Anticoagulation in the elderly
Due to the improvement of healthcare, education and life standard in the industrial nations, the general population is ageing and surviving well into their eighties and beyond. However, ageing is a complex process, not rarely coupled with reduced mobility and greater frailty, with a tendency to fall. These are the most cited arguments to withhold anticoagulation from the elderly, but with the possible consequence of devastating stroke and severe disability. Ironically, because of their higher risk of stroke, the net benefit of antithrombotic therapy may be greater in octogenarians than in younger patients. Physicians’ aversion to cause a hemorrhage may account for the underuse of oral VKA therapy in the very elderly because it is recognized that increasing age is a risk factor for
bleeding, especially in those aged over 85 years. Indeed, there are conditions which appear primarily in elder patients increasing the risk for overdosing warfarin with the consequence of severe bleeding: a)
pharmacodynamic issues, as patients with low body weight or low serum albumin, perhaps due to malnutrition, may require lower doses of warfarin; b) comorbid conditions like liver diseases, congestive heart failure or acute infectious diseases; and c) polypharmacy, especially in patients with self-medication of herbal compounds or unkown vitamin supplementation by caring family members.
Due to the higher prevalence of cardiovascular diseases, platelet inhibitors such as aspirin or clopidogrel or, recently, prasugrel are often prescribed for older patients. Concerning the latter, the TRITON–TIMI 38 study demonstrated a reduction in the risk of myocardial infarction
and coronary stent thrombosis. However, the elderly were one of three subgroups in this trial which ap-
peared to be particularly prone to serious bleeding. Therefore, it would be best to avoid prasugrel in
such patients, especially in those who receive warfarin.
One of the most decisive factors in terms of OAC is the elderly patients’ propensity to fall although the real impact of falls on morbidity including intracranial hemorrhage among patients treated with warfarin remains uncertain. Man-Son-Hing and coworkers stated that persons taking warfarin must fall about 295 times in a year before developing the most serious type of haemorrhage associated with anticoagulation, that is, subdural haematomas given that falls (1 in 10) usually cause other major injuries (i.e. fractures) and, therefore, persons who fall are much more likely to suffer
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other serious morbidities.
Recently, the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA, reaffirmed that warfarin is superior to ASA in stroke prevention also in an elderly population aged > 75 years. On the other hand, the risk of major hemorrhage, including intracranial and hemorrhagic stroke, was similar in both the aspirin (2.0% per year) and warfarin (1.9% per year) treated patients. The authors recommended the use of anticoagulation (warfarin) for all people aged over 75 years who have atrial fibrillation, unless there are contraindications or the patient decides that the size of the benefit is not worth the inconvenience of the treatment.
Bleeding risk under oral anticoagulation
The benefits of anticoagulation do not come without a risk, especially in the presence of comorbid conditions like recent intracerebral or gastrointestinal hemorrhage or, stroke, uncontrolled hypertension, liver disease, cancer, and renal insufficiency . The most dangerous and, therefore, the most feared bleeding complication associated with OAC is intracranial hemorrhage. Fortunately, this condition is rare,but the most common bleeding sites are the gastrointestinal or genitourinary tract. Notably, bleeding phenomena can also often be seen in the microcirculation but they occur independently of the intensity of treatment and are not predictive for future clinically obvious hemorrhage. A meta-analysis of six clinical trials on patients on OAC due to AF with a mean age of 71.7 ± 8.8 revealed major bleeding in 2.2, hemorrhagic stroke in 0.5, or lethal bleeding in 0.4 patients per 100 patient-years. The use of oral anticoagulant significantly increased the rate of major bleeding, with 15.3% of all major bleeding episodes being lethal. On the other hand, patients with a previous history of stroke or transient ischemic attack had an absolute risk reduction of 6.0% per year (number needed to treat (NNT) = 17) while those patients without previous cerebrovascular disease had an absolute risk reduction of 1.2% per year (NNT = 83). Comparably, in the Stroke Prevention in Atrial Fibrillation Trial, the rate of major bleeding in the warfarin group was 2.3% per year. However, for those younger than 75 it was 1.7% and for the elder it was 4.2% per year.
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Hylek and coworkers studied a cohort of 472 patients of whom one third was ≥ 80 years of age compared with a total of 20 patients >75 years in the pooled analysis of the 5 randomized trials that proved efficiacy of anticoagulation, and 91% had ≥ 1 stroke risk factor. The cumulative incidence of major hemorrhage for patients ≥ 80 years of age was 13.1 per 100 person-years and 4.7 for those <80 years of age (P=0.009). A further important finding to be emphasized from Hylek et al. is the enhanced risk of bleeding in patients while starting anticoagulation therapy.
This phenomenon, although known, has been underappreciated by many clinicians. In the SPORTIF III and V trials in which the direct thrombin inhibitor ximelagatran was compared to warfarin for stroke prevention in AF, the rate of intracranial hemorrhage was 0.4%, and the rate for major hemorrhage was 2.5% per year in the warfarin group. In a pooled analysis of patients ≥ 75 (n=2804) and <75 (n=4525) years, ximelagatran was as effective as warfarin in reducing stroke/systemic emboli in the elderly (2.23%/year with ximelagatran vs 2.27%/year with warfarin) as in younger patients (1.25%/year vs 1.28%/year). Total bleeds were significantly lower with ximelagatran compared with warfarin in elderly (40% vs 45%, =0.01) and younger (27% vs 35%, P<0.001) patients.
The results of these clinical trials also clearly indicate that the risk of bleeding depends on warfarin treatment intensity. If an INR value exceeds 4, the risk of hemorrhage is markedly increased. Koo and coworkers reported on a cohort of patients with anticoagulation-associated hemorrhage, in which excessive anticoagulation contributed independently to increased morbidity and mortality . It must be mentioned that overutilization of warfarin in patients at low risk of thrombotic stroke could be demonstrated in the Euro Heart Survey on Atrial Fibrillation and may also contribute to an increased morbidity due to anticoagulation. Even with the use of the more strict 2001 guidelines, the authors reported that 50% of AF patients without stroke risk factors were being treated
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with vitamin K antagonists.
Comparable to the existing stroke risk stratification schemes there are bleeding risk models:
Beyth and coworkers identified four independent risk factors for bleeding: age ≥ 65 years, history of
gastrointestinal bleeding, history of stroke, and one or more of four specific comorbid conditions. They found a cumulative incidence of major bleeding at 48 months of 53% in high-risk patients (three or four risk factors), 12% in middle-risk patients (one or two risk factors), and 3% in low-risk patients (no risk factors).
Kuijer and colleagues developed another prediction model based on age, gender, and the presence of malignancy. In patients classified at high, middle, and low risk, the frequency of major bleeding was 7%, 4%, and 1%, respectively, after 3 months of therapy. Comparable bleeding rates for comparable risk classes were found by Shireman and colleagues (5.4%, 2.0%, and 0.9%, respectively, after 90 days of treatment) using the following criteria: age >70 years; gender; remote bleeding; recent bleeding; alcohol/drug abuse; diabetes; anemia; and antiplatelet use. Gage and colleagues gave 2 points for a prior bleed and 1 point for each of 10 further stroke risk factors and claimed the highest accuracy of all other bleed prediction schemes. Nevertheless, none of these risk prediction schemes has been fully validated in large prospective cohorts of AF patients.
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