In Europe, more than 20% of patients with atrial fibrillation are also affected with ischemic heart disease thus requiring both anticoagulation and antiplatelet treatment.1 This so-called triple antithrombotic treatment has always been a reason for concern in an effort to gain the highest benefit in terms of reduction of adverse cardiovascular events while balancing the risk of bleeding. The practical clinical difficulty of this treatment has not yet received definitive support from evidence-based medicine. The intrinsic difficulties in designing specific large clinical trials and the availability of new anticoagulant treatments have further compounded the problem, such that even the Guidelines of the most authoritative Associations are still elusive.2
Triple antithrombotic therapy and the risk of bleeding
The WOEST trial (What is the Optimal antiplatElet and anticoagulant therapy in patients with oral and coronary StenTing)3 influenced physicians probably beyond its real impact. In this study, 573 patients on antagonist of vitamin K (AVK) who underwent coronary angioplasty were randomized in two treatment groups: clopidogrel and aspirin (triple therapy), and clopidogrel and placebo (double therapy). After 1 year, data on 278 patients were available: bleeding episodes were recorded in 19.4% of the patients on double therapy and in 44% of those on triple therapy [heart rate (HR): 0.36, 95% confidence interval (CI): 0.26–0.50, P < 0 0001]. In the double therapy group 2.2% of the patients had multiple bleeding episodes versus 12% in the triple therapy group; 3.9% versus 9.5% of the patients, respectively, received at least one blood transfusion (HR: 0.39, 95% CI: 0.17–0.84, P = 0.011). The WOEST trial represents the first randomized study investigating the safety of the triple therapy, and although the incidence of bleeding episodes was rather high, it was not dissimilar from the one recorded by observational studies.
The retrospective analysis of the Danish National Registry,4 regarding patients discharged after acute myocardial infarction, focused on 40 812 patients receiving various combinations of AVK, aspirin and clopidogrel followed for a mean period of 476.5 days in whom were analysed the incidence of death, recurrent myocardial infarction and hospital admission for bleeding episodes.
Overall 4.6% of the patients were admitted to the hospital for bleeding episodes, ranging from 2.6% for those on aspirin only, 3.7% for aspirin + clopidogrel, 4.3% for AVK, 5.1% for AVK + aspirin and 12% for triple therapy.
Considering aspirin only as baseline the HR for bleeding was: 1.33 for clopidogrel (95% CI 1.11–1.59), 1.23 for AVK (0.94–1.61), 1.47 for aspirin + clopidogrel (1.28–1.69), 1.84 for aspirin + AVK (1.51–2.23), 3.52 for clopidogrel + AVK (2.42–5.11) and 4.05 (3.08–5.33) for triple therapy.
The number of treated patients needed to record an adverse event was for the same groups 81.2, 45.4, 15.2 and 12.5 respectively.
In a later analysis of various Danish registries5 of patients with atrial fibrillation undergoing elective or emergency coronary angioplasty treatment with AVK + clopidogrel was not associated with increase in adverse cardiovascular events as compared to patients on triple therapy, in whom, on the other hand, there was an increase in strokes and all-cause mortality (HR: 1.52, 95% CI: 1.17–1.99 and HR: 1.60, 95% CI: 1.25–2.05 respectively). In patients treated with AVK + clopidogrel there was a non-significant reduction in bleeding episodes as compared with triple therapy (HR: 0.78, 95% CI: 0.55–1.12).
The ISAR-TRIPLE (Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation)6 a randomized open-label study analysed 614 patients on oral anticoagulant therapy + aspirin who underwent implant of drug eluting coronary stent and were randomized to receive clopidogrel for 6 weeks or 6 months. Primary composite endpoint was death, acute myocardial infarction, stent thrombosis, stroke or TIMI major bleeding episodes after 9 months. The primary endpoint occurred in 9.8% of the patients in the 6-weeks treatment arm and in 8.8% of the patients in the 6-months arm (HR: 1.14, 95% CI: 0.68–1.91, P = 0.63). The equivalence of the treatments was also evident for secondary endpoint as death, stent thrombosis and stroke (4% vs. 4.3%, HR: 0.93, 95% CI: 0.43–2.05, P = 0.87) as well as for TIMI major bleeding episodes (5.3% vs. 4%, HR: 1.35, 95% CI: 0.64–2.84, P = 0.44). The results of this study suggest, at variance from previous studies, the need for individual assessment of thrombotic versus haemorrhagic risk in the recommendations as to the optimal duration of the triple therapy.
A small study7 investigated the different results obtained with prasugrel versus clopidogrel, as third drug in the triple therapy regimen, in patients after coronary stenting. Albeit only 5.6% of the patients actually received prasugrel, this drug was associated with higher incidence of TIMI major and minor bleeding episodes at 6 months than clopidogrel (28.6% vs. 6.7%, HR: 4.6, 95% CI: 1.9–11.4, P = 0.001), while the incidence of adverse cardiovascular events was similar (9.5% vs. 7.0%, HR: 1.4, 95% CI: 0.3–6.1, P 0.61). Implications of the study are that the more powerful prasugrel does not add to the benefit of the triple therapy regimen, but increases its risk.
The MUSICA-2, randomized open-label trial,8 and the LASER prospective registry (Real Life Antithrombotic Stent Evaluation Registry)9 are still on-going and will provide some of the answers regarding the standard triple therapy regimen.
Other on-going trials will investigate the role of the new oral anticoagulant treatment (OAT) in substitution of AVK (PIONEER-PCI, REDUAL-PCI, AUGUSTUS trials).10–12
With all this information still to come it is easy to understand why the Guidelines recommendations are still sketchy.
The American College of Cardiology in September 2013 charged an interdisciplinary group of experts to analyse problems connected with anticoagulant treatment in association with single or dual antiplatelet drugs. A relevant Consensus Document13 was recently published: the recommendations reflect mostly a common sense approach considering the individual risk/benefit ratio on a subject not specifically targeted by the ACC/AHA Guidelines.14
The same issue was tackled by the ESC, European Heart Rhythm Association, European Association of Percutaneous Cardiovascular Interventions and ACCHA Task Force15 in 2014. This study for the first time evaluated data on the association of new OAT and antiplatelet drugs. There has been concern that the use of new OAT could lead to an excess of adverse coronary events when compared with a standard AVK treatment.
In actuality, this phenomenon appears to be negligible (0.19–0.21%/year respectively) and completely disappears when silent myocardial infarctions were included in the analysis.16 Also a Danish Registry17 ruled out the association between dabigatran and increased incidence of myocardial infarct.
The other important elements of the documents are as follows:
a. In acute coronary syndrome, dabigatran is associated with increased risk of bleeding, mainly gastrointestinal and its dosage should be decreased to 110 mg/BID.
b. Apixaban (5 mg/BID) increases the risk of bleeding when given with dual antiplatelet treatment and the advantage over warfarin remains also in patients treated with aspirin.18
c. In patients with previous myocardial infarction, treatment with rivaroxaban was associated with a significant reduction of recurrences after acute coronary syndrome.19 The low doses of rivaroxaban able to decrease recurrences after acute coronary syndrome (2.5 mg/BID) were not tested in stroke prevention.
d. There are no studies comparing new OAT and warfarin in patients with both atrial fibrillation and acute coronary syndrome and there are very few studies on the association of new OAT and double antiplatelet drugs with aspirin and P2Y12 inhibitors, prasugrel and ticagrelor.
e. A meta-analysis pointed out that the association of dabigatran to antiplatelet drug that reduces the risk of ischemic events increases the risk of bleeding, particularly with double antiplatelet drugs (HR: 2.34, 95% CI: 2.06–2.66).20
The panel concluded that the association of new OAT carries the same risk as the association of AVK and antiplatelet drugs, single or double, recommending to use low-dose aspirin, clopidogrel and not the new cytochrome P2Y12 inhibitors, to minimize the duration of triple antithrombotic therapy and to use low dose of new OAT in the association treatment.
The document also suggests the use of an algorithm based on thromboembolic risk (CHA2DS2 VASc), bleeding risk (HAS BLED) and the type of cardiac condition (stable coronary artery disease or acute coronary syndrome) (Fig. 1).
In 2015, a revised version of the Consensus Document21 was published by the EHRA. The updated version suggested for elective coronary stenting procedures duration of triple therapy of 1 month followed by dual therapy (new OAT + aspirin or clopidogrel) for the first year and then anticoagulation only. For acute coronary syndrome, triple therapy was recommended for 6 months, reducing to double therapy for the ensuing 6 months and anticoagulation only after 1 year (Fig. 2).
The document further suggests to consider factors that could support the protracted use of triple therapy such as the use of first generation DES, high atherothrombotic risk (left main, proximal LAD, proximal bifurcation stents and recurrent myocardial infarction) in patients with a low bleeding risk; on the other hand, the suggestion was for decreased duration of the triple therapy in patients with elevated risk of bleeding and low thrombotic risk (SYNTAX score in elective PTCA or GRACE score >118 in PTCA for acute coronary syndrome).
The association of antiplatelet treatment and oral anticoagulation in patients with atrial fibrillation treated with elective or emergency coronary angioplasty is still a complex non-completely resolved problem. The recommendations presently available are based on expert Consensus Documents and accordingly with low degree of evidences supporting them. More definitive answers will be available at the conclusion of the on-going trials.
Conflicts of interest
There are no conflicts of interest.
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