{'fraction_non_alphanumeric': 0.036986301369863014, 'fraction_numerical': 0.020182648401826483, 'mean_word_length': 4.958106637649619, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 2, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Triple Antithrombotic Therapy vs. Double Antithrombotic Therapy: One Scenario, 8 Questions, Many Conclusions

In patients with atrial fibrillation undergoing percutaneous coronary intervention with the placement of stents, a triple antithrombotic therapy is empirically established, which consists of a combination of dual antithrombotic therapy (aspirin plus a P2Y12 inhibitor) and an oral anticoagulant agent. This choice is guided by the desirable result of reducing cerebrovascular and coronary ischemic events. However, there is an unwelcome outcome: an increased incidence of bleeding. On this matter, in 2018, a North American Perspective Update was published, about a year later it was followed by the publication of the European focus update on the dual antiplatelet therapy. After analysing the main differences between these two consensus documents, this review aims at examining the major studies on which they are based on, as a starting point to define the foundation of new trials that can help shed light on this prominent topic.


The Scenario
Approximately 5 to 8% of patients who undergo percutaneous coronary intervention (PCI) have atrial fibrillation (AF) [1]. In this subset of patients, the management of this arrhythmia becomes particularly challenging.
Oral anticoagulation (OAC) therapy is recommended in patients with AF for primary and secondary stroke and systemic embolism prevention, while Dual AntiPlatelet Therapy (DAPT: Aspirin plus a P2Y12 inhibitor) is recommended in patients who are undergoing PCI with stent implantation in order to avoid thrombotic complications. Therefore, in clinical practice, the use of Triple Antithrombotic Therapy (TT), which consists of an OAC combined with DAPT, has been empirically used after PCI in patients with AF requiring OAC therapy, with the belief that the administration of three drugs may minimize the risk of cerebrovascular and coronary ischemic events. In the meantime, this strategy is responsible for an increased incidence of hemorrhage.
Thus patients treated with TT should be considered at high risk of bleeding, hinting the need to implement strategies to minimize this possibility. In this scenario, the identification of an antithrombotic regimen with a better risk/benefit ratio is highly desirable.

What is new about Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention?
Recently, a North American Perspective-2018 Update was published [2]. In comparison with the previous 2016 Update, the key changes are [3]: • A non-vitamin K antagonist oral anticoagulant (NOAC) should be preferred over a vitamin K antagonist (VKA) unless it is contraindicated.
• Clopidogrel is the P2Y 12 inhibitor of choice.
• A double-therapy regimen (Oral Anticoagulant plus single antiplatelet therapy with a P2Y1 2 inhibitor) by the time of hospital discharge might be reasonable for most patients.

What are the main differences between European [4] and North American consensus documents/guidelines [2]?
Summary of key changes between 2016 and 2018 Expert consensus on antithrombotic management of patients with AF undergoing PCI ( Table 1).

What is the main cohort study that investigated this issue?
The Danish nationwide cohort study [5], which selected patients with AF admitted for Myocardial Infarction (MI) or for PCI between January 2001 and December 2009.

What are the main randomized trials on which the guidelines are based?
The main trials are: the WOEST trial [6], the ISAR-TRIPLE trial [7], the PIONEER AF-PCI trial and the RE-DUAL PCI trial [8].

Is AF the only indication for OAC therapy regarding the examined populations?
The answer is positive only for the RE-DUAL PCI trial [8] and the PIONEER AF-PCI trial [1]. However, AF was the predominant indication for OAC in the WOEST trial [6] (approximately 70% of the patients) and in the ISAR-TRIPLE trial [7] (approximately 86% of the patients).

Which investigations have provided accurate angiographic characteristics according to treated lesions?
Only the WOEST trial [6] and the ISAR-Triple trial [7] presented detailed angiographic characteristics.

Is there a discrepancy of the mean CHADSVASC / CHA 2 DS 2 VASC-score regarding the populations examined in these different investigations?
Yes, there is. Considering the patients on TT, in the WOEST Trial [6] a CHA 2 DS 2 -VASC score of 2 and 3 was reported for the 26% and 36% of the study population, respectively.
Considering the same scores, in the ISAR-TRIPLE trial [7], 6,9% and 16,1% of the population showed, respectively, a score of 2 and 3. Finally, in the PIONEER AF-PCI [1], the same scores were reported for 13% and 21% of the population respectively.
Regarding the RE-DUAL PCI trial [8], the percentage of patients for each CHA 2 DS 2 -VASC score was not stated, but it was attested that the mean score varied from 3.3 ±1.5 to 3.8 ±1.5. Moreover, with reference to the patients on TT, the score was <2 for 184 subjects (24.1 %) and >2 for 580 subjects (75.9%) of the examined population.
Finally, in the DANISH COHORT [5] the reported mean CHADS 2 score was 1,5 (SD 1.5). Of note, 36,9% of the entire population had a score of 0 or 1.

Which type of Bleeding Classifications was adopted in these studies?
• The WOEST Trial [6]: TIMI, GUSTO and BARC • The ISAR-TRIPLE trial [7]: TIMI • The PIONEER AF-PCI trial [1]: TIMI • The RE-DUAL PCI trial [8]: ISTH and TIMI • The DANISH COHORT [5]: it was not adopted as an international classification. However, bleeding was recorded as nonfatal or as fatal, which was defined as either first admission with a diagnosis of nonfatal bleeding registered at discharge or as death from bleeding identified through the National Causes of Death Register.  Choice of Anticoagulant A NOAC (rather than a VKA) should be generally preferred in most patients unless contraindicated.
There is no preference between VKA and NOAC.

Choice of P2Y12 inhibitor
Clopidogrel is the P2Y12 inhibitor of choice.
Ticagrelor may represent a reasonable treatment option in selected patients.
Plasugrel should be avoided.
Clopidogrel is the only P2Y12 inhibitor approved.
Plasugrel and Ticagrelor should be avoided.

Strategy (double vs. triple therapy)
A double-therapy regimen (OAC plus P2Y12 inhibitor) immediately after hospital discharge should be considered for most patients.
Extending the use of aspirin beyond hospital discharge should be considered only for selected patients (high ischemic/thrombotic and low bleeding risks) and for a limited period of time (eg, 1 mo).
Triple therapy with aspirin, clopidogrel, and OAC for longer than 1 month and up to 6 months should be considered in patients with high ischaemic (e.g. Acute Coronary Syndrome or elective Percutaneous Coronary Intervention (PCI) with other anatomical/procedural characteristics that outweigh the bleeding risk.
Dual therapy with clopidogrel 75 mg/day and OAC should be considered in patients in whom the bleeding risk outweighs the ischaemic risk.   ∥∥Clopidogrel, prasugrel, or ticagrelor; clopidogrel was used in 94% of the enrolled population. ##Rivaroxaban 10 mg daily if CrCl was 30 to 50 mL/min. ***Aspirin discontinued at 1 month (bare metal stents) or at 3 months (DES). † † †Clopidogrel or ticagrelor; ticagrelor was prescribed in 12% of enrolled patients. ‡ ‡ ‡Patients >80 years of age outside of the United States were randomized to only warfarin or dabigatran 110 mg twice daily. Outcomes SDF Danish Nationwide cohort study [5] Circulation 2012 11480 Retrospective cohort Primary outcome was nonfatal or fatal bleeding defined as either first admission with a diagnosis of nonfatal bleeding registered at discharge or as death from bleeding Secondary outcome: MACE*.
Woest Trial [6] Lancet 2013 573 Superiority The trial was only powered to assess whether clopidogrel alone was better than clopidogrel and aspirin in the prevention of bleeding. Significant differences in favour of the double-therapy group were seen only for mild and moderate bleeding.
isar-triple trial [7] jacc 2015 614 Superiority Trial not powered to detect differences in the individual components of the primary endpoint Pioneer AF-PCI trial [1] nejm 2016 2124 Non inferiority The trial was not powered to definitively establish either superiority or noninferiority. Surprisingly, it has been shown a very low rate of stent thrombosis (0.8%) in group 1 (no DAPT †) and, at the same time, a relatively low rate of stroke in group 2 (1.4% of -patients treated with rivaroxaban 2,5 twice daily. Moreover, 12.8% of patients had a CHADS2 score of 0 points, and 1% of them had a CHA2DS2Vasc of 0 points. inhibitor (clopidogrel or ticagrelor) resulted in a lower risk of major or clinically relevant nonmajor bleeding events than the risk with triple therapy with warfarin; in addition, dual therapy with dabigatran was noninferior to triple therapy with warfarin with respect to the composite efficacy endpoint of thromboembolic events, death, or unplanned revascularization. MACE* = major adverse cardiac events; DAPT † = Dual antiplatelet therapy; CI ‡ = Confidence Interval;

CONCLUSION
The current medical treatment adopted for this subset of patients is based on non-homogenous evidence.
Our knowledge is based predominantly on relatively small (WOEST and ISAR) [6,7] or big (PIONEER and RE-DUAL) [1,8] trials but with an objective of non-inferiority and a sample size derived from an end-point of bleeding.
Nevertheless, the trials mentioned above have represented an important starting point to define the best therapeutic approach between TT and dual therapy (OAC plus clopidogrel) in patients with AF undergoing PCI. Despite the univocal conclusion that patients on TT have more bleeding, these studies have shown some weak points that could guide the design of new trials. It is important to describe the angiographic characteristics of each patient, to take into consideration the number of the implanted stents, and where they were implanted, in order to define the presence of high-risk features of stent-driven recurrent ischaemic events.
It would also be interesting to test the risk/benefit ratio of TT avoiding the use of both Prasugrel and Ticagrelor and shortening its duration from twelve months to a maximum of six months based on the patient's individual risk, in accordance with the current European guidelines [4].
Moreover, these studies have highlighted some controversies about the risk/benefit ratio of MACE / Major Bleeding of this approach. However, the great Confidence Intervals shown in the biggest trials (PIONEER AND RE-DUAL) [6,7] about the single components of MACE suggest major efforts in terms of large double-blind, randomized clinical trials in order to shed light on this critical topic.

CONSENT FOR PUBLICATION
Not applicable.

FUNDING
None.

CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.