Summary of Clinical Evidence
Among all participants, extending DAPT beyond 12 months may reduce the risk of MI and stent thrombosis but may also increase the risk of bleeding. There were no significant differences in the risk of all-cause or cardiovascular death, stroke, urgent target revascularization, MACCE, or gastrointestinal bleeding between extended DAPT (more than 12 months) and standard-duration DAPT (six to 12 months). One large RCT (DAPT Trial) reported an increased risk of non-cardiovascular death among participants who received extended DAPT; however, this finding was not replicated in two smaller RCTs.
Most of the included studies enrolled participants who underwent PCI with DES insertion. The findings for this subgroup were therefore similar to the reference case involving all participants. Two RCTs (DAPT and PRODIGY) included a small proportion of participants with a BMS (15% to 25%), and data were not reported for all the outcomes of interest. The available data for participants with a BMS suggest an increased risk of BARC type 2 and type 3 bleeding with DAPT for more than 12 months; however, no data were available for non-cardiovascular death or urgent revascularization. These findings were based on a small number of participants with a BMS (n = 2,179) and should be interpreted with caution.
Data were limited for some subgroup analyses. We highlight the differences between groups, as follows:
Prior Myocardial Infarction
Participants with a previous MI who received DAPT for more than 12 months had a reduced risk of MI, MACCE, and stent thrombosis but an increased risk of moderate bleeding. No significant differences were found in the risk of death (all-cause, cardiovascular), stroke, urgent revascularization, TIMI minor bleeding, GUSTO severe bleeding, or BARC type 3 or type 5 bleeding.
Participants without a previous MI had an increased risk of all-cause death and moderate bleeding with extended DAPT but with a lower risk of MI and stent thrombosis. No significant differences were found in the risk of stroke, MACCE, GUSTO severe bleeding, or BARC type 5 bleeding.
Acute Coronary Syndrome
Participants with ACS at presentation who received more than 12 months of DAPT had a lower risk of MI and stent thrombosis but an increased risk of moderate bleeding. There were no significant differences between DAPT durations for all-cause or cardiovascular death, stroke, MACCE, TIMI minor bleeding, or GUSTO severe bleeding.
Limited data were available for participants without ACS. There were no significant differences in the risk of MACCE between DAPT durations among patients without ACS, with no data available for the other outcomes.
Diabetes
Participants with diabetes on extended DAPT had an increased risk of BARC type 3 bleeding, with no significant differences between DAPT durations for the risk of death (all-cause, cardiovascular, non-cardiovascular), MI, stroke, stent thrombosis, urgent revascularization, MACCE, and TIMI minor bleeding.
Participants without diabetes had a lower risk of MI, stent thrombosis, and MACCE, but a higher risk of GUSTO moderate or severe bleeding. There were no significant differences between DAPT durations for all-cause death. No data were available for the remaining outcomes.
Age
Participants aged more than 75 years had an increased risk of stroke with extended DAPT compared with DAPT for six to 12 months, as well as increased risk of GUSTO moderate or severe bleeding and BARC type 2, type 3, or type 5 bleeding. There were no significant differences between DAPT durations for the risk of death (all-cause, cardiovascular), MI, stroke, stent thrombosis, urgent revascularization, MACCE, and TIMI minor bleeding.
Participants aged less than 75 years who received extended DAPT had a lower risk of MI but also had an increased risk of GUSTO moderate or severe bleeding and BARC type 2, type 3, or type 5 bleeding. There were no significant differences between DAPT durations for the risk of death (all-cause, cardiovascular), stent thrombosis, MACCE, and TIMI minor bleeding. No data were available for the remaining outcomes.
Smoking
Both smokers and non-smokers had a reduced risk of MI and stent thrombosis with extended DAPT, with no significant difference in the risk of GUSTO moderate or severe bleeding or BARC type 2, type 3, or type 5 bleeding.
Participants who smoked had a reduced risk of MACCE with extended DAPT; no difference in the risk of MACCE was observed among non-smokers.
Data for the other outcomes were not available.
Interpretation of the Clinical Results
This systematic review builds on previously published reviews by considering the benefits and harms of extended DAPT for more than 12 months in clinically important patient subgroups, following PCI with stenting in order to determine groups to best target long-term DAPT. The protocol for this review was registered a priori and followed rigorous systematic procedures throughout the review process.
Overall, extended DAPT beyond 12 months in patients after PCI was predominantly beneficial in the reduction of stent thrombosis and MI; however, this benefit was accompanied by an increase of bleeding.
Patients with a prior MI, those with ACS at presentation, as well as patient with no diabetes, or aged less than 75 years, may derive the most benefit from extended DAPT; accordingly, individualized risk assessments should be made to determine the optimal duration of therapy.
The findings of this review are generally consistent with our previous umbrella review (review of systematic reviews) of the optimal duration of DAPT,1 which found some patient subgroups, such as those with prior MI or aged less than 75 years, may receive the most benefit from extended DAPT. This is also consistent with the guideline-proposed concept of individualizing therapy based on risk factors. The identified subgroups with differences in ischemic and bleeding outcomes are also consistent with the components of previously proposed risk scores, such as the DAPT score.17
In 2014, the FDA issued a Safety Communication concerning the increased risk of death observed in the DAPT trial.82 In this study, participants who received 30 months of DAPT were at higher risk of death compared to those who received 12 months of DAPT.23 Specifically, the DAPT study reported an increase in the risk of all-cause death, primarily due to an increased number of non-cardiovascular deaths, among those who received extended DAPT. In 2015, the FDA issued an update to their 2014 Safety Communication stating that, in their meta-analysis involving the DAPT trial and “other long-term clinical trials,” they had found no increased risk of all-cause death with extended DAPT (more than 12 months) compared with short-term (six months or less) DAPT.83 Also, a patient-level meta-analysis of cardiovascular trials assessing the impact of continued clopidogrel use on mortality and cancer was published in 2018. While results indicate that prolonged clopidogrel therapy has no overall effect on mortality or cancer, they also indicate that such therapy reduces ischemic events, including MI and stroke, but increases rates of bleeding, including a 0.12% absolute increase in fatal bleeding (P = 0.03). It should be noted, however, that this meta-analysis was interested in a more diverse cardiovascular population than ours. Indeed, while this meta-analysis included three trials that enrolled patients with coronary artery disease after PCI or ACS, including patients on clopidogrel from the DAPT trial, it also included one trial of patients with recent lacunar stroke, one trial of patients at high risk of atherothrombotic events and one trial of patients with atrial fibrillation. Of interest, while it is reassuring that no increase in mortality was observed, results of this meta-analysis do, however, raise potential questions on the net health impact of prolonged clopidogrel therapy when accounting for the competing effects of clopidogrel therapy on ischemic and bleeding events.84
In the present review, we compared extended DAPT to DAPT for six to 12 months, with a similar finding of no increased risk of all-cause death with extended DAPT. However, for non-cardiovascular death, the findings are inconsistent: although the DAPT trial reported an increased risk of non-cardiovascular death with extended DAPT, these findings were not replicated in two smaller RCTs.22,29 Although we aimed to investigate the effect of patient characteristics on this risk, limited subgroup data were available for this outcome at the time of the review.
In the current review, we observed an increased risk of all-cause death among participants without prior MI and an increased risk of stroke among those aged more than 75 years who received extended DAPT. Again, these findings highlight the importance of performing individualized assessments of risk and tailoring the duration of DAPT to both patients’ clinical characteristics, as well as to their individual preferences and values related to the potential benefits and harms.
Strengths and Limitations of the Clinical Systematic Review
Strengths
We performed a comprehensive review of published RCTs that aimed to compare extended DAPT (more than 12 months) with standard DAPT; i.e., for six to 12 months. The review followed an a priori protocol and used standard approaches for the identification of evidence, data abstraction, quality assessment, and reporting. Our review also analyzed data for important subgroups of patients who may derive benefits or experience harms with prolonged DAPT, thus providing clinicians with considerations for patient characteristics that may change or influence decisions about the duration of DAPT following PCI.
Limitations
This review has several limitations that merit consideration. Although all of the included trials involved the random allocation of participants to treatment arms, most were open-label. However, all of the included outcomes were objective and unblinding should not have affected the effect estimates.
Most of the included trials involved the use of clopidogrel as the P2Y12 inhibitor associated with ASA; limited subgroup data were available for prasugrel and none for ticagrelor. As such, the findings of this review mainly apply to clopidogrel. Given that clopidogrel is still currently widely used after PCI, these findings are nonetheless important for clinicians looking to optimize the care of their patients who have undergone PCI. The findings are also relevant to the policy questions of this review. There is a need to understand whether reimbursement policies for thromboembolic prophylaxis with P2Y12 inhibitors (as part of DAPT regimens) initiated immediately after PCI should accommodate the renewal of the reimbursement of the P2Y12 inhibitor for a period extending beyond the first 12 months.
The lack of data for ticagrelor in the current review may require jurisdictions to consider the findings of the PEGASUS-TIMI 54 trial,34 which randomized participants to receive ticagrelor or placebo. This study did not meet the eligibility criteria for this review (as described in Appendix 12) but the results may be informative to clinical and policy decisions in practice.
Because of the current clinical use of ticagrelor, at a dose of 60 mg twice daily for patients with a previous MI (as opposed to the currently indicated 90 mg twice daily post-ACS prophylaxis), reimbursement of this drug is a policy issue related to the policy questions being considered in this report. Importantly, the 60 mg dose of ticagrelor in the PEGASUS-TIMI 54 trial reduced the rate of this trial’s primary efficacy end point (i.e., a composite of cardiovascular death, MI, or stroke). This is reflected in the 2016 listing recommendation from the CADTH Canadian Drug Expert Committee which, among other criteria or condition, involves meeting the inclusion criteria of the PEGASUS-TIMI 54 trial in order to obtain reimbursement for this secondary prevention regimen for up to three years.85 More specifically, patients must meet the following criteria:
Patients who are between 12 and 24 months from their most recent MI, and less than 12 months since dual antiplatelet coverage with ASA and an adenosine diphosphate receptor inhibitor, with a high risk of subsequent cardiovascular events, defined as requiring at least one of:
age of 65 years or greater
diabetes requiring medication
second prior spontaneous MI (more than one year ago)
angiographic evidence of multi-vessel coronary artery disease
chronic renal dysfunction (defined as creatinine clearance of less than 60 mL/min).
85
The 2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of Guidelines for the Use of Antiplatelet Therapy includes a DAPT regimen of ASA 81 mg daily and ticagrelor 60 mg twice daily up to three years as an option in patients with ACS who tolerate one year of DAPT without a major bleeding event and who are not at high risk of bleeding. Other P2Y12 options for extended therapy include clopidogrel 75 mg daily or prasugrel 10 mg once daily. In these recommendations, the first year of DAPT must involve the use of ASA 81 mg daily with either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily or clopidogrel 75 mg daily.6
The RCTs included in this review enrolled heterogeneous populations, with important differences in the inclusion criteria, particularly related to the baseline inclusion of high-risk participants. Because some high-risk patients may have been excluded based on the inclusion criteria, the findings may not be generalizable to all patients in clinical practice. As well, first-generation DES’s were used in some of the participants in the DES-LATE,26 ARCTIC-Interruption,33 and DAPT23 trials, which may limit generalizability to current clinical practice where these stents are no longer in use.
The timing of randomization of patients varied between trials. Four trials22,24,30,31 randomized patients within the first 30 days after stenting. In contrast, in four trials (DAPT,23 DES-LATE,26 OPTIDUAL,29 and ARCTIC-Interruption33), patients who had completed the first 12 months of DAPT after stenting without experiencing an adverse event were then randomized to continue or discontinue DAPT, which may have excluded some high-risk patients who may have obtained a larger benefit from extended DAPT.
The outcome definitions varied among the included RCTs. In particular, the definition of MACCE and major bleeding differed in important ways between trials. In order to increase homogeneity, we reported separately data that were assessed by using different bleeding classification scales and did not pool data where they were not deemed to be clinically similar. For MACCE, we pooled only data from trials that used a comparable definition of the composite outcome.
Limited data were available for some patient subgroups, limiting the power of these analyses to detect differences between DAPT durations. The majority of subgroup data were obtained from one RCT (the DAPT trial). Randomization may not hold in the subgroups, potentially leading to imbalances between the comparison groups. As well, the small number of participants in some subgroups may increase the probability of a false-negative finding. It should be noted that a statistically non-significant finding does not preclude a potentially clinically important finding. Because of these limitations, the results of the subgroup analyses should be interpreted with caution.
Interpretation of the Economic Evaluation
The economic analyses showed that, when considering the estimated lifetime impacts, extending DAPT beyond the initial six to 12 months is a dominant option; i.e., generating a small incremental benefit (i.e., 0.0160 QALY) and small savings (i.e., $707). However, 98% of this benefit was accrued in the post-extended DAPT phase of the model. In the extended DAPT phase of the model (i.e., the first 19 months following the initial 6- to 12-month DAPT treatment), the incremental benefit was only 0.0003 QALY; there were incremental costs ($161), and the ICUR was $546,427 per QALY.
In our economic analysis, it is unknown if the impact of extended DAPT will remain beyond three to four years, the latter time period being the duration of the studies included in CADTH meta-analysis. Evidence of an increase in stent thromboses, strokes, and MIs once extended DAPT is discontinued (rebound effect) has been observed in the DAPT study but will have to be confirmed in additional studies.23 Several assumptions needed to be made on the risk of events (e.g., death post-MI or stroke, second MI or stroke, etc.), in particular in the post-extended DAPT phase of the model. As 98% of the extended DAPT incremental benefit came from the post-extended DAPT phase of the model, it is possible that using other assumptions or inputs for this phase of the model could have led to different results. Several scenarios were designed to address this and resulted in conclusions similar to that of the base case except in four cases. These were when ticagrelor was the sole P2Y12 inhibitor in the DAPT regimen (assuming that clinical impact is the same across agents), when extended DAPT duration was 24 to 30 or 36 to 48 months, and when the analysis was limited to the duration of the trials included in the CADTH meta-analysis.
Analyses per patient subgroups should only be considered as exploratory, as data to inform these analyses were coming from only one or two studies and required additional assumptions to be made. Exploratory subgroup analyses indicated that extended DAPT was more effective and less costly, and hence would be the preferred option in patients who had a prior MI and those presenting with ACS. Extended DAPT was less effective and also less costly (ICUR below $18,706 per QALY) in patients with diabetes and patients with no prior MI. In patients older than 75 years of age, extended DAPT was less effective and more costly than six to 12 months of DAPT (i.e., six- to 12-month DAPT is dominant). In patients less than 75-years-old, extended DAPT was more effective and more costly, with an ICUR of $37,901 per QALY. However, more evidence would be required to provide more robust conclusions.
