Triple antithrombotic therapy, including NAO, in patients after coronary stenting

Greco, Cesare

Journal of Cardiovascular Medicine: January 2017 - Volume 18 - Issue - p e125–e128
doi: 10.2459/JCM.0000000000000472
SPECIAL ISSUE GUEST EDITORS: Francesco Prati, MD Mario Albertucci, MD

Department of Medicine, Cardiology and Rehabilitative Cardiology Unit, San Giovanni-Addolorata Hospital, Rome, Italy

Correspondence to Cesare Greco Viale Parioli 47 00197 Roma E-mail:

Received 4 July, 2016

Accepted 17 July, 2016

Article Outline

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

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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.

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Guidelines recommendations

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).

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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.

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Conflicts of interest

There are no conflicts of interest.

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1. Kirchoff P, Ammentorp B, Darius H, et al. Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC Guidelines on atrial fibrillation: primary results of the PREvention oF thromboemolic events–European Registry in atrial Fibrillation (PREFER in AF). Europace 2014; 16:6–14.
2. Lane D, Raicherd S, Moore D, et al. Combined anticoagulation and antiplatelet therapy for high risk patients in atrial fibrillation: a systematic review. Health Technol Assess 2013; 17:1–188.
3. Dewilde WJM, Orbans T, Vereught FWA, et al. For the WOEST Study Investigators 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; 381:1107–1115.
4. Sorensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009; 374:1967–1974.
5. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol 2013; 62:981–989.
6. Fiedler KA, Maeng M, Mehill J, et al. Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation: the ISAR-TRIPLE trial. J Am Coll Cardiol 2015; 65:1619–1622.
7. Sarafoff N, Martischnig A, Wealer J, et al. Triple therapy with aspirin, prasugrel and vitamin K antagonists in patients with drug eluting stent implantation and indication for oral anticoagulation. J Am Coll Cardiol 2013; 61:2060–2066.
8. Sambola J, Montoro JB, De Blanco BG, et al. Dual antiplatelet therapy versus oral anticoagulation plus dual antiplatelet therapy in patients with atrial fibrillation and low-to-moderate thromboembolic risk undergoing coronary stenting: design of the MUSICA-2 randomized trial. Am Heart J 2013; 166:669–675.
9. LASER: Real Life Antithrombotic Stent Evaluation Registry.
10. A Study Exploring Two Strategies of Rivaroxaban (JNJ39039039; BAY-59–7939) and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) http://clinicaltrials. Gov:NCT01651780.
11. Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting (REDUAL-PCI)
12. Apixaban to Vitamin K Antagonist for the Prevention of Stroke or Systemic Embolism and Bleeding in Patients With Nonvalvular Atrial Fibrillation and Acute Coronary Syndrome/Percutaneous Coronary Intervention
13. Kovacs RJ, Flaker GC, Saxonhouse SJ, et al. Practical management of anticoagulation in patients with atrial fibrillation. J Am Coll Cardiol 2015; 65:1340–1360.
14. January CT, Wann LS, Alpert JS, et al. 2014 ACC/AHA/HRS Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199–e267.
15. Lip GH, Windecker S, Huber K, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014; 35:3155–3179.
16. Connolly N. Newly identified events in RELY. N Engl J Med 2010; 153:1875–1876.
17. Larsen TB, Rasmussen LH, Skjot F, et al. Efficacy and safety of dabigatran exetilate and warfarin in ‘real world’ patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013; 61:2264–2273.
18. Alexander JH, Lopes RD, Thomas L, et al. Apixaban versus warfarin with concomitant aspirin on patients with atrial fibrillation; insights from the ARISTOTELE Trial. Eur Heart J 2014; 35:224–232.
19. Manaffey KW, Stevens SR, White HD, et al. Ischemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET-AF Trial. Eur Heart J 2014; 34:233–241.
20. Oldgren J, Wallentin L, Alexander JH. New oral anticoagulants in addition to single or dual antiplatelet therapy after acute coronary syndromes: a systematic review and metaanalysis. Eur Heart J 2013; 34:1670–1680.
21. Heidbuchel H, Verhammer P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of nonvitamin K antagonist anticoagulants in patients with nonvalvular atrial fibrillation. Europace 2015; 17:1467–1507.

anticoagulants; antiplatelet; triple antithrombotic therapy

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