Second-Generation DES Implantation and 6- vs 12-Mo DAPT
Second-Generation DES Implantation and 6- vs 12-Mo DAPT
The main results of the SECURITY trial are as follows:
Introduction of DES in clinical practice drastically changed the efficacy of PCI by reducing the need for repeated target lesion and target vessel revascularization. However, several retrospective analyses from real-world registries and clinical trials reported a higher incidence of late and very late ST with first-generation DES use compared with bare-metal stents. The pathological basis of late clinical events with DES seems related mainly to delayed vascular healing and local stent strut hypersensitivity. Concerns regarding ST focused the scientific community's attention on the optimal DAPT duration following DES implantation. Several studies initially suggested potential benefits of long-term DAPT to prevent late thrombotic events. Moreover, several observational studies found a significant association between early DAPT discontinuation and occurrence of thrombotic complications following DES implantation. Current guideline recommendations for DAPT following PCI arose from these initial observations. The American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend, in patients who have undergone DES-PCI, a DAPT duration of 12 months or 6 to 12 months in patients not at high risk for acute coronary syndrome and not at high risk of bleeding, respectively. Although these initial observations were done in the first-generation DES era, guideline recommendations for DAPT were extended to newer-generation DES, notwithstanding the lack of supporting evidence from RCTs.
Before our study, several randomized trials demonstrated the safety and efficacy of reduced-term versus prolonged-term DAPT. The REAL-LATE (Correlation of Clopidogrel Therapy Discontinuation in Real-World Patients Treated With Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events) and the ZEST-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) trials demonstrated no significant benefit in preventing major adverse cardiovascular events with clopidogrel continuation compared with clopidogrel discontinuation after 12 months in patients with DES implantation. Similarly, the DES-LATE (Optimal Duration of Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation) trial explored the use of DAPT for an additional 24 months in patients who were on 12-month DAPT without complications. Again, prolonged DAPT did not reduce major adverse cardiovascular events compared with aspirin alone. Moreover, the EXCELLENT trial reported the noninferiority of 6 months versus 12 months of DAPT in preventing major adverse cardiovascular events following everolimus-eluting or sirolimus-eluting stent implantation. However, the EXCELLENT study was designed to demonstrate the noninferiority of target vessel failure (cardiac death, MI, or ischemia-driven revascularization), the noninferiority margin was wide, and the study was underpowered for death or MI as the primary endpoint. Additionally, the PRODIGY trial demonstrated the noninferiority of 6 months of DAPT compared with 24 months, in terms of death, ST, MI, or cerebrovascular accident in patients who received a balanced mixture of DES or bare-metal stents.
Several reports suggested the association of second-generation DES with reduced rates of very late ST, compared with first-generation DES. However, the optimal DAPT duration following second-generation DES implantation is still debated. A pre-specified subanalysis from the PRODIGY trial reported reduced ST rates with paclitaxel-eluting stents and a prolonged (24-month) DAPT regimen. Conversely, no differences in ST between 24-month and 6-month DAPT were observed with the other stent types. In addition, the RESET trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following zotarolimus-eluting stent implantation) demonstrated noninferiority for the primary composite endpoint (cardiac death, MI, ST, target vessel revascularization, or bleeding) at 1 year with 3 months of DAPT following Endeavor zotarolimus-eluting stent implantation compared with 12 months of DAPT after other DES use. A substudy from the PROTECT (Patient Related OuTcomes with Endeavor vs. Cypher stenting Trial) study found a strong interaction among stent type used, DAPT duration, and ST events. Specifically, very late ST events (>1 year) with sirolimus-eluting stents were related to DAPT discontinuation, whereas no differences in very late ST events with Endeavor zotarolimus-eluting stents were observed in the presence of DAPT. Finally, the OPTIMIZE noninferiority trial, comparing 3 versus 12 months of DAPT in 3,119 patients with stable coronary artery disease undergoing PCI with zotarolimus-eluting stents, first demonstrated the noninferiority of 3 months versus 12 months of DAPT using 1 specific type of second-generation DES.
Our study, suggesting the noninferiority of 6 months versus 12 months of DAPT following implantation of different types of second-generation DES in the primary study endpoint, contributes to the evidence that reduced DAPT is safe and effective with currently used DES in patients with the characteristics of our study population.
One of the most evident results of our study, compared with previous studies, is the low rate of adverse cardiovascular events at clinical follow-up. This is consistent with improvements related to the introduction of second-generation DES in clinical practice and the low-risk clinical and lesion profiles of the patients in our study (Table 1 and Table 2). Consequently, at 1-year clinical follow-up, the overall primary composite endpoint and definite or possible ST rates were 4.5% and 3.7%, respectively, in the 6-month versus the 12-month group. Definite or possible ST rates observed in our study compared favorably with reported rates in the OPTIMIZE trial (using zotarolimus-eluting stents) of 0.8% at 1 year in both the 3-month and 12-month DAPT groups. Our study also compared favorably in this respect to the PRODIGY and EXCELLENT trials, which reported ST incidences of 1.5% and 0.9%, respectively, in the 6-month DAPT group. However, almost 74% of patients in the PRODIGY trial and 50% of patients in the EXCELLENT trial presented with an acute coronary syndrome. Conversely, our results are very similar to those of the RESET trial, which reported a 1-year ST incidence of 0.2% using the Endeavor zotarolimus-eluting stent plus 3 months of DAPT, and 0.3% using sirolimus-eluting, everolimus-eluting, or Resolute zotarolimus-eluting stent plus 12 months of DAPT. Similar to our study, the majority of RESET trial patients (85%) presented with stable or unstable angina.
Following multivariable adjustment, DAPT duration did not independently predict the primary endpoint in our study, further demonstrating the safety of a 6-month regimen. By contrast, factors reflecting the burden of coronary artery stenting (mean stent length, size, and number of stents implanted) were strong independent primary endpoint predictors, even with second-generation DES. Independent of DAPT duration, patients in whom multiple smaller or longer stents are implanted may benefit from high-potency P2Y inhibitors. Finally, as expected, age ≥75 years was another independent predictor of mortality. Because of the low event rates and the implantation of an Endeavor Resolute DES in >40% of patients, we cannot draw conclusions regarding the correlation between primary endpoint occurrence and a specific stent type. The association of increased events with Resolute stent implantation should be interpreted cautiously, as the low event number, combined with the high Resolute implantation rate, increases the probability that this is due to chance.
Of note, our study did not find any difference in bleeding events between reduced and prolonged DAPT. The PRODIGY trial reported a significantly higher risk of hemorrhagic complications in patients allocated to the 24-month DAPT cohort. Most probably, our study population's low risk profile and the 12-month DAPT duration were both insufficient to increase the hazard of bleeding events.
Our study has several important limitations to consider:
Discussion
The main results of the SECURITY trial are as follows:
In our study population undergoing PCI with second-generation DES, 6 months of DAPT appeared noninferior to a 12-month regimen with respect to the primary composite endpoint of cardiac death, MI, stroke, definite or probable ST, or BARC type 3 or 5 bleeding at 12 months of clinical follow-up.
Multivariable analysis found age ≥75 years, stent type used, mean number of stents implanted, mean stent length, and mean stent size as significant independent predictors of the primary endpoint. Of note, following multivariable adjustment, results for 6 versus 12 months of DAPT were not significant.
With respect to incidence of the secondary composite endpoints defined by the study protocol, 6 months DAPT appeared noninferior to 12 months.
Introduction of DES in clinical practice drastically changed the efficacy of PCI by reducing the need for repeated target lesion and target vessel revascularization. However, several retrospective analyses from real-world registries and clinical trials reported a higher incidence of late and very late ST with first-generation DES use compared with bare-metal stents. The pathological basis of late clinical events with DES seems related mainly to delayed vascular healing and local stent strut hypersensitivity. Concerns regarding ST focused the scientific community's attention on the optimal DAPT duration following DES implantation. Several studies initially suggested potential benefits of long-term DAPT to prevent late thrombotic events. Moreover, several observational studies found a significant association between early DAPT discontinuation and occurrence of thrombotic complications following DES implantation. Current guideline recommendations for DAPT following PCI arose from these initial observations. The American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend, in patients who have undergone DES-PCI, a DAPT duration of 12 months or 6 to 12 months in patients not at high risk for acute coronary syndrome and not at high risk of bleeding, respectively. Although these initial observations were done in the first-generation DES era, guideline recommendations for DAPT were extended to newer-generation DES, notwithstanding the lack of supporting evidence from RCTs.
Before our study, several randomized trials demonstrated the safety and efficacy of reduced-term versus prolonged-term DAPT. The REAL-LATE (Correlation of Clopidogrel Therapy Discontinuation in Real-World Patients Treated With Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events) and the ZEST-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) trials demonstrated no significant benefit in preventing major adverse cardiovascular events with clopidogrel continuation compared with clopidogrel discontinuation after 12 months in patients with DES implantation. Similarly, the DES-LATE (Optimal Duration of Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation) trial explored the use of DAPT for an additional 24 months in patients who were on 12-month DAPT without complications. Again, prolonged DAPT did not reduce major adverse cardiovascular events compared with aspirin alone. Moreover, the EXCELLENT trial reported the noninferiority of 6 months versus 12 months of DAPT in preventing major adverse cardiovascular events following everolimus-eluting or sirolimus-eluting stent implantation. However, the EXCELLENT study was designed to demonstrate the noninferiority of target vessel failure (cardiac death, MI, or ischemia-driven revascularization), the noninferiority margin was wide, and the study was underpowered for death or MI as the primary endpoint. Additionally, the PRODIGY trial demonstrated the noninferiority of 6 months of DAPT compared with 24 months, in terms of death, ST, MI, or cerebrovascular accident in patients who received a balanced mixture of DES or bare-metal stents.
Several reports suggested the association of second-generation DES with reduced rates of very late ST, compared with first-generation DES. However, the optimal DAPT duration following second-generation DES implantation is still debated. A pre-specified subanalysis from the PRODIGY trial reported reduced ST rates with paclitaxel-eluting stents and a prolonged (24-month) DAPT regimen. Conversely, no differences in ST between 24-month and 6-month DAPT were observed with the other stent types. In addition, the RESET trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following zotarolimus-eluting stent implantation) demonstrated noninferiority for the primary composite endpoint (cardiac death, MI, ST, target vessel revascularization, or bleeding) at 1 year with 3 months of DAPT following Endeavor zotarolimus-eluting stent implantation compared with 12 months of DAPT after other DES use. A substudy from the PROTECT (Patient Related OuTcomes with Endeavor vs. Cypher stenting Trial) study found a strong interaction among stent type used, DAPT duration, and ST events. Specifically, very late ST events (>1 year) with sirolimus-eluting stents were related to DAPT discontinuation, whereas no differences in very late ST events with Endeavor zotarolimus-eluting stents were observed in the presence of DAPT. Finally, the OPTIMIZE noninferiority trial, comparing 3 versus 12 months of DAPT in 3,119 patients with stable coronary artery disease undergoing PCI with zotarolimus-eluting stents, first demonstrated the noninferiority of 3 months versus 12 months of DAPT using 1 specific type of second-generation DES.
Our study, suggesting the noninferiority of 6 months versus 12 months of DAPT following implantation of different types of second-generation DES in the primary study endpoint, contributes to the evidence that reduced DAPT is safe and effective with currently used DES in patients with the characteristics of our study population.
One of the most evident results of our study, compared with previous studies, is the low rate of adverse cardiovascular events at clinical follow-up. This is consistent with improvements related to the introduction of second-generation DES in clinical practice and the low-risk clinical and lesion profiles of the patients in our study (Table 1 and Table 2). Consequently, at 1-year clinical follow-up, the overall primary composite endpoint and definite or possible ST rates were 4.5% and 3.7%, respectively, in the 6-month versus the 12-month group. Definite or possible ST rates observed in our study compared favorably with reported rates in the OPTIMIZE trial (using zotarolimus-eluting stents) of 0.8% at 1 year in both the 3-month and 12-month DAPT groups. Our study also compared favorably in this respect to the PRODIGY and EXCELLENT trials, which reported ST incidences of 1.5% and 0.9%, respectively, in the 6-month DAPT group. However, almost 74% of patients in the PRODIGY trial and 50% of patients in the EXCELLENT trial presented with an acute coronary syndrome. Conversely, our results are very similar to those of the RESET trial, which reported a 1-year ST incidence of 0.2% using the Endeavor zotarolimus-eluting stent plus 3 months of DAPT, and 0.3% using sirolimus-eluting, everolimus-eluting, or Resolute zotarolimus-eluting stent plus 12 months of DAPT. Similar to our study, the majority of RESET trial patients (85%) presented with stable or unstable angina.
Following multivariable adjustment, DAPT duration did not independently predict the primary endpoint in our study, further demonstrating the safety of a 6-month regimen. By contrast, factors reflecting the burden of coronary artery stenting (mean stent length, size, and number of stents implanted) were strong independent primary endpoint predictors, even with second-generation DES. Independent of DAPT duration, patients in whom multiple smaller or longer stents are implanted may benefit from high-potency P2Y inhibitors. Finally, as expected, age ≥75 years was another independent predictor of mortality. Because of the low event rates and the implantation of an Endeavor Resolute DES in >40% of patients, we cannot draw conclusions regarding the correlation between primary endpoint occurrence and a specific stent type. The association of increased events with Resolute stent implantation should be interpreted cautiously, as the low event number, combined with the high Resolute implantation rate, increases the probability that this is due to chance.
Of note, our study did not find any difference in bleeding events between reduced and prolonged DAPT. The PRODIGY trial reported a significantly higher risk of hemorrhagic complications in patients allocated to the 24-month DAPT cohort. Most probably, our study population's low risk profile and the 12-month DAPT duration were both insufficient to increase the hazard of bleeding events.
Study Limitations
Our study has several important limitations to consider:
Considering the low event rates observed during the trial, our study was underpowered to demonstrate any difference in single outcomes such as cardiac death, MI, ST, bleeding, or stroke. Studies specifically designed to demonstrate differences in single outcomes are currently ongoing (NCT00977938 and NCT00661206).
Our study population included patients with reasonably low-risk clinical profiles; therefore, generalization of our results to patients at moderate or high risk cannot be made. Moreover, the lesion risk profile of our study population had low prevalence of bifurcation lesions and complex lesions. Our conclusions are therefore applicable to a subset of patients at low risk and relatively simple coronary anatomy.
The primary endpoint rate was lower than expected at the interim analysis (4.5% vs. 6%). Therefore, keeping all the other assumptions of the study design unchanged, the sample size was reduced from 3,600 (originally expected) to 2,800. The actual number of 1,399 included patients allowed declaration of noninferiority, given the superimposable occurrence of the primary endpoint in the 2 groups. Because of the reduced number of enrolled patients, compared with the original sample size, and the small difference in primary endpoint occurrence between the 2 study groups, the power is lower than originally planned (around 60% following recalculation). Nevertheless, the upper limit of the CI is lower than the preset margin of 2%, confirming the noninferiority hypothesis.
As a practical approach, we randomized patients at the time of the index procedure, rather that at 6 months, which should be considered a debatable limitation.
Almost 34% of patients in the 6-month group continued DAPT after 6 months. As this could have affected our results, the per-protocol analysis excluding these patients (948 excluded patients with 32 primary events) confirmed the results of the intention-to-treat analysis.
Although stent type appeared to be a predictor of the primary endpoint, because several types were allowed by the study protocol, and because the majority of patients were treated with the Endeavor Resolute DES, we cannot determine the real association between the stent type used and occurrence of the primary endpoint.
We cannot exclude that the low incidence of major adverse cardiovascular events in our trial could have been due to under-reporting of adverse events by the participating centers, notwithstanding the continuous monitoring of the sites by an independent clinical research organization. However, source data verification was performed in 40% of patients.
