Selecting antithrombotic therapy for patients with atrial fibrillation

TARGET-SPECIFIC ORAL ANTICOAGULANTS

Although effective, warfarin requires frequent monitoring and dosage adjustment, has a delayed onset and protracted offset, and interacts with commonly consumed vitamin K–containing foods and frequently used drugs. These drawbacks prompted evaluation of existing antiplatelet agents, in combination or in conjunction with lower adjusted or fixed-dose warfarin. These regimens proved inferior,^39–42 spurring interest in developing alternative oral anticoagulants.

TSOACs act by directly inhibiting thrombin (factor IIa) or by reducing thrombin production indirectly by inhibiting factor Xa. Three TSOACs are approved. Each was compared with adjusted-dose warfarin in randomized controlled trials.

Dabigatran

Dabigatran etexilate was the first TSOAC approved in the United States.

Pharmacokinetics. Dabigatran etexilate has a bioavailability of 3% to 7% after oral administration. Its absorption is enhanced in an acidic gastric environment and is limited by P-glycoprotein-facilitated transport out of enterocytes. Dabigatran etexilate is hydrolyzed to its active metabolite dabigatran, which directly inhibits thrombin. Maximal plasma drug concentration and peak anticoagulant effect are achieved within 0.5 to 2 hours after administration.

Dabigatran is predominantly excreted by the kidneys, and has a half-life of 12 to 17 hours in patients with normal renal function. The half-life extends to 27 hours in those with moderately severe renal impairment (creatinine clearance 15–30 mL/min). The recommended dose of 150 mg twice daily should be reduced to 75 mg twice daily in patients with a creatinine clearance of 15 to 30 mL/min. This drug is contraindicated in patients with a creatinine clearance less than 15 mL/min.^43,44

Efficacy. The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial⁴⁵ randomly assigned 18,113 patients with nonvalvular atrial fibrillation at risk of thromboembolism (mean CHADS₂ score 2.1) to receive either dabigatran (either 150 mg twice daily or 110 mg twice daily) or warfarin (adjusted to an INR of 2.0 to 3.0). Of note, the lower approved dose of dabigatran (75 mg twice daily) was not tested in RE-LY.

At 2 years, higher-dose dabigatran was significantly more effective than both warfarin (RR 0.65, 95% CI 0.52–0.81, P < .05) and lower-dose dabigatran (RR 0.73, 95% CI 0.58–0.91, P < .05) in reducing the rate of systemic embolic events.

The risk of combined major bleeding events was no different with higher-dose dabigatran than with warfarin (RR 0.93, 95% CI 0.81–1.07, P < .05), but the rate of hemorrhagic stroke was significantly less with dabigatran than with warfarin (RR 0.26, 95% CI 0.14–0.49, P < .05). Higher rates of major gastrointestinal bleeding and dyspepsia occurred with dabigatran.

Post hoc analysis found more myocardial infarctions with dabigatran than with warfarin

Concern about the safety of dabigatran was raised when post hoc evaluation of RE-LY found a higher incidence of myocardial infarction with dabigatran than with warfarin (RR 1.38, 95% CI 1–1.91, P = .048).⁴⁶ Corroborating data were reported by Uchino and Hernandez,⁴⁷ comparing dabigatran with either warfarin or low-molecular-weight heparin. However, without directly comparing dabigatran and placebo, it is unclear whether the small increase in myocardial infarction reflects a direct effect of dabigatran or absence of a protective effect of warfarin or low-molecular-weight heparin.

Rivaroxaban

Rivaroxaban is a direct factor Xa inhibitor that blocks the amplified burst of thrombin production and in turn inhibits platelet aggregation and thrombus formation.

Pharmacokinetics. Rivaroxaban’s oral bioavailability is 80% to 100% after a single 15- or 20-mg dose taken with food. Its maximal anticoagulant effect is achieved within 2 hours. Two-thirds of the active drug is metabolized by either CYP450-dependent (CYP3A4, 2J2) or CYP-independent mechanisms; the inactive drug is then excreted in the urine and feces. The remaining, active drug is removed by the kidneys using the P-glycoprotein transporter.

The half-life of rivaroxaban is 5 to 9 hours. The recommended dosage of 20 mg daily should be reduced to 15 mg daily if the creatinine clearance rate is 30 to 50 mL/min, or to 10 mg if the creatinine clearance rate is 15 to 30 mL/min. Rivaroxaban is contraindicated in patients whose creatinine clearance rate is less than 15 mL/min.^48–52

Efficacy and safety. In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF),⁵³ 14,264 at-risk patients with nonvalvular atrial fibrillation (mean CHADS₂ score 3.5) were randomly assigned to receive either rivaroxaban 20 mg daily (or 15 mg daily if their creatinine clearance was 30–49 mL/min; the lowest dose of rivaroxaban, 10 mg, was not studied in this trial) or warfarin (target INR 2.0–3.0). Outcomes with rivaroxaban compared with warfarin:

• Systemic embolism:
  HR 0.79, 95% CI 0.66–0.96, P < .01, noninferiority
• Total bleeding: no difference
• Intracranial bleeding:
  HR 0.67, 95% CI 0.47–0.93, P = .02
• Fatal bleeding:
  HR 0.50, 95% CI 0.31–0.79, P = .003
• Major gastrointestinal bleeding:
  3.2% vs 2.2%, P < .001.

Apixaban

Apixaban is also a direct factor Xa inhibitor.

Pharmacokinetics. Apixaban’s oral bioavailability is 50%, with maximal blood concentration achieved at 3 to 4 hours. One-quarter of the drug is metabolized via CYP3A4. The remaining active drug is excreted by the kidneys and biliary/intestinal system via the P-glycoprotein transporter. Apixaban’s half-life is 9 to 14 hours.

Target-specific oral anticoagulants have no approved antidotes, but several have been suggested

The recommended dosage is 5 mg twice daily, but it should be reduced to 2.5 mg twice daily if at least two of the following characteristics are present: age 80 or older, weight 60 kg or less, and serum creatinine 1.5 mg/dL or more.^54,55

Efficacy and safety. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial⁵⁶ enrolled 18,201 patients with nonvalvular atrial fibrillation (mean CHADS₂ score 2.1) randomly assigned to receive either apixaban (5 mg twice daily with dosage reduction to 2.5 mg twice daily as noted above) or warfarin (target INR 2.0–3.0).

Compared with warfarin, apixaban was associated with lower risk of:

• Systemic embolism
  (HR 0.79, 95% CI 0.66–0.95, P = .01)
• Major bleeding
  (HR 0.69, 95% CI 0.60–0.80, P < .001)
• Intracranial hemorrhage
  (HR 0.42, 95% CI 0.30–0.58, P < .001)
• All-cause mortality
  (HR 0.89 95% CI 0.80–0.99, P = .047).

Drug interactions with the novel oral anticoagulants

TSOACs were developed with the intent to avoid many of the shortcomings of warfarin. Each has a broader therapeutic window and a rapid onset of action, enabling fixed dosing without need for serial monitoring. Compared with warfarin, they have significantly fewer dietary and drug interactions.

Nonetheless, drug interactions do exist and are important to recognize (Tables 1–3). These primarily result from inhibition or induction of cytochrome P450 enzyme activity or P-glycoprotein transporter action, involved in metabolism and elimination of active drug.

Reversibility of the target-specific oral anticoagulants

While the anticoagulant effects of warfarin can be reversed by vitamin K, fresh-frozen plasma, and prothrombin complex concentrate, TSOACs have no currently approved antidotes. Management of bleeding due to these agents was recently reviewed in this journal by Fawole et al.⁵⁷

Several nonspecific hemostatic agents have been suggested, including recombinant factor VIIa or prothrombin complex concentrates. The anticoagulant effect of rivaroxaban has been shown to be reversed by prothrombin complex concentrate in vitro; clinical effect has not been demonstrated.⁵⁸ PRT06445 (andexanet alfa), a recombinant protein antidote specific for factor Xa inhibitors, has entered clinical studies, with a phase 2 trial reporting high reversing capability for apixaban.⁵⁹

Unlike rivaroxaban and apixaban, which are highly bound to plasma protein, dabigatran can be effectively removed with hemodialysis. Liesenfeld et al⁶⁰ showed that longer dialysis duration was the most relevant variable for reducing dabigatran plasma levels. Current clinical experience is limited, and standard recommendations and formal guidance are lacking.

Switching oral anticoagulants

Suggested approaches for switching between anticoagulants are listed in Table 4.⁶¹

CHOOSING ANTITHROMBOTIC THERAPY

In valvular atrial fibrillation: warfarin

Anticoagulation with warfarin is advised for valvular atrial fibrillation. Patients with bioprosthetic heart valves or rheumatic valvular disease were not evaluated in randomized controlled trials of TSOACs. Dabigatran in particular is contraindicated in patients with mechanical heart valves, as the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement (RE-ALIGN)⁶² found higher rates of stroke, valve-related thrombosis, and myocardial infarction in patients receiving dabigatran.