Efficacy and safety of vitamin K antagonists compared to antiplatelet agents in very old patients with atrial fibrillation

Keywords: very old, anticoagulation, atrial fibrillation

Background

Due to demographic changes there is a growing population of old and very old patients (≥85 years) in the western world [1]. In this fast growing population of very old patients, the prevalence of atrial fibrillation (AF) is high (>15%) [2]. It is well known that AF increases the risk of thromboembolic events and is associated with higher stroke severity. These events may cause disabilities and lead to death [3,4]. The first randomised controlled trial comparing warfarin and aspirin to prevent thromboembolic complications in AF patients was published in 1989 [5]. Five years later, the first study of a vitamin K antagonist (VKA) in AF patients with an explicit focus on very old patients was published [6]. Back then, people aged 75 years and older were classified as very old. In this trial no net clinical benefit for warfarin was shown, although the stroke risk was reduced significantly compared to aspirin alone. However, the accepted international normalised ratio (INR) range was 2.0 to 4.5 and thus a relevant rate of bleeding complications in the warfarin group occurred.

Today, the target INR range for anticoagulation with VKAs in AF patients is between 2.0 and 3.0, and oral anticoagulation (OAC) is recommended in the current guidelines for all AF patients above 75 years with the absence of contraindications [7]. However, advanced age is also associated with higher bleeding risks and therefore older patients are frequently left without oral anticoagulation [8,9]. The most frequent reasons for not prescribing OAC in older patients are risk of falls, poor prognosis, bleeding history, refusal by patient or family, and dementia [9]. Furthermore, very old patients are not relevantly represented in most trials, and therefore data on treatment and treatment recommendations are scarce.

These points clearly demonstrate that it is complex to identify an appropriate therapeutic option for these very old patients with AF. We aimed to highlight and summarise relevant treatment options for this patient population with a special focus on the use of VKAs.

Advantages of vitamin K antagonists

Anticoagulation with a VKA is highly effective in reducing the risk of stroke in patients with AF. VKAs are well investigated, available worldwide and there is broad experience among almost all general physicians concerning initial dosage, dose adjustment, therapeutic range, bridging possibilities, interactions and contraindications. Self-measurement by the patient after appropriate instruction from a healthcare professional is also possible if they are in good mental and physical health. Another advantage is the broad experience in literally all hospitals around the world in the treatment of patients with a critically increased INR with and without bleedings. For very old patients, the necessity of regular INR controls might be advantageous since it allows a more frequent medical supervision. This might be helpful in order to recognise other medical conditions in a timely manner. Furthermore, the treatment with a VKA can be performed independently from impaired renal function and low body mass index often present in very old patients [10,11].

Disadvantages of vitamin K antagonists

There are some aspects linked directly to the use of VKAs and their pharmacokinetics and pharmacodynamics. In particular, the interaction with vitamin K-bearing food and the narrow therapeutic window combined with the need for routine INR controls can lead to complications. Timing in the therapeutic range is crucial. Therefore, patients with unstable INR have an increased risk both of stroke and of bleeding. The increased bleeding risk persists even if the INR is within the therapeutic range. Further problems include the fact that very old patients a) are often on a poly-medication, which might interact with VKAs; b) have an inherently higher risk of falling; c) are more likely to  have deficiencies in cognition and memory and to develop dementia; d) are more likely to have occult diseases and therefore may be disposed to haemorrhagic complications; and e) are more likely to have deficiency in auditory and visual acuity [10,11].

Vitamin k treatment in octogenarians and very old people with atrial fibrillation

The WASPO and BAFTA trials

In 2007, a randomised controlled trial of Warfarin versus Aspirin for Stroke Prevention in Octogenarians with atrial fibrillation (WASPO) was published. Seventy-five participants were included and randomised to either aspirin 300 mg (n=39) or warfarin treatment (target INR of 2-3). The primary endpoint was a composite of death, thromboembolism (stroke, transient ischaemic attack [TIA] or systemic embolism), serious bleeding and withdrawal from the study for any reason. Due to the relatively small number of patients, only one ischaemic event was detected, which appeared in the aspirin group. Interestingly, more serious bleeding events were documented in the aspirin group. In conclusion, warfarin was significantly better tolerated with fewer adverse events than aspirin [12]. Despite the overt weaknesses of this investigation, it demonstrated that medication with a VKA in octogenarians with AF was well tolerated and safe. Therefore, this study may be seen as a basis for further investigations into VKAs in octogenarians.

In the same year another randomised controlled trial, the Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA) investigating the harms and benefits of an antiplatelet agent (aspirin) vs. VKA treatment (with warfarin) in older patients with AF, was published. The BAFTA trial enrolled 973 patients with a follow-up of 2.7 years. The primary endpoint was a composite of fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage, or clinically significant arterial embolism. The authors reported fewer primary events in patients taking warfarin than in patients taking aspirin (yearly risk 1.8% vs. 3.8%; relative risk 0.48; 95% CI: 0.28-0.80; p=0.003). The authors concluded that age itself should not be seen as a contraindication to anticoagulation with VKAs; on the contrary, they recommended preferring VKAs with a target INR range of 2-3 in AF patients older than 75 years instead of antiplatelet agents. The study population also included a subgroup of 190 very old patients (≥85 years) (Table 1). The subgroup analysis confirmed that VKA treatment was as effective in very old patients as in younger patients. However, these results need to be interpreted carefully, since statistical significance was not met.

Table 1. Main similarities and differences of methods and results concerning very old patients (≥85 years), of the BAFTA trial and the PREFER in AF study [8,13].

* Calculated based on the numbers given for patients ≥85 years with thromboembolic events and major bleeding with and without OAC.
^# 6% of all very old patients were treated with a NOAC.

AP: antiplatelet; NOAC: non–vitamin K antagonists; OAC: oral anticoagulation; RCT: randomised controlled trial; TIA: transient ischaemic attack; VKA: vitamin K antagonist

In the total study population, the risk of bleeding was similar in the aspirin and warfarin arms. In the group of very old patients it was even numerically lower in the VKA than in the antiplatelet group. Nevertheless, the risk of bleeding in both groups was >3% in patients aged 85 years and older [13].

A sub-analysis from the PREFER in AF study

The PREvention oF Thromboembolic Events–European Registry in Atrial Fibrillation (PREFER in AF) study is a prospective, international, multicentre, real-world registry of more than 7,000 patients with AF. Patients were enrolled consecutively and followed for one year [14]. Based on these data, the authors performed a substudy analysing 505 very old patients (≥85 years) (Table 1). The group of patients treated with OAC consisted mainly of patients under VKA treatment; however, 6% of all very old patients were treated with a non-vitamin K antagonist (NOAC). No further sub-analyses with respect to the difference between NOACs and VKAs were performed. There was no statistically significant difference between very old patients under OAC and very old patients without OAC concerning the combined endpoint of stroke/TIA and thromboembolic events (adjusted OR 0.64, 95% CI: 0.24-1.69; p=0.37). However, there was a trend towards a higher incidence of thromboembolic events in very old patients without OAC (6.3 per 100 patients/year vs. 4.3 per 100 patients/year with OAC). There was no significant difference in bleeding events between very old patients with and without oral anticoagulation (4.0 vs. 4.2 per 100 patients/year, p=0.77). Further analyses showed a similarly high risk for major bleeding in patients with OAC compared to patients with antiplatelet therapy (4.1 per 100 patients/year vs. 3.9 per 100 patients/year; OR 1.05, 95% CI: 0.30-3.68; p=0.75), whereas the bleeding risk was increased in OAC patients compared to patients without OAC and without antiplatelet treatment (4.1 vs. 2.8 per 100 patients/year). The highest risk of bleeding was found in patients with a combination of OAC and antiplatelet therapy (6.4 per 100 patients/year). The calculated net clinical benefit favoured a treatment with OAC. The authors concluded that the major concern in very old patients with AF is the thromboembolic risk rather than the bleeding risk induced by OAC [8].

Do the results of WASPO, BAFTA and PREFER in AF fit into the real world?

Study populations only partially represent real-world patients. The number of patients with AF fulfilling all inclusion criteria for studies investigating VKAs in AF ranges from 7-40% [5,15]. The authors of the BAFTA trial assumed that only about 10% of patients who would have met the inclusion criteria would eventually have been enrolled in the study [13]. Therefore, cohort studies are important in order to obtain a view on real-world patients’ problems and incidences. A retrospective observational cohort study investigating the use of antithrombotic therapy and predictors for stroke and death in 561 very old patients (≥85 years) with AF was published in 2015. Unfortunately, the risk of bleeding was not investigated and no information about the kind of OAC was reported. However, the analysed OAC treatment time points were before March 2012, indicating a relevant VKA treatment fraction. The multivariate analyses performed showed a significant reduction of the all-cause mortality in patients under OAC (OR 0.59, 95% CI: 0.36-0.99). Furthermore, it was shown that antiplatelet treatment was an independent predictor of stroke in multivariate analysis (OR 2.45, 95% CI: 1.05-5.70). Only 36% of the very old patients with AF received OAC, whereas 49% received antiplatelet therapy [16].

VKA vs. NOAC IN VERY OLD PATIENTS - FUTURE PERSPECTIVE

In line with current guidelines there is an increased use of NOACs in very old patients. NOACs provide a more convenient treatment compared to VKAs. There is no need for regular monitoring. It is only recommended to check the renal and liver function regularly to avoid accumulation. Strong evidence in terms of randomised controlled trials comparing NOACs with VKAs in large groups of very old patients is not available. In all pivotal phase III trials comparing VKAs and NOACs only a few very old patients were enrolled. However, logical considerations and large cohort studies investigating partially the risks and benefits of VKAs and NOACs in very old patients indicates a non-inferiority for the usage of full-dose NOACs in very old patients [17,18].

Conclusion

Anticoagulation with VKAs in very old patients is far more effective in stroke prevention than a monotherapy with an antiplatelet agent [8,12,13]. The WASPO trial showed that medication with VKAs in octogenarians with AF was well tolerated and safe. The BAFTA trial confirmed these results and indicated that age itself should not be seen as a contraindication for anticoagulation with VKAs. The PREFER in AF substudy in the very old, comparing mainly patients under VKA treatment with patients under antiplatelet therapy, did not reach significance for the combined endpoint of stroke/TIA and thromboembolic events. Indeed, numerically, stroke burden was reduced and a weighted net benefit analysis assessing the advantage of the reduced risk for stroke in relation to the increased risk of bleeding was significantly in favour of anticoagulation, performed with VKA in most cases. Therefore, aspirin alone is not recommended for stroke prevention in very old AF patients. This is in line with the current guideline recommendations of the European Society of Cardiology [7]. Consistent with the actual guidelines and based on logical considerations and the existing study results, NOACs may be seen as the first choice in therapy-naive very old patients with AF, whereas in patients previously treated with VKAs the VKA treatment may be continued [7,17,18].