Treating atrial fibrillation with antiplatelet drugs in the elderly: pro and contra arguments

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the aged population and it is associated with significant mortality and morbidity [1]. AF independently increases stroke risk by fivefold and accounts for a greater proportion of strokes with increasing age [2]. Age >75 years is arbitrarily used to dichotomise risk in clinical trials and reviews. AF can also lead to unrecognised medical problems such as dementia and depression [3]. Treatment with oral anticoagulants (OAC) is considered the standard of care in patients with AF and a moderate to high risk of thromboembolism. However, OAC can be challenging in elderly patients who present with several comorbidities such as chronic kidney disease (CKD) and anaemia, increased risk of intracerebral haemorrhage and increased risk of falls. Although antiplatelet therapy is less effective than OAC for the prevention of embolic stroke, it is still used as an alternative to OAC in patients in whom an OAC is contraindicated or not preferred [4].

Age and stroke risk in AF

The American Stroke Association (ASA) and the American Heart Association (AHA) estimate that 15% of strokes result from untreated AF [5]. In addition, AF is the source of 45% of all embolic strokes in the United States [6]. The risk of ischaemic stroke increases up to fivefold in patients with AF. The risk of stroke in AF increases sharply with age over 65 years and it increases 1.45-fold per decade [7]. Strokes associated with AF are disabling and associated with a high mortality rate. The incidence of strokes in patients with AF also increases with associated comorbidities. Risk stratification algorithms have evolved from CHADS2 to CHA2DS2-VASc. These point out the risk factors associated with the development of strokes in such patients [8]. The risk factors included in the CHA2DS2-VASc scoring system are more important in determining the thromboembolic risk than the presence of the atrial arrhythmia alone [9,10].

Antithrombotic therapy in elderly patients with AF

Antiplatelet agents and OAC reduce the risk of stroke in AF patients, with OAC being more effective than antiplatelets. Oral anticoagulation, although highly effective for stroke prevention in AF patients, is underutilised in the elderly and there is a relatively high rate of discontinuation of the anticoagulant therapy [11]. This undertreatment of the very elderly represents a paradox because older patients are at higher risk of stroke and are more likely to need anticoagulant therapy compared to younger patients. Clinical data on elderly patients are limited since they are often underrepresented in clinical trials. Most ischaemic strokes in patients with AF are due to cardiogenic embolism; however, up to 35% of cases may be caused by intrinsic small vessel cerebrovascular disease [12].

Aspirin reduces the risk of stroke by 25% in AF patients and it prevents mostly non-cardiogenic embolic strokes. OAC are associated with a risk reduction of about 60% in comparison with placebo [13].  With increasing age, the benefit of aspirin decreases and appears to be ineffective in patients above 80 years, whereas the absolute benefit of OAC is highest in very elderly patients where it by far outweighs the risk of bleeding [14].

Age correlates with both ischaemic and bleeding events. Several risk scores have been developed to predict bleeding during OAC therapy. HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history/predisposition, labile international normalised ratio [INR], elderly >65 and drug/alcohol abuse) score has been widely used and incorporated in guidelines on the management of patients with AF. Many of the factors that predict bleeding are also risk factors for stroke. This limits the possibility of predicting the benefit and risk of OAC, particularly in elderly patients. Nevertheless, the benefit of OAC runs parallel with increasing embolic risk even in those at higher bleeding risk (HAS-BLED >3 in which age >65 years is a key determinant) [15].

Table 1. Clinical risk factors for stroke, transient ischaemic attack, and systemic embolism in the CHA2DS2-VASc score.

With approval from [16] Kirchhof P et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37:2893-962.

Antiplatelet therapy – mechanisms of action

Aspirin, clopidogrel and dipyridamole are the antiplatelet drugs approved by the Food and Drug Administration (FDA) for stroke prevention. They play their role at multiple phases of the platelet aggregation pathway and cause platelet activation inhibition.

Aspirin inhibits cyclooxygenase irreversibly and acetylates, the hydroxyl group of this enzyme, selectively. Thus, conversion of arachidonate to prostaglandin G2/H2 and thromboxane A2 is blocked and platelet aggregation does not occur [17].

Clopidogrel is a thienopyridine derivative that blocks adenosine 5-diphosphate binding to glycoprotein IIb/IIIa. Therefore, it prevents binding of fibrinogen to this receptor [18].

Dipyridamole has different mechanisms of action. Mainly, it inhibits platelet phosphodiesterase causing a rise in intraplatelet cyclic adenosine monophosphate. Thus, it can significantly increase the inhibitory actions of prostacyclin on platelets. It also directly causes release of eicosanoid from vascular endothelium. Eicosanoid, in turn, prevents the uptake and metabolism of adenosine, causing further inhibition of platelet aggregation [19].

Randomised trials comparing antiplatelet therapy versus warfarin in elderly patients with AF

The first trial comparing the efficacy and safety of aspirin and warfarin with placebo for stroke prevention in AF was the SPAF trial. The superiority of both warfarin and aspirin resulted in early termination of the study [21].

A subsequent trial (SPAF II) directly compared warfarin with aspirin therapy in two age groups and showed that warfarin was more effective than aspirin in the prevention of ischaemic and cardioembolic strokes [22].

The BAFTA (Birmingham Atrial Fibrillation Treatment of the Aged) study provided evidence about the risks and benefits of warfarin versus aspirin for stroke prevention in elderly (more than 75 years) AF patients. The primary endpoints were fatal or non-fatal disabling stroke (ischaemic or haemorrhagic) or significant arterial embolism. Warfarin had fewer primary events than aspirin (24, 1.8% per year vs. 48, 3.8% per year) with a 52% relative risk reduction in all strokes or systemic embolism compared to aspirin. Stroke risk increased with aging from 2% (age 75-79) to 2.8% (age 85 and older) in the warfarin group and in the aspirin group from 2.8% to 5.6%. Risk of intracranial or extracranial haemorrhage was not significantly different in warfarin compared to aspirin (1.1% annual risk in the warfarin group and 0.8% in the aspirin group) [23].

A meta-analysis of randomised trials including 29,044 patients with a mean age of 71 years confirmed the superiority of warfarin over antiplatelet agents in reducing stroke risk. The increased bleeding risk on warfarin compared to aspirin was outweighed by the absolute stroke risk reduction [7].

In a sub-analysis of the PREFER in AF (PREvention of Thromboembolic Events-European Registry in Atrial Fibrillation) study in very elderly patients with AF, outcomes with and without OAC were estimated in different age groups. In patients over 85 years the incidence of thromboembolic events was 6.3%/year versus 4.3%/year (2% absolute reduction). In these very elderly patients, the risk of bleeding was higher than in the younger patients but similar in those on OAC and in those on antiplatelet therapy (4%/year versus 4.2%/year, p=0.77). The absolute benefit of OAC was found as a function of age and was highest in elderly patients, where it by far outweighed the bleeding risk [24].

These findings were confirmed in a sub-analysis of an elderly cohort in an AF trial of non-vitamin K oral anticoagulants (NOACS) compared with warfarin in which the effectiveness and safety of NOACS was confirmed in elderly patients and was potentially even greater with improved safety performance and similar safety when compared to aspirin [25].

Aspirin and clopidogrel in combination was studied for stroke prevention in atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Event (ACTIVE-W) and the ACTIVE-A trials [26,27]. The ACTIVE-W was a randomised clinical trial in patients with a history of atrial fibrillation along with one or more risk factors for stroke. They received oral anticoagulants along with either clopidogrel (75 mg/day) or aspirin (75-100 mg/day) in order to have a target INR of 2.0-3.0. This study was prematurely terminated as OAC were found to be superior to dual antiplatelet therapy (annual risk of primary outcome, 3.93% vs. 5.60%, respectively; RR, 1.44, p=0.0003). Annual risk of haemorrhagic stroke associated with oral anticoagulation was found statistically significant when compared to dual antiplatelets. (0.36% vs. 0.12%; p=0.036). Therefore, this trial supported the use of oral anticoagulants over antiplatelets in stroke prevention for AF.

In the ACTIVE-A study, 7,554 atrial fibrillation patients who were considered unfit for anticoagulation were prescribed either clopidogrel (75 mg; n=3,772) or placebo (n=3,782) in addition to aspirin 75 to 100 mg daily [27]. After follow-up of 3.6 years, it was found that clopidogrel plus aspirin caused a statistically significant reduction in the primary outcome over aspirin alone (6.8% vs. 7.6% per year, respectively; RR, 0.89, p=0.01). Combination therapy caused a greater reduction in ischaemic stroke. Major bleeding was noted annually at 2% in clopidogrel plus aspirin and 1.3% in the aspirin alone group (RR, 1.57, p<0.001). A statistically significant increase of intracranial haemorrhage was seen with clopidogrel plus aspirin over aspirin alone (0.4% vs. 0.2% per year, respectively).

Table 2. Effects of antiplatelet and anticoagulation therapy for stroke prevention in patients with atrial fibrillation: trial summaries.

Merits and demerits of antiplatelet agents

Merits

Antiplatelets have varied mechanisms of action, thus they give different degrees of vascular protection. Also, combination therapy is more effective in reducing vascular events, reducing stroke risk by 22% [13]. Aspirin is prescribed for patients with low risk of stroke (i.e., CHADS score=0 or 1). Dual antiplatelets are used in those unsuitable for oral anticoagulants. The 2019 focused update of the American Heart Association (AHA), American College of Cardiology (ACC), and Heart Rhythm Society (HRS) to the 2014 Atrial Fibrillation Management Guideline does not mention the role of aspirin in the management of AF with a CHA₂DS₂-VASc score of 0 or 1. High-risk patients with acute coronary syndrome who underwent percutaneous coronary intervention and with a CHA₂DS₂-VASc score ≥2 are eligible for triple therapy with aspirin and a P2Y₁₂ inhibitor in combination with NOAC or a vitamin K antagonist for four to six weeks. After that, a P2Y₁₂ inhibitor, especially clopidogrel, is considered to be safer (P2Y₁₂ inhibitor + OAC) in terms of risk and benefit [28]. Further studies, such as the EPSP-2, report that aspirin and aspirin plus dipyridamole have similar efficacy for stroke prevention. The SPAF trial showed superior efficacy of aspirin over placebo [21].

Demerits

Aspirin alone and DAPT are less effective than OAC in stroke reduction. A meta-analysis for comparison of aspirin alone with placebo or no treatment from seven trials (n=3,990) showed only a non-significant 19% (95% CI: −1 to 35%) reduction in stroke incidence. The European Society of Cardiology does not support antiplatelet monotherapy for stroke prevention irrespective of stroke risk [8]. Antiplatelet therapy increases bleeding risk, especially DAPT (2% vs. 1.3% with monotherapy, p<0.001), with bleeding rates similar to those on OAC. The BAFTA study showed no difference in major bleeding rates as compared to warfarin. Thus, aspirin is not safer in frail, elderly AF patients. The benefit of aspirin on vascular disease in the absence of other risk factors is negligible [29]. The Prevention of Progression of Arterial Disease and Diabetes trial showed that aspirin is not that useful for prevention of cardiovascular events and death in diabetics with peripheral artery disease. Also, the addition of aspirin to OAC can raise the bleeding risk with OAC. The SPORTIF trial analysis found that those taking both aspirin and warfarin do not have any additional reduction of stroke or myocardial infarction. Instead, they are more susceptible to major bleeding (3.9% per year). Strokes can recur even when these drugs are used in therapeutic doses. This is known as “treatment failure”. It can result from multiple causes such as patient non-adherence and comorbid conditions. Antiplatelet resistance presents when aspirin or clopidogrel biochemically does not lead to platelet activation, as evidenced by platelet function assays [30]. Drug-drug interactions and genetic polymorphisms of antiplatelet metabolism or the drug-receptor site can cause it. Non-steroidal anti-inflammatory drugs compete with the COX-2 receptor site where aspirin binds. Thus, it can affect the efficacy of aspirin. The action of clopidogrel is diminished by drugs that inhibit CYP3A4 and CYP2C19 enzyme systems. These cytochromes are needed for conversion from prodrugs to active metabolites.

Conclusions

Aspirin therapy has a limited role in the prevention of stroke in elderly patients with AF. Aspirin as monotherapy is less effective than OAC in reduction of cardioembolic stroke and is associated with a similar risk of haemorrhagic events compared with warfarin and NOACs. Thus, aspirin is not safer in frail, elderly AF patients. Although clinical data in elderly patients are limited, the BAFTA trial and meta-analysis of randomised trials in subgroups of patients with advanced age demonstrate that the benefit of OAC is maintained in elderly patients as compared to aspirin, and the increased bleeding risk on warfarin compared to aspirin is outweighed by the absolute stroke risk reduction. Data supporting the use of DAPT in elderly patients as an alternative to OAC are limited and inconclusive. The European Society of Cardiology does not support antiplatelet monotherapy for stroke prevention irrespective of stroke risk. The 2019 AHA/ACC/HRS focused update omits any recommendation for aspirin in patients with low risk. Dual antiplatelet therapy (aspirin and clopidogrel) is not considered as an alternative when OAC are unsuitable or contraindicated. Aspirin use is mentioned only in the setting of ACS with a CHA₂DS₂-VASc score of ≥2 for a short duration (4-6 weeks) triple therapy. Then a P2Y₁₂ inhibitor with OAC is preferred in terms of safety.