Treating atrial fibrillation in very old patients with new oral anticoagulation drugs: arguments pro and contra

Introduction

The incidence of atrial fibrillation (AF) increases with age. The risk of stroke is increased four- to five-fold in old patients with AF. In the Framingham Study, 23.5% of strokes in patients aged 80 and older were attributable to AF [1]. Advanced age is also associated with a progressive increase in the risk of major bleeding in subjects ≥85 years, particularly if treated by oral anticoagulants (OAC) [2].

Only 20% of patients >75 years were included in randomised controlled trials (RCTs) involving OACs in AF, due to the high risk of falls and bleeding, especially intracranial haemorrhage (ICH) [2].

The management of anticoagulation in the very elderly represents a challenging issue because they are at high thromboembolic risk, and also at high haemorrhagic risk [3].

In deciding when to employ anticoagulation in an individual with advanced age (a person over 80 years of age according to the World Health Organization), risk scores such as CHA2DS2-VASc and HAS-BLED should be considered [4].

Stroke risk

Stroke risk is estimated using the CHA2DS2-VASc score which includes: 1 point each for congestive heart failure, hypertension, age 65-74 years, diabetes mellitus, vascular disease (coronary artery disease, peripheral arterial disease, aortic aneurysm), female gender; 2 points for age ≥75 years and for prior stroke or transient ischaemic attack [4]. Troponin (high-sensitivity troponin T or I) and N-terminal pro-B-type natriuretic peptide may provide additional prognostic information in selected cases [4].

Bleeding risk

Bleeding risk is calculated using the HAS-BLED score and includes 1 point each for: hypertension, abnormal liver function, abnormal renal function, stroke, bleeding history, labile INR, age >65 years, drugs, and alcohol abuse. Factors such as older age, hypertension and prior stroke predict the risk both of stroke and of bleeding [4]. A high bleeding risk score is not a contraindication for anticoagulation as long as risk factors are identified and corrected [4]. OAC are more effective in reducing the risk of ischaemic strokes than antiplatelet agents but they are underutilised because of the increased risk of haemorrhage and multiple comorbidities with advanced age [4]. The great majority of elderly patients with AF should receive anticoagulant therapy, unless there is an unequivocal contraindication [2]. To determine the best therapeutic approach, the risk of stroke and bleeding should be assessed in every patient and also periodically analysed. Unless the risk of bleeding is exceedingly high, anticoagulation is required [5]. When bleeding risk exceeds the risk of stroke, treatment should be discontinued; however, this is associated with an increased risk of death and thromboembolic complications [5].

Options for oral anticoagulation in very old patients: vitamin k antagonists (VKAs) and non-vitamin K antagonist oral anticoagulants (NOACs)

VKAs were associated with a reduction in the risk of ischaemic stroke compared with placebo or no treat­ment [2]. Given that NOACs are as efficient as warfarin in reducing stroke and systemic emboli, we may conclude that they are also better than placebo or no treatment.

NOACs for elderly patients with AF are more selective in their anticoagulant mechanisms and easier to administer compared with VKAs [4]. Dabigatran, apixaban, rivaroxaban and edoxaban have been approved for clinical use. In all phase 3 trials NOACs have been shown to be at least non-inferior to dose-adjusted warfarin for stroke prevention [6]. However, few data are available about very old patients [3].

Direct thrombin inhibitors (DTI)

Dabigatran etexilate

Dabigatran etexilate is a prodrug administered orally twice daily. It is converted into dabigatran by catalysed hydrolysis of esterase in plasma and the liver; 80% is excreted by the kidneys and it is contraindicated in severe renal disease (creatinine clearance [CrCl] <30 ml/min) [2].

In the Randomised Evaluation of Long-term Anticoagulant TherapY (RE-LY) trial, two doses of dabigatran (110 mg and 150 mg twice daily) were compared with warfarin in patients with non-valvular atrial fibrillation (NVAF). In this trial, 40% of patients were aged ≥75 years [7].

Dabigatran 150 mg bid was associated with a lower risk of stroke/systemic embolism (SE) compared to warfarin [8]. Dabigatran 110 mg twice daily was non-inferior to warfarin for prevention of stroke/SE [8].

In patients ≥75 years, dabigatran 150 mg was associated with an increased risk of major extracranial bleeding and dabigatran 110 mg showed a 20% reduction of relative risk of major bleeding, compared to warfarin, in the presence of a comparable thromboembolic risk. Both doses reduced the rate of ICH compared with warfarin, irrespective of age [7].

Subgroup analyses stratified by age and gender showed that risk of major gastrointestinal (GI) bleeding was increased for women aged ≥75 and for men aged ≥85 vs. warfarin. This supports the use of dabigatran 110 mg twice daily in patients ≥80 years [7].

Direct factor XA inhibitors

Rivaroxaban

Rivaroxaban is predominantly metabolised by the liver and is less dependent on renal excretion [9]. It was compared with warfarin in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) [9]. Rivaroxaban was dosed at 20 mg once/day (15 mg in patients with moderate renal dysfunction – CrCl: 15-49 mL/min). Patients with severe renal disease were excluded. In the trial, 44% of patients were aged ≥75 years. Rivaroxaban was not inferior to warfarin in preventing stroke/SE in patients with or without reduced CrCl [10].

Compared with warfarin, the risk of ICH was lower, and the risk of GI bleedings was higher with rivaroxaban. The same pattern was found in patients >75 years [10].

Apixaban

Apixaban was compared with warfarin in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study [11] and with aspirin in patients intolerant of warfarin in the Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for vitamin K Antagonist Treatment (AVERROES) study [12].

In both studies, in patients who had a serum creatinine concentration >1.5 mg/dl (133 mmol/l) and either age >80 years or a body weight <60 kg, the dose of apixaban was reduced from 5 mg to 2.5 mg. In the ARISTOTLE trial, apixaban was more effective than warfarin in reducing strokes and all-cause mortality and had a lower risk of major bleeding irrespective of age. In patients aged ≥75 years (31% of the whole study population), apixaban was associated with a reduction of both the incidence of stroke/SE and the rate of major bleedings similar to warfarin, with an advantage regarding major bleedings in patients with renal dysfunction. The absolute benefits of apixaban were greater in the older population [11].

In the AVERROES trial, the rate of stroke/SE was significantly reduced with apixaban, compared to aspirin, with similar effects on major bleedings or ICH, irrespective of age. This suggests that apixaban should be considered a viable alternative, especially for elderly patients ≥80 years unsuitable for warfarin therapy. There was no significant increase in the risk of major bleeding in this group [12].

Edoxaban

The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE AF) trial involved the largest number of elderly patients - 40.2% aged ≥75 years [13]. Patients were randomised to edoxaban 60 mg/day or warfarin; 30 mg/day of edoxaban was administered if any of the following was present: CrCl ≤50 mL/min, body weight ≤60 kg, concomitant use of potent P-glycoprotein inhibitors. In the subgroup of elderly patients >80 years, edoxaban 30 mg/day showed similar efficacy to warfarin in preventing stroke/SE with the advantage of a greater reduction in major bleeding. In the elderly with renal dysfunction, the need to individualise the dosage should be taken into consideration. ICHs were lower for edoxaban versus warfarin, but the rate of major GI bleeding was higher with high-dose edoxaban [13].

In the ENGAGE AF-TIMI 48 trial, the risk of major bleeding increased markedly with increasing age [14].

Challenges with anticoagulation in very old patients with AF

Pharmacokinetics

Pharmacokinetics are modified in the elderly due to ageing, body composition changes with reduction in muscle mass and total body water [3]. No dose adjustment is required for dabigatran or rivaroxaban in patients with body weight <50 kg, but a close follow-up is recommended [6]. For apixaban, the recommended dose is 2.5 mg twice daily in patients with at least two of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL [15]. For edoxaban, the recommended dose is 30 mg/day in patients with body weight <60 kg or estimated CrCl of 30-50 mL/min [14].

Polymedication

Polymedication contributes to the increased risk of pharmacological interactions. In general, NOAC use is not recommended in combination with drugs that are strong inhibitors of both CYP3A4 and P-glycoprotein P-gp. Conversely, strong inducers of P-glycoprotein P-gp and/or CYP3A4 will markedly reduce NOAC plasma levels. Such combinations should be avoided or used with great caution and surveillance [15]. Since NOACs present a reduced pharmacological and dietary interaction compared to VKA, they may be preferred in very old patients with AF [4].

Frailty

Frailty is defined as a decline in functional and physiological reserve associated with aging, in the presence of comorbidities; it was associated with vascular dementia, but this should not be considered an absolute contraindication for anticoagulation [3]. Worsening of cognitive function in patients taking VKAs may be related to a poor INR control in these patients and NOACs could be the choice. Observational findings suggest that, paradoxically, the frail patient may gain advantages from anticoagulation [3]. The benefits of NOACs appear to outweigh the risks when compared to warfarin for stroke prevention in AF in elderly frail patients [15].

Risk of falls

The incidence and prevalence of falls increase with age and predispose to ICH.  The absolute risk is generally lower than the risk of stroke in elderly patients with AF [2]. If the factors involved in falls are corrected, anticoagulation can normally be prescribed. Compared with warfarin, NOACs have a lesser risk of ICH, including traumatic intracranial bleeding, so are recommended over VKAs in patients with a high risk of falls [15].

Comorbidities

Chronic kidney disease (CKD)

The prevalence of renal disease increases with advancing age, patients with CKD having three times the risk of AF compared with patients without CKD. The efficacy of NOAC therapy for stroke prevention in old patients with CKD is based on a sub-analysis of clinical trials. Renal function should be determined before starting treatment with NOACs (and then at least every year), and more frequently (at least once every 6 months) when renal dysfunction exists, worsening renal function is suspected, or in case of frailty [6].

The most recent European Heart Rhythm Association (EHRA) recommendations are:

• Mild to moderate CKD: VKAs reduce stroke and mortality in these patients but, compared with warfarin, all four NOACs showed efficacy and safety [6]. Dabigatran 110 mg/daily is recommended in patients with CrCl <50 mL/min at high risk of bleeding [15].
• CrCl of 15-29 mL/min: there are no RCT data on the use of NOACs for stroke prevention in AF patients with severe CKD or on renal replacement therapy (RRT). NOAC trials essentially excluded patients with a CrCl of <30 ml/min (except apixaban which was used at CrCl 25-30 mL/min) [6]. Doses of apixaban and edoxaban must be reduced by 50% and rivaroxaban by 25% in patients with CKD (stage 4, CrCl of 15-29 mL/min) [6]. Dabigatran is contraindicated in patients with creatinine clearance <30 ml/min (in Europe). In the USA, a low-dose dabigatran 75 mg regimen has been approved for patients with severe CKD (a CrCl of 15-29 mL/ min) [6].
• CrCl of 15 mL/min and on dialysis: rivaroxaban, apixaban and edoxaban are not recommended in subjects with CrCl <15 ml/min [6]. Studies with NOACs in patients with end-stage renal dysfunction and on dialysis are ongoing [6].

Hepatic impairment

These patients were excluded from RCTs with NOACs. Consequently, all NOACs are contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk [6].

Patient preferences for anticoagulation

Patient preferences for anticoagulation should be considered before making decisions about anticoagulation [6].

Major advantages of NOACs over VKAs in very old patients

The major advantages of NOACs over VKAs in very old patients are predictable pharmacokinetics, characterised by a fast onset of action (2-4 hours) compared with warfarin (72 hours), a short half-life and a wide therapeutic window, allowing a safe use without the need for anticoagulation monitoring, and a low risk of drug–drug or drug–food interactions. NOACs are effective for the prevention of stroke/SE and mortality in very old patients with AF [4].

The most recent guideline indications are:

• Oral anticoagulation therapy to prevent thromboembolism is recommended for all male AF patients with a CHA2DS2-VASc score of 2 or more (I A) or 1, considering individual characteristics and patient preferences (IIa B) and for all females with a CHA2DS2-VASc score of 3 or more (I A) or 2 considering individual characteristics and patient preferences (IIa B).
• NOACs (apixaban, dabigatran, edoxaban, or rivaroxaban) are recommended in preference to VKAs (I A) and, if the option is a VKA, the time in therapeutic range (TTR) should be kept as high as possible and closely monitored (I A).
• Antiplatelet therapy is not recom­mended for the prevention of cardioembolic stroke in atrial fibrilla­tion (class of recommendation III) [4].

The need to achieve a TTR >70% to ensure appropriate efficacy represents a major disadvantage for VKAs comparing to NOACs [4].

Regarding the bleeding risk in very old patients, NOACs have a net clinical benefit, mainly determined by the reduction in ICH compared to VKAs [4]. In patients >75 years, the risk of major GI bleeding was similar between the dabigatran 110 mg dose and warfarin, and greater with the dabigatran 150 mg dose, rivaroxaban and edoxaban, and inferior with apixaban irrespective of age [4].

A head-to-head comparison between NOACs is not currently available. A meta-analysis of eleven RCTs that included all four NOACs and analysed data of patients aged >75 years with AF has shown that every NOAC was at least comparable to VKAs in reducing the risk of stroke/SE [4].

Principal disadvantages of NOACs

The main disadvantage of NOACs is the absence of antidotes to reverse bleeding. However, a fully humanised antibody fragment called idarucizumab neutralises the effects of dabigatran. Fortunately, NOACs have a short half-life (between 5 and 17 hours), much lower than that of warfarin (36-42 hrs) [16].

Another disadvantage of the novel oral anticoagulants is their higher cost [15]. Current guidelines support the use of OACs in all patients >75 years for the prevention of ischaemic stroke in the absence of any clear contraindications [4].

Main recommendations in very old patients with AF

• If the risk of bleeding is not very high, anticoagulation is required.
• Current ESC guidelines recommend NOACs for anticoagulation, based on the positive results of the large outcome trials [6].
• To reduce the risk of bleeding: in patients taking NOACs, dosage should be carefully prescribed according to age, weight, and creatinine clearance, and the use of non-steroidal anti-inflammatory drugs or antiplatelet agents as well as alcohol abuse should be avoided [2].
• In patients with renal dysfunction: if the dysfunction is moderate, NOACs can be safe, but dose adjustment is required [2].
• Frailty, dementia, quality of life, life expectancy, and other comorbidities should be periodically re-evaluated [2].
• In patients at risk of falls, the beneficial effect of anticoagulation is higher than the risk of ICH and it is reasonable to recommend the use of NOACs over VKAs [2].
• Antiplatelet agents should only be considered in patients with concomitant vascular disease who refuse anticoagulants [2].

Conclusion

Except when there is a high risk of bleeding, OACs are associated with a net clinical benefit, which increases with age in patients with AF. No specific study has been performed in an elderly population, but different results of substudies in patients aged 75 years or older have shown that, compared with VKAs, the efficacy and safety of NOACs were consistent with those pertaining to the overall population. After assessment of renal function and evaluation of the specific clinical context, OACs can be considered as thromboprophylaxis for very elderly patients, with NOACs being the more favourable choice. Direct randomised comparisons of these novel agents are necessary to delineate clear roles for the individual agents.