Laboratory Monitoring of Non-Vitamin K Antagonist Oral Anticoagulant Use in Patients With Atrial Fibrillation: A Review.

Importance: The non-vitamin K antagonist oral anticoagulants (NOACs) apixaban, dabigatran, edoxaban, and rivaroxaban are administered in fixed doses without anticoagulant monitoring. Randomized trials show that unmonitored NOAC therapy is at least as effective as and safer than dose-adjusted warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. Subgroup analyses indicate that plasma drug levels or anticoagulant activity of the NOACs predict stroke and bleeding. This review examines the historical basis for anticoagulant monitoring, discusses methods to measure and interpret drug levels, and critically assesses the role of routine laboratory monitoring in the management of NOAC therapy. Observations: The predictable anticoagulant response of NOACs has provided the pharmacological basis for their administration in fixed doses without routine coagulation monitoring. Although it is possible to accurately measure NOAC drug levels, within-patient variability complicates interpretation of these results. Furthermore, patient characteristics, such as age and renal function, confound the association between NOAC drug levels and clinical outcomes. Information is lacking on the optimal drug level in particular patient groups (eg, elderly, the renally impaired, and those with high bleeding risk), the appropriate dose adjustment to achieve expected levels, and whether routine laboratory monitoring and dose adjustment will improve clinical outcomes. A benefit of a management strategy that incorporates routine therapeutic drug monitoring and dose adjustment over current standard-of-care metrics without such monitoring remains unproven. Conclusions and Relevance: Robust evidence from patients with atrial fibrillation randomized to NOACs or warfarin demonstrates that unmonitored NOAC therapy is at least as effective and safe as monitored warfarin, with lower rates of intracranial hemorrhage and reduced mortality. Further research is required to determine whether routine laboratory monitoring might provide a net benefit for patients. Until such data are available, clinicians should continue to prescribe NOACs in fixed doses without routine monitoring.

New oral anticoagulants for stroke prevention in atrial fibrillation: impact of study design, double counting and unexpected findings on interpretation of study results and conclusions.

Four recently introduced new oral anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban) have been shown to be at least as efficacious and safe as warfarin for stroke prevention in patients with atrial fibrillation in their respective trials. The first three have been approved, while edoxaban is awaiting regulatory approval. Several guidelines have endorsed the approved new oral anticoagulants over warfarin because of their favourable risk-benefit ratio, low propensity for food and drug interactions, and lack of requirement for routine coagulation monitoring. In this invited review, we summarise the results of the four studies and discuss widely held conclusions. We take a step further and discuss how differences in study design, analysis plan, and unexpected events affect the interpretation of the study results. Finally, we take our re-interpretation of study results and discuss how they might impact clinical practice and anticoagulant choice for patients.

Translational success stories: development of direct thrombin inhibitors.

Anticoagulants are the cornerstone of therapy for conditions associated with arterial and venous thrombosis. Direct thrombin inhibitors (DTIs) are anticoagulants that bind to thrombin and block its enzymatic activity. The bivalent parenteral DTIs hirudin and bivalirudin were based on the observation that the salivary extracts of medicinal leeches prevented blood from clotting. Key events that facilitated the subsequent development of small molecule active site inhibitors, such as argatroban, were the observation that fibrinopeptide A had antithrombotic properties and determination of the crystal structure of thrombin. Hirudin and argatroban have found their niche for the treatment of patients with heparin-induced thrombocytopenia, whereas bivalirudin is approved as an alternative to heparin for patients undergoing percutaneous coronary intervention. The development of orally active direct thrombin inhibitors was challenging because of the need to convert water-soluble, poorly absorbable, active site inhibitors into fat-soluble prodrugs that were then transformed back to the active drug after intestinal absorption. Dabigatran etexilate was the first new oral anticoagulant to be approved for long-term anticoagulant treatment in 6 decades. This Review highlights the development of DTIs as a translational success story; an example in which the combination of scientific ingenuity, structure-based design, and rigorous clinical trials has created a new class of anticoagulants that has improved patient care.

Direct thrombin inhibitors in cardiovascular disease.

Limitations of commonly used anticoagulants, unfractionated heparin, low-molecular-weight heparin, and oral vitamin K antagonists have prompted the development of alternative therapies. Direct thrombin inhibitors are a new class of anticoagulants that bind directly to thrombin and inhibit its interaction with substrates. In this Review, we critically examine the evidence from randomized controlled trials for the efficacy and safety of the parenteral direct thrombin inhibitors bivalirudin and argatroban, and the novel oral direct thrombin inhibitor dabigatran etexilate, in cardiovascular and thrombotic disease.

Electrical foot stimulation: a potential new method of deep venous thrombosis prophylaxis.

The purpose of this study was to compare venous blood flow velocity of intermittent pneumatic compression to electrical stimulation of the foot. A prospective randomized controlled study of 40 healthy volunteers was conducted. Subjects were seated for 4 hours during which they received electrical stimulation of the sole of the foot or intermittent pneumatic compression of the foot... Short-term electrical foot stimulation is at least as effective as foot intermittent pneumatic compression in increasing popliteal and femoral blood flow velocity. [corrected] Popliteal and femoral venous blood flow velocities were measured via Doppler ultrasonography. Blood flow velocity in the nonstimulated or noncompressed lower extremity served as a simultaneous control. For both the femoral and popliteal veins, the electrical foot stimulation group exhibited a greater increase in blood flow velocity than the intermittent pneumatic compression group. Electrical foot stimulation was noninferior relative to standard intermittent pneumatic compression. Specifically, this result of a greater increase in blood flow velocity is achieved at time = 120 minutes for the femoral vein (t = 2.70; p = .005) and time = 120 (t = 2.75; p = .004) and 240 (t = 2.27; p = .014) minutes for the popliteal vein. Short-term electrical foot stimulation is at least as effective as knee-high intermittent pneumatic compression in increasing popliteal and femoral blood flow velocity. Electrical foot stimulation has the potential to be an effective method of deep venous thrombosis prophylaxis.

Electrical foot stimulation and implications for the prevention of venous thromboembolic disease.

BACKGROUND: Venous stasis caused by immobility is an important risk factor for deep vein thrombosis following surgery and lower limb trauma, in bed-ridden medical patients, and in high-risk long distance air travelers. A safe and convenient method for reducing venous stasis would be useful in patients while in hospital and after discharge during their rehabilitation. SUBJECTS AND METHODS: 49 healthy subjects aged 51-76 were seated for 4 hours during which they received mild electrical stimulation of the calf, or sole of the foot (plantar muscles). Popliteal and femoral venous blood flow velocities were measured via doppler ultrasound. The non-stimulated lower extremity served as the simultaneous control. Subjects completed a questionnaire regarding their acceptance and tolerance of the electrical stimulation. RESULTS: There was a significant increase in venous femoral and popliteal blood flow for both calf (p < 0.035, p < 0.003), and plantar muscles (p < 0.0001, p < 0.009) on the stimulated side compared to the unstimulated side. The magnitude of the effect was similar for calf and plantar muscle stimulation. Subjects did not find the experience uncomfortable, and would use an electrical stimulator if told by their physician that they were at risk for developing blood clots. CONCLUSIONS: Mild electrical stimulation of the feet, as well as the calf, is a safe effective and convenient method for counteracting venous stasis and therefore has the potential to reduce the risk of deep vein thrombosis and pulmonary embolism for subjects who are immobilized.