Direct Oral Anticoagulants in Special Populations: History
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Contributor:
Andreina Carbone
,
Roberta Bottino
,
Antonello D’Andrea
,
Vincenzo Russo

Direct oral anticoagulants (DOACs) are the first-line anticoagulant strategy in patients with non-valvular atrial fibrillation (NVAF). For special populations, such as elderly and frail patients, subjects with extreme body weight, cancer, and bioprosthetic heart valves (BHV), the indications and the choice of the optimal OAC therapy are a challenge because of the poor representation of these populations in major randomized clinical trials (RCTs).

  • direct oral anticoagulant
  • stroke prevention
  • atrial fibrillation

1. Introduction

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, and it is associated with an increased risk of ischemic stroke and mortality [1]. The estimated prevalence of AF in adults is between 2% and 4%, increasing in view of the progressive increase in life expectancy [1].
The European Society of Cardiology (ESC) guidelines recommend the assessment of stroke risk using the CHA2DS2-VASc score, considering oral anticoagulation (OAC) prescription for scores of ≥1 in males and ≥2 in females [1]. OAC with vitamin K antagonists (VKAs) decrease the risk of stroke by 68% [2], but at the cost of routine monitoring of anticoagulation levels [International Normalized Ratio (INR) determination], due to their pharmacokinetic variability and frequent food and drug interactions [2][3].
Direct oral anticoagulants (DOACs) have emerged as an alternative to VKAs as they have demonstrated comparable efficacy in stroke prevention with less major bleeding than warfarin in patients with non-valvular AF [4]. Moreover, DOACs do not require routine monitoring of anticoagulation parameters as they are characterized by a predictable pharmacokinetic and few drug and food interactions [4]. Dabigatran etexilate is the first established factor IIa (thrombin) inhibitor. It is a prodrug converted into the active form of dabigatran by microsomal carboxylesterases in the liver [1][3]. The mechanism of action of rivaroxaban, apixaban, and edoxaban is the inhibition of prothrombinase complex-bound and clot-associated factor Xa, resulting in a reduction of the thrombin burst during the propagation phase of the coagulation cascade [1].
For special populations, such as elderly and frail patients, subjects with extreme body weight, cancer, and bioprosthetic heart valves (BHV), the indications and the choice of the optimal OAC therapy are a challenge because of the poor representation of these populations in major randomized clinical trials (RCTs).

2. DOACs in Elderly Patients

Older age increases both ischemic (especially stroke events) and bleeding risk [5][6]. In older patients with AF, VKAs prevent stroke with increased bleeding risk and the need for frequent INR monitoring [7][8]. Likewise, the elderly often present with multiple comorbidities, so an integrated approach to prevent stroke events, including tailored therapy and careful drug-dose monitoring, is mandatory [9][10][11]. To date, DOACs are the first-line therapy for stroke prevention and are characterized by a more favorable pharmacological profile than VKA. The efficacy and safety profile of DOACs in patients >75 years have been analyzed in various studies, but their use in octogenarians and frail patients is still poorly explored. Table 1 summarizes the main characteristics of principal DOAC trials and outcomes in patients ≥75 years.
In a sub-analysis of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial [12][13], both dabigatran 110 mg BID and 150 mg BID were found comparable to VKAs for the combined endpoint of stroke/systemic embolism and major bleeding. However, comparing dabigatran dosages with warfarin showed a lower risk of intracranial bleeding but similar or higher extracranial bleeding events [13]. These results were confirmed for stroke and systemic embolism events in both patients ≥80 years [dabigatran 110 mg bid (HR = 0.75; p = non-significant [NS]) and 150 mg bid (HR = 0.67; p = NS)] and ≥85 years old [dabigatran 110 mg bid (HR = 0.52, p = NS) and 150 mg bid (HR = 0.70; p = NS)] [14].
Finally, compared to warfarin, the use of dabigatran in women aged 75 years and older seems to be related to an increased risk of major gastrointestinal bleeding (HR 1.50; p < 0.05) as well as in men aged 85 years and older (HR 1.55; p < 0.05) [15]. In women ≥85 years, no effect on mortality was found using the dabigatran [15].
A sub-analysis of ROCKET-AF (Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial found that in elderly patients (≥75 years old; n = 6229), rivaroxaban had similar efficacy in reducing stroke and systemic embolism (HR = 0.88; p < 0.05) with a lower rate of intracranial bleeding (HR = 0.80; p < 0.05) when compared with warfarin [16]. Anyway, patients on rivaroxaban showed a higher risk of the combined bleeding endpoint due to more frequent non-major gastrointestinal bleeding (2.81% versus 1.66%/100 patient years; HR 0.70; p: 0.0002) [16].
The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial included 5678 patients ≥75 years (31%) and 2436 patients (18%) ≥80 years at baseline [17]. Apixaban showed absolute clinical benefits in the older population with a significant reduction of stroke or systemic embolism (HR 0.81; p < 0.05), major bleeding (HR: 0.66; p < 0.05), and intracranial hemorrhage (HR 0.36; p < 0.05) in patients ≥80 years compared to warfarin [17].
In a study cohort of 14,214 AF patients (mean age 78.1), the risk of stroke/systemic embolism (HR: 0.65, p < 0.001), major bleeding (HR: 0.53, p < 0.001), and gastro-intestinal bleeding (HR: 0.53, p < 0.001) was lower in the apixaban group when compared with the same number of elderly patients on warfarin (7107 patients in each group) [18]. These results were later confirmed by Yao et al. in a cohort of AF patients with a median age of 73 years old, in which apixaban patients showed a 33% lower risk of stroke/systemic embolism (HR = 0.67 p = 0.04) and 55% lower risk of major bleeding (HR 0.45, p < 0.001) compared to VKAs [19].
In the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48), 40.2% of the enrolled patients were aged over 75 years old and 17% over 80 years old (8474 and 1440 patients, respectively). While the incidence of stroke/systemic embolism in AF patients aged ≥75 years was similar between edoxaban and warfarin (1.5% per year in warfarin group; 1.18% per year in edoxaban group; HR vs. warfarin, HR 0.79; p < 0.001 for noninferiority, p = 0.02 for superiority), the incidence of major bleeding was lower in the edoxaban group (3.43% per year in warfarin group and 2.75% in edoxaban group) [20].
In a meta-analysis of the randomized controlled trial (RCT), DOACs were associated with equal or greater efficacy than VKAs, without relevant bleeding among patients of ≥75 years [21].
The ELDERCARE-AF (Edoxaban Low-Dose for EldeR CARE AF patients) compared the safety and efficacy of once-daily edoxaban 15 mg versus placebo in AF Japanese patients aged ≥80 years for whom standard oral anticoagulants were contraindicated [22][23]. Edoxaban 15 mg was superior to a placebo in reducing stroke or systemic embolism, but the study was limited by race clustering (all patients were Asian) and by a low mean of the body weight of the cohort (about 50 kg).
The safety profile of DOACs is also maintained in patients aged ≥90 years, as shown by the analysis of 15,756 AF patients sourced from the Taiwan National Health Insurance Research Database (NHIRD) [24]. Indeed, while the risk of ischemic stroke was found to be comparable between VKAs and DOAC users among elderly patients (4.07%/y versus 4.59%/y; HR: 1.16; p = 0.654), the DOAC group showed a lower risk of intracranial hemorrhage (0.42%/year versus 1.63%/year; HR 0.32; p = 0.044) [24].
In addition, it is worth mentioning that inappropriate DOAC dosage prescription affects up to 15% of AF patients [25], especially older patients [1][25].
In a multicenter study of AF patients aged ≥80 years who received DOAC treatment (n = 253), Carbone et al. showed that nearly one-third of octogenarians with AF received an inappropriate dose of DOACs [26]. Several clinical factors were associated with DOAC overdosing [diabetes mellitus type II (OR 18; p < 0.001), previous bleeding (OR 6.4; p = 0.03)] or underdosing [male gender (OR 3.15; p < 0.001), coronary artery disease (OR 3.60; p < 0.001), and higher body mass index (OR 1.27; p < 0.001)] [26]. Octogenarians with inappropriate DOAC underdosing showed less survival (p < 0.001) [26].
Table 1. Characteristics of DOAC principal trials and outcomes in patients aged ≥75 years.
  RE-LY [12] ROCKET-AF [16] ARISTOTLE [17] ENGAGE [20]
DOACs vs. VKAs
Dose
Reduced dose		 dabigatran
150 mg bid
110 mg bid		 rivaroxaban
20 mg qd
15 mg qd		 apixaban
5 mg bid
2.5 mg bid		 edoxaban
60 mg qd
30 mg qd
Patients (n) 18,113 14,264 18,201 14,071
Age (mean in years) 72 73 70 72
Patients ≥75 years, n (%) 7258 (40) 6229 (44) 5678 (31) 5668 (40)
ClCr in ≥75 years at baseline
  • ≥80 mL/min: 12%
  • 50–79 mL/min: 57%
  • <50 mL/min: 26%
 Median 55 mL/min (IQR 44, 68).
  • >80 mL/min: 10.5%
  • 51–80 mL/min: 51.5%
  • 31–50 mL/min: 33.6%
  • ≤30 mL/min: 3.9%
  • >80 mL/min: 12%
  • 51–80 mL/min: 52%
  • ≤50 mL/min: 37%
Stroke or systemic embolism in patients ≥75 years
Event rates (DOACs vs. VKAs %/years)
HR (or RR for dabigatran) (IC 95%)		 1.9 (110 mg bid) vs. 2.1
1.4 (150 mg bid) vs. 2.1
0.88 (0.66–1.17) (110 bid)
0.67 (0.49–0.90) (150 bid)		 2.3 vs. 2.9
0.80 (0.63–1.02)		 1.6 vs. 2.2
0.71 (0.53–0.95)		 1.9 vs. 2.3
0.83 (0.67–1.04)
Major bleedings in patients ≥75 years
Event rates (DOACs vs. VKAs %/years)
HR (or RR for dabigatran) (IC 95%)		 4.4 (110 mg bid) vs. 4.4
5.1 (150 mg bid) vs. 4.4
1.01 (0.83–1.23) (110 bid)
1.18 (0.98–1.42) (150 bid)		 4.9 vs. 4.4
1.11 (0.92–1.34)		 3.3 vs. 5.2
0.64 (0.52–0.79)		 4.0 vs. 4.8
0.83 (0.70–0.89)
Gastrointestinal bleedings in patients ≥75 years
Event rates (DOACs vs. VKAs %/years)
HR (or RR for dabigatran) (IC 95%)		 2.2 (110 mg bid) vs. 1.6
2.8 (150 mg bid) vs. 1.6
1.39 (1.03–1.98) (110 bid)
1.79 (1.35–2.37) (150 bid)		 2.8 vs. 1.7
1.69 (1.19–2.39)		 1.3 vs. 1.3
0.99 (0.69–1.42)		 2.2 vs. 1.7
1.32 (1.01–1.72)
Intracranial bleeding in patients ≥75 years
Event rates (DOACs vs. VKAs %/years)
HR (or RR for dabigatran) (IC 95%)		 0.37 (110 mg bid) vs. 1
0.41 (150 mg bid) vs. 1
0.37 (0.21–0.64) (110 bid)
0.42 (0.25–0.70) (150 bid)		 0.66 vs. 0.83
0.80 (0.50–1.28)		 0.43 vs. 1.29
0.34 (0.20–0.57)		 0.5 vs. 1.2
0.40 (0.26–0.62)

3. DOACs and Frailty

“Frailty” is defined as a vulnerability to infectious processes and physical and emotional stresses [27]. The prevalence of such a condition increases with age and ranges from 9% in 75–79-year-old patients to 26% in patients ≥85 years [28].
Frail subjects are less likely to receive OAC despite evidence supporting the use of OAC in this population [15][29]. According to the results of RCTs [30][31], meta-analyses [4][21], and large registries [15][24][32], when compared to warfarin, DOACs demonstrate a better risk-benefit profile in frail patients [11][24][30][33][34]. The prescription of a reduced dose of OAC is less effective in preventing adverse outcomes [35][36][37].
In the systematic review by Oqab et al. [38], it was highlighted that 40% of hospitalized elderly patients with AF (over the age of 80) were classified as frail, and the rate of OAC prescription was lower in these patients than in non-frail patients (OR 0.49, 95% CI 0.32–0.74) [38]. Among frailty characteristics, cognitive impairment, malnutrition risk, depression, and falls were recognized as the main reasons for the under-prescription of oral anticoagulants [38].
The FRAIL-AF study [39] showed that severely frail patients are much less likely to be prescribed with DOACs than non-frail, mildly or moderately frail patients (OR 3.4), regardless of the individual patient’s thrombotic and bleeding risk. This evidence suggests that frailty, in clinical practice, significantly influences the prescription of DOACs [39].
Thus, the best antithrombotic therapeutic strategy in frail AF patients remains unclear at present. Moreover, comparison studies between different DOACs are still not available. Anyhow, apixaban seems to have a good risk/benefit profile in older patients, especially in those with renal failure [40][41][42]. On the other hand, it could be reasonable to avoid dabigatran and rivaroxaban because of the increased risk of gastrointestinal bleeding described in patients aged ≥75 years [43].

4. DOACs in Patients with AF and Active Cancer

AF is commonly diagnosed in the setting of active cancer [44]. Antithrombotic prevention against the risk of cerebral stroke and systemic embolism in patients with AF and cancer disease is essential [45], and the risk of bleeding also depends on the type of tumor [46].
Due to the low life expectancy and high bleeding risk of cancer patients, the major RCTs of DOACs have included few patients with AF and cancer [12][17][47][48]. Therefore, data on this sub-population remain lacking and uncertain. In this regard, several observational studies and meta-analyses have investigated the efficacy and safety of DOACs in this population [49][50][51][52], assessing their viability when compared to warfarin [49][51][52] (Table 2).
Russo et al. published a systematic review of the literature of six eligible studies, founding that the efficacy and safety of DOACs in cancer patients are similar to that of the general population [49]. In particular, authors found a low annual incidence of bleeding and thrombotic events in cancer patients treated with DOACs compared to those treated with warfarin. Moreover, the risk of such events was comparable to non-cancer patients regardless of the treatment used (DOACs or VKAs) [49].
A systematic review and metanalysis of three sub-studies of ARISTOTLE [53], ROCKET-AF [54], and ENGAGE-TIMI 48 trials [55] showed no significant differences in safety and efficacy outcomes between cancer and non-cancer patients in OAC therapy (all p < 0.05) [51]. Moreover, DOAC therapy resulted in a significantly lower risk of stroke/systemic embolism (p = 0.04), venous thromboembolism (p < 0.0001), and a decreased risk of intracranial or gastrointestinal bleeding compared with warfarin (p = 0.04) [51].
Yang et al., in a network meta-analysis [52], showed that in AF patients with cancer, apixaban was associated with the lowest risk of stroke/systemic embolism (OR 0.12, 95% confidence interval [CI] 0.05–0.52), followed by rivaroxaban, dabigatran, edoxaban, and warfarin. Apixaban was also the best treatment option to avoid major bleeding, followed by dabigatran and edoxaban (OR 0.39, 95% CI 0.18–0.79) [52].
A large meta-analysis (46,424 DOAC users and 182,797 VKA users) comparing the efficacy and safety of DOACs and VKAs in cancer patients has shown that DOACs are more effective in preventing strokes in the course of the AF [56]. Indeed, DOACs, compared to VKAs, significantly reduced the risk of both ischemic (RR 0.84; p = 0.007) and hemorrhagic stroke (RR 0.61, p < 0.00001) [56]. Moreover, the risk of major bleeding was significantly reduced by up to 32% (RR 0.68, p = 0.01) and the risk of systemic embolism or any type of stroke by 35% with DOACs compared with VKA (RR 0.65, p < 0.0001) [56]. Similarly, the use of DOACs versus VKAs significantly reduced the risk of intracranial or gastrointestinal bleeding (RR 0.64, p = 0.006) [56].
Furthermore, in a study of 16,096 patients with AF and active cancer [57], the bleeding rate was similar with rivaroxaban and dabigatran but significantly lower with apixaban (HR 0.37; p = 0.002). None of the anticoagulants showed greater efficacy in reducing the incidence of ischemic stroke [57].
The Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) recommends that individual decisions should be made for a patient with cancer and AF, considering the risk of stroke and bleeding [58]. In patients who had initiated anticoagulation before anti-cancer treatment, therapy should not be modified if there are no significant interactions with oncological drugs. In the case of newly diagnosed AF during chemotherapy, DOACs should be preferred over VKAs or low-molecular-weight heparin (LMWH) if no significant drug–drug interactions are found. The exception is patients with gastrointestinal neoplasms or other gastrointestinal tract diseases predisposing to bleeding, where the OAC prescription should be strongly individualized. LMWH in therapeutic doses should only be recommended when the patient cannot take oral anticoagulants. VKAs are recommended in patients with mechanical heart valves or moderate-to-severe mitral stenosis.
In conclusion, several preliminary pieces of evidence suggest that DOACs are effective and safe in cancer patients with AF, but RCTs should improve these findings. The choice of the DOAC should be individualized, considering the prothrombotic risk related to cancer disease and the risk of bleeding.
Table 2. Results of the main studies exploring the efficacy and safety of direct oral anticoagulants in cancer patients with atrial fibrillation.
Authors, Reference Main Study Characteristics Ischemic Events Major Bleeding Conclusions
Russo et al. [49] Systematic Review of retrospective studies
(6 studies included)
DOACs in AF cancer patients
Cancer
Vs.
Non-cancer patients		 Annual incidence range
0 to 4.9%
versus
1.3 to 5.1%		 Annual incidence range
1.2 to 4.4%
versus
1.215 to 3.1%		 No significant differences
in safety and efficacy outcomes between cancer and no-cancer patients with AF on DOACs
Deng et al. [51] Systematic Review and Meta-Analysis
(5 studies included)
DOACs
Vs.
Warfarin		 SSE Intracranial or GI In cancer patients, DOACs have similar rates or lower rates of ischemic and bleeding events and a reduced risk of venous thromboembolism compared with warfarin.
RR = 0.52
95% CI, 0.28–0.99
p = 0.04		 RR = 0.65
95% CI, 0.42–0.98
p = 0.04
VTE MB
RR = 0.37
95% CI, 0.22–0.63
p < 0.0001		 RR = 0.73
95% CI, 0.53–1.00
p = 0.05
IS MB or CRNMB
RR = 0.63
95% CI, 0.40–1.00
p = 0.05		 RR = 1.00
95% CI, 0.86–1.17
p = 0.96
MI Any bleeding
RR = 0.75
95% CI, 0.45–1.25
p = 0.26		 RR = 0.93;
95% CI, 0.78–1.10
p = 0.39
Mariani et al. [56] Meta-analysis
(9 studies included)
DOACs
versus
Warfarin		 SSE HS In patients with cancer and non-valvular AF, the use of DOACs is associated with a significant reduction of thromboembolic and bleeding events
in patients when compared to warfarin
RR 0.65
95% CI, 0.52–0.81
p = 0.001		 RR 0.61
95% CI 0.52–0.71
p = 0.00001
IS MB
RR 0.84
95% CI 0.74–0.95
p = 0.007		 RR 0.68
95% CI 0.50–0.92
p = 0.01
MI Intracranial or GI
RR 0.71
95% CI 0.48–1.04
p = 0.08		 RR 0.64
95% CI 0.47–0.88
p = 0.006
  MB or CRNMB
RR 0.94; 95%
CI 0.78–1.13; p 0.50
Any bleeding
RR 0.91
95% CI 0.78–1.06
p = 0.24
DOACs: direct oral anticoagulants; AF: atrial fibrillation; SSE: stroke/systemic embolism; VTE: venous thromboembolism; IS: ischemic stroke; MI: myocardial infarction; GI: gastrointestinal; MB: major bleeding; CRNMB: clinically relevant non-major bleeding; HS: hemorrhagic stroke.

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11010131

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