Anticoagulant response differs in the elderly
VKAs such as warfarin have been the treatment of choice in past decades when chronic anticoagulation was needed. However, coumarin therapy is complex, especially in the elderly, due to factors such as wide variation in the dosage among patients, multiple drug and food interactions, and bleeding complications. Several studies have shown that older individuals have increased sensitivity to its anticoagulant effect.32 Froom et al. indicated that for every 10‐year increase in age, there was a 15% increase in the risk of International Normalized Ratio (INR) values ≥5 and that elderly age was associated with increased maximum INR value, decreased minimum value, decreased weekly warfarin dose, and increased number of tests per year to evaluate INR.33 It seems that oral anticoagulant requirements decline33,34 with age. In another paper, Schwartz reported that individuals ≥75 presented 50% variability in the daily warfarin dose compared to those <35 for an equivalent INR,35 as Routledge had proposed before.32
Table 25.1 Characteristics of bleeding risk assessment tools.
| Assessment tools | Descriptions and scores | Defined cut‐off values | Advantages (A) and disadvantages (D) |
|---|---|---|---|
| HAS‐BLED | Hypertension, abnormal renal/liver function (1 point each), stroke, bleeding history or predisposition, labile INR, elderly drugs/alcohol concomitantly (1 point each); maximum 9 points. | 0‐2; >=3 | Simple and easy to operate; balanced predictive sensitivity and specificity (A) |
| HEMORR2AGES | Liver/renal disease, ETOH abuse, malignancy, age >75, low platelet count or function, rebleeding risk, uncontrolled hypertension, anaemia, genetic factors (CYP2C9), risk of fall or stroke; 1 point for each risk factor present and 2 points for previous bleed. | 0–1; >=2 | Including geriatric syndromes such as risk of fall and cognitive impairment (A) More complex, with conventional genetic polymorphisms testing limiting its clinical application (D). |
| ATRIA | Anaemia (3); severe renal disease (GFR <30 ml/min) (3); age >=75 (2); any prior bleeding (1); diagnosed hypertension (1). Maximum 10 points. | <4; >=4 | High specificity (A). |
| ORBIT | Age ≥75 (1); abnormal haemoglobin/hematocrit (2); bleeding history (2); insufficient kidney function (GFR <60 ml/min/1.73 m2) (1); treatment with antiplatelets (1). Maximum 7 points. | <3; >=3 | High specificity. Similar discrimination with better sizing than HAS‐BLED and ATRIA scores, according to ROCKET‐AF trial (A). |
| ABC bleeding | Age (y); biomarkers (growth differentiation factor‐15, high‐sensitivity cardiac troponin T, haemoglobin), previous bleeding. | 1%, 1–2%, and >2% risk for bleeding within 1 year | More appropriate 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
