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SMART-DATE: Shorter DAPT duration noninferior to longer duration, but increases MI risk
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ORLANDO, Fla. — Six months of dual antiplatelet therapy was noninferior to 12 months’ duration, but shorter therapy was associated with a significantly increased risk for MI in patients with ACS who underwent PCI with a drug-eluting stent, according to new data from the SMART-DATE trial.
In the intention-to-treat analysis, the cumulative rate of the primary endpoint of MACCE — a composite of all-cause death, MI or stroke at 18 months — did not differ significantly in patients assigned to 6 months of DAPT compared with those assigned to at least 12 months of DAPT (4.7% vs. 4.2%; absolute risk difference, 0.5%; upper limit of one-sided 95% CI, 1.8%; P = .03 for noninferiority).
However, risk for MI was about twice as high in the shorter-duration DAPT group (1.8% vs. 0.8%; HR = 2.41; 95% CI, 1.15-5.05), according to Hyeon-Cheol Gwon, MD, from the Samsung Medical Center, Sungkyunkwan University School of Medicine, South Korea.
The randomized, open-label, noninferiority trial enrolled 2,712 patients from 2012 to 2015 at 31 centers in South Korea. Patients had unstable angina, non-STEMI or STEMI and had undergone PCI with an everolimus-eluting stent (Xience Prime, Abbott Vascular), a zotarolimus-eluting stent (Resolute Integrity, Medtronic) or a biolimus-eluting stent (Biomatrix Flex, Biosensors).
After enrollment, patients were loaded with aspirin and P2Y12 inhibitors and then randomly assigned to 6 months of DAPT (n = 1,000) or at least 12 months of DAPT (n = 1,297), with stratification by site, clinical presentation and diabetes.
At baseline, the median age was 62 years, more than one-quarter had diabetes and about one-third had STEMI. Per protocol, each of the three stents were used in about one-third of patients.
About 80% of patients received clopidogrel, as newer antiplatelet agents were not yet available in Korea early in the study, Gwon noted.
In addition to the intention-to-treat analysis, the researchers also performed a post-hoc landmark analysis and a per-protocol analysis among patients who adhered to the study protocol.
In terms of the primary endpoint, the absolute difference in the rate of MACCE between the two groups was 0.5%, which was below the prespecified noninferiority margin of 2%, Gwon noted. In the landmark analysis, however, the risk for the primary endpoint was higher in the shorter-duration DAPT group vs. the longer-duration DAPT group (HR = 1.69; 95% CI, 0.97-2.94).
There were no significant differences between the shorter- and longer-duration DAPT groups in all-cause mortality (2.6% vs. 2.9%; HR = 0.9; 95% CI, 0.57-1.42), stroke (0.8% vs. 0.9%; HR = 0.92; 95% CI, 0.41-2.08), stent thrombosis (1.1% vs. 0.7%; HR = 1.5; 95% CI, 0.68-3.35) or Bleeding Academic Research Consortium-defined 2 to 5 major bleeding (2.7% vs. 3.9%; HR = 0.69; 95% CI, 0.45-1.05).
Results were similar for these secondary endpoints in the landmark analysis, including the increased risk for MI in the shorter-duration DAPT group vs. the longer-duration DAPT group (HR = 5.06; 95% CI, 1.46-17.5). The per-protocol analysis also yielded similar results to the intention-to-treat analysis, and findings were consistent across all subgroups, according to Gwon.
Adherence to study protocol was 73.7% in the shorter-duration DAPT group and 95.7% in the longer-duration DAPT group.
He also highlighted some limitations of the study, including randomization at the index procedure as opposed to 6 months after, when treatment has changed; its open-label design; a considerable cross-over rate in the 6-month DAPT group; and the fact that clopidogrel was the predominantly used P2Y12 inhibitor. Also, the results only apply to patients with ACS undergoing PCI with DES.
“Although the noninferiority of the 6-month DAPT compared to 12-month or longer DAPT was met, the increased MI risk with 6-month DAPT prevent us from concluding that short-term DAPT is safe in ACS patients undergoing PCI with current-generation DES,” Gwon said during his presentation. “Prolonged DAPT in ACS patients without excessive risk of bleeding should remain standard of care.” – by Melissa Foster
References:
Gwon H-C. Late-Breaking Clinical Trials: Interventional. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.
Hahn J-Y, et al. Lancet. 2018;doi: 10.1016/S0140-6736(18)30493-8.
Disclosures: This study was supported by Abbott Vascular Korea, Biosensors, Dong-A ST and Medtronic Vascular Korea. Gwon reports he has received consulting fees/honoraria from Medtronic Asia Pacific and research/research grants from Abbott Korea, Boston Scientific Korea and Medtronic Korea.
Perspective
Back to TopDipti Itchhaporia , MD, FACC
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.
Perspective
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Gregg W. Stone , MD
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.
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