New Oral Anticoagulants in Elderly Adults
New Oral Anticoagulants in Elderly Adults
The results of the literature search are presented in Figure 1. Ten randomized trials included a total of 25,031 elderly adults. Five of the identified trials evaluated rivaroxaban, three apixaban, and two dabigatran. The indications for anticoagulation are listed in Table 1 . Two trials were for treatment of acute VTE or pulmonary embolism and three for extended treatment of VTE. Four trials included individuals with AF, and one was for thromboprophylaxis in medically ill individuals. Only one trial with acute coronary syndrome reported data related to elderly adults, although the definition of safety outcome was different (thrombolysis in myocardial infarction bleeding instead of bleeding according to the ISTH criteria) and hence was excluded from the present analysis. Another study for extended treatment of VTE did not report group-specific data for the elderly population.
(Enlarge Image)
Figure 1.
Search strategy and study selection according to the PRISMA checklist.
The basic baseline demographic characteristics of participants in the included trials are summarized in Table 1 . The length of follow-up ranged from 35 days to 2 years. The risk of bias assessment showed overall good quality of the included trials, but reporting bias was common. Most of the trials with dabigatran did not report the bleeding outcomes related to an elderly subgroup. Variables that might influence bleeding risk in elderly adults such as renal function and body mass index (BMI) were also not reported.
NOACs did not cause greater major or clinically relevant bleeding than conventional therapy in individuals aged 75 and older (6.4% with NOAC vs 6.3% with conventional anticoagulants; OR = 1.02, 95% CI = 0.73–1.43) (Figure 2). Similar results were observed with NOACs and pharmacologically active agents (6.4% vs 6.3%; OR = 0.98, 95% CI = 0.70–1.37). These results showed high heterogeneity (I = 86%, P < .001), which the AF trials mainly contributed, although separate analysis for acute VTE trials did not show any heterogeneity (Supporting Information). NOACs also did not cause extra bleeding for treatment of acute VTE or pulmonary embolism, extended treatment of VTE, or AF except thromboprophylaxis for acutely ill medical individuals.
(Enlarge Image)
Figure 2.
New oral anticoagulants versus conventional therapy for participants aged 75 and older: major or clinically relevant bleeding. CI = confidence interval.
Risk of stroke and systemic embolism was significantly lower with NOACs than conventional therapy or pharmacologically active agents (3.3% vs 4.7%; OR = 0.65, 95% CI = 0.48–0.87; absolute risk reduction (ARR) = 1.4%, number needed to treat (NNT) = 71) (Figure 3).
(Enlarge Image)
Figure 3.
New oral anticoagulants versus conventional therapy for participants aged 75 and older: stroke or systemic embolism.
NOAC also resulted in a significantly lower risk of VTE or VTE-related death than conventional therapy (3.7% vs 7.0%; OR = 0.45, 95% CI = 0.27–0.77; ARR = 3.3%, NNT = 30) (Figure 4) and pharmacologically active agents (3.9% vs 6.6%; OR = 0.61, 95% CI = 0.45–0.81; ARR = 2.6%, NNT = 38).
(Enlarge Image)
Figure 4.
New oral anticoagulants versus conventional therapy for participants aged 75 and older: venous thromboembolism (VTE) or VTE-related death.
Rivaroxaban. Rivaroxaban did not cause greater major or clinically relevant bleeding than conventional therapy in elderly adults (4.5% vs 4.5%; OR = 1.18, 95% CI = 0.64–2.19). Rivaroxaban was noninferior to or more effective than conventional therapy in prevention of stroke or systemic embolism and VTE or VTE-related death.
Apixaban. The risk of major or clinically relevant bleeding was not higher with apixaban (5.1% vs 7.3%; OR = 0.80, 95% CI = 0.43–1.51) (Figure 2). Risk of stroke or systemic embolism and VTE or VTE-related death was equal to or lower than with apixaban than with conventional therapy.
Dabigatran. Safety data on dabigatran was more limited. Major or clinically relevant bleeding was similar with dabigatran and conventional therapy (9.3% vs 8.7%; OR = 1.07, 95% CI = 0.90–1.28) (Figure 2). Dabigatran was more effective than conventional agents in the prevention of stroke or systemic embolism (3.2% vs 4.3%; OR = 0.75, 95% CI = 0.58–0.96 ARR = 1.1%, NNT = 95).
Subgroup Analysis According to Type of Conventional Anticoagulant. NOACs did not cause greater bleeding than warfarin (6.5% vs 7.1%; OR = 0.76, 95% CI = 0.51–1.12) or LMWH or LMWH followed by VKA (6.9% vs 5.3%; OR = 1.27, 95% CI = 0.54–2.98).
Sensitivity Analysis. The summary effect estimates were consistent with the primary analyses when analyses were repeated using a fixed-effects model. Sensitivity analyses with two different doses of dabigatran (110 and 150 mg twice a day) showed results similar to the primary analysis. Sensitivity analyses with various subgroups based on study design, blinding, and risk of bias also showed consistent results, similar to the current study's primary analysis.
Follow-Up Adjusted Analysis. The follow-up adjusted analysis showed that risk of major or clinically relevant bleeding was not significantly different with NOACs and conventional therapy in elderly adults (OR = 1.17, 95% CI = 0.73–1.9).
Publication Bias. There was no evidence of small study effects (publication bias) according to visual inspection of funnel plots and the Egger test.
Results
The results of the literature search are presented in Figure 1. Ten randomized trials included a total of 25,031 elderly adults. Five of the identified trials evaluated rivaroxaban, three apixaban, and two dabigatran. The indications for anticoagulation are listed in Table 1 . Two trials were for treatment of acute VTE or pulmonary embolism and three for extended treatment of VTE. Four trials included individuals with AF, and one was for thromboprophylaxis in medically ill individuals. Only one trial with acute coronary syndrome reported data related to elderly adults, although the definition of safety outcome was different (thrombolysis in myocardial infarction bleeding instead of bleeding according to the ISTH criteria) and hence was excluded from the present analysis. Another study for extended treatment of VTE did not report group-specific data for the elderly population.
(Enlarge Image)
Figure 1.
Search strategy and study selection according to the PRISMA checklist.
The basic baseline demographic characteristics of participants in the included trials are summarized in Table 1 . The length of follow-up ranged from 35 days to 2 years. The risk of bias assessment showed overall good quality of the included trials, but reporting bias was common. Most of the trials with dabigatran did not report the bleeding outcomes related to an elderly subgroup. Variables that might influence bleeding risk in elderly adults such as renal function and body mass index (BMI) were also not reported.
NOAC Use in Elderly Adults (≥75)
NOACs did not cause greater major or clinically relevant bleeding than conventional therapy in individuals aged 75 and older (6.4% with NOAC vs 6.3% with conventional anticoagulants; OR = 1.02, 95% CI = 0.73–1.43) (Figure 2). Similar results were observed with NOACs and pharmacologically active agents (6.4% vs 6.3%; OR = 0.98, 95% CI = 0.70–1.37). These results showed high heterogeneity (I = 86%, P < .001), which the AF trials mainly contributed, although separate analysis for acute VTE trials did not show any heterogeneity (Supporting Information). NOACs also did not cause extra bleeding for treatment of acute VTE or pulmonary embolism, extended treatment of VTE, or AF except thromboprophylaxis for acutely ill medical individuals.
(Enlarge Image)
Figure 2.
New oral anticoagulants versus conventional therapy for participants aged 75 and older: major or clinically relevant bleeding. CI = confidence interval.
Risk of stroke and systemic embolism was significantly lower with NOACs than conventional therapy or pharmacologically active agents (3.3% vs 4.7%; OR = 0.65, 95% CI = 0.48–0.87; absolute risk reduction (ARR) = 1.4%, number needed to treat (NNT) = 71) (Figure 3).
(Enlarge Image)
Figure 3.
New oral anticoagulants versus conventional therapy for participants aged 75 and older: stroke or systemic embolism.
NOAC also resulted in a significantly lower risk of VTE or VTE-related death than conventional therapy (3.7% vs 7.0%; OR = 0.45, 95% CI = 0.27–0.77; ARR = 3.3%, NNT = 30) (Figure 4) and pharmacologically active agents (3.9% vs 6.6%; OR = 0.61, 95% CI = 0.45–0.81; ARR = 2.6%, NNT = 38).
(Enlarge Image)
Figure 4.
New oral anticoagulants versus conventional therapy for participants aged 75 and older: venous thromboembolism (VTE) or VTE-related death.
Effects of Individual NOACs
Rivaroxaban. Rivaroxaban did not cause greater major or clinically relevant bleeding than conventional therapy in elderly adults (4.5% vs 4.5%; OR = 1.18, 95% CI = 0.64–2.19). Rivaroxaban was noninferior to or more effective than conventional therapy in prevention of stroke or systemic embolism and VTE or VTE-related death.
Apixaban. The risk of major or clinically relevant bleeding was not higher with apixaban (5.1% vs 7.3%; OR = 0.80, 95% CI = 0.43–1.51) (Figure 2). Risk of stroke or systemic embolism and VTE or VTE-related death was equal to or lower than with apixaban than with conventional therapy.
Dabigatran. Safety data on dabigatran was more limited. Major or clinically relevant bleeding was similar with dabigatran and conventional therapy (9.3% vs 8.7%; OR = 1.07, 95% CI = 0.90–1.28) (Figure 2). Dabigatran was more effective than conventional agents in the prevention of stroke or systemic embolism (3.2% vs 4.3%; OR = 0.75, 95% CI = 0.58–0.96 ARR = 1.1%, NNT = 95).
Subgroup Analysis According to Type of Conventional Anticoagulant. NOACs did not cause greater bleeding than warfarin (6.5% vs 7.1%; OR = 0.76, 95% CI = 0.51–1.12) or LMWH or LMWH followed by VKA (6.9% vs 5.3%; OR = 1.27, 95% CI = 0.54–2.98).
Sensitivity Analysis. The summary effect estimates were consistent with the primary analyses when analyses were repeated using a fixed-effects model. Sensitivity analyses with two different doses of dabigatran (110 and 150 mg twice a day) showed results similar to the primary analysis. Sensitivity analyses with various subgroups based on study design, blinding, and risk of bias also showed consistent results, similar to the current study's primary analysis.
Follow-Up Adjusted Analysis. The follow-up adjusted analysis showed that risk of major or clinically relevant bleeding was not significantly different with NOACs and conventional therapy in elderly adults (OR = 1.17, 95% CI = 0.73–1.9).
Publication Bias. There was no evidence of small study effects (publication bias) according to visual inspection of funnel plots and the Egger test.
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