Is Bleeding a Necessary Evil?
Is Bleeding a Necessary Evil?
The shortcomings of warfarin inform many of the characteristics identified for the ideal anticoagulant (Table 3). In 2004, ximelagatran was the first available NOAC but had to be withdrawn due to hepatotoxicity in 2006. Since then dabigatran, rivaroxaban and apixaban have been investigated in large-scale randomized controlled trials and now represent valid alternatives to warfarin for stroke prevention in AF.
Dabigatran etexilate is an oral prodrug, which is converted in the liver to its active compound, dabigatran – a competitive reversible direct thrombin inhibitor (DTI). The final step of the coagulation pathway requires thrombin to convert fibrinogen to fibrin. By binding to thrombin and disrupting its interaction with substrates, DTIs prevent fibrin production and can inhibit fibrin-bound thrombin (Figure 1). It has a rapid onset of action, a half-life of 17 h with multiple doses (7–9 h with single doses) and reaches clinical steady state within 2.5 days of initiation. Dabigatran is predominantly cleared by the kidneys and neither the prodrug nor its metabolite exerts an effect on the CYP system, thus dabigatran has fewer food and drug interactions than warfarin. There is, however, an age effect on pharmacokinetic parameters.
The RE-LY trial established that dabigatran 110 mg two-times a day (b.i.d.) was non-inferior and 150 mg b.i.d. was superior to adjusted dose warfarin for the prevention of stroke and systemic embolism. The rate of stroke or systemic embolism occurred at 1.69% per year in patients assigned to warfarin compared with 1.53% in the dabigatran 110 mg group (RR: 0.91; 95% CI: 0.74–1.11; p < 0.001 for non-inferiority; p = 0.34 for superiority compared with warfarin) and 1.11% in the dabigatran 150 mg group (RR: 0.66; 95% CI: 0.53–0.82; p < 0.001 for non-inferiority and superiority compared with warfarin).
Of note, life-threatening bleeding occurred less frequently with dabigatran at both doses; similarly, ICH also occurred significantly less often with dabigatran than with warfarin. As the most feared complication of anticoagulant therapy, this significant reduction in ICH represents a considerable advantage for dabigatran. High-dose dabigatran was associated with a significantly increased risk of major gastrointestinal hemorrhage compared with low-dose dabigatran or warfarin. This is considered most likely secondary to the acidic core of dabigatran, which also explains its propensity to cause dyspepsia. The trial reported a TTR of 64% in the warfarin arm, which is in line with previous results from the literature (Table 4).
Rivaroxaban is an oral, reversible, direct factor Xa inhibitor with high oral bioavailability and rapid absorption. It has a half-life of 9 h in young and healthy subjects and 12 h in those aged over 75; the onset of action is fast with peak concentrations reached between 2 and 4 h. There is a dual mode of elimination: the kidneys clear one-third and the remaining two-thirds are hepatically metabolized. The pharmacokinetics of rivaroxaban are dose-dependent and unaffected by gender, body weight or age. Although drugs that interact with CYP3A4 can theoretically affect rivaroxaban, a low potential for clinically significant drug or food interactions has been reported.
ROCKET-AF established rivaroxaban as an alternative to warfarin for stroke prevention in AF. Enrolment of patients without prior stroke, TIA or systemic embolism and only two risk factors was capped at 10% of the overall study population. This meant 86% of the total population had a CHADS2 score of ≥3 with an overall mean CHADS2 score higher than that seen in the RE-LY trial (3.5 vs. 2.1), suggesting a higher risk cohort was studied. Indeed, patients with CHADS2 score 0–1 were not part of the trial inclusion criteria.
Rivaroxaban was non-inferior to warfarin for the primary efficacy end point of prevention of stroke and systemic embolism. In the per protocol analysis, there was a 21% reduction in the primary end point in the rivaroxaban arm (rivaroxaban 1.7% per year vs. warfarin 2.2% per year; HR: 0.79; 95% CI: 0.66–0.96; p < 0.001 for non-inferiority). Major and non-major clinically relevant bleeding was similar in the two groups. The rivaroxaban group demonstrated significantly less fatal bleeding and ICH although more patients receiving rivaroxaban had a hemoglobin decrease of ≥2 g/dl and required a blood transfusion (Table 5). The trial reported a TTR of 55%, which was much lower than in the RE-LY study. However, the TTR was calculated using a different method.
Apixaban is an oral, selective, reversible direct factor Xa inhibitor with high oral bioavailability and onset of action within 3 h. The half-life is 12 h and the drug is predominantly cleared in the faeces, with 25% of clearance being renal. Apixaban is metabolized mainly via CYP3A4 with minor contributions from CYP1A2, 2C8, 2C9, 2C19 and 2J2.
The AVERROES study was designed to evaluate the use of apixaban for stroke prophylaxis by comparing it with aspirin in patients unsuitable for warfarin. The study was ended prematurely because of the superiority of apixaban. After a year, patients taking apixaban were found to have a 55% reduction in the primary end point of stroke or systemic embolism (1.6% vs. 3.7% per year; HR: 0.45; 95% CI: 0.32–0.62; p < 0.001). The rate of major bleeding was similar in both groups: 1.4% per year for apixaban and 1.2% per year for aspirin (HR: 1.13; 95% CI: 0.74–1.75; p = 0.57).
The ARISTOTLE trial compared apixaban with warfarin in patients with AF. The rate of the primary outcome (ischemic or hemorrhagic stroke or systemic embolism) in ARISTOTLE was 1.27% per year in the apixaban group versus 1.60% per year in the warfarin group (HR with apixaban 0.79; 95% CI: 0.66–0.95; p < 0.001 for non-inferiority; p = 0.01 for superiority). The reduction in stroke was primarily driven by a reduction in hemorrhagic stroke, as the rates of ischemic stroke were comparable with warfarin. Apixaban demonstrated less minor and major bleeding, and mortality was significantly lower with apixaban than with warfarin by 11% (Table 6). The trial reported a TTR of 62%.
Novel Oral Anticoagulants
The shortcomings of warfarin inform many of the characteristics identified for the ideal anticoagulant (Table 3). In 2004, ximelagatran was the first available NOAC but had to be withdrawn due to hepatotoxicity in 2006. Since then dabigatran, rivaroxaban and apixaban have been investigated in large-scale randomized controlled trials and now represent valid alternatives to warfarin for stroke prevention in AF.
Dabigatran
Dabigatran etexilate is an oral prodrug, which is converted in the liver to its active compound, dabigatran – a competitive reversible direct thrombin inhibitor (DTI). The final step of the coagulation pathway requires thrombin to convert fibrinogen to fibrin. By binding to thrombin and disrupting its interaction with substrates, DTIs prevent fibrin production and can inhibit fibrin-bound thrombin (Figure 1). It has a rapid onset of action, a half-life of 17 h with multiple doses (7–9 h with single doses) and reaches clinical steady state within 2.5 days of initiation. Dabigatran is predominantly cleared by the kidneys and neither the prodrug nor its metabolite exerts an effect on the CYP system, thus dabigatran has fewer food and drug interactions than warfarin. There is, however, an age effect on pharmacokinetic parameters.
Clinical Trials of Dabigatran
The RE-LY trial established that dabigatran 110 mg two-times a day (b.i.d.) was non-inferior and 150 mg b.i.d. was superior to adjusted dose warfarin for the prevention of stroke and systemic embolism. The rate of stroke or systemic embolism occurred at 1.69% per year in patients assigned to warfarin compared with 1.53% in the dabigatran 110 mg group (RR: 0.91; 95% CI: 0.74–1.11; p < 0.001 for non-inferiority; p = 0.34 for superiority compared with warfarin) and 1.11% in the dabigatran 150 mg group (RR: 0.66; 95% CI: 0.53–0.82; p < 0.001 for non-inferiority and superiority compared with warfarin).
Of note, life-threatening bleeding occurred less frequently with dabigatran at both doses; similarly, ICH also occurred significantly less often with dabigatran than with warfarin. As the most feared complication of anticoagulant therapy, this significant reduction in ICH represents a considerable advantage for dabigatran. High-dose dabigatran was associated with a significantly increased risk of major gastrointestinal hemorrhage compared with low-dose dabigatran or warfarin. This is considered most likely secondary to the acidic core of dabigatran, which also explains its propensity to cause dyspepsia. The trial reported a TTR of 64% in the warfarin arm, which is in line with previous results from the literature (Table 4).
Rivaroxaban
Rivaroxaban is an oral, reversible, direct factor Xa inhibitor with high oral bioavailability and rapid absorption. It has a half-life of 9 h in young and healthy subjects and 12 h in those aged over 75; the onset of action is fast with peak concentrations reached between 2 and 4 h. There is a dual mode of elimination: the kidneys clear one-third and the remaining two-thirds are hepatically metabolized. The pharmacokinetics of rivaroxaban are dose-dependent and unaffected by gender, body weight or age. Although drugs that interact with CYP3A4 can theoretically affect rivaroxaban, a low potential for clinically significant drug or food interactions has been reported.
Clinical Trials of Rivaroxaban
ROCKET-AF established rivaroxaban as an alternative to warfarin for stroke prevention in AF. Enrolment of patients without prior stroke, TIA or systemic embolism and only two risk factors was capped at 10% of the overall study population. This meant 86% of the total population had a CHADS2 score of ≥3 with an overall mean CHADS2 score higher than that seen in the RE-LY trial (3.5 vs. 2.1), suggesting a higher risk cohort was studied. Indeed, patients with CHADS2 score 0–1 were not part of the trial inclusion criteria.
Rivaroxaban was non-inferior to warfarin for the primary efficacy end point of prevention of stroke and systemic embolism. In the per protocol analysis, there was a 21% reduction in the primary end point in the rivaroxaban arm (rivaroxaban 1.7% per year vs. warfarin 2.2% per year; HR: 0.79; 95% CI: 0.66–0.96; p < 0.001 for non-inferiority). Major and non-major clinically relevant bleeding was similar in the two groups. The rivaroxaban group demonstrated significantly less fatal bleeding and ICH although more patients receiving rivaroxaban had a hemoglobin decrease of ≥2 g/dl and required a blood transfusion (Table 5). The trial reported a TTR of 55%, which was much lower than in the RE-LY study. However, the TTR was calculated using a different method.
Apixaban
Apixaban is an oral, selective, reversible direct factor Xa inhibitor with high oral bioavailability and onset of action within 3 h. The half-life is 12 h and the drug is predominantly cleared in the faeces, with 25% of clearance being renal. Apixaban is metabolized mainly via CYP3A4 with minor contributions from CYP1A2, 2C8, 2C9, 2C19 and 2J2.
Clinical Trials of Apixaban
The AVERROES study was designed to evaluate the use of apixaban for stroke prophylaxis by comparing it with aspirin in patients unsuitable for warfarin. The study was ended prematurely because of the superiority of apixaban. After a year, patients taking apixaban were found to have a 55% reduction in the primary end point of stroke or systemic embolism (1.6% vs. 3.7% per year; HR: 0.45; 95% CI: 0.32–0.62; p < 0.001). The rate of major bleeding was similar in both groups: 1.4% per year for apixaban and 1.2% per year for aspirin (HR: 1.13; 95% CI: 0.74–1.75; p = 0.57).
The ARISTOTLE trial compared apixaban with warfarin in patients with AF. The rate of the primary outcome (ischemic or hemorrhagic stroke or systemic embolism) in ARISTOTLE was 1.27% per year in the apixaban group versus 1.60% per year in the warfarin group (HR with apixaban 0.79; 95% CI: 0.66–0.95; p < 0.001 for non-inferiority; p = 0.01 for superiority). The reduction in stroke was primarily driven by a reduction in hemorrhagic stroke, as the rates of ischemic stroke were comparable with warfarin. Apixaban demonstrated less minor and major bleeding, and mortality was significantly lower with apixaban than with warfarin by 11% (Table 6). The trial reported a TTR of 62%.