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Dual-Antithrombotic Therapy With DOACs After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Atrial Fibrillation: A Meta-analysis of Randomized Controlled Trials
Journal Pre-proof Dual antithrombotic therapy with DOACs after ACS or PCI in Atrial Fibrillation: A meta-analysis of Randomized Controlled Trials Mohammed Shurrab, MD MSc, Asaf Danon, MD MSc, Sami Alnasser, MD, Benedict Glover, MD, Anna Kaoutskaia, BScH, Mark Henderson, MD, David Newman, MD, Eugene Crystal, MD, Dennis Ko, MD MSc PII:
S0828-282X(19)31428-X
DOI:
https://doi.org/10.1016/j.cjca.2019.11.005
Reference:
CJCA 3511
To appear in:
Canadian Journal of Cardiology
Received Date: 30 June 2019 Revised Date:
1 November 2019
Accepted Date: 4 November 2019
Please cite this article as: Shurrab M, Danon A, Alnasser S, Glover B, Kaoutskaia A, Henderson M, Newman D, Crystal E, Ko D, Dual antithrombotic therapy with DOACs after ACS or PCI in Atrial Fibrillation: A meta-analysis of Randomized Controlled Trials, Canadian Journal of Cardiology (2019), doi: https://doi.org/10.1016/j.cjca.2019.11.005. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.
Dual antithrombotic therapy with DOACs after ACS or PCI in Atrial Fibrillation: A metaanalysis of Randomized Controlled Trials
Mohammed Shurrab MD MSc,1,2,3,4, Asaf Danon MD MSc,5 Sami Alnasser MD,1,3 Benedict Glover MD,6 Anna Kaoutskaia BScH,7 Mark Henderson MD,1,3 David Newman MD,6 Eugene Crystal MD,6 Dennis Ko MD MSc 4,6,8 1. Cardiology Department, Health Sciences North, Sudbury, Ontario, Canada. 2. Health Sciences North Research Institute, Sudbury, Ontario, Canada. 3. Northern Ontario School of Medicine, Laurentian University, Sudbury, Ontario, Canada. 4. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. 5. Electrophysiology Unit, Cardiology Department, Hillel Yaffe Medical Center, Hadera, Israel 6. Division of Cardiology, Schulich Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. 7. St. Matthew’s University School of Medicine, Grand Cayman, Cayman Islands. 8. Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada. Corresponding author: Mohammed Shurrab MD, MSc Cardiology Department, Health Sciences North Health Sciences North Research Institute Northern Ontario School of Medicine Laurentian University, Sudbury, Ontario, Canada Email: [email protected]
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Short title: DOACs after ACS or PCI in AF
Conflict of interest •
Mohammed Shurrab is supported by a Fellowship Award from the Canadian Institutes of Health Research (CIHR).
•
Dennis T. Ko is supported by a Mid-Career Investigator Award from the Heart and Stroke Foundation of Canada (HSFC), Ontario Provincial Office.
Sources of Funding: None
Moderated presentation at the Canadian Cardiovascular Congress (CCC): DUAL ANTITHROMBOTIC THERAPY WITH DIRECT-ACTING ORAL ANTICOAGULANTS AFTER ACUTE CORONARY SYNDROME OR PCI IN ATRIAL FIBRILLATION: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS Thursday October 24, 2019
Brief Summary The choice of antithrombotic therapy for atrial fibrillation (AF) patients who have an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is challenging. In our meta-analysis, the use of dual antithrombotic therapy with DOACs was associated with less major bleeding, and major bleeding or clinically relevant non-major bleeding. The use of Dual therapy has shown non-significantly higher composite of death or ischemic events but no difference in mortality.
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Abstract Background: The choice of antithrombotic therapy for atrial fibrillation (AF) patients who have an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is challenging. We aimed to assess outcomes between dual antithrombotic therapy with DOACs plus an antiplatelet agent (Dual therapy) in comparison to warfarin plus two antiplatelet agents (Triple therapy) after PCI or ACS for AF patients.
Methods: Systematic searches of multiple major databases were performed from inception until September 2019. We included only randomized controlled trials. Odd ratios were pooled using a randomeffects model.
Results: We identified 4 RCTs, which included 7168 patients. In comparison to triple antithrombotic therapy with warfarin, Dual antithrombotic therapy with DOACs was associated with a significant reduction in major bleeding (odds ratio [OR] 0.56 [95% confidence interval [CI] 0.38 to 0.82], p 0.003) as well as major bleeding or clinically relevant non-major bleeding (OR 0.53 [95% CI 0.38 to 0.75], p<0.001). The rate of composite of death or ischemic events (stroke or myocardial infarction) was not statistically different between both groups (OR 1.21 [95% CI 0.99 to 1.49], p=0.06). There was no significant difference between both groups in the rate of death (OR 1.20 [95% CI 0.95 to 1.53], p=0.13).
Conclusions: In patients with AF and recent ACS or PCI, the use of dual antithrombotic therapy with DOACs was associated with less major bleeding, and major bleeding or clinically relevant non-major bleeding, compared to triple therapy. The use of dual therapy also shows non-significantly higher composite of death/ischemic events but no difference in mortality.
Keywords: atrial fibrillation, acute coronary syndrome and percutaneous coronary intervention
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Introduction Dual antiplatelet therapy (DAPT) has been consistently shown to reduce major cardiovascular adverse events in patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI).(1) In the last few years, Direct-acting oral anticoagulants (DOACs) like dabigatran, rivaroxaban, apixaban and edoxaban have been rapidly adopted into practice for stroke prophylaxis in patients with AF given their efficacy, safety and ease of use in comparison to warfarin.(2) The overall number of anticoagulation therapies prescriptions in Canada has increased annually since 2008.(3)
Optimal antithrombotic therapy for patients with atrial fibrillation (AF) following ACS or PCI is uncertain particularly given the availability of various antithrombotic agents.(4,5) The combination of antithrombotic agents, particularly triple therapy with warfarin and DAPT, increase the risk of bleeding. (6-8) Hence dual antithrombotic therapy with DOACs plus an antiplatelet agent has emerged as an attractive alternative regimen to the standard triple antithrombotic therapy with warfarin after PCI or ACS for patients with AF. Recent data have shown a reduction in bleeding, but were underpowered to test for efficacy (ischemic events), which remains a major concern with such regimen.(9)
We conducted a meta-analysis to assess the safety and efficacy of dual antithrombotic therapy with DOACs plus an antiplatelet agent in comparison to triple antithrombotic therapy with warfarin plus two antiplatelet agents after PCI or ACS for patients with AF.
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Methods Literature search and data sources An electronic literature search was performed by two investigators (MS, AK) in accordance with the recommendations of Cochrane collaboration using Pubmed, Embase, Scopus, and Cochrane Central Register of Controlled Trials from inception until September 21, 2019. The search terms were: (atrial fibrillation) AND (anticoagulation) AND (percutaneous coronary intervention OR acute coronary syndrome). Neither language nor demographic restrictions were applied. All references from papers obtained through the databases were reviewed manually. We included only full papers and excluded abstracts/reports that did not provide full data about the outcomes of interest. The electronic search has been archived and is available upon request.
Study selection and quality assessment The inclusion was limited to the studies which are: 1) Randomized controlled trials (RCT) that compared Dual antithrombotic therapy with DOACs to standard Triple therapy with warfarin after PCI or ACS in patients with AF; 2) included adult population >18 years old; and 3) provided data on outcomes of interest. The selection of studies was assessed independently by 3 assessors (MS, AK, AD). We excluded non-randomized and non-comparative trials, crossover studies, case reports, editorials, letters, replies, and reviews. The quality of the randomized studies was evaluated based on the five-point scale outlined by Jadad et al., with criteria for the following: randomization with proper concealment
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of the allocation sequence, blinding of the patient and investigator to treatment allocation with description of the blinding method, and completeness of follow-up.(10) Data extraction and outcomes of interest Two reviewers (MS, AK) independently extracted data from published sources; disagreements were resolved by discussion and, when necessary, in consultation with other coauthors. The following outcomes were identified as relevant and consistent measures to compare between the studied groups: The primary (safety) outcomes were: 1) major bleeding and 2) major bleeding or clinically relevant non-major bleeding. Major bleeding and clinically relevant non-major bleeding were similarly described across all included trials as defined by the International Society on Thrombosis and Haemostasis (ISTH). ISTH major bleeding was defined as bleeding that resulted in death, occurred in a critical organ (intraspinal, intracranial, intraocular, retroperitoneal, pericardial etc) or was associated with either a decrease in hemoglobin level of at least 2 g per deciliter, or necessitating a transfusion of greater than 2 units of packed red blood cells. Clinically relevant bleeding is defined as bleeding that required hospitalization, medical/surgical intervention, an unscheduled clinic visit, or a change in antithrombotic therapy. The secondary (efficacy) outcomes were: 1) death; 2) composite of death or ischemic events (stroke or myocardial infarction); 3) stroke; 4) myocardial infarction and 5) definite stent thrombosis. Those outcomes have been chosen as the only available homogeneously reported outcomes across the trials where data could be retrieved and analyzed.
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Statistics The software package RevMan (version 5) provided by the Cochrane Collaboration was used for combining outcomes from the individual studies and statistical analysis. Outcomes were pooled using a random effects model described by DerSimonian and Laird.(11) Summary estimates and 95% confidence interval (CI) were reported for dichotomous variables as odds ratio (OR). The heterogeneity between studies was assessed using Cochrane’s X2 and I2. An I2 > 50% was considered to represent significant heterogeneity.(12) Statistical significance was set as P < 0.05. A sensitivity analysis was performed to include the RE-DUAL PCI dual therapy with Dabigatran 150 mg group.
Results Summary of the studies The literature search resulted in 439 studies (335 from electronic databases and 104 from other resources including web searches and reference lists). We identified four RCTs that met all applied inclusion criteria of this meta-analysis.(13-16) The information relevant to the literature search is shown in Figure 1.
The Dual therapy group in the PIONEER AF-PCI trial was the low-dose Rivaroxaban (15mg daily or a dose of 10mg daily if they had moderate renal impairment) and a P2Y12 inhibitor (clopidogrel 75mg daily, ticagrelor 90mg twice daily, or prasugrel 10mg daily). The control group was the standard triple therapy consisting of Dual antiplatelet therapy (DAPT) and warfarin.(14) In the RE-DUAL PCI trial the Dual therapy group comprised of patients receiving dabigatran (110mg twice daily) with a P2Y12 inhibitor (clopidogrel 75mg daily or ticagrelor
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90mg twice daily), and the control group were receiving the triple therapy (DAPT and warfarin).(13) The AUGUSTUS trial randomized patients via a two-by-two factorial design. For the purposes of our analysis, we compared the outcomes of the specific group of apixaban and placebo with a P2Y12 inhibitor, to a Vitamin K antagonist with aspirin and a P2Y12 inhibitor.(15) In the ENTRUST trial’s , the treatment group consisted of patients receiving edoxaban regimen at a dose of 60 mg once daily and a P2Y12 inhibitor once daily for 12 months. The control group received a Vitamin K antagonist in combination with a P2Y12 inhibitor and 100 mg of aspirin daily for up to 12 months in duration.(16)
Baseline characteristics of patients and Outcomes of interest We identified 4 RCTs that included 7168 patients. Dual antithrombotic therapy with DOACs was used in 3581patients (dabigatran in 981, rivaroxaban in 696 patients, apixaban in 1153 patients, and edoxaban in 751). We specifically examined the groups that adopted DOACs in the dual therapy in comparison to the long used standard triple therapy with warfarin. Baseline demographics and clinical characteristics of the examined groups could not be pooled due to heterogeneity of reported data and are summarized in Table 1. We also summarized the characteristics of the included trials. (Table 1S) In comparison to triple antithrombotic therapy with warfarin, Dual antithrombotic therapy with DOACs was associated with a significant reduction in major bleeding (odds ratio [OR] 0.56 [95% confidence interval [CI] 0.38 to 0.82], p 0.003) as well as major bleeding or clinically relevant non-major bleeding (OR 0.53 [95% CI 0.38 to 0.75], p<0.001). (Figures 2 & 3). A sensitivity analysis was performed to include the RE-DUAL PCI Dual Therapy with
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Dabigatran 150 mg group. This showed similar results to the Dual Therapy with Dabigatran 110 mg group included in the main analysis. (Figure S1 and S2). There was a trend of a higher rate of the composite of death or ischemic events (stroke or myocardial infarction) with Dual antithrombotic therapy with DOACs, but this was not statistically significant (OR 1.21 [95% CI 0.99 to 1.49], p=0.06). (Figure 4) There was no significant difference between both groups in the rate of death (OR 1.20 [95% CI 0.95 to 1.53], p=0.13). (Figure 5) There were no differences between the two groups in the rate of stroke (OR 1.10 [95% CI 0.68 to 1.78], p=0.71) (Figure 6), myocardial infarction (OR 1.27 [95% CI 0.93 to 1.74], p=0.13) (Figure 7), or definite stent thrombosis (OR 1.56 [95% CI 0.86 to 2.83], p=0.14) (Figure 8).
Discussion Our study examined outcomes between dual antithrombotic therapy with DOACs plus an antiplatelet agent in comparison to the standard triple therapy with warfarin plus two antiplatelet agents after PCI or ACS for patients with AF. Our meta-analysis showed the following important findings: DAPT with DOACs was associated with: 1) less major bleeding and major or clinically relevant non-major bleeding and 2) non-significantly higher composite of death or ischemic events (stroke or myocardial infarction) but no difference in mortality. Furthermore, when ischemic events (stroke, myocardial infarction, and definite stent thrombosis) were analyzed separately there was no difference in the rates between the groups.
We specifically looked at trials that adopted DOACs in the dual therapy in comparison to the long used standard triple therapy with warfarin. This is based on the fact that dual therapy
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with DOACs has been widely accepted in current clinical practice supported by recent guidelines.(17) In patients with AF undergoing PCI for ACS or high- risk elective PCI, the current Canadian guidelines recommend: (17) If age ≥ 65 years or CHADS2 ≥ 1, an initial regimen of triple therapy with ASA 81 mg daily plus clopidogrel 75 mg daily plus reduced dose anticoagulation. ASA may still be discontinued as early as the following day post PCI or it can be continued for up to 6 months of treatment, depending on the risk of recurrent coronary events versus major bleeding. The choice of recommended anticoagulation therapy is between rivaroxaban 15 mg daily, dabigatran 110 mg or 150 mg BID or warfarin. Trials evaluating apixaban and edoxaban in patients with AF who undergo PCI were still ongoing at the time and hence were not reflected in the guidelines. Data have shown that combined dual antiplatelet therapy and a vitamin K antagonist (i.e., triple therapy) are associated with a high risk of bleeding. (6-8) The adoption of Dual therapy with DOACs has led to less bleeding rates whether major bleeding or combined major and clinically relevant non- major bleeding among all RCTs included in this meta-analysis. A recent meta-analysis and systematic review conducted by Golwala et al.(18) studied the safety and efficacy of dual versus triple antithrombotic therapy in patients with AF undergoing PCI. Our current review is different as the focus of our analysis was on the comparison between dual therapy including DOACs versus the classic triple therapy with warfarin. While both meta-analyses have shown reduction in bleeding, our analysis specifically targeted DOACs in the Dual antithrombotic therapy group, which is quite different than Golwala et al’s comparative groups including warfarin. Overall, our findings of dual antithrombotic therapy with DOACs association with less major bleeding and major or clinically relevant nonmajor bleeding and no difference in mortality are in line with the conclusion reached by Golwala et al. thereby highlighting the safety of this approach with DOACs. Finally, a recently published
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meta-analysis in the context of the ENTRUST-AF PCI trial has shown similar results.(16) However we provide a comprehensive review and analysis with important sensitivity analysis.
In our meta-analysis we pooled the efficacy data across the available trials and have found a concerning signal of less efficacy (composite of death and ischemic events) with dual therapy with DOAC in comparison to triple therapy with warfarin. This observation might be driven by a higher coronary ischemic event rate, as DOACs are known to have similar efficacy to warfarin in stroke prophylaxis among AF patients.(2) A recent network meta-analysis has shown that omitting aspirin caused less bleeding, including intracranial bleeding, without significant difference in major adverse cardiovascular events, compared with strategies including aspirin.(19) This should be investigated in further studies. Nevertheless, when we pulled the events of stroke, myocardial infarction, and definite stent thrombosis separately, there was no significant difference in these events between groups.
It should be emphasized that all trials enrolled patients several days after the PCI. For example, In AUGUSTUS trial, the median time from PCI to enrolment was 6 days. Thus, the PCI procedure itself and the first days thereafter were performed with DAPT treatment.(15) We do not know whether patients can be treated safely with a single antiplatelet drug during the first week following the PCI, even if combined with a DOAC.
Future studies should focus on the important clinical question of Dual therapy (DOACs and a single antiplatelet therapy) versus triple therapy (DOACs and DAPT). More so, a focus
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should be on the appropriate duration of each regimen. This would help in identifying the best regimen among patients with AF after PCI or ACS and solve a challenging clinical dilemma.
Limitations The small number of randomized controlled trials available for inclusion in this analysis could limit our conclusions. The difference in the definition of outcomes and the duration of dual therapy and triple therapy among the included trials is an important limitation. Additional limitations of this study include the use of trial level data rather than patient-specific data, and the inability to statistically analyze certain subgroups (such as type of index event or type of stent) due to the heterogeneity across trial designs, and could possibly affect the interpretation of the results. We have tried to conduct a publication bias but the small number of trials precluded such evaluation. The difference in follow up among the included trials is an important limitation of our conclusions.
Conclusions In patients with AF and recent ACS or PCI, the use of dual antithrombotic therapy with DOACs was associated with less major bleeding and major bleeding or clinically relevant nonmajor bleeding. The use of Dual therapy has shown non-significantly higher composite of death or ischemic events (stroke or myocardial infarction) but no difference in mortality. Future studies should focus on the efficacy of Dual antithrombotic therapy with DOACs in patients with AF and a recent ACS or PCI.
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Figure Legends
Figure 1. Flow diagram of literature search and study selection.
Figure 2. Forest plots of the individual and combined rates of major bleeding (ISTH).
Figure 3: Forest plots of the individual and combined rates of major bleeding (ISTH) or clinically relevant non-major bleeding.
Figure 4: Forest plots of the individual and combined rates of the composite of death or ischemic events (stroke or myocardial infarction).
Figure 5: Forest plots of the individual and combined rates of death.
Figure 6. Forest plots of the individual and combined rates of cerebrovascular accidents.
Figure 7. Forest plots of the individual and combined rates of myocardial infarctions.
Figure 8. Forest plots of the individual and combined rates of definite stent thrombosis.
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Figure 1. Flow diagram of literature search and study selection
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Figure 2: Forest plots of the individual and combined rates of major bleeding (ISTH).
Figure 3: Forest plots of the individual and combined rates of major bleeding (ISTH) or clinically relevant non-major bleeding.
Figure 4: Forest plots of the individual and combined rates of the composite of death or ischemic events (stroke or myocardial infarction).
Figure 5: Forest plots of the individual and combined rates of death.
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Figure 6. Forest plots of the individual and combined rates of cerebrovascular accidents.
Figure 7. Forest plots of the individual and combined rates of myocardial infarctions.
Figure 8. Forest plots of the individual and combined rates of definite stent thrombosis.
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Figure S1: Forest plots of the individual and combined rates of major bleeding (ISTH), including the RE-DUAL PCI Dual Therapy with Dabigatran 150 mg group
Figure S2: Forest plots of the individual and combined rates of major bleeding (ISTH) or clinically relevant non-major bleeding, including the RE-DUAL PCI Dual Therapy with Dabigatran 150 mg group
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Table 1. Summary of patient baseline characteristics Gibson (2016)
Cannon (2017)
Lopes (2019)
DT
TT
DT
TT
DT
TT
DT
Vranckx (2019) TT
709
706
981
981
2306
2308
751
755
70.4 ± 9.1
69.9 ± 8.7
71.5 ± 8.9
71.7 ± 8.9
70.4*
70.9*
69*
70*
Gender (Male) n(%)
528 (74.5%)
518 (73.4%)
728 (74.2%)
750 (76.5%)
1636 (70.9%)
1641 (71.1%)
557 (74%)
563 (75%)
Diabetes Mellitus n(%)
204 (28.8%)
221 (31.3%)
362 (36.9%)
371/980 (37.9%)
842 (36.5%)
836 (36.2%)
259 (34%)
258 (34%)
>2
520 (73%)
559 (79%)
751 (76.6%)
788 (80.3%)
n/a
n/a
n/a
n/a
mean
n/a
n/a
3.7±1.6
3.8±1.5
3.9±1.6
4.0±1.6
Paroxysmal
300 (42.4%)
313 (44.4%)
487 (49.6%)
484 (49.4%)
n/a
n/a
402 (54%)
358 (47%)
Persistent
146 (20.6%)
149 (21.1%)
174 (17.7%)
178 (18.2%)
n/a
n/a
140 (19%)
146 (19%)
Permanent
262 (37%)
243 (34.5%)
320 (32.6%)
318 (32.4%)
n/a
n/a
209 (28%)
250 (33%)
Duration of follow-up
12 months
1, 6, or 12 months
Patients (n) Age (mean ± SD)
CHA2DS2-VASc score 4.0 (IQR 3.0–5.0)*
Atrial Fibrillation type
14 months
* median DT indicates dual therapy with DOAC group; TT indicates triple therapy with VKA group ** Gibson et al DT group AF denominator is 708 patients; TT group is 705 patients
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6 months
364 days (IQR 361–368)*
Table 2. Summary of safety and efficacy outcomes Patients (n) Study Gibson (2016) Cannon (2017) Lopes (2019) Vranckx (2019)
Tx 696 981 1153 751
Ctrl 697 981 1154 755
Major bleeding n (%) Tx 14 (2%) 49 (5%) 23 (2%) 45 (6%)
Ctrl 20 (2.9%) 90 (9.2%) 62 (5.4%) 48 (6%)
Clinically relevant non-major bleeding n (%) Tx 109 (16.8%) 151 (15.4%) 84 (7.3%)
Ctrl 167 (26.7%) 264 (26.9%) 210 (18.7%)
Death n (%) Tx 15/694 (2.4%) 55 (5.6%) 39 / 1153 (3.4%) 46 (6.1%)
Ctrl 11/695 (1.9%) 48 (4.9%) 34 / 1154 (2.9%) 37 (4.9%)
Composite of death or ischemic events (MI or CVA) n (%) Tx 41/694 (5.9%) 108 (11%) 72 / 1153 (6.2%) 49 (7%)*
DT indicates dual therapy with DOAC group; TT indicates triple therapy with VKA group * Main efficacy outcome (composite of cardiovascular death, stroke, systemic embolic event, myocardial infarction, or definite stent thrombosis)
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Ctrl 36/695 (5.1%) 83 (8.5%) 66 / 1154 (5.7%) 46 (6%)*
Table 1S. Included trials’ characteristics Patient groups
Therapy dosage received
Group 1 (Treatment): Apixaban with ASA or placebo)* + P2Y12 inhibitor
Apixaban (5 mg BID or 2.5 mg BID) if met 2 or more of the following dose-reduction criteria: at least 80 years of age, weight of < 60 kg, or creatinine level of at least 1.5 mg per deciliter (133 µmol per liter); ASA = 81mg; Clopidogrel (2.5mg BID) for 6 months
Group 2 (Control): Vitamin K antagonist with ASA or placebo + P2Y12 inhibitor***
Vitamin K antagonist (warfarin) dose adjusted to reach target INR range 2.0-3.0; ASA = 81mg; Clopidogrel (2.5mg BID) for 6 months
Group 1 (Treatment): Rivoraxaban + P2Y12 inhibitor
Rivoraxaban (15mg daily or 10mg daily if moderate renal impairment CrCl of 30-50 ml / min); P2Y12 inhibitor (clopidogrel = 75mg daily, prasugrel = 10mg daily, or ticagrelor = 90 mg BID) for 12 months
Lopes 2019
Inclusion criteria
Primary end point
Secondary end point
Patients with atrial fibrillation status post ACS or PCI. To be eligible patients were required to be planning to use an approved P2Y12 inhibitor for >6 months.
Major or clinically relevant non-major bleeding as defined by ISTH**
Composite of death or hospitalization, and the compoiste of death or ischemic events (MI, CVA, stent thrombosis, or urgent revascularization).
Non-valvular Atrial Fibrillation who had undergone PCI with stenting.
Clinically significant bleeding (TIMI major or minor), or bleeding requiring medical attention.
Occurrence of a major adverse cardiovascular event (composite of death from CVS, MI or stroke), stent thrombosis, and each component of major adverse cardiovascular event end point.
Nonvalvular Atrial Fibrillation who had undergone PCI with a baremetal or drug-eluting stent (with indication of ACS or stable CAD).
First major or clinically relevant nonmajor bleeding event during as defined by ISTH
Composite efficacy end point of thromboembolic events (MI, stroke, systemic embolism), death, unplanned revascularization (PCI or CABG). Combined end point of thrombembolic events or death, as well as individual
Gibson 2016 Group 2: Rivoraxaban 2.5mg+ P2Y12 inhibitor (not included in our analysis)
Group 3 (Control): VKA + DAPT
Group 1 (Treatment): Dabigatran + P2Y12 inhibitor; All US and All international patients Cannon 2017
Rivoraxaban (2.5mg daily + DAPT ASA 75100mg daily and clopidogrel 75 mg daily (or ticagrelor 90 mg BID, or prasugrel = 10 mg daily) for 1, 6, or 12 months
Warfarin daily (dose adjusted to reach target INR 2.0-3.0) plus DAPT with ASA (75-100 mg per day) + clopidogrel 75 mg daily or ticagrelor 90 mg BID or prasugrel 10mg daily for 1, 6, or 12 months
Dabigatran 110mg BID + clopidogrel 75 mg daily or ticagrelor 90 mg daily
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Group 2 Dabigatran + P2Y12 inhibitor; US and non-elderly international patients
Dabigatran 150mg BID + clopidogrel 75 mg daily or ticagrelor 90 mg daily
Group 3 (control): vitamin k antagonist + P2Y12 inhibitor + aspirin; matched to Group 1
Warfarin daily (dose adjusted to reach target INR 2.0-3.0) + ASA <100mg daily + clopidogrel 75 mg daily or ticagrelor 90 mg daily
Group 4: vitamin k antagonist + P2Y12 inhibitor + aspirin; matched to Group 2
Warfarin daily (dose adjusted to reach target INR 2.0-3.0) + ASA <100mg daily + clopidogrel 75 mg daily or ticagrelor 90 mg daily
Group 1 (Treatment): edoxaban + P2Y12 inhibitor
Edoxaban (60 mg once daily) + Clopidogrel (75mg once daily) (or prasugrel 5mg or 10 mg once daily, or ticagrelor 90mg BID). Edoxaban dose reduced to 30mg once daily for patients with renal impairment (Cr clearance 15-50mL/min), <60kg body weight, or concurrent use of specific potent Pglycoprotein inhibitors.
Vranckx 2019 Group 2 (Control): Vitamin K antagonist in combination with a P2Y12 inhibitor and aspirin (100 mg once daily)
thromboembolic events and definite stent thrombosis.
Patients with non-valvular atrial fibrillation status post successful PCI for stable coronary artery disease or acute coronary syndrome.
Vitamin K antagonist dose adjusted to INR range 2.0-3.0; Clopidogrel (75 mg daily) (or prasugrel 5mg or 10 mg once daily or ticagrelor 90 mg BID); ASA 100 mg once daily
Major or clinically relevant non-major (CRNM) bleeding as defined by ISTH. Main efficacy outcome: composite of cardiovascular death, stroke, systemic embolic events, myocardial infarction, definite stent thrombosis.
Other secondary outcomes: net clinical benefit, ISTH-defined major, clinically relevant non-major, and minor bleeding and any ISTH-defined bleeding, intracranial and fatal bleeding, bleeding as per the BARC and TIMI definitions. Secondary efficacy outcomes: stroke (ischemic / haemorrhagic), systemic embolic events, MI, definite/probable stent thrombosis, allcause death, cardiovascular or unexplained death.
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ISTH: International Society on Thrombosis and Haemostatis defines major bleeding as bleeding that results in death, occurred in critical organ (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, intramuscular with compartment syndrome, or pericardial), or associated with a decrease in Hb level of at least 2g / dL or a transfusion of at least 2 units of packed RBCs. Clinically relevant non major bleeding results in hospitalization, medical or surgical intervention for bleeding, and unscheduled clinical visit, or change in antithrombotic therapy. 2 TIMI: Thrombolysis in Myocardial Infarction criteria: A TIMI Major bleeding event is defined as: any symptomatic intracranial hemorrhage, or clinically overt signs of hemorrhage (including imaging) associated with a drop in hemoglobin of ≥ 5 g/dL (or when the hemoglobin concentration is not available, an absolute drop in hematocrit of ≥ 15%). 3
VKA: Vitamin K antagonist
4
DAPT: dual antiplatelet therapy (ASA + P2Y12 inhibitor)
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References 1.
Degrauwe S, Pilgrim T, Aminian A, Noble S, Meier P, Iglesias JF. Dual antiplatelet therapy for secondary prevention of coronary artery disease. Open Heart 2017;4:e000651. 2. Ruff CT, Giugliano RP, Braunwald E et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet 2014;383:955-62. 3. Weitz JI, Semchuk W, Turpie AG et al. Trends in Prescribing Oral Anticoagulants in Canada, 2008-2014. Clin Ther 2015;37:2506-2514 e4. 4. Angiolillo DJ, Goodman SG, Bhatt DL et al. Antithrombotic Therapy in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A North American Perspective-2016 Update. Circ Cardiovasc Interv 2016;9. 5. Andrade JG, Deyell MW, Wong GC, Macle L. Antithrombotic Therapy for Atrial Fibrillation and Coronary Disease Demystified. Can J Cardiol 2018;34:1426-1436. 6. Moser M, Olivier CB, Bode C. Triple antithrombotic therapy in cardiac patients: more questions than answers. Eur Heart J 2014;35:216-23. 7. Enomoto Y, Iijima R, Tokue M et al. Bleeding risk with triple antithrombotic therapy in patients with atrial fibrillation and drug-eluting stents. Cardiovasc Interv Ther 2014;29:193-9. 8. Sambola A, Ferreira-Gonzalez I, Angel J et al. Therapeutic strategies after coronary stenting in chronically anticoagulated patients: the MUSICA study. Heart 2009;95:1483-8. 9. Dewilde WJ, Oirbans T, Verheugt FW et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107-15. 10. Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12. 11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. 12. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0, Updated March 2011. 13. Cannon CP, Bhatt DL, Oldgren J et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med 2017;377:1513-1524. 14. Gibson CM, Mehran R, Bode C et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med 2016;375:2423-2434. 15. Lopes RD, Heizer G, Aronson R et al. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med 2019;380:1509-1524. 16. Vranckx P, Valgimigli M, Eckardt L et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet 2019;394:1335-1343.
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17.
18.
19.
Mehta SR, Bainey KR, Cantor WJ et al. 2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of the Guidelines for the Use of Antiplatelet Therapy. Can J Cardiol 2018;34:214-233. Golwala HB, Cannon CP, Steg PG et al. Safety and efficacy of dual vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of randomized clinical trials. Eur Heart J 2018;39:1726-1735a. Lopes RD, Hong H, Harskamp RE et al. Safety and Efficacy of Antithrombotic Strategies in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A Network Meta-analysis of Randomized Controlled Trials. JAMA Cardiol 2019.
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Figure 1. Flow diagram of literature search and study selection
335 records identified through electronic database literature search (PubMed)
104 studies obtained from other resources including manual web searches, reference lists, and review articles
Total of 439 potentially relevant studies identified through literature search and screened
397 studies excluded based on review of titles and abstracts • Exclusion criteria: non-comparative studies, replies, experimental studies, surveys, descriptive studies, pediatric patient population, in vitro, animal models
42 full-text articles reviewed and assessed further for eligibility to be potentially included in meta-analysis
38 excluded after review of full text articles based on: • Reviews, meta-analyses, incomplete data, case reports, lack of outcomes of interest, non-randomized controlled trials
4 Randomized Controlled Trials included in quantitative synthesis of meta-analysis
S0828-282X(19)31428-X
DOI:
https://doi.org/10.1016/j.cjca.2019.11.005
Reference:
CJCA 3511
To appear in:
Canadian Journal of Cardiology
Received Date: 30 June 2019 Revised Date:
1 November 2019
Accepted Date: 4 November 2019
Please cite this article as: Shurrab M, Danon A, Alnasser S, Glover B, Kaoutskaia A, Henderson M, Newman D, Crystal E, Ko D, Dual antithrombotic therapy with DOACs after ACS or PCI in Atrial Fibrillation: A meta-analysis of Randomized Controlled Trials, Canadian Journal of Cardiology (2019), doi: https://doi.org/10.1016/j.cjca.2019.11.005. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.
Dual antithrombotic therapy with DOACs after ACS or PCI in Atrial Fibrillation: A metaanalysis of Randomized Controlled Trials
Mohammed Shurrab MD MSc,1,2,3,4, Asaf Danon MD MSc,5 Sami Alnasser MD,1,3 Benedict Glover MD,6 Anna Kaoutskaia BScH,7 Mark Henderson MD,1,3 David Newman MD,6 Eugene Crystal MD,6 Dennis Ko MD MSc 4,6,8 1. Cardiology Department, Health Sciences North, Sudbury, Ontario, Canada. 2. Health Sciences North Research Institute, Sudbury, Ontario, Canada. 3. Northern Ontario School of Medicine, Laurentian University, Sudbury, Ontario, Canada. 4. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. 5. Electrophysiology Unit, Cardiology Department, Hillel Yaffe Medical Center, Hadera, Israel 6. Division of Cardiology, Schulich Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. 7. St. Matthew’s University School of Medicine, Grand Cayman, Cayman Islands. 8. Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada. Corresponding author: Mohammed Shurrab MD, MSc Cardiology Department, Health Sciences North Health Sciences North Research Institute Northern Ontario School of Medicine Laurentian University, Sudbury, Ontario, Canada Email: [email protected]
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Short title: DOACs after ACS or PCI in AF
Conflict of interest •
Mohammed Shurrab is supported by a Fellowship Award from the Canadian Institutes of Health Research (CIHR).
•
Dennis T. Ko is supported by a Mid-Career Investigator Award from the Heart and Stroke Foundation of Canada (HSFC), Ontario Provincial Office.
Sources of Funding: None
Moderated presentation at the Canadian Cardiovascular Congress (CCC): DUAL ANTITHROMBOTIC THERAPY WITH DIRECT-ACTING ORAL ANTICOAGULANTS AFTER ACUTE CORONARY SYNDROME OR PCI IN ATRIAL FIBRILLATION: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS Thursday October 24, 2019
Brief Summary The choice of antithrombotic therapy for atrial fibrillation (AF) patients who have an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is challenging. In our meta-analysis, the use of dual antithrombotic therapy with DOACs was associated with less major bleeding, and major bleeding or clinically relevant non-major bleeding. The use of Dual therapy has shown non-significantly higher composite of death or ischemic events but no difference in mortality.
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Abstract Background: The choice of antithrombotic therapy for atrial fibrillation (AF) patients who have an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is challenging. We aimed to assess outcomes between dual antithrombotic therapy with DOACs plus an antiplatelet agent (Dual therapy) in comparison to warfarin plus two antiplatelet agents (Triple therapy) after PCI or ACS for AF patients.
Methods: Systematic searches of multiple major databases were performed from inception until September 2019. We included only randomized controlled trials. Odd ratios were pooled using a randomeffects model.
Results: We identified 4 RCTs, which included 7168 patients. In comparison to triple antithrombotic therapy with warfarin, Dual antithrombotic therapy with DOACs was associated with a significant reduction in major bleeding (odds ratio [OR] 0.56 [95% confidence interval [CI] 0.38 to 0.82], p 0.003) as well as major bleeding or clinically relevant non-major bleeding (OR 0.53 [95% CI 0.38 to 0.75], p<0.001). The rate of composite of death or ischemic events (stroke or myocardial infarction) was not statistically different between both groups (OR 1.21 [95% CI 0.99 to 1.49], p=0.06). There was no significant difference between both groups in the rate of death (OR 1.20 [95% CI 0.95 to 1.53], p=0.13).
Conclusions: In patients with AF and recent ACS or PCI, the use of dual antithrombotic therapy with DOACs was associated with less major bleeding, and major bleeding or clinically relevant non-major bleeding, compared to triple therapy. The use of dual therapy also shows non-significantly higher composite of death/ischemic events but no difference in mortality.
Keywords: atrial fibrillation, acute coronary syndrome and percutaneous coronary intervention
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Introduction Dual antiplatelet therapy (DAPT) has been consistently shown to reduce major cardiovascular adverse events in patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI).(1) In the last few years, Direct-acting oral anticoagulants (DOACs) like dabigatran, rivaroxaban, apixaban and edoxaban have been rapidly adopted into practice for stroke prophylaxis in patients with AF given their efficacy, safety and ease of use in comparison to warfarin.(2) The overall number of anticoagulation therapies prescriptions in Canada has increased annually since 2008.(3)
Optimal antithrombotic therapy for patients with atrial fibrillation (AF) following ACS or PCI is uncertain particularly given the availability of various antithrombotic agents.(4,5) The combination of antithrombotic agents, particularly triple therapy with warfarin and DAPT, increase the risk of bleeding. (6-8) Hence dual antithrombotic therapy with DOACs plus an antiplatelet agent has emerged as an attractive alternative regimen to the standard triple antithrombotic therapy with warfarin after PCI or ACS for patients with AF. Recent data have shown a reduction in bleeding, but were underpowered to test for efficacy (ischemic events), which remains a major concern with such regimen.(9)
We conducted a meta-analysis to assess the safety and efficacy of dual antithrombotic therapy with DOACs plus an antiplatelet agent in comparison to triple antithrombotic therapy with warfarin plus two antiplatelet agents after PCI or ACS for patients with AF.
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Methods Literature search and data sources An electronic literature search was performed by two investigators (MS, AK) in accordance with the recommendations of Cochrane collaboration using Pubmed, Embase, Scopus, and Cochrane Central Register of Controlled Trials from inception until September 21, 2019. The search terms were: (atrial fibrillation) AND (anticoagulation) AND (percutaneous coronary intervention OR acute coronary syndrome). Neither language nor demographic restrictions were applied. All references from papers obtained through the databases were reviewed manually. We included only full papers and excluded abstracts/reports that did not provide full data about the outcomes of interest. The electronic search has been archived and is available upon request.
Study selection and quality assessment The inclusion was limited to the studies which are: 1) Randomized controlled trials (RCT) that compared Dual antithrombotic therapy with DOACs to standard Triple therapy with warfarin after PCI or ACS in patients with AF; 2) included adult population >18 years old; and 3) provided data on outcomes of interest. The selection of studies was assessed independently by 3 assessors (MS, AK, AD). We excluded non-randomized and non-comparative trials, crossover studies, case reports, editorials, letters, replies, and reviews. The quality of the randomized studies was evaluated based on the five-point scale outlined by Jadad et al., with criteria for the following: randomization with proper concealment
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of the allocation sequence, blinding of the patient and investigator to treatment allocation with description of the blinding method, and completeness of follow-up.(10) Data extraction and outcomes of interest Two reviewers (MS, AK) independently extracted data from published sources; disagreements were resolved by discussion and, when necessary, in consultation with other coauthors. The following outcomes were identified as relevant and consistent measures to compare between the studied groups: The primary (safety) outcomes were: 1) major bleeding and 2) major bleeding or clinically relevant non-major bleeding. Major bleeding and clinically relevant non-major bleeding were similarly described across all included trials as defined by the International Society on Thrombosis and Haemostasis (ISTH). ISTH major bleeding was defined as bleeding that resulted in death, occurred in a critical organ (intraspinal, intracranial, intraocular, retroperitoneal, pericardial etc) or was associated with either a decrease in hemoglobin level of at least 2 g per deciliter, or necessitating a transfusion of greater than 2 units of packed red blood cells. Clinically relevant bleeding is defined as bleeding that required hospitalization, medical/surgical intervention, an unscheduled clinic visit, or a change in antithrombotic therapy. The secondary (efficacy) outcomes were: 1) death; 2) composite of death or ischemic events (stroke or myocardial infarction); 3) stroke; 4) myocardial infarction and 5) definite stent thrombosis. Those outcomes have been chosen as the only available homogeneously reported outcomes across the trials where data could be retrieved and analyzed.
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Statistics The software package RevMan (version 5) provided by the Cochrane Collaboration was used for combining outcomes from the individual studies and statistical analysis. Outcomes were pooled using a random effects model described by DerSimonian and Laird.(11) Summary estimates and 95% confidence interval (CI) were reported for dichotomous variables as odds ratio (OR). The heterogeneity between studies was assessed using Cochrane’s X2 and I2. An I2 > 50% was considered to represent significant heterogeneity.(12) Statistical significance was set as P < 0.05. A sensitivity analysis was performed to include the RE-DUAL PCI dual therapy with Dabigatran 150 mg group.
Results Summary of the studies The literature search resulted in 439 studies (335 from electronic databases and 104 from other resources including web searches and reference lists). We identified four RCTs that met all applied inclusion criteria of this meta-analysis.(13-16) The information relevant to the literature search is shown in Figure 1.
The Dual therapy group in the PIONEER AF-PCI trial was the low-dose Rivaroxaban (15mg daily or a dose of 10mg daily if they had moderate renal impairment) and a P2Y12 inhibitor (clopidogrel 75mg daily, ticagrelor 90mg twice daily, or prasugrel 10mg daily). The control group was the standard triple therapy consisting of Dual antiplatelet therapy (DAPT) and warfarin.(14) In the RE-DUAL PCI trial the Dual therapy group comprised of patients receiving dabigatran (110mg twice daily) with a P2Y12 inhibitor (clopidogrel 75mg daily or ticagrelor
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90mg twice daily), and the control group were receiving the triple therapy (DAPT and warfarin).(13) The AUGUSTUS trial randomized patients via a two-by-two factorial design. For the purposes of our analysis, we compared the outcomes of the specific group of apixaban and placebo with a P2Y12 inhibitor, to a Vitamin K antagonist with aspirin and a P2Y12 inhibitor.(15) In the ENTRUST trial’s , the treatment group consisted of patients receiving edoxaban regimen at a dose of 60 mg once daily and a P2Y12 inhibitor once daily for 12 months. The control group received a Vitamin K antagonist in combination with a P2Y12 inhibitor and 100 mg of aspirin daily for up to 12 months in duration.(16)
Baseline characteristics of patients and Outcomes of interest We identified 4 RCTs that included 7168 patients. Dual antithrombotic therapy with DOACs was used in 3581patients (dabigatran in 981, rivaroxaban in 696 patients, apixaban in 1153 patients, and edoxaban in 751). We specifically examined the groups that adopted DOACs in the dual therapy in comparison to the long used standard triple therapy with warfarin. Baseline demographics and clinical characteristics of the examined groups could not be pooled due to heterogeneity of reported data and are summarized in Table 1. We also summarized the characteristics of the included trials. (Table 1S) In comparison to triple antithrombotic therapy with warfarin, Dual antithrombotic therapy with DOACs was associated with a significant reduction in major bleeding (odds ratio [OR] 0.56 [95% confidence interval [CI] 0.38 to 0.82], p 0.003) as well as major bleeding or clinically relevant non-major bleeding (OR 0.53 [95% CI 0.38 to 0.75], p<0.001). (Figures 2 & 3). A sensitivity analysis was performed to include the RE-DUAL PCI Dual Therapy with
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Dabigatran 150 mg group. This showed similar results to the Dual Therapy with Dabigatran 110 mg group included in the main analysis. (Figure S1 and S2). There was a trend of a higher rate of the composite of death or ischemic events (stroke or myocardial infarction) with Dual antithrombotic therapy with DOACs, but this was not statistically significant (OR 1.21 [95% CI 0.99 to 1.49], p=0.06). (Figure 4) There was no significant difference between both groups in the rate of death (OR 1.20 [95% CI 0.95 to 1.53], p=0.13). (Figure 5) There were no differences between the two groups in the rate of stroke (OR 1.10 [95% CI 0.68 to 1.78], p=0.71) (Figure 6), myocardial infarction (OR 1.27 [95% CI 0.93 to 1.74], p=0.13) (Figure 7), or definite stent thrombosis (OR 1.56 [95% CI 0.86 to 2.83], p=0.14) (Figure 8).
Discussion Our study examined outcomes between dual antithrombotic therapy with DOACs plus an antiplatelet agent in comparison to the standard triple therapy with warfarin plus two antiplatelet agents after PCI or ACS for patients with AF. Our meta-analysis showed the following important findings: DAPT with DOACs was associated with: 1) less major bleeding and major or clinically relevant non-major bleeding and 2) non-significantly higher composite of death or ischemic events (stroke or myocardial infarction) but no difference in mortality. Furthermore, when ischemic events (stroke, myocardial infarction, and definite stent thrombosis) were analyzed separately there was no difference in the rates between the groups.
We specifically looked at trials that adopted DOACs in the dual therapy in comparison to the long used standard triple therapy with warfarin. This is based on the fact that dual therapy
9
with DOACs has been widely accepted in current clinical practice supported by recent guidelines.(17) In patients with AF undergoing PCI for ACS or high- risk elective PCI, the current Canadian guidelines recommend: (17) If age ≥ 65 years or CHADS2 ≥ 1, an initial regimen of triple therapy with ASA 81 mg daily plus clopidogrel 75 mg daily plus reduced dose anticoagulation. ASA may still be discontinued as early as the following day post PCI or it can be continued for up to 6 months of treatment, depending on the risk of recurrent coronary events versus major bleeding. The choice of recommended anticoagulation therapy is between rivaroxaban 15 mg daily, dabigatran 110 mg or 150 mg BID or warfarin. Trials evaluating apixaban and edoxaban in patients with AF who undergo PCI were still ongoing at the time and hence were not reflected in the guidelines. Data have shown that combined dual antiplatelet therapy and a vitamin K antagonist (i.e., triple therapy) are associated with a high risk of bleeding. (6-8) The adoption of Dual therapy with DOACs has led to less bleeding rates whether major bleeding or combined major and clinically relevant non- major bleeding among all RCTs included in this meta-analysis. A recent meta-analysis and systematic review conducted by Golwala et al.(18) studied the safety and efficacy of dual versus triple antithrombotic therapy in patients with AF undergoing PCI. Our current review is different as the focus of our analysis was on the comparison between dual therapy including DOACs versus the classic triple therapy with warfarin. While both meta-analyses have shown reduction in bleeding, our analysis specifically targeted DOACs in the Dual antithrombotic therapy group, which is quite different than Golwala et al’s comparative groups including warfarin. Overall, our findings of dual antithrombotic therapy with DOACs association with less major bleeding and major or clinically relevant nonmajor bleeding and no difference in mortality are in line with the conclusion reached by Golwala et al. thereby highlighting the safety of this approach with DOACs. Finally, a recently published
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meta-analysis in the context of the ENTRUST-AF PCI trial has shown similar results.(16) However we provide a comprehensive review and analysis with important sensitivity analysis.
In our meta-analysis we pooled the efficacy data across the available trials and have found a concerning signal of less efficacy (composite of death and ischemic events) with dual therapy with DOAC in comparison to triple therapy with warfarin. This observation might be driven by a higher coronary ischemic event rate, as DOACs are known to have similar efficacy to warfarin in stroke prophylaxis among AF patients.(2) A recent network meta-analysis has shown that omitting aspirin caused less bleeding, including intracranial bleeding, without significant difference in major adverse cardiovascular events, compared with strategies including aspirin.(19) This should be investigated in further studies. Nevertheless, when we pulled the events of stroke, myocardial infarction, and definite stent thrombosis separately, there was no significant difference in these events between groups.
It should be emphasized that all trials enrolled patients several days after the PCI. For example, In AUGUSTUS trial, the median time from PCI to enrolment was 6 days. Thus, the PCI procedure itself and the first days thereafter were performed with DAPT treatment.(15) We do not know whether patients can be treated safely with a single antiplatelet drug during the first week following the PCI, even if combined with a DOAC.
Future studies should focus on the important clinical question of Dual therapy (DOACs and a single antiplatelet therapy) versus triple therapy (DOACs and DAPT). More so, a focus
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should be on the appropriate duration of each regimen. This would help in identifying the best regimen among patients with AF after PCI or ACS and solve a challenging clinical dilemma.
Limitations The small number of randomized controlled trials available for inclusion in this analysis could limit our conclusions. The difference in the definition of outcomes and the duration of dual therapy and triple therapy among the included trials is an important limitation. Additional limitations of this study include the use of trial level data rather than patient-specific data, and the inability to statistically analyze certain subgroups (such as type of index event or type of stent) due to the heterogeneity across trial designs, and could possibly affect the interpretation of the results. We have tried to conduct a publication bias but the small number of trials precluded such evaluation. The difference in follow up among the included trials is an important limitation of our conclusions.
Conclusions In patients with AF and recent ACS or PCI, the use of dual antithrombotic therapy with DOACs was associated with less major bleeding and major bleeding or clinically relevant nonmajor bleeding. The use of Dual therapy has shown non-significantly higher composite of death or ischemic events (stroke or myocardial infarction) but no difference in mortality. Future studies should focus on the efficacy of Dual antithrombotic therapy with DOACs in patients with AF and a recent ACS or PCI.
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Figure Legends
Figure 1. Flow diagram of literature search and study selection.
Figure 2. Forest plots of the individual and combined rates of major bleeding (ISTH).
Figure 3: Forest plots of the individual and combined rates of major bleeding (ISTH) or clinically relevant non-major bleeding.
Figure 4: Forest plots of the individual and combined rates of the composite of death or ischemic events (stroke or myocardial infarction).
Figure 5: Forest plots of the individual and combined rates of death.
Figure 6. Forest plots of the individual and combined rates of cerebrovascular accidents.
Figure 7. Forest plots of the individual and combined rates of myocardial infarctions.
Figure 8. Forest plots of the individual and combined rates of definite stent thrombosis.
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Figure 1. Flow diagram of literature search and study selection
14
Figure 2: Forest plots of the individual and combined rates of major bleeding (ISTH).
Figure 3: Forest plots of the individual and combined rates of major bleeding (ISTH) or clinically relevant non-major bleeding.
Figure 4: Forest plots of the individual and combined rates of the composite of death or ischemic events (stroke or myocardial infarction).
Figure 5: Forest plots of the individual and combined rates of death.
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Figure 6. Forest plots of the individual and combined rates of cerebrovascular accidents.
Figure 7. Forest plots of the individual and combined rates of myocardial infarctions.
Figure 8. Forest plots of the individual and combined rates of definite stent thrombosis.
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Figure S1: Forest plots of the individual and combined rates of major bleeding (ISTH), including the RE-DUAL PCI Dual Therapy with Dabigatran 150 mg group
Figure S2: Forest plots of the individual and combined rates of major bleeding (ISTH) or clinically relevant non-major bleeding, including the RE-DUAL PCI Dual Therapy with Dabigatran 150 mg group
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Table 1. Summary of patient baseline characteristics Gibson (2016)
Cannon (2017)
Lopes (2019)
DT
TT
DT
TT
DT
TT
DT
Vranckx (2019) TT
709
706
981
981
2306
2308
751
755
70.4 ± 9.1
69.9 ± 8.7
71.5 ± 8.9
71.7 ± 8.9
70.4*
70.9*
69*
70*
Gender (Male) n(%)
528 (74.5%)
518 (73.4%)
728 (74.2%)
750 (76.5%)
1636 (70.9%)
1641 (71.1%)
557 (74%)
563 (75%)
Diabetes Mellitus n(%)
204 (28.8%)
221 (31.3%)
362 (36.9%)
371/980 (37.9%)
842 (36.5%)
836 (36.2%)
259 (34%)
258 (34%)
>2
520 (73%)
559 (79%)
751 (76.6%)
788 (80.3%)
n/a
n/a
n/a
n/a
mean
n/a
n/a
3.7±1.6
3.8±1.5
3.9±1.6
4.0±1.6
Paroxysmal
300 (42.4%)
313 (44.4%)
487 (49.6%)
484 (49.4%)
n/a
n/a
402 (54%)
358 (47%)
Persistent
146 (20.6%)
149 (21.1%)
174 (17.7%)
178 (18.2%)
n/a
n/a
140 (19%)
146 (19%)
Permanent
262 (37%)
243 (34.5%)
320 (32.6%)
318 (32.4%)
n/a
n/a
209 (28%)
250 (33%)
Duration of follow-up
12 months
1, 6, or 12 months
Patients (n) Age (mean ± SD)
CHA2DS2-VASc score 4.0 (IQR 3.0–5.0)*
Atrial Fibrillation type
14 months
* median DT indicates dual therapy with DOAC group; TT indicates triple therapy with VKA group ** Gibson et al DT group AF denominator is 708 patients; TT group is 705 patients
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6 months
364 days (IQR 361–368)*
Table 2. Summary of safety and efficacy outcomes Patients (n) Study Gibson (2016) Cannon (2017) Lopes (2019) Vranckx (2019)
Tx 696 981 1153 751
Ctrl 697 981 1154 755
Major bleeding n (%) Tx 14 (2%) 49 (5%) 23 (2%) 45 (6%)
Ctrl 20 (2.9%) 90 (9.2%) 62 (5.4%) 48 (6%)
Clinically relevant non-major bleeding n (%) Tx 109 (16.8%) 151 (15.4%) 84 (7.3%)
Ctrl 167 (26.7%) 264 (26.9%) 210 (18.7%)
Death n (%) Tx 15/694 (2.4%) 55 (5.6%) 39 / 1153 (3.4%) 46 (6.1%)
Ctrl 11/695 (1.9%) 48 (4.9%) 34 / 1154 (2.9%) 37 (4.9%)
Composite of death or ischemic events (MI or CVA) n (%) Tx 41/694 (5.9%) 108 (11%) 72 / 1153 (6.2%) 49 (7%)*
DT indicates dual therapy with DOAC group; TT indicates triple therapy with VKA group * Main efficacy outcome (composite of cardiovascular death, stroke, systemic embolic event, myocardial infarction, or definite stent thrombosis)
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Ctrl 36/695 (5.1%) 83 (8.5%) 66 / 1154 (5.7%) 46 (6%)*
Table 1S. Included trials’ characteristics Patient groups
Therapy dosage received
Group 1 (Treatment): Apixaban with ASA or placebo)* + P2Y12 inhibitor
Apixaban (5 mg BID or 2.5 mg BID) if met 2 or more of the following dose-reduction criteria: at least 80 years of age, weight of < 60 kg, or creatinine level of at least 1.5 mg per deciliter (133 µmol per liter); ASA = 81mg; Clopidogrel (2.5mg BID) for 6 months
Group 2 (Control): Vitamin K antagonist with ASA or placebo + P2Y12 inhibitor***
Vitamin K antagonist (warfarin) dose adjusted to reach target INR range 2.0-3.0; ASA = 81mg; Clopidogrel (2.5mg BID) for 6 months
Group 1 (Treatment): Rivoraxaban + P2Y12 inhibitor
Rivoraxaban (15mg daily or 10mg daily if moderate renal impairment CrCl of 30-50 ml / min); P2Y12 inhibitor (clopidogrel = 75mg daily, prasugrel = 10mg daily, or ticagrelor = 90 mg BID) for 12 months
Lopes 2019
Inclusion criteria
Primary end point
Secondary end point
Patients with atrial fibrillation status post ACS or PCI. To be eligible patients were required to be planning to use an approved P2Y12 inhibitor for >6 months.
Major or clinically relevant non-major bleeding as defined by ISTH**
Composite of death or hospitalization, and the compoiste of death or ischemic events (MI, CVA, stent thrombosis, or urgent revascularization).
Non-valvular Atrial Fibrillation who had undergone PCI with stenting.
Clinically significant bleeding (TIMI major or minor), or bleeding requiring medical attention.
Occurrence of a major adverse cardiovascular event (composite of death from CVS, MI or stroke), stent thrombosis, and each component of major adverse cardiovascular event end point.
Nonvalvular Atrial Fibrillation who had undergone PCI with a baremetal or drug-eluting stent (with indication of ACS or stable CAD).
First major or clinically relevant nonmajor bleeding event during as defined by ISTH
Composite efficacy end point of thromboembolic events (MI, stroke, systemic embolism), death, unplanned revascularization (PCI or CABG). Combined end point of thrombembolic events or death, as well as individual
Gibson 2016 Group 2: Rivoraxaban 2.5mg+ P2Y12 inhibitor (not included in our analysis)
Group 3 (Control): VKA + DAPT
Group 1 (Treatment): Dabigatran + P2Y12 inhibitor; All US and All international patients Cannon 2017
Rivoraxaban (2.5mg daily + DAPT ASA 75100mg daily and clopidogrel 75 mg daily (or ticagrelor 90 mg BID, or prasugrel = 10 mg daily) for 1, 6, or 12 months
Warfarin daily (dose adjusted to reach target INR 2.0-3.0) plus DAPT with ASA (75-100 mg per day) + clopidogrel 75 mg daily or ticagrelor 90 mg BID or prasugrel 10mg daily for 1, 6, or 12 months
Dabigatran 110mg BID + clopidogrel 75 mg daily or ticagrelor 90 mg daily
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Group 2 Dabigatran + P2Y12 inhibitor; US and non-elderly international patients
Dabigatran 150mg BID + clopidogrel 75 mg daily or ticagrelor 90 mg daily
Group 3 (control): vitamin k antagonist + P2Y12 inhibitor + aspirin; matched to Group 1
Warfarin daily (dose adjusted to reach target INR 2.0-3.0) + ASA <100mg daily + clopidogrel 75 mg daily or ticagrelor 90 mg daily
Group 4: vitamin k antagonist + P2Y12 inhibitor + aspirin; matched to Group 2
Warfarin daily (dose adjusted to reach target INR 2.0-3.0) + ASA <100mg daily + clopidogrel 75 mg daily or ticagrelor 90 mg daily
Group 1 (Treatment): edoxaban + P2Y12 inhibitor
Edoxaban (60 mg once daily) + Clopidogrel (75mg once daily) (or prasugrel 5mg or 10 mg once daily, or ticagrelor 90mg BID). Edoxaban dose reduced to 30mg once daily for patients with renal impairment (Cr clearance 15-50mL/min), <60kg body weight, or concurrent use of specific potent Pglycoprotein inhibitors.
Vranckx 2019 Group 2 (Control): Vitamin K antagonist in combination with a P2Y12 inhibitor and aspirin (100 mg once daily)
thromboembolic events and definite stent thrombosis.
Patients with non-valvular atrial fibrillation status post successful PCI for stable coronary artery disease or acute coronary syndrome.
Vitamin K antagonist dose adjusted to INR range 2.0-3.0; Clopidogrel (75 mg daily) (or prasugrel 5mg or 10 mg once daily or ticagrelor 90 mg BID); ASA 100 mg once daily
Major or clinically relevant non-major (CRNM) bleeding as defined by ISTH. Main efficacy outcome: composite of cardiovascular death, stroke, systemic embolic events, myocardial infarction, definite stent thrombosis.
Other secondary outcomes: net clinical benefit, ISTH-defined major, clinically relevant non-major, and minor bleeding and any ISTH-defined bleeding, intracranial and fatal bleeding, bleeding as per the BARC and TIMI definitions. Secondary efficacy outcomes: stroke (ischemic / haemorrhagic), systemic embolic events, MI, definite/probable stent thrombosis, allcause death, cardiovascular or unexplained death.
1
ISTH: International Society on Thrombosis and Haemostatis defines major bleeding as bleeding that results in death, occurred in critical organ (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, intramuscular with compartment syndrome, or pericardial), or associated with a decrease in Hb level of at least 2g / dL or a transfusion of at least 2 units of packed RBCs. Clinically relevant non major bleeding results in hospitalization, medical or surgical intervention for bleeding, and unscheduled clinical visit, or change in antithrombotic therapy. 2 TIMI: Thrombolysis in Myocardial Infarction criteria: A TIMI Major bleeding event is defined as: any symptomatic intracranial hemorrhage, or clinically overt signs of hemorrhage (including imaging) associated with a drop in hemoglobin of ≥ 5 g/dL (or when the hemoglobin concentration is not available, an absolute drop in hematocrit of ≥ 15%). 3
VKA: Vitamin K antagonist
4
DAPT: dual antiplatelet therapy (ASA + P2Y12 inhibitor)
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Degrauwe S, Pilgrim T, Aminian A, Noble S, Meier P, Iglesias JF. Dual antiplatelet therapy for secondary prevention of coronary artery disease. Open Heart 2017;4:e000651. 2. Ruff CT, Giugliano RP, Braunwald E et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet 2014;383:955-62. 3. Weitz JI, Semchuk W, Turpie AG et al. Trends in Prescribing Oral Anticoagulants in Canada, 2008-2014. Clin Ther 2015;37:2506-2514 e4. 4. Angiolillo DJ, Goodman SG, Bhatt DL et al. Antithrombotic Therapy in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A North American Perspective-2016 Update. Circ Cardiovasc Interv 2016;9. 5. Andrade JG, Deyell MW, Wong GC, Macle L. Antithrombotic Therapy for Atrial Fibrillation and Coronary Disease Demystified. Can J Cardiol 2018;34:1426-1436. 6. Moser M, Olivier CB, Bode C. Triple antithrombotic therapy in cardiac patients: more questions than answers. Eur Heart J 2014;35:216-23. 7. Enomoto Y, Iijima R, Tokue M et al. Bleeding risk with triple antithrombotic therapy in patients with atrial fibrillation and drug-eluting stents. Cardiovasc Interv Ther 2014;29:193-9. 8. Sambola A, Ferreira-Gonzalez I, Angel J et al. Therapeutic strategies after coronary stenting in chronically anticoagulated patients: the MUSICA study. Heart 2009;95:1483-8. 9. Dewilde WJ, Oirbans T, Verheugt FW et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107-15. 10. Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12. 11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. 12. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0, Updated March 2011. 13. Cannon CP, Bhatt DL, Oldgren J et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med 2017;377:1513-1524. 14. Gibson CM, Mehran R, Bode C et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med 2016;375:2423-2434. 15. Lopes RD, Heizer G, Aronson R et al. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med 2019;380:1509-1524. 16. Vranckx P, Valgimigli M, Eckardt L et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet 2019;394:1335-1343.
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Mehta SR, Bainey KR, Cantor WJ et al. 2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of the Guidelines for the Use of Antiplatelet Therapy. Can J Cardiol 2018;34:214-233. Golwala HB, Cannon CP, Steg PG et al. Safety and efficacy of dual vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of randomized clinical trials. Eur Heart J 2018;39:1726-1735a. Lopes RD, Hong H, Harskamp RE et al. Safety and Efficacy of Antithrombotic Strategies in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A Network Meta-analysis of Randomized Controlled Trials. JAMA Cardiol 2019.
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Figure 1. Flow diagram of literature search and study selection
335 records identified through electronic database literature search (PubMed)
104 studies obtained from other resources including manual web searches, reference lists, and review articles
Total of 439 potentially relevant studies identified through literature search and screened
397 studies excluded based on review of titles and abstracts • Exclusion criteria: non-comparative studies, replies, experimental studies, surveys, descriptive studies, pediatric patient population, in vitro, animal models
42 full-text articles reviewed and assessed further for eligibility to be potentially included in meta-analysis
38 excluded after review of full text articles based on: • Reviews, meta-analyses, incomplete data, case reports, lack of outcomes of interest, non-randomized controlled trials
4 Randomized Controlled Trials included in quantitative synthesis of meta-analysis