A total of 4818 patients from two trials were included in the subgroup analyses. Compared with TT, DT reduced the risk of clinical bleeding events in men and women (RR: 0.66, 95% CI: 0.50–0.88, P=0.005; RR: 0.76; 95% CI: 0.60–0.95, P=0.02) (Supplementary Fig. 5, Supplemental digital content 1, http://links.lww.com/MCA/A227), in people at least 75 years old and those less than 75 years old (RR: 0.80; 95% CI: 0.65–0.99, P=0.04; RR: 0.67; 95% CI: 0.58–0.77, P<0.001) (Supplementary Fig. 6, Supplemental digital content 1, http://links.lww.com/MCA/A227), and in patients with bare-metal stents and in patients with drug-eluting stents (RR: 0.65; 95% CI: 0.43–0.99, P=0.05; RR: 0.69; 95% CI: 0.60–0.80, P<0.001) (Supplementary Fig. 7, Supplemental digital content 1, http://links.lww.com/MCA/A227). In terms of MACE in equivalent subgroups, analyses showed no significant difference comparing DT with TT (P=0.57, P=0.85 for male and female; P=0.12, P=0.99 for >75 years old and <75 years old; and P=0.59, P=0.75 for bare-metal stents and drug-eluting stents subgroup, respectively) (Supplementary Figs 8–10, Supplemental digital content 1, http://links.lww.com/MCA/A227). However, based on the age subgroup results, DT appears suitable for patients aged less than 75 but not more than or equal to 75 years.
In the present systematic review and meta-analysis, DT versus TT in patients with an indication for OACs after PCI was associated with a 42% reduction in TIMI major bleeding, a 54% reduction in TIMI minor bleeding, and a 39% reduction in clinical bleeding events, with no increase in the risk of MACE or ST.
The association between DT and lower risk for subsequent bleeding events may be causal. The omission of aspirin significantly reduces bleeding risk because of gastric mucosa protection and no over-inhibition of platelet function. A study showed that risk of receiving excess dosing of antiplatelet and antithrombin agents in ∼42% patients with non-ST-segment elevation acute coronary syndromes was associated with older age, female sex, renal insufficiency, low body weight, diabetes, and congestive heart failure 19.
The 2014 ESC/EACTS Guidelines on myocardial revascularization recommended that TT be used in patients with definite indication for OAC. TT should be used for at least 6 months followed by DT for up to 12 months when patients are at low bleeding risk (HAS-BLED≤2) and for 1 month followed by DT when patients are at high bleeding risk (HAS-BLED≥3). The 2017 ESC/EACTS guidelines on dual antiplatelet therapy in coronary artery disease recommended that TT be used for 6 months followed by DT consisting of OAC plus aspirin or clopidogrel for up to 12 months in patients with indications for OAC after PCI considering high ischemic risk. In consideration of high bleeding risk, TT can be used for 1 month followed by DT for up to 12 months or initiating DT for 12 months. However, as shown in this meta-analysis, despite the bleeding risk, DT could be used as initiating therapy, and compared with TT, DT reduced bleeding risk with no increase in ischemic events.
Because most bleeding events occur within the first month during antiplatelet and anticoagulation management, the strategies recommended by ESC guidelines might not bring many benefits to patients in terms of prevention of bleeding events 20. As shown in ISAR-TRIPLE trial, 6 weeks versus 6 months of triple therapy did not provide additional benefit to patients with respect to TIMI major bleeding. Based on the present meta-analysis, one could posit that regardless of ischemic or bleeding risk level, DT consisting of dabigatran plus clopidogrel or other P2Y12 inhibitor might be an option as initiating therapy for at least 6 months in patients with an indication for OAC after PCI. However, the omission of aspirin may increase the risk of ST by 25%. Furthermore, none of the included three RCTs had enough power to examine ischemic risks including ST and cardiovascular-related death, which would have required inclusion of at least 14 000 patients 21.
New-generation drug-eluting stents (DES) reduce the rate of revascularization by 10–20% and the risk of death, MI or ST, as compared with early DES and bare-metal stents, and the rate of ST by ∼50%, especially in late antithrombotic phase, as compared with early DES 22,23. The three DT versus TT RCTs and meta-analysis thereof favor DT over TT, which differs from early studies, may be partly owing to the extensive use of new-generation DES.
Currently, vitamin K antagonist (VKA) has been widely used for anticoagulation in patients with indication for anticoagulation (AF mostly), and VKA is superior to aspirin or DAPT. For patients after PCI, DAPT is superior to OAC. The use of DAPT after PCI significantly reduces acute or late thrombosis events and mortality rates. VKA use in patients with AF reduces stroke risk by two-third and mortality rate by one-fourth. So far, there is insufficient evidence on optimal antithrombotic strategy to balance bleeding risk and ischemic risk in patients with PCI with an indication for OAC using antiplatelet drugs concomitantly. At first, combined use of DAPT and OAC was recommended by expert consensus 24,25, albeit without strong supporting evidence. The subsequent WOEST clinical trial in 2013 concluded that DT significantly reduced clinical bleeding events in patients at the first year as compared with TT, with no increased ischemic risk. However, there was no significant difference in major bleeding between DT and TT. Because the trial was not powered to test ischemic risk, and other antiplatelet agents and novel OACs were not included, DT did not gain popularity. In real world, the usage of DT is rare, and most doctors prefer TT as recommended by experts. A data analysis from 1269 patients with history of AF treated with PCI at a tertiary care hospital in New York City from 2010 to 2015 showed that 55% of patients were treated with TT, 37% with DAPT, only 12% with DT 26. Recently, several observational studies and pooled analysis of observational studies showed that TT significantly reduced the risk of all-cause mortality, stroke, and thrombosis, with significant increase in bleeding risk, whereas other observational studies showed that TT was associated with a significant increase in bleeding risk with no benefit on cardiovascular death, myocardial infarction, and stroke risk.
With the extensive use of novel OAC, researchers changed VKA to rivaroxaban for new DT in PIONEER AF-PCI trial in 2016. Compared with TT, DT reduced clinical bleeding events by 41%, without significant difference in TIMI major bleeding, TIMI minor bleeding, and MACE. The latter trial differs from the present meta-analysis in terms of TIMI major bleeding and TIMI minor bleeding in that it used rivaroxaban in DT, and rivaroxaban causes more bleeding than dabigatran, as shown by previous studies.
RE-DUAL PCI conducted in 2017 showed that DT consisting of 150 mg dabigatran plus P2Y12 inhibitor reduced TIMI major bleeding by 49% and TIMI major or minor bleeding by 47% when compared with TT, with no increase in ischemic risk; therefore, it is consistent with the results of the present meta-analysis. Compared with PIONEER AF-PCI trial, RE-DUAL PCI trial showed that DT containing dabigatran is safer than DT containing rivaroxaban.
Two meta-analyses were published recently with important design and conclusion differences with ours 13,14. In terms of meta-analysis design, we excluded the ISAR-TRIPLE trial because it evaluated the duration of clopidogrel in TT and not DT versus TT, with patients on long-term aspirin and OAC randomized to 6-week clopidogrel group or 6-month clopidogrel group, and we included 2.5 mg rivaroxaban plus DAPT group in PIONEER AF-PCI trial as TT. There was a discrepancy in the published meta-analysis written by Cavallari et al. 13 in the data from RE-DUAL PCI in terms of TIMI minor bleeding: the number of minor bleeding events should be 26 in DT and 32 in TT, not 56 and 69. They regarded the total number of both minor and major bleeding events as the number of minor bleeding events 17. The aforementioned differences may significantly affect the results of the meta-analysis. As for the conclusion of the meta-analysis, our data suggest that the optimal combination of DT appears to be P2Y12 inhibitor plus 150 mg dose of dabigatran; 110 mg dose of dabigatran may increase the risk of ST by 28%, but more data are warranted. We also conducted subgroup analyses in our meta-analysis. The use of DT reduced the risk of bleeding in men and women by 34 and 24%, respectively, with no increase in the risk of MACE. The use of DT in patients aged more than 75 years reduced bleeding risk by 20% while increasing MACE by 32%, suggesting that there might be no optimal way to concurrently reduce bleeding risk and ischemic risk in this age group. In patients aged less than 75 years, DT reduced bleeding risk by 33%, with no increase in the risk of MACE, rendering it suitable for this age group. In our data, DT also reduced the risk of clinical bleeding events by 45% in patients with HAS-BLED up to 2 and by 47% in those with HAS-BLED more than 2, with no increase in MACE. DT might therefore be beneficial to patients with low bleeding risk, which differs from the current ESC guidelines recommendation for DT as an option only in patients with high bleeding risk after doctors’ prudent consideration and TT in patients even with low bleeding risk.
There are limitations to our meta-analysis. First, evidence remains insufficient in terms of efficacy to support DT. Second, four relevant DT versus TT RCTs are ongoing which might better inform optimal antiplatelet and anticoagulation therapy in patients with AF after PCI: ENTRUST-AF-PCI (1500 patients), P2Y12 inhibitor plus edoxaban versus P2Y12 inhibitor and aspirin plus VKA; AUGUSTUS (4600 patients), P2Y12 inhibitor plus apixaban or VKA versus P2Y12 inhibitor and aspirin plus apixaban or VKA; MANJUSRI (296 patients), ticagrelor plus warfarin versus clopidogrel and aspirin plus warfarin; and RT-AF (420 patients), rivaroxaban plus ticagrelor versus clopidogrel and aspirin plus warfarin.
Among patients with an indication for OAC after PCI, DT may be the optimal antiplatelet and anticoagulation therapy.
This study was supported by Taishan Scholar Program of Shandong Province (tsqn20161065, ts20130911), National Key Research and Development Program (2017YFC0908700, 2017YFC0908703), the grants from Department of Science and Technology of Shandong Province (2017G006013, 2016GSF201235, 2016ZDJS07A14, 2018GSF118003), Evaluation and Management of Patients with Acute Chest Pain in China (EMPACT)(201525), the National Natural Science Foundation of China (81571934, 81570401, 81601717), Natural Science Foundation of Shandong Province (BS2014YY032), Science Foundation of Qilu Hospital of Shandong University (2016QLQN02).
Conflicts of interest
There are no conflicts of interest.
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