results than HAS‐BLED and ORBIT, according to ARISTOTLE and RE‐LY trials (A). Limited advantages in real‐world cohort owing to patients aging and progression of risk factors (D).
A crucial factor involved in the different anticoagulant response in the elderly is renal function. Limdi et al. reported 9.5% lower warfarin dose requirement in patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] of 30–59 ml/min/1.73 m2) and 19% lower warfarin dose requirements in patients with severe kidney impairment (eGFR lower than 30 ml/min/1.73 m2)36, although the full responsible mechanism is not known. This condition is also important in anticoagulation treatment with low‐molecular‐weight heparins (LMWHs) because they are predominantly eliminated by renal excretion, and kidney impairment could lead to prolonged half‐time and accumulation. To prevent these adverse effects, we may reduce dosage or increase the time between doses.37 However, current data is insufficient to establish LMWH dose‐adjustment in older patients with renal impairment.38
Nowadays, LMWH and unfractioned heparin (UFH) are the preferred anticoagulants in situations involving surgery or clinical instability (such as cancer, sepsis, impossibility of oral intake, malabsorption, etc.). UFH travels through the blood bound to many plasma proteins, and this may explain its unpredictable pharmacokinetics – especially in the elderly – due to greater variability in these determinants with older age.37 It has been described as a higher bleeding risk in older adults. Compared to younger adults, patients over 72 have a higher incidence of bleeding when initially treated with UFH for venous thromboembolism, with incidence rates of 14.1% versus 7.1% for a bleeding event and 11.1% versus 3.1% for major bleeding event.39 In addition, in older patients, standard heparin doses that are not adjusted to weight result in higher heparin levels and a tendency for higher APTT.39 Unless there is an absolute contraindication, LMWH has generally replaced UFH and should be preferred because of the predictable pharmacokinetics, efficacy, and safety.37
Finally, the new family of DOACs includes four drugs: dabigatran (an active direct thrombin inhibitor), apixaban, edoxaban, and rivaroxaban (direct factor Xa inhibitors). For dose adjustment of DOACs, we must consider factors such as age, weight, renal function, and concomitant treatment, as summarized in Table 25.2.40
Table 25.2 Usual and adjusted dosages for DOACs.
| DOAC | Dabigatran | Rivaroxaban | Apixaban | Edoxaban |
|---|---|---|---|---|
| Usual dosage | 150 mg/12 h | 20 mg/24 h | 5 mg/12 h | 60 mg/24 h |
| Adjusted dosage | 110 mg/12h:Age ≥80CCr 30–49 ml/minConcomitant treatment with verapamil | 15 mg/24h:CCr 15–49 ml/min | 2.5 mg/12h:Two of the following:Age ≥80Weight ≤60 kgSerum creatinine ≥1.5 mg/dlCCr 15–29 ml/min | 30 mg/24h:CCr 15–40 ml/minWeight ≤60 kgConcomitant treatment with cyclosporine, dronedarone, erythromycin, ketoconazole |
Anticoagulants are effective in the elderly
As the risk of stroke rises dramatically with age, the absolute stroke reduction by oral anticoagulants (OACs) seems to be highest in elderly populations, outweighing the bleeding risk. Singer et al. found that the average net benefit of warfarin anticoagulation for AF was greater, the older the patient, with a substantially greater net clinical benefit for the oldest age group (≥85), suggesting that age 85 or older may be an additional risk indication for anticoagulation.41 Warfarin therapy for three months is preferred in patients age ≥80 with unprovoked VTE.42
The randomised Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial was conducted on AF patients age ≥75. This trial showed that, compared to aspirin 75 mg once a day, the use of warfarin (target INR 2–3) was associated with a significant 52% relative risk reduction of the composite outcome measure, including stroke, systemic embolism, and intracranial bleeding.43 In a sub‐analysis from PREFER in AF (PREvention oF Thromboembolic Events‐European Registry in Atrial Fibrillation), data from 505 patients over 85 years old were analysed. It was found that the incidence of thromboembolic events was 2.8% per year without oral anticoagulant treatment versus 2.3% per year with OAC, which is equal to a 0.5% absolute risk reduction. Moreover, in very old patients, the risk of major bleeding was similar in patients on OAC and those on antiplatelet therapy or without antithrombotic treatment.15
Current evidence shows that DOAC efficacy in elderly patients was similar or superior to VKAs, as a result of summarized data from a meta‐analysis of 11 randomised trials comparing DOACs with VKAs in older patients (≥75) treated for acute venous thromboembolism or stroke prevention in AF.44 In the past decade, the four drugs were evaluated in large Phase III trials as alternatives to VKAs in patients with AF at risk of stroke, proving that DOACs are non‐inferior, if not superior, to warfarin for the prevention of stroke/systemic embolic events and for reducing bleeding.12 However, the results in elderly patients varied according to which drug was used, so different meta‐analyses have evaluated results in patients over 75. All DOACs demonstrated a similar‐to‐lower risk of stroke compared to the warfarin, while only apixaban and edoxaban significantly reduced major haemorrhagic events.2,45‐47
Optimizing the risk‐benefit equation in the elderly
When facing anticoagulation in an older patient, the high risk of bleeding may outweigh the benefit of preventing stroke. More than 50% of patients over 65 with atrial fibrillation do not receive anticoagulant treatment, when the guidelines recommend almost systematic anticoagulation of patients in this age group.48
As mentioned earlier, the risk of bleeding increases with age. Physicians must minimize it by controlling the degree of anticoagulation, its duration, and factors that may predispose to bleeding (falls, digestive tract injury, skin hematomas).
Intensity of anticoagulation
A high INR is one of the most critical factors related to the risk of bleeding – hence the importance of maintaining the lowest effective intensity of anticoagulation in the elderly. Several studies have reported a curvilinear relationship between the degree of anticoagulation and the risk of bleeding (Figure 25.1).49
Currently, a target INR of 2.5 (2 to 3) is recommended for treatment of VTE and primary and secondary stroke prevention in individuals with non‐valvular AF. Higher‐intensity anticoagulation may be needed under specific circumstances, such as preventing thromboembolism in those with prosthetic heart valves (2.5–3.5) or recurrent thromboembolism.50
Figure 25.1 Relationship between the intensity of anticoagulation and the risk of thromboembolism (TE) and bleeding in 1865 patients receiving oral anticoagulants after insertion of St Jude prosthetic heart valves. The single open circle represents 12 patients who received