Characteristic
Physical activity
Low
(N = 367)
Moderate
(N = 310)
High
(N = 311)
p-value
Age
78
76
71
NAa
TTRb
55%
57%
63%
<0.001
Bleeding
Major
18.8%
11.4%
6.2%
<0.001
Clinically
Relevant
22.1%
18.1%
13.4%
<0.001
Fall Related(non-major)
9.9%
3.9%
4.1%
<0.001
Frailty is increasingly recognized as an important comorbid condition. Defined as loss of physiologic reserve, which increases the risk of disability, frailty has been associated with restricted activity, reduction in activities of daily life, and a reduction in cognition and physical performance. It has been shown that frailty increases with age, from less than 4% in individuals 65–74 years old to 25% in individuals 85 years and older. Frail individuals have a 30% increased risk of developing venous thromboembolism compared to nonfrail individuals [11].
4.3 Testing for Venous Thromboembolism
A detailed review of imaging tests for pulmonary embolism and deep venous thrombosis is beyond the scope of this chapter. However, a brief review of the pretest probability model (PTP) and d-Dimer testing to exclude patients from deep vein thrombosis (DVT) is worthwhile.
Deep vein thrombosis (DVT) can be safely and reliably excluded in patients with a low clinical probability and a negative d-Dimer test [14].The d-Dimer is the final fragment of the plasmin-mediated degradation of cross-linked fibrin. d-Dimers are sensitive indicators of the presence of acute thrombus and can be measured with a simple blood test. d-Dimer is the most frequently used laboratory marker of coagulation and endogenous fibrinolytic breakdown of thrombus.
Carrier et al. [15] demonstrated in a review of 2696 patients that the negative predictive values of a low or unlikely PTP score in combination with a negative d-Dimer was 99% for all groups of patients, including the elderly. However, it has been demonstrated that d-Dimer concentration increases with age, thereby reducing the potential clinical value of the d-Dimer assay in the elderly [16].
Recently, Andro et al. [17] performed a review with the intent of improving the performance of d-Dimer in elderly patients. They concluded that an age-adjusted cut-off was appropriate and could be applied to all d-Dimer tests. They recommended that the optimal cut-off value (in mg/L) was equal to the patients’ age in years multiplied by ten in those over 50 years of age who had a low pretest clinical risk of DVT. This age-adjusted cut-off value was externally validated in retrospective studies applied mostly to outpatients with suspected DVT or PE. Various quantitative d-Dimer assays were used. Although their review confirmed the improved usefulness of the age-adjusted cut-off, prospective evaluations are necessary before definitive recommendations can be made.
4.4 Special Considerations in the Elderly
There are numerous age-related problems making the management of the elderly patient with venous thromboembolism more challenging. Elderly patients more often have multiple underlying comorbidities and take medications which alter the monitoring of vitamin K antagonists. The elderly population has a greater percentage of patients that weigh less than 65 kg, a higher percent use platelet inhibitor drugs, and renal dysfunction is more prevalent.
Elderly patients frequently have illnesses and are often immobilized prior to hospitalization. In a prospective study, Oger et al. [18] performed venous ultrasound examinations within 48 h of admission in medically ill patients. Asymptomatic DVT was found in 18% of patients older than 80 years of age, whereas no DVT was found in patients less than 55 years of age [19].
Renal dysfunction is an important risk factor for bleeding in patients receiving anticoagulation [15]. Elderly patients frequently can have normal creatinine levels, which are misleading, since their muscle mass diminishes and, therefore, serum creatinine diminishes. Hence, a serum creatinine within the normal range can exist despite abnormal renal function. Estimating the creatinine clearance is a more effective way to assess renal function. When properly evaluated, creatinine clearance alone has identified approximately 60% of critically ill medical patients aged 70 years and greater as having some degree of renal impairment [20].
4.5 Specific Anticoagulants
Despite the increased risk of thromboembolism in elderly patients, physicians in the real world environment are often reluctant to treat the elderly with anticoagulants because of concerns about bleeding. Recognizing the appropriate balance of risk of thrombosis versus bleeding and how to modify treatment offers patients the best chance of appropriate care
4.5.1 Unfractionated Heparin
Unfractionated heparin is the most commonly recommended anticoagulant for initial therapy in patients with acute VTE. Unfractionated heparin is affected by renal dysfunction. It has been shown that the elderly have an increased risk of bleeding with higher heparin levels after standard heparin doses [17] and that lower doses of unfractionated heparin are required to maintain therapeutic anticoagulation [21]. Since unfractionated heparin has a short half-life, can be rapidly adjusted, and can be fully reversed, it is usually recommended as the initial therapy in patients with renal dysfunction.
4.5.2 Enoxaparin
A number of studies have been performed evaluating the use of enoxaparin at therapeutic doses, adjusted doses, and prophylactic doses in patients with renal dysfunction. Lin et al. [18] published a meta-analysis of patients receiving enoxaparin with compromised renal function (creatinine clearance <30 ml/min). They found that when enoxaparin was administered at routine therapeutic doses, it was associated with a supratherapeutic anti-Xa level and a two to threefold increased risk of major bleeding. When the enoxaparin dose was adjusted, a therapeutic anti-Xa level was maintained without an increased risk of major bleeding. Patients with renal dysfunction accumulated enoxaparin even at prophylactic doses if they were not adjusted.
The manufacturer of enoxaparin recommends that in patients with a creatinine clearance of less than 30, prophylactic doses be reduced to 30 mg once daily and therapeutic doses be reduced to 1 mg/kg once daily.
4.5.3 Dalteparin
A small number of studies in patients of older age and renal impairment have been performed. Data suggest that the administration of prophylactic doses of dalteparin in patients with renal dysfunction is not associated with accumulation, and dose reduction is not recommended [22–24].
Limited data are available to guide therapeutic doses of dalteparin in patients with renal dysfunction [22–25]. These studies demonstrated that when peak anti-Xa levels were measured 4 h after dosing, no bioaccumulation of dalteparin was observed. The use of dalteparin reduced VTE events and was not associated with an increased risk of major hemorrhage. However, patients with profound renal dysfunction were excluded.
The manufacturer of dalteparin does not provide any information about dose adjustment in the elderly or renally impaired patients.
4.5.4 Tinzaparin
Evidence exists that the low-molecular-weight heparin tinzaparin may have a better safety profile in elderly patients with renal dysfunction. Tinzaparin is a larger molecule than other low-molecular-weight heparins, with an average molecular weight of 5500–7500 Da. A small study by Siguret et al. [26] evaluated patients with acute thromboembolic disease with a mean age of 87 years using a dose of 175 anti-Xa IU/kg daily for 10 days. The mean anti-Xa activity was measured as no correlation was found between anti-Xa activity and creatinine clearance. There were no major bleeding complications and no heparin induced thrombocytopenia.
A much larger study by Pautas et al. [27] evaluated the safety profile of tinzaparin in elderly patients with compromised renal function. Median age was 85, with mean creatinine clearance of 51. Patients were treated with tinzaparin 175 anti-Xa IU/kg daily. The measured anti-Xa activity did not correlate with age or creatinine clearance. Complications occurred in 1.5%, and heparin-induced thrombocytopenia occurred in 1%.
The results of these studies suggest that the larger molecular weight tinzaparin may be preferable in elderly patients with compromised renal function in whom a low-molecular-weight heparin therapy is preferred.
The manufacturer of tinzaparin does not recommend dose adjustment in elderly renally impaired patients.
4.5.5 Vitamin K Antagonists
Bleeding is the most feared complication of anticoagulation in patients, especially in older patients. The risk of bleeding significantly increases in older individuals. As mentioned earlier, age is a dose-related risk factor, with the elderly facing considerably increased risk. It has become apparent that age is also a major increased risk factor for bleeding complications. Vitamin K antagonists (VKA) belong to the group of medicines that cause the most adverse drug reactions in older patients [28].
Hutten et al. [29] performed a systematic review and concluded that in patients taking Vitamin K antagonists, there was a twofold increased risk of bleeding in patients greater than 60 years of age than those less than 60 years of age.
Across all age categories, the risk of hemorrhage is higher during the first 3 months after the initiation of VKAs . In the ISCOAT trial, major and minor bleeding complications were 11.0 per 100 patient years in the first 3 months compared to 6.3 per 100 patient years, thereafter (p < 0.001). Older patients are frequently at higher risk for falls than younger patients and, therefore, are presumed to be at an increased risk of intracranial hemorrhage. Often, the risk for falls and subsequent intracranial bleeds are cited as contraindications to antithrombotic therapy in the elderly. However, there are few data to substantiate this concern. Bond et al. [30] evaluated the risk of hemorrhagic complications in patients who fall. In general there is a 5–10% risk of major hemorrhagic injury due to falls; however, patients who take warfarin were not at higher risk than those not taking an anticoagulant [29]. Man-Son-Hing et al. [31] calculated that patients taking warfarin for atrial fibrillation would have to fall 295 times per year for warfarin not to have a favorable risk-benefit ratio.
The rate of major bleeding of patients of all ages being treated with VKAs ranges from 1.2% to 7.4% per year, depending upon the study. Clinical trials, however, report major bleeding rates between 0.5% and 4.2% per year. The bleeding rates in major trials may underestimate those in broad-based clinical practice, due to patient selection and protocols for careful monitoring.
Table 4.2 summarizes selective studies which reveal information regarding age-related bleeding in patients on Vitamin K antagonists. Many of the patients treated in these trials were those with atrial fibrillation; however, the age distinction is what appears important as related to age-related risk.
Table 4.2
Age-related major bleeding on vitamin K antagonists
Clinical trial | INR range | Age categories (years) | Incidence major bleed | Ratio of incidence older: younger |
|---|---|---|---|---|
EAFT [32] | 2.5–3.9 | >75 ≤75 | Overall 2.8% | 3.6 |
SPAF [33] | 2.0–4.5 | >75 ≤75 | 4.2% 1.7% | 2.6 (p = .009) |
ISCOAT [34] | 2.0–4.5 | ≥75 <70 | 2.1% 1.1% | p = 0.19 |
ISCOAT [35] | 1.0–3.5 | >75 ≤75 | 5.1% 1.0% | 6.6 |
Copeland et al. [36] | 2.0–3.0 | ≥75 60–69 | 2.9% 2.8% | p = 0.96 |
Intracranial hemorrhage (ICH) represents a major cause of iatrogenic death in patients treated with VKAs. In the SPAF II trial, advanced age was a predictor of ICH . The rate of ICH was 0.6% per year in patients receiving warfarin who were less than 75 years of age and 1.8% per year in those greater than 75 years of age (p = 0.05) [38]. In the ISCOAT study, ICH was significantly more frequent in the elderly (≥75 years vs. <70 years, RR 6.5; p = 0.047).
There are numerous factors that put elderly patients at risk of bleeding from VKAs. Comorbidities such as impaired liver function, congestive heart failure, diarrhea, and fever have been identified as risk factors for high international normalized ratios (INRs). Acute illness and deterioration of chronic comorbidities as well as changes in weight, physical activity, dietary intake, and alcohol consumption are all contributory. Interestingly, poor compliance is not an issue in most elderly patients. These factors are superimposed upon the generally increased risk of ICH with VKAs due to their intrinsic inhibition of tissue-factor/Factor VIIa complexes. Tissue factor/Factor VIIa complexes are present in high concentrations in the brain, which have neuroprotective properties in the event of injury. Inhibition of this neuroprotective pathway by VKAs may account for the differential rates of ICH between direct oral anticoagulants (DOACs) and VKAs.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
