Patients with AF have a fivefold increased risk of stroke, particularly in patients with valvular heart disease and in the elderly. It is estimated that 15–20 % of all strokes are attributable to AF. Four new agents [apixaban, dabigatran, edoxaban, and rivaroxaban] are vying to replace or greatly reduce the use of the well-tried warfarin. There is little doubt that warfarin is underused and in many the international normalized ratio [INR] is not in the desired range 2–3.

Apixaban is an oral direct factor Xa inhibitor. Bioavailability is high. Importantly, elimination is only 25 % renal, and half-life ≈ 12 h. Similar to rivaroxaban, cytochrome P450 3A4 is involved in the metabolism so that strong inhibitors substantially increase drug levels (Eikelboom and Weitz 2010).

ARISTOTLE.Granger et al 2011: [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial] In this double-blind design trial 18,201 patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke were enrolled and randomly assigned to receive the direct factor Xa inhibitor apixaban (at a dose of 5 mg twice daily) or warfarin (target INR, 2.0–3.0).

Results: Apixaban was not only noninferior to warfarin, but actually superior, reducing the risk of stroke or systemic embolism by 21 % and the risk of major bleeding by 31 %. As compared with warfarin, apixaban significantly reduced the risk of death from any cause by 11 %. Apixaban is the first of the newer anticoagulants to show a significant reduction in the risk of death from any cause as compared with warfarin (hazard ratio, 0.89; P = 0.047). See Table 24-1.

AVERROES compared the efficacy of apixaban 5 mg twice daily with aspirin (81–325 mg once daily) for stroke and systemic embolism prevention in 5599 AF patients considered unsuitable for vitamin K antagonist treatment. The trial was stopped early on recommendation by the Data and Safety Monitoring Board because of clear benefits in regard to stroke reduction favoring apixaban (hazard ratio, 0.46; P < 0.001). Strikingly, apixaban was associated with rates of major bleeding similar to those observed with aspirin (Connolly et al 2011).

Apixaban was better tolerated than aspirin. At 2 years, the rates of permanent discontinuation of the study medication were 17.9 % per year in the apixaban group and 20.5 % per year in the aspirin group (Connolly et al 2011). Apaxiban, compared with warfarin, was associated with fewer intracranial hemorrhages, less adverse events following extracranial hemorrhage, and a 50 % reduction in fatal consequences at 30 days in cases of major hemorrhage (Hylek et al. 2014).

In an RCT Apixaban was superior to enoxaparin VTE prophylaxis after hip replacement.

Rivaroxaban is an oral direct inhibitor of factor Xa with high bioavailability, Elimination is 33 % renal; the half-life ≈ 9–12 h, peak plasma level 2.5–4 h (Abrams and Emerson 2009)

A new drug for myocardial infarction: Rivaroxaban

The ROCKET investigators (Mega et al. 2012) randomly assigned 15,526 patients with a recent acute coronary syndrome [~ STEMI ~ 50 %, NSTEMI ` 25 %, unstable angina %] to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke (Mega et al. 2012). Rivaroxaban significantly reduced the primary efficacy end point of death from cardiovascular causes, myocardial infarction [MI], or stroke, as compared with placebo, with rates of 8.9 % and 10.7 %, respectively, P = 0.008. The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7 % vs. 4.1 %, P = 0.002) and from any cause (2.9 % vs. 4.5 %, P = 0.002). Importantly, rivaroxaban reduced the risk of stent thrombosis (Mega et al. 2012).

ROCKET AF. (Patel et al. 2011) compared a once-daily, fixed dose of rivaroxaban [20 mg] with adjusted-dose warfarin in patients with nonvalvular atrial fibrillation who were at moderate-to-high risk for stroke; rivaroxaban was noninferior to warfarin in the prevention of subsequent stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. In this double-blind design trial rates of intracranial hemorrhage were significantly lower in the rivaroxaban group than in the warfarin group (0.5 % vs. 0.7 % per year; hazard ratio, 0.67; P = 0.02).

The FDA has approved the oral direct factor Xa inhibitor rivaroxaban (Xarelto) for prevention of stroke in patients with nonvalvular atrial fibrillation. See Chap. 22 for details.

Dabigatran etexilate is hydrolyzed to the active dabigatran, with maximum activity ≈ 1 h after administration. Elimination is 80 % renal ; the half-life is 12–17 h.

The RE-LY trial evaluated the direct thrombin inhibitor dabigatran 110 mg and 150 mg, administered twice daily in patients with no valvular atrial fibrillation. The assignments to dabigatran or warfarin were, however, not concealed. The ROCKET AF and ARISTOTLE trials achieved a double-blind design.

In patients with nonvalvular atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage, but this dose is not approved by some National bodies. The 150 mg dose, approved by the FDA as compared with warfarin, was associated with lower rates of stroke, but similar rates of major hemorrhage (Connolly et al. 2009).

The rate of MI, however, was 0.53 % per year with warfarin and was higher with dabigatran: 0.72 % per year in the 110-mg group (relative risk, 1.35; 95 % CI, 0.98–1.87; P = 0.07) and 0.74 % per year in the 150-mg group (relative risk, 1.38, P = 0.048) (Connolly et al. 2009).

There was a significantly higher rate of major gastrointestinal bleeding with dabigatran at the 150-mg dose than with warfarin. Rates of dyspepsia and including abdominal pain were more common with dabigatran (11.8 % in the 110-mg group and 11.3 % in the 150-mg group) as compared with warfarin (5.8 %) (Connolly et al. 2009).

Gastrointestinal bleeding was more common with higher-dose dabigatran than warfarin, and dyspepsia was more common with dabigatran (11.8 % of patients with 110 mg and 11.3 % of patients with 150 mg compared with 5.8 % with warfarin; P < 0.001 for both) (Connolly et al. 2009). There was a small increased risk for acute MI.