SPS



Q&A 224.1

What are the risks of using antiplatelet agents in combination with the Novel Oral Anticoagulants (NOACs) in patients with atrial fibrillation, and how should the potential risks be managed?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

Before using this Q&A, read the disclaimer at ukmi.nhs.uk/activities/medicinesQAs/default.asp

Date prepared: 24th November 2015

Background

Oral anticoagulants (OAC) and antiplatelet agents are often used in combination in patients who require anticoagulation for the prevention of stroke and systemic embolism, and antiplatelet therapy for the prevention of myocardial infarction (MI) or stent thrombosis[i]. Patients with atrial fibrillation (AF), mechanical heart valves or a history of pulmonary emboli are at high risk of stroke or thromboembolism and therefore need anticoagulation to prevent these events[ii].

It has been shown that 34% of patients presenting with AF also have coronary artery disease (CAD) and 6-21% of patients presenting with acute coronary syndromes (ACS) develop AF1.

The optimal strategy to balance bleeding and ischaemic events in patients with AF needing antiplatelet therapy in addition to anticoagulation is subject to debate, since specifically designed and powered randomised trials are not available yet1. Stroke prevention guidelines in Europe and the UK[iii],[iv] now include NOACs. The potential risks and benefits of NOACs for patients with ACS and AF have not been directly assessed, since AF patients requiring anticoagulation were excluded from recent acute coronary syndrome (ACS) trials, and similarly, patients with recent ACS were likely to have been excluded from phase III stroke prevention trials in AF patients[v].

This review will discuss common clinical scenarios where NOACs and antiplatelet agents may be used together. For the reasons discussed above, much of the guidance and advice is extrapolated from data on concurrent use of the vitamin K antagonists (VKAs) such as warfarin with antiplatelets.

Answer

Patients with atrial fibrillation and coronary artery disease

The mechanisms of coronary thrombosis in CAD differ markedly from those that cause left atrial thrombus in AF, so that different antithrombotic agents are necessary. Therefore many people with concomitant AF and ACS may need long-term treatment with both OACs and combination antiplatelet drugs[vi]. The type and level of anticoagulation as well as single vs. dual antiplatelet therapy in combination with OAC, and its duration, need to be highly personalized based on atherothrombotic risk, cardioembolic risk, and bleeding risk[vii]. It is well recognised that people receiving a combination of antiplatelet therapy and oral anticoagulation are at high risk of minor, major and fatal bleeding events. These outcomes are often recurrent and associated with hospitalisation, blood transfusion and interventional procedures2.

i) ACS management in patients on NOACs with AF

The use of dual antiplatelet therapy (DAPT) is recommended in all patients who have experienced an ACS, whether managed conservatively (without stent insertion) or after percutaneous coronary intervention (PCI)2,6. The majority of patients with ACS will be treated with PCI6. In the UK dual antiplatelet therapy with aspirin and either clopidogrel, prasugrel, or ticagrelor is recommended for up to 12 months. Patients considered to be at high risk of developing late stent thrombosis with a drug-eluting stent may require a longer duration of treatment with clopidogrel[viii].

However it is not possible to substitute aspirin and clopidogrel for OACs in patients with AF to prevent stroke. All recent guidelines recommend that patients with AF and a risk of stroke with a CHA2DS2VASc score of ≥ 1 should be treated with OACs6. European consensus recommendations on the management of AF patients with ACS and/or undergoing PCI/stenting, published in 20145 advise that where OACs are recommended, this can either be with well-controlled adjusted dose VKA or with a NOAC. Direct randomised comparisons of NOACs vs VKA in AF patients undergoing PCI are not available, therefore the recommendations are based on post hoc analyses of the RELY (dabigatran) and ARISTOTLE (apixaban) comparison with warfarin in stroke & systemic embolism prevention trials in patients with AF1.

□ In RELY, approximately 38% of patients were receiving an antiplatelet drug at some time during the study (32% aspirin alone, 2% clopidogrel alone and 4.5% on aspirin + clopidogrel).Overall, the rate of major bleeding was higher in patients who used concomitant antiplatelets (4.4% vs 2.6%). The risk of major bleeding was doubled among patients receiving DAPT compared with patients on single antiplatelet therapy. The absolute risk of major bleeding was lowest in the dabigatran 110mg BD group[ix].

□ In ARISTOTLE concomitant use of aspirin increased the major bleeding risk on apixaban from 1.8% per year to 3.4% per year and increased the bleeding risk on warfarin from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.1%) use of concomitant dual antiplatelet therapy[x],[xi].

Vitamin K Antagonists (VKA) plus aspirin/clopidogrel

Studies and reviews have shown up to a 3.7-fold risk in bleeding events with triple therapy (i.e. two antiplatelet agents plus warfarin) compared to warfarin monotherapy and a fourfold increase in risk compared to aspirin monotherapy. A meta-analysis of 10 randomised controlled trials (RCT) found an increase in the relative risk of bleeding of 2.2 when warfarin was part of triple antithrombotic therapy, versus DAPT[xii].

Studies in patients with AF hospitalised with MI and/or undergoing PCI, compared triple with double antithrombotic therapy. Triple therapy was associated with a higher risk of bleeding compared with double therapy (warfarin + clopidogrel) or (warfarin + aspirin). Double therapy was not associated with an increased risk of coronary events, but when an OAC was not given and patients were on DAPT (aspirin + clopidogrel) alone there was double the risk of ischaemic stroke6.

The WOEST study examined the effect of double versus triple antithrombotic therapy in 573 patients with coronary stents taking warfarin for AF (70%) or other indications. The group taking warfarin, clopidogrel and aspirin had a significantly higher risk of bleeding than the group taking warfarin and clopidogrel. There was no increased risk of coronary events or stent thrombosis in the double-therapy group6,[xiii].

Novel oral anticoagulants (NOACs) plus aspirin/clopidogrel

Two meta-analyses have examined the safety of NOACs in addition to single or dual antiplatelet therapy after an ACS12,[xiv]. The first meta-analysis included five published RCTs (1 with dabigatran, 2 with rivaroxaban, and 2 with apixaban). The second meta-analysis14 included two additional trials using NOACs no longer available or not licensed in the UK.

The studies were designed to determine the safety and efficacy of different doses of NOACs vs placebo in preventing the recurrence of major adverse cardiovascular [CV] events in patients with ACS receiving single or dual antiplatelet therapy.

The evidence for a beneficial effect of adding NOACs to single/dual antiplatelet therapy, on CV outcomes i.e. MI, stroke or death from CV causes is inconclusive, since the trials were not powered to detect differences in the incidence of major cardiac events (MACEs)15. There was a trend towards a reduction in the incidence of MACEs; however, as all the above trials had different inclusion criteria and different definitions of bleeding, a direct comparison of efficacy and safety is not possible12.

Overall, combination therapy with antiplatelets (essentially DAPT with aspirin and clopidogrel), plus a NOAC was associated with an approximate two- to four-fold dose-dependent increase in clinically significant bleeding as compared to antiplatelet therapy alone[xv].

A subsequent analysis of APPRAISE-2 found that gastro-intestinal bleeding was the most common cause of major bleeding in the overall cohort and in the apixaban arm. Several risk factors for bleeding were identified including co-morbidities such as concurrent AF and DAPT prior to randomisation. The hazard ratio for major bleeding for patients on DAPT was 2.0 (95% CI 1.17 to 3.42)[xvi].

It is important to recognise that all five of the trials of currently available NOACs in ACS excluded patients who required long-term oral anticoagulant therapy, which includes high-risk AF patients. Also the landmark trials that evaluated the efficacy of NOACs in prevention of thromboembolism in AF also usually excluded patients who required dual antiplatelet therapy, so it is difficult to directly determine the increased risk of bleeding12.

European guidelines advise that where a NOAC is used in combination with clopidogrel and/or low-dose aspirin, the lower tested dose for stroke prevention in AF (i.e. dabigatran 110mg bd, rivaroxaban 15mg od, or apixaban 2.5mg bd) may be considered5. However the manufacturer’s Summary of Product Characteristics (SPC) must always be consulted as such use may be outside the product licence11.

For a summary of the trials please refer to Table1. Appendix 1

VKAs plus prasugrel or ticagrelor

For patients with concomitant AF the routine use of the new P2Y12 inhibitors: prasugrel or ticagrelor, in combination with OAC is not recommended5. This is because there is an increased risk of bleeding compared with clopidogrel1. A small observational study compared prasugrel vs clopidogrel in patients undergoing DES implantation who also received oral anticoagulation. There was a significant 3.2-fold increased risk of major or minor bleeding[xvii] with prasugrel1, without differences in ischaemic endpoints after 6 months of follow-up1. The combination may be considered in exceptional circumstances (e.g. stent thrombosis while on clopidogrel, aspirin and OAC)5.

NOACs plus prasugrel or ticagrelor

There is a paucity of data on the use of NOACs in combination with DAPT with aspirin and one of, prasugrel or ticagrelor. This combination would be expected to expose the patients to an even higher risk of major bleeding, compared with clopidogrel5. A case report exists of severe posterior nasal haemorrhage in a patient on aspirin, prasugrel and rivaroxaban, following a bare metal stent insertion 6 months previously. The patient had renal impairment (creatinine clearance 30mL/minute) which was an additional risk factor for bleeding[xviii].

Guidance

NICE guidance in 2013 recommended: Do not add a new oral anticoagulant (rivaroxaban, apixaban or dabigatran) in combination with dual antiplatelet therapy in people who otherwise need anticoagulation, who have had an MI and consider using warfarin and discontinuing treatment with a new oral anticoagulant (rivaroxaban, apixaban or dabigatran) in people who otherwise need anticoagulation and who have had an MI, unless there is a specific clinical indication to continue it2.

More recent NICE guidance[xix] from 2015 recommends rivaroxaban in patients with no history of stroke or TIA, in combination with aspirin plus clopidogrel or with aspirin alone in patients with ACS and elevated biomarkers. This is based on the results of the ATLAS-ACS 2-TIMI 51 study where addition of rivaroxaban 2.5mg twice daily to aspirin plus clopidogrel or to aspirin alone in patients with ACS and elevated biomarkers, reduced the composite risk of MI, stroke and death from CV causes by 20% compared with aspirin plus clopidogrel or with aspirin alone19. The absolute risk reduction was (10.7 – 9.1= 1.6%)15. However, there was a three times greater risk of major bleeding (0.6% vs. 1.8%)15,19. ATLAS-ACS 2 –TIMI 51 excluded patients with a history of TIA; this may have created a positive bias for both safety and efficacy for rivaroxaban, since these patients are at a higher risk of bleeding and thromboembolism12.

According to the manufacturer, few ACS patients with a prior stroke or TIA have been studied but the limited efficacy data available indicate that these patients do not benefit from treatment[xx].

European guidelines advise that in general, for people with AF with ACS and/or undergoing PCI/stenting the period of triple therapy should be as short as possible followed by OAC plus a single antiplatelet therapy (preferably clopidogrel 75 mg/day, or as an alternative, aspirin 75–100 mg/day) for 12 months and then an OAC for life. The period of triple therapy should not exceed 6 months for patients at low risk of bleeding or 4 weeks for patients at high risk of bleeding. The duration of triple therapy is dependent on a number of considerations: acute vs. elective procedures, bleeding risk, type of stent (with a preference for new generation DES or BMS)5.

The guidelines include an algorithm which gives recommendation for different clinical scenarios for patients needing OACs plus antiplatelet drugs, according to stroke risk, bleeding risk, and clinical setting (ACS or stable CAD)5. European and UK guidelines recommend the use of the CHA2-DS2-VASc score for assessing stroke risk, and the HAS-BLED score for assessing bleeding risk3, 5. Patients with AF and STEMI may receive a combination of therapies including primary PCI, aspirin, clopidogrel, heparin, GP IIb/IIIa inhibitors. European guidelines advise that given the risk of

bleeding with such combination antithrombotic therapies, it may sometimes be prudent to temporarily stop OACs in these circumstances due to the risk of bleeding5. Patients already taking a NOAC and undergoing a PCI (elective or urgent) should have the NOAC discontinued temporarily as this removes the uncertainty around the extent of anti-coagulation and therefore allows safe use of peri-procedural antiplatelets and anticoagulants. Once the patient is able to restart OACs post-procedure it is reasonable to restart the NOAC that the patient was taking before the ACS or elective procedure7.

Gastroprotection with proton pump inhibitors should be considered in all patients on any combination of antiplatelet(s) plus anticoagulant, particularly where aspirin is used5.

ii) Management of patients with stable coronary artery disease (CAD) and AF

In a patient with AF and stable vascular disease (arbitrarily defined as being free from any acute ischaemic event or repeat revascularization for 1 year) the patient should be managed with OAC alone (i.e. whether NOAC or a VKA) and concomitant antiplatelet therapy should not be prescribed on a routine basis, although there are some exceptions listed for very selected cases, in the European guidelines5.

A cohort study of 8700 patients with AF and stable CAD (defined as 12 months from an acute coronary event) examined the risk of CV events and serious bleeding events over 3 years. Relative to VKA monotherapy the risk of MI/coronary death was similar for VKA plus aspirin (hazard ratio, 1.12 [95% confidence interval, 0.94–1.34]) and VKA plus clopidogrel (hazard ratio, 1.53 [95% confidence interval, 0.93–2.52]). The risk of thromboembolism was comparable in all regimens that included VKA, whereas the risk of bleeding increased when aspirin (hazard ratio, 1.50 [95% confidence interval, 1.23–1.82]) or clopidogrel (hazard ratio, 1.84 [95% confidence interval, 1.11–3.06]) was added to VKA. Triple therapy (dual-antiplatelet therapy plus VKA) was associated with the highest risk of serious bleeding, with no benefit on CV outcomes of MI/coronary death or thromboembolism[xxi], [xxii]. This study could not examine the effects of NOACs since data was collected from a time period before the introduction of NOACs into clinical practice.

Although this is an observational study and subject to confounding bias, the results broadly support the recommendation in the European guidelines that 12 months after an acute event patients should be managed by an anticoagulant alone5.

NICE guidance states: after 12 months since the MI, continue anticoagulation and take into consideration the need for ongoing antiplatelet therapy, taking into account: the indication for anticoagulation, thromboembolic risk, bleeding risk, cardiovascular risk and the person's wishes2.

Patients with AF and a history of stroke

A systematic review of combined anticoagulation and antiplatelet therapy for high-risk patients with AF concluded that there appears to be insufficient evidence to suggest a clear benefit of the addition of antiplatelets to OACs compared to OACs alone in reducing the risk of vascular events in an AF population at high risk of thromboembolic events resulting from AF. There was no clear consensus between studies for the risk of bleeding events. The review included one study of a NOAC – the PETRO study of dabigatran with or without concomitant aspirin versus warfarin.

This study reported no major bleeding events in patients on dabigatran 50 mg or 150 mg (in combination with aspirin or given alone). However, a higher proportion of patients on combined therapy of dabigatran 300 mg plus either aspirin 81 mg or 325 mg [1/34 (2.9%), 3/30 (10%) respectively] suffered a major bleeding event than those on dabigatran 300 mg alone [0/105 (0%)] during a mean follow-up period of 22 weeks[xxiii].

Manufacturer’s recommendations

Apixaban

The manufacturer advises that: “Agents associated with serious bleeding are not recommended concomitantly with apixaban, such as: thrombolytic agents, GPIIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel)”11.

Dabigatran

In patients with non-valvular AF who also have other risk factors, “use of acetylsalicylic acid (ASA), clopidogrel or non-steroidal anti-inflammatory drug (NSAID), increase the risk of GI bleeding. In these atrial fibrillation patients a dosage of 220 mg dabigatran given as 110 mg capsule twice daily should be considered”. “The administration of a PPI can be considered to prevent GI bleeding”[xxiv].

Edoxaban

ENGAGE AF-TIMI 48 compared the safety and efficacy of high-dose edoxaban (60mg daily), low-dose edoxaban (30 mg daily) and warfarin in patients with moderate-to-high-risk AF. In each group 29-30% of patients were taking low-dose aspirin and 2 to 2.5% were taking a thienopyridine (e.g. clopidogrel). Use of DAPT was one of the key exclusion criteria[xxv]. According to the manufacturer “In ENGAGE AF-TIMI 48 concomitant use of thienopyridines (e.g. clopidogrel) monotherapy was permitted and resulted in increased clinically relevant bleeding although with a lower risk of bleeding on edoxaban compared to warfarin”[xxvi]. In clinical studies concomitant use of acetylsalicylic acid (ASA) (low dose ≤ 100 mg/day), other antiplatelet agents, and thienopyridines was permitted and resulted in approximately a 2-fold increase in major bleeding in comparison with no concomitant use, although to a similar extent in the edoxaban and warfarin groups. Co-administration of low dose ASA (≤ 100 mg) did not affect the peak or total exposure of edoxaban either after single dose or at steady-state. There is very limited experience on the use of edoxaban with dual antiplatelet therapy or fibrinolytic agents”26.

Rivaroxaban

Rivaroxaban 2.5mg twice daily co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers20. Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk20.

Ongoing trials

At least two randomised trials have been initiated to evaluate the safety and efficacy of a NOAC versus a VKA in patients with AF, undergoing coronary intervention for either stable coronary disease or ACS[xxvii].

In PIONEER AF-PCI patients will be randomized to receive either rivaroxaban 15 mg once daily plus clopidogrel 75 mg daily for 12 months, or rivaroxaban 2.5 mg twice daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months), or dose-adjusted VKA once daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months. All patients will be followed up for 12 months for the primary composite end point of clinically significant bleeding[xxviii].

In RE-DUAL PCI dabigatran 110mg or 150mg twice daily plus clopidogrel or ticagrelor will be compared with a combination of warfarin plus [clopidogrel or ticagrelor] plus aspirin ≤ 100mg daily in patients with AF undergoing PCI with stenting (elective or due to an ACS)[xxix].

Each trial will also evaluate the withdrawal of aspirin from the triple therapy regimen.

In COMPASS a secondary prevention study in patients with CAD, rivaroxaban 2.5mg daily with aspirin will be compared with rivaroxaban 5mg twice daily without aspirin. Patients needing dual antiplatelet therapy will be excluded[xxx],[xxxi].

Appendix 1.

Table 1. Studies of NOACs with concomitant antiplatelet therapy in patients with acute coronary syndrome12,14

|Study |Study treatment |Duration |Study population |Primary safety outcome|Antiplatelet |Outcomes |

| | | | |measure |drugs | |

|RE-DEEM |Dabigatran 50mg, 75mg, 110mg or 150mg bd |6 months |1861 pts with recent STEMI/ |ISTH major or minor |1% aspirin |HR for major bleeding 150mg vs placebo = 4.27 (95% CI |

| |or placebo | |NSTEMI + one other risk factor for |bleeding | |1.86-9.81) |

| | | |IHD | |99% aspirin + |The rates of bleeding were 2.2% , 3.5%, 4.3% , 7.9% and |

| | | | | |thienopyridine |7.8% for placebo, dabigatran 50- , 75-, 110-, 150mg |

| | | | | |(clopidogrel or |groups respectively |

| | | | | |ticlopidine) | |

|ATLAS ACS-TIMI 46 |Rivaroxaban 5mg, 10mg, or 20mg daily |6 months |3491 pts with ACS |TIMI clinically |25% aspirin (stratum |HR for significant bleeding 2.21 for 5mg, 3.35 for 10mg,|

| |(stratum 1), 5-20mg once daily, or in two| | |significant bleeding |1) |3.6 for 15mg, 5.06 for 20mg (total daily doses) |

| |divided doses daily(stratum 2) or placebo| | | | |compared with placebo |

| | | | | |75% aspirin + | |

| | | | | |thienopyridine | |

| | | | | |(stratum 2) | |

|ATLAS ACS2- TIMI 51 |Rivaroxaban 2.5mg bd, 5mg bd, or placebo |Mean =13 months,|15,526 pts with ACS |TIMI major bleeding |7% aspirin |Incidence of bleeding was 2.4% , 1.8% and 0.6% in the |

| | |max. 31months | |not related to CABG | |5mg, 2.5mg, and placebo groups respectively |

| | | | | |93% aspirin + | |

| | | | | |thienopyridine | |

|APPRAISE-1 |Apixaban 2.5mg bd, 10mg daily, 10mg bd, |6 months |1715 pts with STEMI or NSTEMI ACS |ISTH major or |24% aspirin |HR for bleeding was 1.78 and 2.45 for the 2.5mg bd and |

| |20mg daily or placebo (the two | | |clinically relevant | |10mg daily doses of apixaban, respectively compared to |

| |higher-dose apixaban arms were | | |non-major bleeding |76% aspirin + |placebo. Bleeding rates were higher in patients on dual |

| |discontinued during the randomisation | | | |clopidogrel |antiplatelet therapy. |

| |period due to an excess of bleeding | | | | | |

| |events). | | | | | |

|APPRAISE-2 |Apixaban 5mg bd or placebo |6 months |7392 patients with recent STEMI or |TIMI major bleeding |19% aspirin |Trial terminated early due to an excess of bleeding |

| | | |NSTEMI ACS + two additional risk | | |events. Bleeding rate was 1.3% in the apixaban group vs |

| | | |factors for IHD | |81% aspirin + |0.35% in placebo group (HR 2.59, p=0.001) |

| | | | | |thienopyridine | |

Limitations

□ This Q&A only discusses orally administered antiplatelet agents

□ The risks of using antiplatelets in patients receiving NOACs for treatment or prophylaxis of VTE or PE are not discussed in this Q&A

□ It is not intended to be a comprehensive review of clinical uses of antiplatelet/NOAC combinations

□ NOACs not licensed in the UK are not discussed

References

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[i]. Rohla M, Weiss TW, Wojta J et al. Double or triple antithrombotic combination therapy in patients who need anticoagulation and antiplatelet therapy in parallel. Eur Heart J –Cardiovascular Pharmacotherapy doi:10.1093/ehjcvp/pvv014. Published April 16, 2015. Accessed via on 24/04/15

[ii]. National Institute for Health and Care Excellence. Secondary prevention in primary and secondary care for patients following a myocardial infarction. NICE Clinical Guideline 172. Issued November 2013. Accessed via on 29/05/15

[iii]. National Institute for Health and Care Excellence. Atrial fibrillation: the management of atrial fibrillation. NICE Clinical Guideline 180. Issued: June 2014 last modified: August 2014. Accessed via on 22/05/15

[iv]. Camm AJ, Lip GY, De Caterina R et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation—developed with the special contribution of the European Heart Rhythm Association. Europace 2012;14:1385–1413. Accessed via on 22/05/15

[v]. Lip GYH, 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) Task Force. European Heart Journal doi:10.1093/eurheartj/ehu298 2014. Accessed via on 26/05/15

[vi]. Thompson PL , Verheugt FWA. Managing antithrombotic therapy in patients with both atrial fibrillation and coronary heart disease. Clin Ther 2014; 36: 1176-81

[vii]. Heidbuchel H, Verhamme P, Alings M et al. Updated EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015; 17: 1467-1507 doi:10.1093/europace/euv309 Accessed via on 20/11/15

[viii]. Khanderia S (managing editor). British National Formulary. Accessed online via: on 04/06/15

[ix]. Dans AL Connolly SJ , Wallentin L et al. Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Trial. Circulation. 2013; 127: 634-640.)

[x]. Bristol-Myers Squibb-Pfizer. Medical Information Department. Personal Communication 01/07/15

[xi]. Summary of Product Characteristics – Eliquis 2.5mg (apixaban). Bristol-Myers Squibb-Pfizer. Accessed via on 22/056/15 [date of revision of text 28/07/14].

[xii]. Tsu LV, Dager WE. Safety of new oral anticoagulants with dual antiplatelet therapy in patients with acute coronary syndromes. Ann Pharmacother 2013; 47: 573-7

[xiii]. Dewilde WJM 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

[xiv]. Oldgren J, Wallentin L, Alexander JH et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J 2013; 34: 1670-80

[xv]. Rubboli A, Oldgren J, Marin F et al. Combination of a new oral anticoagulant, aspirin and clopidogrel after acute coronary syndrome: new therapeutic standard? Intern Emerg Med 2013; 8:673-680

[xvi]. Khan R, Lopes RD, Neely ML et al. Characterising and predicting bleeding in high-risk patients with an acute coronary syndrome. Heart Published Online First: 24 June 2015. doi:10.1136/heartjnl-2014-307346. Accessed via on 26/06/15

[xvii]. Mehran R, Rao SV, Bhatt DL et al. Standardized bleeding definitions for cardiovascular clinical trials. Circulation. 2011;123: 2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449 Accessed via on 04/06/15

[xviii]. Gruenebaum DD, Alsarah A, Alsara O, et al. Bleeding complication of triple therapy of rivaroxaban, prasugrel and aspirin: a case report and general discussion. Case Rep Cardiol 2014; Article ID 293476. Accessed via on 22/05/2015

[xix]. National Institute for Health and Care Excellence. Rivaroxaban for preventing adverse outcomes after acute management of acute coronary syndrome. NICE technology appraisal guidance TA 335. March 2015. Accessed via on 18/06/15

[xx]. Summary of Product Characteristics – Xarelto 2.5mg (rivaroxaban). Bayer plc. Accessed via on 19/06/15 [date of revision of the text December 2014].

[xxi]. Lamberts M, Gislason GH, Lip GYH et al. Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant. Circulation 2014; 129:1577-85

[xxii]. National Institute for Health and Care Excellence. Medicines Evidence Commentary. Antithrombotic treatment for people with atrial fibrillation and stable coronary artery disease. July 2014. Accessed via on 22/05/15

[xxiii]. Lane D, S Raichand S, Moore D et al. Combined anticoagulation and antiplatelet therapy for high-risk patients with atrial fibrillation: a systematic review. Health Technology Assessment 2013; Vol. 17: No. 30 DOI: 10.3310/hta17300. Accessed via journalslibrary.nihr.ac.uk on 30.6.15

[xxiv]. Summary of Product Characteristics – Pradaxa 150mg. Boehringer Ingelheim Limited. Accessed via on 29/07/15 [date of revision of the text December 2014].

[xxv]. Giugliano RP et al. for the ENGAGE AF-TIMI 48 investigators. Edoxaban versus warfarin in patients with atrial fibrillation. New Engl J Med 2013; 369: 2093-104

[xxvi]. Summary of Product Characteristics – Lixiana 15mg. Daiichi Sankyo UK Limited. Accessed via on 29/07/15 [date of first authorisation 19th June 2015].

[xxvii]. Verheugt FWA, Granger CB. Oral anticoagulants for stroke prevention in atrial fibrillation: current status, special situations, and unmet needs. Lancet Published online 13 March 2015. Accessed via (15)60245-8 on 17/03/15 and on 11/09/15.

[xxviii]. Gibson CM, Mehran R, Bode C et al. An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). Am Heart J. 2015 Apr;169(4):472-8.e5. doi: 10.1016/j.ahj.2014.12.006. Accessed via on 27/07/15

[xxix]. Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting (REDUAL-PCI)

[xxx]. Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS)

[xxxi]. Verheugt FWA. Combined antiplatelet and novel oral anticoagulant therapy after acute coronary syndrome; is three a crowd? Eur Heart J 2013; 34:1618-20

Quality Assurance

Prepared by

Julia Kuczynska, South West Medicines Information and Training, University Hospitals Bristol NHS Foundation Trust

Date Prepared

24th November 2015

Checked by

Trevor Beswick, South West Medicines Information and Training, University Hospitals Bristol NHS Foundation Trust

Date of check

25th November 2015

Search strategy

□ MEDLINE: [ DABIGATRAN.ti,ab; OR RIVAROXABAN.ti,ab OR APIXABAN.ti,ab] AND

exp *PLATELET AGGREGATION INHIBITORS [Limit to: Humans]; date of search 22/05/15

□ EMBASE: [ exp *RIVAROXABAN/ OR exp *APIXABAN/ OR exp *DABIGATRAN/ OR NOAC.ti,ab] AND exp *ANTITHROMBOCYTIC AGENT [Limit to: Human];date of search 22/05/15

□ EMBASE: exp *EDOXABAN/ AND [exp *ANTITHROMBOCYTIC AGENT/ OR antiplatelet*.ti,ab]; date of search 23/07/15

□ NHS Evidence: antiplatelet treatment NOACs OR antiplatelet treatment new oral anticoagulants *FIRST 50 references*. Date of search 22/05/15

□ Micromedex: Dabigatran, Rivaroxaban, Apixaban. Date of search: 22/04/15 and 26/05/15

□ GOOGLE: NOACs and antiplatelets site:nhs.uk – first 20 references, NOACs and antiplatelets – first 30 references. Date of search 26/05/15

□ In-house database. Date of search 23/04/15

□ Manufacturer : Bristol-Myers-Squibb, Medical Information, Personal Communication 01/07/15

□ Clinical Expert: Consultant Pharmacist Anticoagulation & Co- Chair UKCPA Haemostasis, Anticoagulation and Thrombosis (HAT) Group. Personal Communication 03/11/15

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Summary

Patients who develop Acute Coronary Syndrome (ACS) whilst being treated with anticoagulants for AF related stroke prevention:

The optimal strategy to balance the risk of bleeding events and recurrent ischaemic events in people needing antiplatelets and anticoagulants is subject to debate as specifically designed and powered studies are not available. The choice of therapy and its duration is individualised, based on atherothrombotic risk, cardioembolic risk, and bleeding risk.

This is a complex problem to manage because:

□ Dual antiplatelet therapy reduces the risk of ischaemic cardiac events but not AF related thrombotic stroke.

□ Anticoagulants reduce the risk of AF related thrombotic stroke but not of cardiac ischaemic events.

□ The combination of dual-antiplatelet therapy plus anticoagulant (referred to as “triple oral antithrombotic therapy” or “triple therapy”) increases the risk of bleeding events by about 2-4 times compared to anticoagulant or aspirin alone.

European guidelines advise on the choice of therapy (i.e. anticoagulant + single or dual antiplatelet therapy) in AF patients with ACS according to the clinical setting and stroke risk versus bleeding risk.

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