The optimal antiaggregant therapy after coronary stenting in patients receiving oral anticoagulants (OACs) is currently debated. MEDLINE and Cochrane Library were searched for studies reporting outcomes of patients who underwent PCI and who were on triple therapy (TT) or dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel or dual therapy (DT) with OAC and clopidogrel. Major bleeding was the primary end point, whereas all-cause death, myocardial infarction (MI), stent thrombosis, and stroke were secondary ones. Results were reported for all studies and separately for those deriving from randomized controlled trials or multivariate analysis. In 9 studies, 1,317 patients were treated with DAPT and 1,547 with TT. DAPT offered a significant reduction of major bleeding at 1 year for overall studies and for the subset of observational works providing adjusted data (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.39 to 0.68, I 2 60% and OR 0.36, 95% CI 0.28 to 0.46) compared to TT. No increased risk of major adverse cardiac events (MACE: death, MI, stroke, and stent thrombosis) was reported (OR 0.71, 95% CI 0.46 to 1.08), although not deriving from randomized controlled trials or multivariate analysis. Six studies tested OAC and clopidogrel (1,263 patients) versus OAC, aspirin, and clopidogrel (3,055 patients) with a significant reduction of bleeding (OR 0.79, 95% CI 0.64 to 0.98), without affecting rates of death, MI, stroke, and stent thrombosis (OR 0.90, 95% CI 0.69 to 1.23) also when including clinical data from randomized controlled trials or multivariate analysis. In conclusion, compared to TT, both aspirin and clopidogrel and clopidogrel and OAC reduce bleeding. No difference in major adverse cardiac events is present for clopidogrel and OAC, whereas only low-grade evidence is present for aspirin and clopidogrel.
Current evidence supports the use of both aspirin and an adenosine diphosphate receptor antagonists such as clopidogrel, prasugrel, or ticagrelor in patients to reduce the risk of stent thrombosis or recurrent myocardial infarction (MI), and oral anticoagulants (OAC) to prevent cardioembolic neurologic events. Conversely, the combination of OACs and dual-antiplatelet therapy (DAPT) is associated with an annual risk of fatal and nonfatal bleeding episodes of approximately 10%, with an exponential increase in those patients (female, renal insufficiency) more prone to bleeding. Correct management of these patients is still debated. Bleeding was demonstrated to be more frequent for triple therapy (TT; aspirin, clopidogrel, and OAC) in recent studies. Moreover in the randomized What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) trial, a significant reduction in bleeding was demonstrated without enhanced risk of vascular events in patients randomized to clopidogrel and OAC versus TT. This meta-analysis was performed to assess the clinical outcomes of DAPT or DT versus TT.
Methods
The Preferred Reporting Items for Systematic reviews and Meta-Analyses amendment to the Quality of Reporting of Meta-analyses statement and recommendations from the Cochrane Collaboration and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) were followed during the development of the present systematic review.
Pertinent articles were searched in MEDLINE, Cochrane Library, Biomed Central, and Google Scholar without time limit in keeping with established methods with MeSH strategy and with the following terms: (((triple AND therapy) OR (oral AND anticoagulant) OR oac) AND aspirin AND (clopidogrel) AND (PCI) OR (pci) OR (coronary AND ((percutaneous AND intervention) OR angioplasty OR stent))). Research was ended on June 20, 2014.
Two independent reviewers (F.DA. and G.B.Z.) screened the retrieved citations through the title and/or abstract, and divergences were resolved through consensus. If potentially pertinent, studies were then appraised as complete reports according to the following explicit selection criteria. Studies were included if (1) reporting outcomes of patients on aspirin and clopidogrel or OAC and clopidogrel versus TT, (2) reporting either bleeding or ischemic events or both as clinical end point, and (3) with at least 6 months of follow-up, whereas exclusion criteria were (1) nonhuman setting, (2) duplicate reporting (in which case, the manuscript reporting the largest sample of patients was selected), and (3) use of antiplatelet agents different from clopidogrel (prasugrel or ticagrelor currently without indication with OAC).
Two independent reviewers (F.DA. and G.B.Z.) abstracted the following data on prespecified forms: authors, journal, year of publication, location of the study group, and choice of DAPTl or DT, baseline clinical and interventional features, and definition of bleeding. Data extraction was conducted by mutual agreement, and all potential disagreement was solved by consensus.
Incidence of major bleeding in patients assuming DAPT versus those assuming TT and in patients assuming DT versus TT was the primary end point, whereas a composite end point of all-cause death, MI, stent thrombosis, and stroke the secondary one. Results were reported for all studies, and separately for those deriving from randomized controlled trials (RCTs) or multivariate analysis.
Unblinded independent reviewers (F.DA. and G.B.Z.) evaluated quality of included studies on prespecified forms. Modifying the MOOSE items to take into account the specific features of the included studies, data were abstracted separately including study design; setting; data source; and risk of analytical, selection, adjudication, detection, and attrition bias (expressed as low, moderate, or high risk of bias and incomplete reporting leading to inability to ascertain the underlying risk of bias).
Continuous variables are reported as mean (standard deviation) or median (interquartile). Categorical variables are expressed as n (%). Statistical pooling was performed according to a random-effect model with generic inverse-variance weighting, computing risk estimates with 95% confidence intervals (CIs), using RevMan 5 (The Cochrane Collaboration, The Nordic Cochrane Centre, and Copenhagen, Denmark). Pairwise meta-analysis was performed both for overall studies, both appraising separately data derived from RCTs or from multivariate analysis, that is after adjusting for clinical confounders.
Results
A total of 250 studies were identified after the initial search: of them, 18 were appraised for possible inclusion. Of them, 1 study was excluded because evaluating only in-hospital outcomes, 3 studies because not comparing DAPT versus TT, and 1 study because of the evaluation of prasugrel ( Figure 1 ).
Ultimately, 15 studies (2 randomized controlled trials and 13 observational registries) encompassing 7,182 patients were included. In all studies, patients assumed DAPT, or clopidogrel alone for 12 months, most of them assuming 100 mg of aspirin.
In 9 studies, 1,317 patients received DAPT and 1,547 received TT, whereas in 6 studies, 1,263 were treated with DT and 3,055 with TT (1 study included both patients receiving DT and patients receiving DAPT).
Their median age was 69 years (64.0 to 73.0), 33% (26.6% to 36.0%) being women. Diabetes mellitus, hypertension, chronic heart failure, previous stroke, and bleeding were reported, respectively, in 27% (23.5% to 32.4%), 72.6% (50.4% to 76.0%), 27.5% (18.3% to 30.5%), 14.6% (8.2% to 23.4%), and 9% (4.5% to 33.0%) of patients ( Table 1 ).
| Number of patients | Follow up (years) | Study design | Triple therapy | Double therapy | Duration of aspirin and clopidogrel therapy (months) | Dose of aspirin (mg/d) | Indications for OAC | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Atrial fibrillation/flutter (%) | Mechanical valves (%) | deep vein thrombosis/pulmonary embolism | ||||||||
| Woest, Lancet 13 | 563 | 1 | RCT | Aspirin, clopidogrel and OAC | Clopidogrel and OAC | 12 | 80-100 | 69 | 11 | |
| Lamberts, Jacc 13 | 12165 | 1 | Observational, prospective | Aspirin, clopidogrel and OAC | Clopidogrel and OAC | 12 | – | 100 | ||
| Denas, 13 | 460 | 1 | Observational, retrospective | Aspirin, clopidogrel and OAC | Aspirin and clopidogrel | 12 | 100 | 59 | 8 | 32 |
| Rubboli, 12 | 632 | 1 | Observational, retrospective | Aspirin, clopidogrel and OAC | Aspirin and clopidogrel (306); Aspirin and OAC (11) | 12 | – | 58 | 7 | 30 |
| Personn, 11 | 27972 | 1 | Observational, prospective | Aspirin, clopidogrel and OAC | Clopidogrel and OAC | 12 | 100 | 27 | ||
| Gao, 10 | 622 | 1 | Observational, prospective | Aspirin, clopidogrel and OAC | Clopidogrel and OAC | 12 | 100 | 100 | ||
| Schwalm, 10 | 20 | ¼ | RCT | Aspirin, clopidogrel and OAC | Aspirin and clopidogrel | 12 | 100 | – | ||
| Sambola, 09 | 405 | ½ | Observational, prospective | Aspirin, clopidogrel and OAC | Aspirin and clopidogrel (20%); Clopidogrel and OAC (10%) | 12 | 100 | 71 | 17 | 12 |
| Manzano, 08 | 64 | 1 | Observational, retrospective | Aspirin, clopidogrel and OAC | Clopidogrel and OAC | 12 | 100 | 100 | ||
| Rossini, 08 | 102 | 1.6 | Observational, prospective | Aspirin, clopidogrel and OAC | Aspirin and clopidogrel | 12 | 100 | 67 | 33 | |
| Ruiz-Nodar, 08 | 426 | 1 | Observational, retrospective | Aspirin, clopidogrel and OAC | Aspirin and clopidogrel | 12 | 100 | 100 | ||
| Sarafoff, 08 | 515 | 1 | Observational, prospective | Aspirin, clopidogrel and OAC | Aspirin and clopidogrel | 12 | 100 | 85 | 15 | |
| De Eugenio, 07 | 184 | 1 | Observational, retrospective | Aspirin, clopidogrel and OAC | Aspirin and clopidogrel | 12 | 100 | 50 | 7 | 43 |
| Karjalainen , 07 | 151 | Observational, retrospective | Aspirin, clopidogrel and OAC | Clopidogrel and OAC | 12 | 100 | 70 | 4 | 10 | |
| Khurram, 06 | 107 | 1 | Observational, retrospective | Aspirin, clopidogrel and OAC | Aspirin and clopidogrel | 12 | 100 | 80 | 5 | 15 |
AF was the indication for OAC in 90% (61.0% to 95.0%) of the patients, whereas mechanic cardiac valves and deep vein thrombosis/pulmonary embolism were less frequent. Pertaining to PCI, radial access was used in 25% (21.0% to 29.75%), with a diagnosis of multivessel disease in 25% (25.0% to 25.5%) and implantation of drug eluting stents in 66% (58.25% to 67.0%; Tables 2 and 3 ).
| Age(years) | Female | Diabetes Mellitus | Hypertension | Previous stroke | Chronic heart failure | Previous bleeding | Chronic Kidney disease | Acute coronary syndrome at baseline | |
|---|---|---|---|---|---|---|---|---|---|
| Woest, Lancet 13 | 71 | 20% | 24% | 69% | 18% | 25% | 5% | 17% | 27% |
| Lamberts, Jacc 13 | 75 | 40% | 12% | 74% | 47% | 33% | 88% | – | – |
| Denas, 13 | 64 | 23% | 25% | 73% | 12% | 15% | – | – | 80% |
| Rubboli, 12 | 73 | 27% | 31% | 88% | 6% | 35% | – | 9% | 63% |
| Personn, 11 | 64 | 30% | 17% | 36% | 7% | 16% | 3% | – | – |
| Gao, 10 | 71 | 28% | 38% | 73% | 16% | 19% | 9% | 23% | 12% |
| Schwalm, 10 | 61 | 30% | 30% | 30% | – | 30% | – | – | 100% |
| Sambola, 09 | 71 | 19% | 33% | 64% | – | – | – | 6% | 71% |
| Manzano, 08 | 72 | 30% | 52% | 82% | 24% | 42% | 14% | 61% | 55% |
| Rossini, 08 | 67 | 20% | 23% | 51% | 14% | 6% | 80% | ||
| Ruiz-Nodar, 08 | 72 | 30% | 40% | 74% | 16% | 26% | 8.8% | 15% | 83% |
| Sarafoff, 08 | 71 | 25% | 26% | 88% | 3% | – | – | – | 33% |
| De Eugenio, 07 | 69 | 41% | 34% | – | – | – | 4% | 4% | – |
| Karjalainen , 07 | 70 | 26% | 30% | 67% | 13% | 14% | – | – | 34% |
| Khurram, 06 | 69 | 32% | 31% | 82% | 5.6% | – | – | – | – |
| Multivessel coronary artery disease | Drug eluting stent | |
|---|---|---|
| Woest, Lancet 13 | 25% | 66% |
| Lamberts, Jacc 13 | – | – |
| Denas, 13 | 26% | 70% |
| Rubboli, 12 | 20% | 25% |
| Personn, 11 | 35% | |
| Gao, 10 | 47% | – |
| Schwalm, 10 | – | – |
| Sambola, 09 | – | 46% |
| Manzano, 08 | 25% | 66% |
| Rossini, 08 | 47% | 47% |
| Ruiz-Nodar, 08 | 58% | 40% |
| Sarafoff, 08 | 78% | – |
| De Eugenio, 07 | – | – |
| Karjalainen , 07 | – | 42% |
| Khurram, 06 | – | – |
After a follow-up of 1 year, major bleedings were reported in 2.5% (2.2% to 4.5%), for patients receiving DAPT, and in 5.5% (3.0% to 11%) for those on TT. A significant reduction of major bleeding for DAPT was demonstrated, both for overall studies and for those reporting clinically adjusted data (odds ratio [OR] 0.51, 95% CI 0.39 to 0.68, I 2 60%, and OR 0.36, 95% CI 0.28 to 0.46, I 2 0%). No increased risk of secondary outcome was reported (OR 0.71, 95% CI 0.46 to 1.08, I 2 42%), although not deriving from RCTs or multivariate analysis ( Figures 2–5 ).
For those assuming DT, major bleedings were reported in 3.0% (2.6% to 4.0%) and in 6.0% (3.0% to 10%) of TT. Pooled analysis indicated that DT significantly reduced the risk of bleeding (OR 0.79, 95% CI 0.64 to 0.98, I 2 0%), without affecting rates of death, MI, stroke, and stent thrombosis (OR 0.92, 95% CI 0.69 to 1.23, I 2 0%) also when including clinical data deriving from RCTs or multivariate analysis ( Figures 6 and 7 ).
