actual guidelines and recommendations commonly extrapolate study results from younger patients to the sicker elderly because elderly multimorbid patients are underrepresented in many randomized and nonrandomized clinical studies of VTE1 and AF.2
Many landmark clinical trials of VTE prophylaxis and treatment excluded patients with an increased bleeding risk, renal failure, or recent stroke. In the last century, several prospective cohort studies and registries, such as the RIETE registry,3 the Elderly Patients followed by Italian Centres for Anticoagulation (EPICA) study,4 and the SWIss venous Thromboembolism Cohort (SWITCO65+)5 have been carried out to study short‐ and long‐term clinical outcomes in older patients with VTE.
AF is a major risk for thrombotic disease, and many patients with AF are managed with anticoagulation for primary or secondary prevention of these events. Nonetheless, studies specifically designed in the elderly population are not yet available, and the current evidence excludes multimorbidity patients, polypharmacy, geriatric syndromes and evaluates benefits using health indicators with low clinical impact in this population.6–8 In addition, the mean age of the patients included in clinical trials is 5 to 10 years younger than the mean age of real‐life patients with non‐valvular atrial fibrillation (NVAF). Because of that, the current guidelines cannot make strong recommendations for individuals 85 years of age or older.9,10 In an effort to solve this lack of evidence, data from subgroup phase III pivotal trials have been used, including over 30,000 patients older than 75, to demonstrate the efficacy of direct oral anticoagulants (DOACs) in comparison to vitamin K antagonists (VKAs), showing an equal safety profile in older and younger people11–13. The ARISTOPHANES (Anticoagulants for Reduction in Stroke: Observational Pooled analysis on Health Outcomes and Experience of Patients [NCT03087487]) study aimed to provide complementary information for older patients (age ≥80) by evaluating and comparing the rates of stroke/systemic embolism and major bleeding among NVAF patients newly prescribed apixaban, dabigatran, rivaroxaban, or warfarin.14 Additionally, extracted data from two large real‐world prospective European registries (PREFER in AF and Prefer in AF PROLONGATION15) evaluated the net clinical benefit at one year with DOACs versus VKAs; the results showed that major bleeding with DOACs was also lower in higher‐risk patients with low body mass index or age ≥85.16
This family of oral anticoagulants has been available in Europe since 2011 with different therapeutic indications: (i) prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery; (ii) prevention of stroke and systemic embolism in adult patients with non‐valvular atrial fibrillation (NVAF), and one or more risk factors (such as prior stroke or transient ischaemic attack [TIA]), age ≥75, hypertension, diabetes mellitus, or symptomatic heart failure (NYHA Class ≥II); and (iii) treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE in adults. The emergence of this novel oral anticoagulant offers patients and providers options to consider beyond warfarin.17 Decision‐making should address safety, tolerability, efficacy, price, simplicity of use, and patient preference, so decisions should be individualized for each patient.
The elderly are more prone to thromboembolism
The elderly are more prone to arterial as well as venous thromboembolism, and thrombotic disease is the commonest cause of hospital admission, disability, and death in patients over 50 in the developed world.
The incidence of a first acute VTE, defined as DVT and/or PE, rises exponentially with age, ranging from approximately 1 per 10,000 subjects age 25–30 to a rate of nearly 8 per 1000 in the population 85 and older.18 Overall, >60% of all VTE events occur in people ≥65.19
Several factors could explain the higher incidence of thromboembolism in the elderly:
1 Increased prevalence in the elderly of cancer, stroke, heart failure, recent myocardial infarction, severe infection, diabetes mellitus, obesity, chronic obstructive pulmonary disease, inflammatory bowel disease, frailty, hospitalization, nursing home residence, immobilization, and history of VTE, all of which are considered risk factors for VTE.1 Elderly patients are more likely to have cancer‐related VTE than younger patients.
2 Atrial fibrillation (AF) is the most common arrhythmia in our daily clinical practice, affecting 4.5 million people in Europe and approximately 33.5 million people globally.20 Estimates suggest a significant increase in AF incidence with age from 4.1/1000 under age 75 to 26.3/1000 in people older than 75.21 In the same way, its prevalence rises from 0.1% in people under 55 to 9% of those older than 80. Due to the increase in life expectancy, the number of elderly people over 80 with NVAF will increase fourfold by 2050; therefore, this group will represent over 50% of total patients with this arrhythmia, and the stroke risk will increase 25–36% in elderly individuals between 80 and 89.21
3 Age‐related endothelial dysfunction and alterations in platelet function may contribute to the increased risk of VTE in the elderly.22 The levels of several plasma components (fibrinogen, factor VII, factor VIII, D‐dimer, and homocysteine) increase with age, although it is unclear whether this has a clinically meaningful impact on the risk of VTE.22
4 Hyperglycaemia is associated with enhanced thrombin formation in patients with diabetes or cardiovascular disease, which are more common in older people, increasing the risk of thromboembolic events.23
The elderly are more prone to haemorrhage
Bleeding risk is the antithrombotic treatment most important complication, so this requires us to personalize decision‐making, especially in elderly patients with multimorbidity, geriatric syndromes, frailty, or disability. Due to the higher prevalence of comorbid diseases, drug interactions, and age‐related conditions, the risk of anticoagulation‐related major and clinically relevant non‐major bleeding is increased in patients 65 and older versus younger patients. Schulman has comprehensively summarized the increasing body of evidence indicating that age is an independent risk factor for major bleeding in patients receiving oral anticoagulant therapy, with an average twofold increase.24
Increased age also appears to be a risk factor specifically for intracranial haemorrhage. Age ≥75 is associated with at least a two‐fold increase in intracranial haemorrhage risk due to high‐risk conditions such as cerebral amyloid microangiopathy and leukoaraiosis.25,26
Several scores were developed to help measure bleeding risk in AF27, with no intention of contraindicating oral anticoagulation but rather to modify it with our intervention to increase the anticoagulation therapy’s security profile. The most widespread is the HAS‐BLED score, which includes different determinants, all of which can be modified except age. Other scores, like HEMORR2AGES, add aspects that are included in the Comprehensive Geriatric Assessment (CGA), such as falls and cognitive impairment, which are usually assessed and managed by a geriatrician. The ATRIA Bleeding Risk Score takes into account five parameters and stratifies the bleeding risk into three levels.28,29 The ORBIT risk score proposes five determinants: age, anaemia, previous bleeding episodes, renal impairment, and antiplatelet therapy. It demonstrates similar discrimination with better sizing than HAS‐BLED and ATRIA scores, according to the ROCKET‐AF trial.30 The ABC‐bleeding score includes age, previous bleeding episodes, and three serum biomarkers (haemoglobin, troponin T, and GDF‐15 or cystatin C/creatinine clearance) and obtains more appropriate results than HAS‐BLED and ORBIT, according to the ARISTOTLE and RE‐LY trials28; but the biomarkers are not standardized, and there is no defined cut‐off point (class IIb indication) (Table 25.1). The results of a recent study suggest that the bleeding risk assessment tools with high sensitivity should be used for AF patients at high risk of bleeding, and bleeding risk assessment tools with high specificity
