The role of triple antithrombotic therapy in patients with atrial fibrillation and coronary stent insertion

SUMMARY

Triple antithrombotic therapy or ‘triple therapy’ describes the combination of 3 oral antithrombotic medications – an anticoagulant drug (warfarin, apixaban, rivaroxaban or dabigatran) and 2 antiplatelet drugs (usually aspirin plus clopidogrel). Most commonly, triple therapy is indicated for patients who require both dual antiplatelet therapy following coronary stent insertion for acute coronary syndrome and long-term anticoagulation for atrial fibrillation.

Current evidence supports shorter durations of triple therapy to mitigate bleeding risks without compromising ischaemic protection. Recent guidelines advocate up to 1 week of triple therapy for most patients, extending up to 1 month for those at high ischaemic risk.

In practice, the approach to antithrombotic therapy is individualised by the patient’s cardiologist, balancing bleeding and ischaemic risks. General practitioners and pharmacists have an important role in supporting patients in their step-down plan to dual therapy with the oral anticoagulant drug and one of the antiplatelet drugs, and then ongoing monotherapy with the oral anticoagulant drug.

 

Introduction

Triple antithrombotic therapy, referred to as ‘triple therapy’ in this article, involves the combination of an oral anticoagulant drug (warfarin, apixaban, rivaroxaban or dabigatran) and dual antiplatelet therapy (DAPT) (aspirin plus a P2Y₁₂ inhibitor, usually clopidogrel). Triple therapy is used in patients who have both an indication for long-term anticoagulant therapy, such as atrial fibrillation, a mechanical heart valve or venous thromboembolism, and have had an endovascular or cardiac intervention requiring DAPT.

Triple therapy carries a high risk of bleeding and determining the optimal duration of therapy is challenging. Current evidence supports a trend towards shorter durations of triple therapy, to mitigate bleeding risks without compromising ischaemic protection. However, because of the complexity of patient-specific factors, an individualised approach is determined by the patient’s cardiologist.

This article focuses on the use of triple therapy in patients who have experienced acute coronary syndrome requiring coronary stents and have a pre-existing or new diagnosis of atrial fibrillation. The article discusses the rationale for triple therapy, the choice and dosing of drugs used in the regimen, the duration of triple therapy and step-down approach, and recommendations to reduce bleeding risks. The use of dual antithrombotic therapy (an oral anticoagulant drug and a single P2Y₁₂ inhibitor), referred to as ‘dual therapy’ in this article, is discussed as part of the step-down approach to triple therapy. Dual therapy as an alternative to triple therapy is outside the scope of this review.

 

Risk of stent thrombosis and rationale for triple therapy

Antiplatelet drugs are well established for secondary prevention of atherosclerotic cardiovascular events in patients with acute coronary syndrome.¹ When a metal stent is used to open an artery following an acute coronary syndrome, the indication for antiplatelet therapy is even greater because of the additional risk of stent thrombosis, which often presents as an ST elevation myocardial infarction (STEMI). The use of DAPT has been shown to prevent stent thrombosis.²

The risk of stent thrombosis is highest early after implantation before the stent endothelialises, as the stent induces platelet adhesion and activation, necessitating DAPT during this period. Originally, coronary artery stents were bare metal and endothelialised within 6 to 12 weeks after implantation;³ however, these stents often became narrowed by overgrown smooth muscle tissue, causing restenosis. Drug-eluting stents were developed to reduce restenosis by releasing a cytotoxic drug that inhibits smooth muscle growth, but this also delays endothelialisation, prolonging the high-risk period for stent thrombosis.³

The duration of DAPT is determined by the patient’s cardiologist, considering both procedural and patient factors that increase the risk of stent thrombosis.⁴ Examples of procedural risk factors include the use of multiple stents or stents with a small diameter. Patient risk factors include diabetes, kidney failure, smoking and left ventricular dysfunction. The risk is also increased when stenting is performed after a myocardial infarction.

Patients with atrial fibrillation require long-term anticoagulant therapy to prevent thromboembolic complications, such as stroke. If these patients experience an acute coronary syndrome requiring coronary stents, they then have an additional indication for DAPT, thus requiring triple therapy for a period of time. Patients on DAPT following coronary stent insertion can also develop a new diagnosis of atrial fibrillation, resulting in an indication for triple therapy. Triple therapy is indicated because oral anticoagulants are not effective in preventing stent thrombosis and DAPT is inferior to oral anticoagulant therapy in preventing thromboembolic complications in patients with atrial fibrillation.^5,6

 

Bleeding risk with triple therapy

Triple therapy is associated with a higher risk of bleeding than dual therapy with an oral anticoagulant drug and a P2Y₁₂ inhibitor antiplatelet drug, or a single antithrombotic drug.⁷ In the first year after coronary stent insertion, 44.4% of patients receiving triple therapy experienced a bleeding event compared with 19.4% of patients receiving dual therapy.⁸ The difference was statistically significant for any bleeding event, and when major and minor bleeds were pooled, but not significant for major bleeds alone.⁸ Definitions of major bleeding differ between trials, but usually include bleeding that is fatal or potentially fatal, that causes a significant drop in haemoglobin, or that requires a blood transfusion.

An oral proton pump inhibitor (e.g. pantoprazole) is usually prescribed for the duration of triple therapy, to reduce bleeding risk.⁶ Other medicines that increase bleeding risk (e.g. nonsteroidal anti-inflammatory drugs) are also avoided in patients on triple therapy.

 

Choice and dosing of drugs for triple therapy

The choice of drugs in the triple therapy regimen is important for both efficacy in preventing ischaemic events and to reduce the bleeding risk.

For DAPT, guidelines recommend aspirin with a P2Y₁₂ inhibitor. After stent placement, ticagrelor or prasugrel are the preferred P2Y₁₂ inhibitors;^2,6 however, in the context of triple therapy, clopidogrel is usually used with aspirin because this combination has the most supporting evidence and may result in lower rates of bleeding.⁹

The choice of oral anticoagulant in the triple therapy regimen is determined by the indication for long-term anticoagulant use. In patients with atrial fibrillation who have rheumatic mitral stenosis and/or a mechanical heart valve, warfarin is preferred because of its proven efficacy. In all other patients with atrial fibrillation, evidence supports the use of a direct-acting oral anticoagulant (apixaban, rivaroxaban or dabigatran) over warfarin as they have a lower bleeding risk.^6,10

For patients on triple therapy, standard atrial fibrillation dosing for apixaban based on age, weight and serum creatinine concentration should be used.¹¹ Standard atrial fibrillation dosing also applies for the other direct-acting oral anticoagulants; however, if the bleeding risk outweighs the ischaemic risk, rivaroxaban may be reduced from 20 mg daily to 15 mg daily and dabigatran from 150 mg twice daily to 110 mg twice daily. For those on warfarin, standard international normalised ratio (INR) targets apply; however, in those with an elevated bleeding risk, a lower target INR of 2.0 to 2.5 and a time in therapeutic range of greater than 70% are advised to minimise bleeding complications.¹¹

 

Duration of triple therapy

Following acute coronary syndrome, DAPT is typically recommended for 12 months for drug-eluting stents with the duration individualised based on the risk of stent thrombosis.⁶ In patients with acute coronary syndrome and atrial fibrillation, the duration of DAPT needs to be carefully determined in the context of triple therapy, to balance the risks of bleeding with the risks of ischaemic events.

Older guidelines suggested triple therapy for at least 1 month, extending up to 6 months for patients with a high ischaemic risk;¹⁰ however, recent guidelines have recommended shorter durations of triple therapy as evidence demonstrates this reduces bleeding risk without significantly compromising ischaemic protection.^5,11-14 The 2024 European atrial fibrillation guidelines¹¹, the 2023 European acute coronary syndrome guidelines¹⁴ and the 2023 American atrial fibrillation guidelines⁵ recommend a significantly shorter duration, advocating up to 1 week of triple therapy for most patients, and extending up to 1 month for those at high ischaemic risk (e.g. STEMI, prior stent thrombosis, complex coronary procedures, prolonged cardiac instability).^*

The evidence supporting shorter durations of triple therapy is derived from clinical trials where patients were randomised to either dual therapy (an oral anticoagulant drug and a single antiplatelet drug) or triple therapy.^8,15-18 Shorter durations of triple therapy were shown to reduce major or clinically significant bleeding, while the incidence of ischaemic stroke remained comparable between the dual therapy and triple therapy groups. Slightly higher rates of stent thrombosis and myocardial infarction were observed in the dual therapy group, but the differences were not statistically significant and there was a neutral effect on trial-defined major adverse cardiovascular events (MACE) and all-cause mortality.

Numerous meta-analyses further demonstrate significant reductions in major and minor bleeding in patients on shorter durations of triple therapy with no significant differences in MACE, all-cause mortality, cardiac death, myocardial infarction or stroke compared with dual therapy.^19-23

Although a statistically significant increase in stent thrombosis was not consistently demonstrated in patients on dual therapy compared with triple therapy in the meta-analyses, the individual trials were not powered to detect rare outcomes such as stent thrombosis and the trials did not include adequate numbers of high-risk patients. Therefore, a period of up to 1 week of triple therapy is still recommended for most patients. It has also been demonstrated that the risk of stent thrombosis is highest within the first 30 days following stent insertion.²⁴ Consequently, it is recommended that patients with high ischaemic risk continue triple therapy for up to 1 month. In practice, the patient’s cardiologist determines an individualised duration of triple therapy, considering the patient’s bleeding risk, ischaemic risk and overall clinical context, ensuring optimal outcomes through a balanced approach.

 

Stepping down from triple therapy

Triple therapy is followed by dual therapy, continuing the oral anticoagulant drug and one of the antiplatelet drugs (preferably the P2Y₁₂ inhibitor rather than aspirin), before stepping down to the oral anticoagulant drug alone ongoing. Table 1 summarises the step-down approach to antithrombotic therapy, but in practice an individualised approach to duration of therapy at each step is determined by the treating cardiologist considering the patient’s bleeding risk, ischaemic risk and overall clinical context.

Table 1 Step-down approach to antithrombotic therapy following coronary stent insertion for acute coronary syndrome in patients requiring long-term anticoagulation for atrial fibrillation [NB1]

Step	Antithrombotic therapy	Duration of therapy
1	triple therapy (an oral anticoagulant [NB2] plus dual antiplatelet therapy [NB3])	patients at high ischaemic risk [NB4]: up to 1 month all other patients: up to 1 week
2	dual therapy (an oral anticoagulant [NB2] plus an antiplatelet drug [NB3])	patients with a high bleeding risk [NB5]: 6 months (including duration of triple therapy) all other patients: 12 months (including duration of triple therapy)
3	an oral anticoagulant [NB2]	ongoing
STEMI = ST elevation myocardial infarction NB1: An individualised approach to duration of therapy at each step is determined by the treating cardiologist considering the patient’s bleeding risk, ischaemic risk and overall clinical context. NB2: In patients with rheumatic mitral stenosis and/or a mechanical heart valve, warfarin is the preferred oral anticoagulant drug. In all other patients with atrial fibrillation, a direct-acting oral anticoagulant (apixaban, rivaroxaban or dabigatran) is preferred. NB3: Dual antiplatelet therapy is usually with aspirin and clopidogrel, and then aspirin is stopped first. NB4: Factors that increase ischaemic risk include STEMI, prior stent thrombosis, complex coronary procedures and prolonged cardiac instability. NB5: Although not developed for this clinical scenario, the HAS-BLED score and the PRECISE-DAPT score may be useful in assessing the risk of bleeding.

The timing of discontinuing antiplatelet therapy in patients on triple therapy at high bleeding risk was considered in a sub-analysis of the MASTER DAPT trial.²⁵ The study found that stopping one antiplatelet drug after 1 month and the other antiplatelet drug after 6 months, while continuing the oral anticoagulant, did not increase the risk of ischaemic events in patients requiring long-term oral anticoagulant therapy.²⁵ This finding supports ceasing antiplatelet therapy after 6 months of dual therapy in patients with a high bleeding risk. For all other patients, ceasing antiplatelet therapy after 12 months of dual therapy is recommended based on the AFIRE trial.²⁶ The trial determined that in patients with stable coronary artery disease (i.e. no acute coronary syndrome events in the past 12 months), the combination of an oral anticoagulant drug with a single antiplatelet drug increases all-cause mortality compared with an oral anticoagulant drug alone.²⁶

There is no specific tool to assess a patient’s bleeding risk while on dual therapy; however, the following bleeding risk tools validated for other scenarios may be considered:

• HAS-BLED score, developed to assess bleeding risk in patients prescribed long-term anticoagulation for atrial fibrillation²⁷
• PRECISE-DAPT score, developed to assess bleeding risk in patients prescribed DAPT following coronary stent insertion for coronary artery disease.²⁸ However, patients with an indication for long-term anticoagulation, such as atrial fibrillation, were specifically excluded from the validation study
• Academic Research Consortium High Bleeding Risk evaluator, developed to identify high bleeding risk in patients undergoing percutaneous coronary intervention.²⁹

If the dose of rivaroxaban or dabigatran was reduced in the context of triple therapy, this is typically changed back to standard dosing when the patient is stepped down to dual therapy. Similarly, if the target INR for warfarin was adjusted, this is typically changed back to the standard target.

 

Ongoing management of patients on triple therapy

A step-down plan is essential for patients receiving triple therapy to ensure triple therapy is not continued longer than required, unnecessarily exposing the patient to additional bleeding risk.

As the step-down actions are likely to be initiated when the patient is in the community, patient safety after discharge relies on effective transition of care from hospital to home. Clear advice should be provided by the hospital team to the patient and their general practitioner, indicating the duration of triple therapy and the step-down plan to dual therapy with the oral anticoagulant drug and a single antiplatelet drug, and then ongoing monotherapy with the oral anticoagulant drug.

The treating team should also consider referring patients to cardiac rehabilitation programs or cardiac care support services.^6,30 These services should also be informed of any medication changes, step-down plans and follow-up requirements for the patient.

Optimising medication safety in this vulnerable patient cohort involves education on managing adverse effects, particularly bruising and bleeding, and when to seek help. Interruptions to antithrombotic therapy (e.g. perioperative interruption for noncardiac surgery) should only be made in consultation with the patient’s cardiologist.

 

Conclusion

Determining the optimal duration of triple therapy is complex, with current evidence suggesting shorter durations of up to 1 week to 1 month (depending on ischaemic and bleeding risks) are safe and efficacious. Communication to primary care providers is vital when transitioning patients from hospital to community care to ensure triple therapy is stepped down when clinically appropriate.

^*The Australian clinical guidelines for managing and diagnosing acute coronary syndromes, published by the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand, are currently being reviewed. The new guidelines are scheduled for release in 2025.

This article was finalised on 24 December 2024.

Conflicts of interest: none declared

This article is peer reviewed.

 

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