Several trials have examined the issue of optimal duration of dual antiplatelet therapy in patients with ACS. This open-label, randomized study comparing shorter-duration with longer-duration DAPT — 6 vs. 12 months — is slightly different in that it had an 18-month endpoint that included stroke. Although consistent with some previous trials in this area, not all of the other studies included stroke in their endpoint, nor did most have an 18-month endpoint period.

Designed as a noninferiority trial, SMART-DATE showed no significant difference in the composite endpoint as described with 6 vs. 12 months of DAPT. However, not unexpectedly, there was a substantial difference in rates of MI, which primarily drove the difference between the two groups with regards to the composite endpoint. The researchers also found increased bleeding in the prolonged therapy group, but the findings were on par with what has been reported in previous studies.

Overall, this study effectively falls in line with other trials evaluating DAPT duration. Not only were the findings consistent with previous results, but SMART-DATE has many of the same strengths and weaknesses as well. In terms of strengths, the study was as well done as can be expected for an open-label study and had a noninferiority trial design, which, in my opinion, is the best way to conduct this type of research.

The trial was also interesting in that all enrolled patients were Asian, giving us a bit of insight into how the Asian population may fare with this treatment. This is relevant for several reasons. First, we have relatively limited information about DAPT use in Asian populations globally. Second, about 80% of patients in the study received clopidogrel as the second antiplatelet drug, which is an issue because Asians do not metabolize clopidogrel as well as other ethnicities. In the past, we have been concerned about potentially undertreating Asian patients by using clopidogrel, but that debate has quieted down as alternative drugs, such as ticagrelor, have become available in the Asian market. So, the important news for me from this standpoint is that the observations we have made in other large-scale trials seem to be playing out similarly in Asian populations.

However, the question still remains about whether we should use DAPT for a shorter vs. longer period of time. Very few physicians do not believe that prolonging DAPT reduces risk for MI — a fact that stands out with relative consistency across the trials. The major problem has been that there’s not a clear mortality advantage with prolonging DAPT. In fact, there may even be signals that mortality is perhaps higher with longer DAPT duration. Moreover, it is indisputable that longer exposure to these drugs is associated with a greater risk for bleeding. Therefore, we as physicians are left with weighing the risk for bleeding against the risk for MI in individual patients.

Unfortunately, this study won’t resolve the debate regarding DAPT duration. It has told us, however, that the same discussion needs to be happening for Asian populations as it has for other patients

We know that patients with ACS have a higher risk for recurrent ischemic events, which forms the basis for the current guidelines recommending dual antiplatelet therapy for 12 months or longer in these patients.

However, as interventionalists, we have had more of a conversation about bleeding risk, thus the movement toward radial access and attempting shorter durations of therapy so that we can decrease that bleeding risk. And, there are many of us in the interventional community who have felt that maybe some of the trials that have directed the guidelines are based on older platforms of drug-eluting stents and that perhaps with more current DES, this may change.

Dr. Gwon and his colleagues have nicely shown, though, an increased risk for MI with 6-month DAPT with current-generation DES. Therefore, these newer-generation stents are still not enough to make us feel comfortable because the ACS patient is a fundamentally different patient.

Right now, I would say we have to stick to our current guidelines. These results have shown that there is not a significant increase in bleeding risk, so we can be comfortable treating these patients with ACS for a minimum of 12 months and potentially longer based on clinical criteria.

SMART-DATE is an interesting and well-conducted trial that offers insight into an important question regarding duration of dual antiplatelet therapy after PCI for ACS. Although it has its strengths, the trial also has limitations that should give us pause when interpreting how these results may influence clinical practice.

Unlike in previous trials such as DAPT-STEMI or DAPT, patients were randomly assigned to a shorter-term (6 months) or longer-term (12 months) DAPT duration at the time of the PCI procedure as opposed to the later time point at which DAPT therapy would be changed. The trial also did not have a blinded control group, which may have resulted in differential adherence to the study protocol between the treatment groups, with more patients in the 6-month vs. 12-month DAPT group breaking protocol and continuing treatment with their P2Y12 inhibitor.

Another interesting — and potentially problematic — feature of the trial was the researchers’ decision to randomly assign patients to three different DES types: Biomatrix Flex , Resolute Integrity and Xience Prime . There are important potential differences between these stents, specifically with respect to strut thickness, which can influence thrombosis rates. When evaluating an aspect of treatment such as DAPT duration, it would have been beneficial to use the same stent to avoid adding another variable.

It would also have been interesting to see what the results would have been had the researchers decided to apply the DAPT risk score in these patients at 6 months to optimize extended DAPT with respect to ischemic benefit while minimizing bleeding risk.

Overall, though, the observations made in this study are important. The availability of second- and third-generation stents — particularly devices with thinner struts — make it more difficult to show a stent related benefit of DAPT beyond 6 months. However, people with ACS events, specifically those with biomarker-positive ACS, are a high-risk group with multifocal, multicentric atherothrombotic disease. The reduction in MI observed in this trial was in part unrelated to stent thrombosis; rather, MI reduction was related to non-stented disease. Similar to results from the PROSPECT study, a significant percentage of events experienced during follow-up were attributable to non-culprit stenoses. Therefore, in patients with ACS and more extensive disease, longer DAPT duration is likely to provide greater benefit.

One of the takeaway messages from this trial is that a therapeutic dichotomy appears to exist between treating the stent and treating the patient. By definition, a larger portion of MI events in the shorter DAPT duration (6 months) arm of SMART-DATE were not related to the stent. This potential excess of MI events was suppressed in the longer (12 month) DAPT arm. Although the cohort included STEMI, non-STEMI or unstable angina in roughly equal (1/3) portions, I suspect that the events observed in the shorter DAPT duration group at 18 months in the landmark analysis were more frequent in patients who were biomarker-positive (non-STEMI or STEMI) than in those with unstable angina.

These findings reaffirm those from previous studies that patient-related (versus stent-related) factors are critically important when determining optimal DAPT duration.

The investigators are to be congratulated because these are difficult trials to perform, and a 2,700-patient randomized trial in any fashion deserves appreciation. That said, these are complicated trials, and, as mentioned, this study had some limitations, in particular the high crossover rate from one study arm to the other arm.

An important study design issue is apparent in this trial also seen in many of the other trials of short-term DAPT. The optimal time to randomize is at the time at which you’re going to switch the DAPT duration, in this case 6 months. Anything that happens before 6 months just adds noise of the trial, biasing toward noninferiority and away from superiority. Indeed, in this study, there were some small differences in the groups, by chance, before 6 months, further adding study imprecision. The researchers did an appropriate landmark analysis, but the optimal way to conduct this type of trial is by randomizing patients at 6 months. This would duplicate the clinical question that needs to be addressed; in patients without an event at 6 months who have been compliant with their medications, should DAPT be continued or down-graded to a single anti-platelet agent?

The study also included unstable angina patients, who I presume were biomarker-negative, and we weren’t shown the subgroup results according to the breakdown of STEMI, non-STEMI and unstable angina. Biomarker-negative unstable angina patients behave more like stable angina patients in terms of prognosis, stent thrombosis and non-target vessel MI, and 6 months of DAPT is adequate in such patients. The true question to address regards DAPT duration in patients with biomarker-positive ACS.

It is also worth noting that these results are not that different from those of the REDUCE trial presented at TCT 2017, in which one particular type of DES — the Combo Dual Therapy Stent (OrbusNeich) — was used. REDUCE showed strong trends toward increased death and stent thrombosis with shorter-duration DAPT. Finally, the PLATO trial, an 18,600-patient double-blind randomized trial, demonstrated that the more potent P2Y12 inhibitor ticagrelor compared with the less potent P2Y12 inhibitor clopidogrel in biomarker-positive ACS patients reduced mortality as well as MI, benefits that continued to accrue and indeed increased through 12 months of follow-up.

Therefore, I personally do believe that these data showing an increased risk of MI after 6 months, coupled with the findings from REDUCE and PLATO, support a longer duration of DAPT (at least 12 months), not a shorter duration of DAPT, in biomarker-positive ACS patients who are at not at high bleeding risk.