Duration of Dual Antiplatelets in Patients With ACS
Duration of Dual Antiplatelets in Patients With ACS
This is, to our knowledge, the largest outcome analysis of varying DAPT durations in patients discharged from hospital with ACS. Our data show that clopidogrel co-administered with aspirin for >3 months compared with 3 months was associated with a statistically significantly lower incidence of death/stroke or re-infarction in patients post-ACS. Baseline characteristics, as well as comorbidity and overall bleeding risk were similar between treatment groups, indicating a similar background for ischaemic and bleeding risk in treatment groups.
In the analyses, we excluded patients with events that occurred within the first 3 months of the index event during which the antiplatelet treatment was the same in the DAPT duration groups, since events during that period were likely to interfere with and alter the initial treatment duration strategy, either by interruption due to bleeding events or prolongation due to ischaemic events. Therefore, it is unlikely that the treatment duration effect is influenced by the early risk hazard associated with an unsuspected event that would change the initial treatment strategy. Also for the individual endpoints of myocardial infarction and death, there tended to be lower event rates with a prolonged treatment duration >3 months. For myocardial infarction, this difference reached statistical significance. The observed consistency between these outcome measures, with a lower event rate with the >3 month treatment duration, also strengthens the conclusion of a lower ischaemic event rate after the initial 3 months of treatment. However, in contrast to the ischaemic endpoints of death and MI, repeat revascularizations occurred more frequently in the >3 month DAPT group compared with the 3-month group. This difference was mostly driven by the fact that patients who were not revascularized during the index event, underwent revascularization later in time leading to prolongation of the DAPT.
The potentially negative consequence of prolonged antiplatelet treatment is increased bleeding risk. In our study, bleeding was more common in groups with longer treatment duration. This is consistent with previous findings that DAPT duration correlates with the risk of bleeding, which in turn negatively influences outcomes after coronary stenting.
Recently, several independent but moderately large trials have suggested that a shorter DAPT duration after stent placement may be as beneficial as longer duration. An extended clopidogrel therapy >12 months in patients after implantation of drug-eluting stents did not reduce myocardial infarction or death. Similarly, shortening DAPT duration to 6 vs. 12 months after drug-eluting stenting did not increase the combined endpoint of cardiac death, myocardial infarction, and ischaemia-driven target vessel revascularization in the EXCELLENT (Efficacy of Xience/Promus Versus Cypher in Reducing Late Loss After Stenting) study. Finally, 24 months of DAPT after drug-eluting and bare metal stenting was no more effective in reducing ischaemic events that 6 months in the in the Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY). In summary, a limited sample size and the inclusion of mainly low-risk patients with low event rates in these trials make conclusions about the safety of short-term DAPT uncertain.
Three larger randomized trials evaluating the effects of DAPT duration are on-going. First, The Safety And Efficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) will evaluate a 6- or 12-month DAPT duration and secondly, The Optimized Duration of clopidogrel therapy following treatment with the endeavor zotarolimus-eluting stent in real-world clinical practice (OPTIMIZE) trial will evaluate 3 months vs. 12 months DAPT. Lastly, the Dual Antiplatelet Therapy (DAPT) study aims to compare 12 vs. 30 months of DAPT in preventing cardiovascular events in subjects undergoing PCI with drug-eluting stents. After 12 months of DAPT, and exclusion of patients with major ischaemic or bleeding events during that time, patients will be randomized to either placebo or continued DAPT up to 30 months. The study allows different stent types and either clopidogrel or prasugrel at the investigator's discretion but no analyses of those features are planned. Therefore, this trial's major limitation is the fact that the potential differential effects on stent thrombosis or bleeding of clopidogrel and prasugrel will not be examined.
Our study has important possible limitations. The DAPT duration was defined using information on number of dispensed tablets, and not on those actually ingested. It is possible that some patients with small quantities of clopidogrel dispensed (only one dispensing occasion), in the 3 months' treatment group, tended to be less compliant with treatment than those with larger quantities dispensed (which normally requires at least a second filling of a prescription). This could possibly lead to an overestimation of the positive effect of longer treatment, since patients who were in reality partly untreated, were used as comparators. We cannot exclude the possibility that factors associated with longer DAPT duration, such as repeat revascularization, also contributed to increased bleeding in the >3-month treatment duration group. Despite adjusting for propensity scores including a high number of variables, the possibility remains that the treatment groups were different due to unknown confounders. Nonetheless, our study conclusions are strengthened by the fact that data collection was independent of both treatment and outcome.
In conclusion, in this large study of a contemporary, real-life ACS population, a DAPT duration of >3 months compared with a shorter treatment duration was associated with a reduction of the composite outcomes of death, re-infarction, or stroke.
Discussion
This is, to our knowledge, the largest outcome analysis of varying DAPT durations in patients discharged from hospital with ACS. Our data show that clopidogrel co-administered with aspirin for >3 months compared with 3 months was associated with a statistically significantly lower incidence of death/stroke or re-infarction in patients post-ACS. Baseline characteristics, as well as comorbidity and overall bleeding risk were similar between treatment groups, indicating a similar background for ischaemic and bleeding risk in treatment groups.
In the analyses, we excluded patients with events that occurred within the first 3 months of the index event during which the antiplatelet treatment was the same in the DAPT duration groups, since events during that period were likely to interfere with and alter the initial treatment duration strategy, either by interruption due to bleeding events or prolongation due to ischaemic events. Therefore, it is unlikely that the treatment duration effect is influenced by the early risk hazard associated with an unsuspected event that would change the initial treatment strategy. Also for the individual endpoints of myocardial infarction and death, there tended to be lower event rates with a prolonged treatment duration >3 months. For myocardial infarction, this difference reached statistical significance. The observed consistency between these outcome measures, with a lower event rate with the >3 month treatment duration, also strengthens the conclusion of a lower ischaemic event rate after the initial 3 months of treatment. However, in contrast to the ischaemic endpoints of death and MI, repeat revascularizations occurred more frequently in the >3 month DAPT group compared with the 3-month group. This difference was mostly driven by the fact that patients who were not revascularized during the index event, underwent revascularization later in time leading to prolongation of the DAPT.
The potentially negative consequence of prolonged antiplatelet treatment is increased bleeding risk. In our study, bleeding was more common in groups with longer treatment duration. This is consistent with previous findings that DAPT duration correlates with the risk of bleeding, which in turn negatively influences outcomes after coronary stenting.
Recently, several independent but moderately large trials have suggested that a shorter DAPT duration after stent placement may be as beneficial as longer duration. An extended clopidogrel therapy >12 months in patients after implantation of drug-eluting stents did not reduce myocardial infarction or death. Similarly, shortening DAPT duration to 6 vs. 12 months after drug-eluting stenting did not increase the combined endpoint of cardiac death, myocardial infarction, and ischaemia-driven target vessel revascularization in the EXCELLENT (Efficacy of Xience/Promus Versus Cypher in Reducing Late Loss After Stenting) study. Finally, 24 months of DAPT after drug-eluting and bare metal stenting was no more effective in reducing ischaemic events that 6 months in the in the Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY). In summary, a limited sample size and the inclusion of mainly low-risk patients with low event rates in these trials make conclusions about the safety of short-term DAPT uncertain.
Three larger randomized trials evaluating the effects of DAPT duration are on-going. First, The Safety And Efficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) will evaluate a 6- or 12-month DAPT duration and secondly, The Optimized Duration of clopidogrel therapy following treatment with the endeavor zotarolimus-eluting stent in real-world clinical practice (OPTIMIZE) trial will evaluate 3 months vs. 12 months DAPT. Lastly, the Dual Antiplatelet Therapy (DAPT) study aims to compare 12 vs. 30 months of DAPT in preventing cardiovascular events in subjects undergoing PCI with drug-eluting stents. After 12 months of DAPT, and exclusion of patients with major ischaemic or bleeding events during that time, patients will be randomized to either placebo or continued DAPT up to 30 months. The study allows different stent types and either clopidogrel or prasugrel at the investigator's discretion but no analyses of those features are planned. Therefore, this trial's major limitation is the fact that the potential differential effects on stent thrombosis or bleeding of clopidogrel and prasugrel will not be examined.
Our study has important possible limitations. The DAPT duration was defined using information on number of dispensed tablets, and not on those actually ingested. It is possible that some patients with small quantities of clopidogrel dispensed (only one dispensing occasion), in the 3 months' treatment group, tended to be less compliant with treatment than those with larger quantities dispensed (which normally requires at least a second filling of a prescription). This could possibly lead to an overestimation of the positive effect of longer treatment, since patients who were in reality partly untreated, were used as comparators. We cannot exclude the possibility that factors associated with longer DAPT duration, such as repeat revascularization, also contributed to increased bleeding in the >3-month treatment duration group. Despite adjusting for propensity scores including a high number of variables, the possibility remains that the treatment groups were different due to unknown confounders. Nonetheless, our study conclusions are strengthened by the fact that data collection was independent of both treatment and outcome.
In conclusion, in this large study of a contemporary, real-life ACS population, a DAPT duration of >3 months compared with a shorter treatment duration was associated with a reduction of the composite outcomes of death, re-infarction, or stroke.
Source...