Treatment of venous thromboembolism in elderly patients in the era of direct oral anticoagulants

Abstract

The incidence of venous thromboembolism (VTE) and VTE-related morbidity and mortality increase with advancing age. Over the past decade, substantial advances in the treatment of VTE have been achieved. Most notably, direct oral anticoagulants (DOACs) were introduced, which offer simple treatment regimens across a broad spectrum of patients with VTE and have become the first-choice anticoagulants in many individuals in this population. Even though elderly patients are underrepresented in clinical trials, the extrapolation of overall study results to the elderly subpopulation can be considered justified regarding acute VTE treatment and the choice of anticoagulant agent. In the elderly, DOACs are not only associated with a lower bleeding risk but they also appear to be even more efficacious than vitamin K antagonists in preventing recurrent VTE during the acute treatment period. Determining the optimal treatment duration is the most challenging aspect of VTE management in elderly patients. The risk of bleeding increases with advancing age, and several risk factors for recurrent VTE after stopping anticoagulation are also more frequent in the elderly. Clinical decision rules estimating the risk of recurrent VTE and bleeding have limited utility in elderly patients. Shared decision making considering patients’ preferences and values is therefore crucial to help determine individual treatment duration in these patients.

Introduction

Venous thromboembolism (VTE), defined as pulmonary embolism (PE) or deep vein thrombosis (DVT), is a common disease in the elderly population. The incidence of VTE increases exponentially with age and is 4 to 12 per 1000 person-years in those aged 80 years and older, which reflects a 5- to 10-fold higher risk of developing VTE compared with individuals aged 40 to 50 years.¹ Whereas the incidence of DVT has remained stable or even decreased over time,^2,3 that of PE has increased in both the younger and elderly populations in recent decades.³ The latter is partly related to the widespread use of sensitive multidetector computed tomography pulmonary angiography, which results in diagnosing smaller, potentially insignificant PE more frequently than with the use of single-detector computed tomography or ventilation-perfusion scanning.^4-6 Not only the incidence of VTE but also its clinical presentation, prognostic factors, and outcome rates differ between younger and older patients with acute VTE.^7,8 Furthermore, evidence regarding the optimal treatment of VTE in the elderly, including first-choice anticoagulant agents and duration of anticoagulation, is limited, because elderly patients have been underrepresented in clinical trials.^7,9 As a consequence, the 2016 American College of Chest Physicians (ACCP) and the 2019 European Society of Cardiology (ESC) guidelines do not make specific recommendations for elderly patients and only acknowledge the higher risk of bleeding in this population.^10,11

Over the past decade, substantial advances in the treatment of VTE have been made.¹² Most notably, direct oral anticoagulants (DOACs) were introduced, which offer simple treatment regimens across a broad spectrum of patients with VTE. In light of the significant proportion of the elderly among patients with VTE and their distinct risk of VTE-related outcomes, in this review, we summarized the evidence of VTE treatment with DOACs in elderly patients and discussed situations in which other anticoagulants may be preferred.

Definition of the elderly and analyses for this review

The United States Census Bureau defines the elderly as the population aged 65 years and older; most of other developed countries have accepted similar definitions. Definitions of the elderly adopted in studies in the field of VTE are more heterogenous. Subgroup analyses of recent pivotal randomized controlled trials used the age of 75 years as a cutoff; in recent cohort studies, cutoffs ranged from 60 to 80 years. In this review, we reported results using the definition of the pertinent reference.

Regarding previously published evidence, we also reported pooled risk ratios of phase 3 trials of DOACs for the treatment of VTE by age. Relative risks with corresponding 95% CIs were calculated based on crude event numbers reported in the trial publications, in which the intention-to-treat population was used for efficacy outcomes, and the safety population, for bleeding outcomes. If not available in the original publication, event numbers were extracted from a meta-analysis that included subgroup analyses based on additional information from the corresponding authors and sponsors of the study.¹³ Pooled relative risks were calculated using the Mantel–Haenszel method. The between-study variance was estimated using the DerSimonian–Laird method, and heterogeneity was reported with the I² statistic. All analyses were performed with the R software, version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria),¹⁴ using the meta package, version 4.9–7.¹⁵

Pharmacokinetics and pharmacodynamics of direct oral anticoagulants

Direct oral anticoagulants specifically target single steps in the coagulation pathway by direct inhibition of activated factor X (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran). Rivaroxaban at doses of 15 mg or 20 mg daily needs to be taken with food, as this increases its bioavailability (66% without food; 80% to 100% with food), which is not required for other DOACs.¹⁶ Dabigatran is a prodrug and it should not be crushed before ingestion, as this results in a 75% increase of its bioavailability.¹⁶ Rivaroxaban, apixaban, and edoxaban can be administered in the crushed form if patients are unable to swallow Tablets.^17-19 Direct oral anticoagulants have a dual mode of elimination including hepatic metabolization and renal excretion at different degrees depending on the drug used. The proportion of renal clearance to nonrenal clearance of the absorbed DOAC is 27% for apixaban, 35% for rivaroxaban, 50% for edoxaban, and 80% for dabigatran.¹⁶ Elimination half-lives in persons with normal kidney function range between 5 to 9 hours (rivaroxaban) and 12 to 17 hours (dabigatran). Exposure to DOACs increases with age, but this association is confounded by the influence of age on the kidney function. For instance, the area under the concentration-time curve for a single 10-mg dose of rivaroxaban increased by 41% on average in healthy elderly individuals (weighted mean age, 77 years) compared with younger persons (weighted mean age, 32 years), which was, however, at least partially explained by the lower creatinine clearance in the elderly (weighted mean clearance, 55 ml/min vs 121 ml/min).²⁰ Similarly, point estimates of edoxaban trough levels in patients with atrial fibrillation were higher in the elderly, irrespective of the dose regimen adopted,²¹ and edoxaban trough concentrations in patients receiving edoxaban for atrial fibrillation at a dose of 60 mg daily showed an inverse relationship with kidney function.²² Despite being higher on average, DOAC exposure and trough levels in the elderly were within the observed interindividual variability of the overall study populations.^20,21,23-26 Accordingly, dose adjustment based on age was not required in any of the phase 3 trials of DOACs for the treatment of VTE. Of note, the product monograph of dabigatran recommends adjusting the dose of dabigatran to 110 mg twice daily for VTE treatment in patients aged 80 years and older and in those aged 75 years and older with 1 or more risk factors for bleeding. Dabigatran at a dose of 110 mg twice daily has not been assessed for VTE treatment in a clinical trial, but the recommended dose reduction might be justified by results from the pooled analysis of phase 3 trials for the treatment of acute VTE, which showed that the bleeding risk reduction with dabigatran was influenced by age. Compared with vitamin K antagonists (VKAs), dabigatran was associated with a reduced risk of bleeding in younger patients, but this effect was inverse in patients above 85 years in whom the use of VKAs was related to a lower risk of bleeding than that of dabigatran.²⁷

Direct oral anticoagulants have fewer food and drug interactions compared with VKAs; still, such interactions have to be considered before prescribing a DOAC.¹⁶ This is particularly important in elderly patients, since the number of medications and comorbidities increases with age. The most relevant drug–drug interactions leading to clinically significant alteration in DOAC plasma levels concern drugs metabolized by cytochrome P450 3A4 in patients on apixaban and rivaroxaban or potent P-glycoprotein inhibitors in patients on any DOAC. No studies have indicated that drug–drug interactions differ between elderly and younger patients, but there is insufficient evidence to draw any firm conclusions.²⁸

In essence, predictable pharmacodynamics and pharmacokinetics allow for a fixed-dose regimen across all patients eligible for DOAC treatment. Edoxaban is the only DOAC for acute VTE treatment requiring dose adjustment in certain circumstances including any of the following: impairment of kidney function (ie, creatinine clearance of 30 to 50 ml/min), body weight below 60 kg, and concomitant treatment with potent P-glycoprotein inhibitors. It has not been evaluated in a clinical trial whether the dabigatran dose adjustment in elderly patients, as recommended in the product monograph, is appropriate for the treatment of acute VTE, but it may be justified by a secondary analysis of the RE-COVER trials.²⁷ On the other hand, inappropriate DOAC dose reduction during the initial and long-term treatment of VTE occurs more frequently in elderly patients and is associated with an increased risk of recurrent VTE.²⁹

Treatment of acute venous thromboembolism

The choice of treatment for acute VTE depends on clinical presentation, site of VTE, and benefits and risks of anticoagulation, which should be carefully weighed when determining the optimal therapeutic approach.

Thrombolysis

Hypotension is associated with increased short-term mortality in patients with acute PE.^30,31 Guidelines recommend systemic thrombolysis in such patients to achieve rapid improvement of pulmonary obstruction and subsequent reduction of the risk of PE-related death.^10,11 This benefit comes at the cost of an increased risk of bleeding, which is higher in patients above 75 years of age than in younger patients (13% vs 3% for major bleeding; 1.4% vs 0.5% for intracranial bleeding).^32,33 The 2016 ACCP guidelines therefore specify that age over 75 years is a relative contraindication to thrombolysis, whereas the 2019 ESC guidelines do not make any age-specific recommendations.^10,11 Data from the Nationwide Inpatient Sample, collected between 1999 and 2008, indicate that unstable elderly patients are less likely to undergo systemic thrombolysis than younger patients regardless of the presence of comorbidities.³⁴ Whether this represents undertreatment or appropriate withholding of systemic thrombolysis due to an unacceptably high bleeding risk remains to be determined.

In normotensive patients with PE, primary thrombolysis is not recommended in any age group.^10,11 The PEITHO (Pulmonary Embolism Thrombolysis) trial randomized hemodynamically stable PE patients with increased troponin levels and right ventricular dysfunction on imaging to systemic thrombolysis plus heparin or placebo plus heparin.³⁵ The risk of death or hemodynamic deterioration in patients over 75 years of age was similar between the thrombolysis and placebo groups (4.3% vs 6.7%), but thrombolysis was associated with an increased risk of major bleeding (11.1% vs 0.6%).³⁵ Preliminary evidence indicates that bleeding risk could be mitigated by reduced-dose or catheter-directed thrombolysis,^36,37 but methodologically rigorous trials are required before such treatment can be recommended.

In patients with iliofemoral DVT, catheter-directed thrombolysis in addition to anticoagulation reduced the risk of postthrombotic syndrome at 2 and 5 years of follow-up in the CAVENT (Catheter-Directed Venous Thrombolysis) trial.^38,39 These results were not confirmed in 2 recent trials.^40,41 The ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) trial, which randomized 692 patients with proximal DVT to receive pharmacomechanical thrombolysis (ie, catheter-directed lysis, mechanical thrombus removal, or both) plus anticoagulation or anticoagulation alone, showed no difference between the treatment arms with regard to occurrence of recurrent VTE, mortality, postthrombotic syndrome, and quality of life between 6 and 24 months after diagnosis.⁴⁰ Similar results were seen in the smaller CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis Versus Anticoagulation) trial.⁴¹ The lack of efficacy and, moreover, the increased risk of major bleeding with the addition of catheter-directed thrombolysis to anticoagulation (3.3% vs 0%, 1.7% vs 0.3%, and 5% vs 0% in the CAVENT, ATTRACT, and CAVA trials, respectively),^38,40,41 support current guideline recommendations to consider thrombolysis only if the limb is threatened.¹⁰ Given the increased risk of bleeding in elderly patients, this conservative approach can be likely extrapolated to patients aged over 75 years who were excluded from the CAVENT and ATTRACT trials and underrepresented in the CAVA trial (median [interquartile range] age, 52 [38–67] years).

Oral anticoagulants for the treatment of acute venous thromboembolism

In normotensive patients with VTE, anticoagulation is the mainstay of treatment. The choice of the optimal anticoagulant agent mainly depends on VTE etiology, kidney function, and comedications. In patients without cancer or severe kidney disease, DOACs are the first-choice anticoagulants.^10,11 Since there are no head-to-head DOAC trials, one DOAC cannot be recommended over another.⁴² Direct oral anticoagulants for the treatment of acute VTE have been compared with VKA therapy in 6 phase 3 trials using a noninferiority study design. The proportion of participants over 75 years of age ranged from 10% to 15% across these studies (Table 1), indicating underrepresentation of the elderly population, as epidemiologic studies show that this age group represents approximately 25% of the VTE population.⁴³ Whereas the overall risk of recurrent VTE did not differ between elderly and younger patients, concerns of a higher risk of bleeding in elderly patients were confirmed in the trials on the use of DOACs; there was an almost 3-fold higher risk of major bleeding in patients aged over 75 years compared with younger patients, irrespective of treatment allocation (Figures 1A and 2A). In patients over 75 years of age, the risk of recurrent VTE was consistently lower in patients on a DOAC compared with those on a VKA, with a pooled overall relative risk reduction of 44% (95% CI, 0.38–0.82; I² = 0%) (Figure 1B).¹³ This risk reduction was not seen in younger patients (risk ratio [RR], 0.99; 95% CI, 0.85–1.17; I² = 0%). As similarly shown in younger patients, DOACs were associated with a lower risk of major bleeding than VKAs in elderly patients (RR, 0.51; 95% CI, 0.30–0.85; I² = 60%) (Figure 2B).¹³ In summary, the risk of bleeding increased with age for both VKAs and DOACs, but DOACs were associated with a lower risk of bleeding compared with VKAs. Subgroup analyses of the Hokusai-VTE trial also indicated that efficacy of edoxaban as well as its lower risk of bleeding compared with VKA therapy were preserved in elderly patients with multimorbidity and polypharmacy.⁴⁴ In a large United States claim database study, frail patients, defined as per the Johns Hopkins Claims-based Frailty Indicator score, were less likely to experience recurrent VTE on rivaroxaban than on a VKA with no difference in the risk of bleeding.⁴⁵ Postmarketing phase 4 trials and DOAC registries confirmed that DOACs are safe and effective alternatives to VKAs for the treatment of VTE in routine clinical practice.⁴⁶ Interestingly, the mean age of patients enrolled in those studies (range, 56–62 years) was similar to that of patients enrolled in the large phase 3 randomized controlled trials (range, 55–58 years).^27,46-51

**Table 1.** Phase 3 trials of direct oral anticoagulants for acute and extended treatment of venous thromboembolism in the subgroup of elderly patients
Study	Design	Patients at age >75 y^a	Intervention arm	Control arm	Treatment duration, mo	Primary efficacy outcome	Primary safety outcome
Acute VTE treatment
RE-COVER pooled^27,47	Double-blinded	529/5107 (10)	LMWH for ≥5 days, then dabigatran 150 mg twice daily	LMWH for ≥5 days, then VKA (INR, 2–3)	6	Recurrent VTE	Not specified
EINSTEIN pooled^48,49	Open-label	1283/8281 (15)	Rivaroxaban 15 mg twice daily for 21 days, then 20 mg once daily	LMWH for ≥5 days, then VKA (INR, 2–3)	6, or 12^b	Recurrent VTE	Clinically relevant bleeding^c
AMPLIFY⁵⁰	Double-blinded	749/5244 (14)	Apixaban 10 mg twice daily for 7 days, then 5 mg twice daily	LMWH for ≥5 days, then VKA (INR, 2–3)	6	Recurrent VTE	Major bleeding
Hokusai-VTE⁵¹	Double-blinded	1104/8240 (13)	LMWH for ≥5 days, then edoxaban 60 mg once daily^d	LMWH for ≥5 days, then VKA (INR, 2–3)	6, or 12^b	Recurrent VTE	Clinically relevant bleeding^c
Extended VTE treatment
RE-MEDY⁸⁸	Double-blinded	259/2856 (9)	Dabigatran 150 mg twice daily	VKA (INR, 2–3)	6–36	Recurrent VTE	Not specified
RE-SONATE⁸⁸	Double-blinded	452/1343 (33)^e	Dabigatran 150 mg twice daily	Placebo	12	Recurrent VTE	Not specified
EINSTEIN-EXT⁴⁸	Open-label	188/1196 (16)	Rivaroxaban 20 mg once daily	Placebo	6–12	Recurrent VTE	Major bleeding
EINSTEIN-CHOICE⁸⁹	Double-blinded	394/3365 (12)	Rivaroxaban 20 mg once daily; rivaroxaban 10 mg once daily	Aspirin 100 mg once daily	6–12	Recurrent VTE	Major bleeding
AMPLIFY-EXT⁹⁰	Double-blinded	329/2482 (13)	Apixaban 5 mg twice daily; apixaban 2.5 mg twice daily	Placebo	12	Recurrent VTE and all-cause death	Major bleeding
a Data are presented as the number of patients older than 75 years per the total number of the study patients (percentage). b Treatment duration at the discretion of the physician c Clinically relevant bleeding was defined as major bleeding or clinically relevant nonmajor bleeding. d Dose adjustment (edoxaban 30 mg once daily) in patients with a creatinine clearance of 30–50 ml/min or body weight <60 kg and in patients receiving concomitant treatment with potent P-glycoprotein inhibitors e Subgroup analysis for age <65 years vs ≥65 years, as subgroup analysis for age ≤75 vs >75 years was not reported. Abbreviations: LMWH, low-molecular-weight heparin; INR, international normalized ratio; VKA, vitamin K antagonist; VTE, venous thromboembolism

**Figure 2**. Major bleeding in phase 3 trials on the use of direct oral anticoagulants for acute venous thromboembolism treatment: A – association of major bleeding with age over 75 years by treatment arm; B – major bleeding by age
Abbreviations: see Table 1 and Figure 1

**Figure 1**. Recurrent venous thromboembolism (VTE) in phase 3 trials on the use of direct oral anticoagulants for acute VTE treatment: A – association of recurrent VTE with age over 75 years by treatment arm; B – recurrent VTE by age
Abbreviations: DOAC, direct oral anticoagulant; RR, risk ratio; others, see Table 1

In patients with cancer, the choice of an anticoagulant agent is less obvious and should be individualized incorporating patients’ preferences and values, cancer type, additional risk factors for bleeding, and comedications.⁵² In recent randomized controlled trials, DOACs for the treatment of cancer-associated VTE were related to a higher risk of bleeding (RR, 1.74; 95% CI, 1.05–2.88) and possibly a lower risk of recurrent VTE (RR, 0.65; 95% CI, 0.42–1.01) compared with treatment with a low-molecular-weight heparin.⁵³ The Hokusai-VTE cancer study is the only randomized controlled trial assessing DOACs versus low-molecular-weight heparin for cancer-associated VTE which reported results on the subgroup of patients by age (age <65 years vs ≥65 years and age <75 years vs ≥75 years).⁵⁴ The primary composite outcome of recurrent VTE or major bleeding did not differ by age.⁵⁴ Similarly to the findings in the entire study cohort, in patients aged 65 years or older, the risk of recurrent VTE appeared to be lower (6.9% vs 9.9%), and the risk of major bleeding (8% vs 4.2%) to be higher with edoxaban than with dalteparin.⁵⁴

Given that DOAC clearance depends on renal function, patients with severe renal failure (ie, creatine clearance <25–30 ml/min) have been excluded from phase 3 DOAC trials. Therefore, VKAs remain the anticoagulants of choice in these patients. Although chronic kidney disease becomes more prevalent with increasing age, severe renal failure remains relatively rare in the general elderly population, as 3.2% of persons aged 75 years or older have an estimated glomerular filtration rate below 30 ml/min.^55,56 Retrospective data have suggested that apixaban may be associated with lower risks of bleeding, thromboembolic events, and mortality compared with VKAs in patients with atrial fibrillation and end-stage kidney disease.⁵⁷ Whether these benefits hold true for the treatment of VTE in a randomized study is uncertain. The results of the ongoing VERDICT (Venous Thromboembolism in Renally Impaired Patients and Direct Oral Anticoagulants) study (ClinicalTrials.gov identifier, NCT02664155) will address whether reduced doses of apixaban and rivaroxaban for the treatment of VTE in patients with moderate-to-severe kidney disease (ie, 15–50 ml/min) are noninferior to the standard of care (ie, a parenteral anticoagulant plus a VKA). While awaiting more data in patients with severe kidney disease, we consider DOACs efficacious and safe in those with nonsevere kidney disease. Even though the risk of bleeding increases with declining kidney function, DOACs were associated with a lower risk of bleeding than VKAs in patients with nonsevere kidney disease, without any difference in treatment efficacy.^13,58

Extended treatment of venous thromboembolism

Duration of treatment

Once the acute phase of VTE treatment (ie, first 3 months after diagnosis) is completed, determination of whether to continue or stop anticoagulation is based on balancing the risks of bleeding and recurrent VTE on and off anticoagulant treatment, including associated case-fatality rates. The risk of recurrent VTE is mainly determined by the etiology of VTE. Patients with a strong, transient provoking factor (eg, major surgery) are at low risk of recurrence, and treatment should be stopped after 3 months.¹⁰ Patients with unprovoked VTE are at high risk of recurrence and continuing treatment is recommended, unless the risk of bleeding is high.¹⁰ Continuing treatment reduces the risk of recurrent VTE by 80% to 90% when patients are on anticoagulants, but it does not reduce the risk of recurrence once therapy is discontinued.⁵⁹ Whether the risk of recurrent VTE after stopping anticoagulation is higher in the elderly remains controversial.^60-68 In contrast, the risk of major bleeding was consistently shown to be about 2- to 3-fold higher in patients aged above 75 years regardless of the anticoagulant drug used (Figure 2A).^13,63,69 Similarly, patients with VTE in the context of active cancer are at high risk of recurrence and, as such, extended treatment is recommended for cancer-associated VTE unless the risk of bleeding outweighs the benefit of anticoagulation.¹⁰ This recommendation is mainly based on expert opinions, given that only a few prospective studies have assessed extended anticoagulant treatment in patients with cancer.^70-74 There is only 1 randomized controlled trial that aimed to assess anticoagulation versus placebo for the extended treatment of cancer-associated VTE, but it was prematurely terminated owing to slow recruitment.⁷⁴

Although the risk of recurrence after stopping anticoagulation is overall high in patients with first unprovoked VTE (10% in the first year, 25% at 5 years, and 36% at 10 years),⁷⁵ efforts have been made to identify a subgroup of patients with a low enough risk to justify stopping anticoagulation after 3 to 6 months. As the risk of bleeding and possibly the risk of recurrent VTE increase with age, it is uncertain whether the generally recommended threshold of an acceptable recurrence risk of 5% in the first year after stopping treatment can be applied in the elderly population.⁷⁶ Four clinical decision rules (HERDOO2, Vienna Prediction Model, DASH, and PIT-STOP) have been developed to help clinicians determine the risk of recurrence after first unprovoked VTE.^65-67,77 The only rule that has been validated in a management study is the HERDOO2 rule. It allows clinicians to identify women at low risk of recurrence based on age, D-dimer levels, signs of postthrombotic syndrome, and body mass index.⁷⁸ The subgroup analyses of the study, however, indicated that among women classified as low-risk, the risk of recurrence was substantially higher in women above 50 years of age (5.7 events per 100 patient-years) than in those below 50 years of age (2 events per 100 patient-years).⁷⁸ Furthermore, the proportion of patients identified at low risk of recurrence is smaller in the elderly given that not only the age of 65 years or older but also other score criteria are more frequent in the elderly: advanced age is a risk factor for postthrombotic syndrome,^79,80 and normal D-dimer values are rare in elderly patients with unprovoked VTE.⁸¹ In elderly patients, both the Vienna Prediction Model and the DASH score showed poor discriminative power in external validation studies,^82,83 limiting their utility to identify a subgroup of elderly patients at low risk of recurrence. No elderly-specific data are available for the PIT-STOP model, which includes age, sex, site of VTE, and D-dimer levels to generate estimates of recurrent VTE on a continuous scale.⁷⁷

Not only the assessment of the risk of recurrent VTE but also the estimation of the risk of bleeding are difficult in elderly patients. Several scores have been developed to estimate the risk of bleeding in patients on anticoagulants; most of them in cohorts of patients with atrial fibrillation. When applied in elderly patients with VTE, the Outpatient Bleeding Risk Index, ACCP, HAS-BLED, RIETE, HEMORR₂HAGES, and ATRIA scores showed only a poor-to-moderate discriminative ability (C statistics ranging from 0.49 to 0.6).^84,85 The VTE-BLEED score was specifically developed to estimate the risk of bleeding in patients on anticoagulant treatment beyond 6 months of VTE diagnosis,⁸⁶ but it lacks validation in elderly patients. Seiler et al⁸⁷ have recently proposed a new bleeding score, which was derived in a cohort of patients with VTE aged 65 years or older and treated with a VKA. Independent risk factors for major bleeding included in the score were previous major bleeding, active cancer, low physical activity, anemia, thrombocytopenia, concomitant antiplatelet drug use, and poor INR control.⁸⁷ However, its use cannot be recommended before external validation studies are available, and inclusion of variables specific for VKA treatment may make it less useful for patients on DOACs.

Overall, no validated clinical decision rules are available, which could help clinicians assess the risk of recurrent VTE and bleeding in elderly patients with VTE. Therefore, shared decision making incorporating information on consequences of continuing or stopping anticoagulation and patients’ preferences and values should be highly encouraged in elderly patients.

Anticoagulants for extended treatment

When opting for anticoagulant treatment beyond 3 months, the same anticoagulant options are available as for acute treatment, and guidelines do not suggest to change the anticoagulant after the first 3 months.^10,11 Vitamin K antagonists, dabigatran, rivaroxaban, and apixaban have been specifically evaluated in randomized controlled trials for secondary prevention of VTE in patients without cancer. As shown in the trials of acute VTE treatment, the proportion of elderly study participants was below 20% in phase 3 trials of DOACs for extended treatment (Table 1). Compared with placebo, active treatment reduced the risk of recurrent VTE and increased the risk of bleeding in both younger and elderly patients (Figures 3 and 4). The RE-MEDY trial is the only study that specifically compared VKA therapy with a DOAC for extended VTE treatment. Overall, dabigatran was noninferior to VKA therapy for preventing recurrent VTE and associated with a lower risk of major and clinically relevant nonmajor bleeding (hazard ratio, 0.54; 95% CI, 0.41–0.71).⁸⁸ Only 9% of study participants were 75 years old or older, and in those 239 patients no recurrent VTE occurred in either treatment arm. Subgroup analyses for bleeding events were not reported. Rivaroxaban and apixaban are also approved at reduced doses (ie, 10 mg daily for rivaroxaban and 2.5 mg twice daily for apixaban) during extended VTE treatment for secondary prevention of recurrent VTE, because they are superior to aspirin and placebo, respectively.^89,90 The point estimates of risk of recurrent VTE appear to be similar in the subgroup of elderly patients, but a limited number of elderly participants and low event rates preclude judgment on statistical significance (Figure 3). Low-dose aspirin reduces the risk of recurrent VTE by about 1/3 compared with placebo.⁹¹ There is, however, little role for aspirin for extended VTE treatment,⁹² because a reduced dose of rivaroxaban was more efficacious and not associated with a higher risk of bleeding compared with aspirin in the EINSTEIN-CHOICE (Reduced-Dosed Rivaroxaban in the Long-term Prevention of Recurrent Symptomatic Venous Thromboembolism) trial.⁸⁹

**Figure 3**. Primary efficacy outcome in phase 3 trials of direct oral anticoagulants for extended venous thromboembolism treatment by age
Abbreviations: see Table 1 and Figure 1

**Figure 4**. Primary safety outcome in phase 3 trials of direct oral anticoagulants for extended venous thromboembolism treatment by age
Abbreviations: see Table 1 and Figure 1

Based on the few prospective studies reporting on extended anticoagulant treatment for cancer-associated VTE, it seems reasonable to suppose that there is no need to change the choice of an anticoagulant after the first 3 months.^70-74 None of these studies reported subgroup analysis by age.

Conclusions

The incidence of VTE increases with age, and elderly patients are at higher risk of VTE-related morbidity and mortality. Even though elderly patients are underrepresented in clinical trials, the extrapolation of study results from younger patients to the elderly appears justified for acute VTE treatment and for the choice of an anticoagulant agent. The subgroup analyses of phase 3 DOAC trials indicate that during the acute VTE treatment phase, DOACs are not only associated with a lower risk of bleeding but also appear to be even more efficacious than VKAs in preventing recurrent VTE in the elderly.

The most challenging aspect of VTE management in elderly patients is the determination of optimal treatment duration. The risk of bleeding increases with age, but several risk factors for recurrent VTE are also more frequent in the elderly. Clinical decision rules to help estimate the risk of recurrence and bleeding have only limited utility in elderly patients. Therefore, shared decision making considering patients’ preferences and values is essential in determining individualized treatment duration in the elderly.

Correspondence to

Tobias Tritschler, MD, MSc, Department of General Internal Medicine, Inselspital, Bern University Hospital, Freiburgstrasse 18, 3010 Bern, Switzerland, phone:+41 031 632 21 11, email: tobias.tritschler@insel.ch

Received

February 27, 2020.

Accepted

February 27, 2020.

Published online

March 3, 2020.

Contribution statement

TT performed the meta-analysis and wrote the manuscript. All authors reviewed and revised the manuscript before approving the submission of its final version.

Acknowledgments

TT, LAC, and GLG are members of the CanVECTOR Network; the Network receives grant funding from the Canadian Institutes of Health Research (CDT-142654). TT holds an Early Postdoc. Mobility Award from the Swiss National Science Foundation (SNSF P2ZHP3_177999) and a Fellowship Award from the CanVECTOR Network. LAC is supported by the Heart & Stroke Foundation of Canada National New Investigator and Ontario Clinician Scientist Phase I award programs. GLG holds an Early Researcher Award from the Province of Ontario, a mid-career clinician scientist award from the Heart and Stroke Foundation of Ontario, and the Chair on the Diagnosis of Venous Thromboembolism, Department of Medicine, University of Ottawa, Canada.

Conflict of interest

TT received travel and congress fees from Pfizer. Other authors declare no conflict of interest.

How to cite

Tritschler T, Castellucci LA, Van Es N, et al. Treatment of venous thromboembolism in elderly patients in the era of direct oral anticoagulants. Pol Arch Intern Med. 2020; 130: 529-538. doi:10.20452/pamw.15225

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