REAL-LATE/ZEST-LATE.
Finally, specific subgroups of patients may derive differential benefit from longer duration DAPT. For example, in 749 consecutive diabetic patients described by Brar who were treated with either drug-eluting stents or bare-metal stents and then stratified by DAPT duration (<6 months, 6 to 9 months, and >9 months), a step-wise reduction in death or MI in follow-up was observed with longer duration DAPT therapy. Similarly, in EXCELLENT, there is a highly significant interaction observed among the diabetic cohort for a reduction in target vessel failure with longer duration (12 months) DAPT vs shorter duration (6 months).
I believe that patient substrate matters and specific subsets such as diabetics may derive differential or preferential benefit from longer duration DAPT therapy. I also think that stent platform matters. For example, the EES polyvinylidene fluoride fluoro co-polymer has a lower rate of stent thrombosis than do non-EES drug-eluting stents or bare-metal stents. In recent network meta-analyses of multiple stent randomized trials, EES have the lowest incidence of stent thrombosis over a 2-year follow-up period.
DR. STONE: We certainly need to wait for the results of the large-scale DAPT study to fully understand whether DAPT has late benefits—not only with respect to preventing stent thrombosis but also systemically for secondary prevention. There are also large trials of early DAPT discontinuation that are ongoing, such as Safety and Efficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE)14 and others that are in the planning phase. Dr. Colombo’s opinion was to aim for 1 year for everybody, but 6 months is acceptable. Dr. Kirtane, what do you do for your patients in terms of DAPT duration?
DR. KIRTANE: I try to screen patients for their ability to adhere to DAPT in advance, and I go through a variety of factors that might affect that decision. If we implant a bare-metal stent, I’ll use DAPT for a minimum of 4 to 6 weeks. If the clinical scenario is an acute coronary syndrome, I’ll extend therapy for a year. If we implant a drug-eluting stent, I’ll do pretty much what Dr. Colombo said. If they can take DAPT for a year, that would be ideal, particularly if they have an acute coronary syndrome. If not, then it’s 3 to 6 months, in general.
DR. STONE: It seems as if we’re all pretty much on the same page: on the basis of the current evidence, 1 year should still be the goal, although 3 to 6 months might be safe with the best current technology.
In what percentage of your patients are you implanting bare-metal stents today? Additionally, in whom are you implanting these stents? For example, you may be dealing with a patient with an acute coronary syndrome or a lesion with thrombus, a noncompliant patient who you’re not confident will take at least 6 months of DAPT, or a patient requiring surgery in the short term who will have to discontinue DAPT. Alternatively, do you use drug-eluting stents in 100% of patients (as reported in certain regions in Asia)?