Evaluation of safety and efficacy outcomes of direct oral anticoagulants versus warfarin in normal and extreme body weights for the treatment of atrial fibrillation or venous thromboembolism.

Despite evolving evidence, the use of direct oral anticoagulants (DOACs) in patients with extremes of body weight remains controversial. This study aimed to measure the impact of DOACs compared to warfarin on safety and efficacy outcomes in extreme body weight patients. This multi-center, health system, retrospective study examined the outcomes of patients with all body weights and extreme body weights prescribed a DOAC (rivaroxaban, apixaban, dabigatran, edoxaban) or warfarin for atrial fibrillation or venous thromboembolism over a 9-year period. The primary outcome was a composite of thromboembolism, symptomatic recurrent VTE, or severe bleeding; analyzed by pre-determined BMI cutoffs. A total of 19,697 patients were included in the study: 11,604 in the DOAC group and in the 8093 in the warfarin group. 295 patients were underweight and 9108 patients were pre-obese to obese class 3. After adjusting for potential confounders, warfarin patients had higher odds of experiencing the composite outcome compared to DOAC patients (OR 1.337, 95% CI 1.212-1.475). Additionally, obese patients were 24.6% more likely to experience the outcome compared to normal BMI patients. Adjusted modeling showed that warfarin patients experienced higher bleed rates compared to DOAC patients (OR 1.432, 95% CI 1.266-1.620). Obese patients were less likely to be diagnosed with a bleed (OR 0.749, 95% CI 0.658-0.854), and underweight patients were more likely to be diagnosed with a bleed (OR 1.522, 95% CI 1.095-2.115) compared to normal BMI patients. In conclusion, DOACs for atrial fibrillation or VTE in patients with extreme body weights appear safe and effective when compared to warfarin.

Antidotes for reversal of direct oral anticoagulants.

The main advantage of the direct oral anticoagulants over vitamin K antagonists is reduced rates of major bleeding, especially intracranial hemorrhage. While use of different clotting factor supplements have been used in patients with direct oral anticoagulant induced major bleeding or when there is need for urgent surgery, the lack of preclinical and clinical data are concerning. Idarucizumab is a specific antibody developed with a 350-fold greater affinity for dabigatran than its pharmacologic target thrombin. Andexanet is a modified factor Xa molecule that binds the direct and indirect Xa inhibitors without being enzymatically active. Ciraparantag, has potential to reverse the anticoagulant activity of multiple agents. The pharmacology, preclinical, and clinical data that have developed these specific antidotes are reviewed in this manuscript.

Management of Venous Thromboembolism: Recent Advances in Oral Anticoagulation Therapy.

OBJECTIVE: To review clinical data on direct oral anticoagulants (DOACs) used in the acute treatment of venous thromboembolism (VTE) as well as practical considerations when using these products. DATA SOURCES: Searches of PubMed and Google Scholar for VTE, deep vein thrombosis, pulmonary embolism, and relevant drug international nonproprietary names were conducted. Additional online searches were conducted for prescribing information. STUDY SELECTION AND DATA EXTRACTION: Relevant articles on dabigatran, rivaroxaban, apixaban, and edoxaban for the management of VTE compared with oral vitamin K antagonists (VKAs; published between 1966 and December 2015) were reviewed and summarized, together with information on dosing, pharmacokinetics/pharmacodynamics, and drug-drug interactions. DATA SYNTHESIS: The DOACs have the potential to circumvent many of the disadvantages of VKAs. At a minimum, they greatly increase the available therapeutic options, thus providing a greater opportunity for clinicians to select a management option that best fits the needs of individual patients. Despite the significant advance that DOACs represent, they are not without risk and require careful consideration of a number of clinical issues to optimize safety and efficacy. CONCLUSIONS: The emergence of DOACs for the management of thromboembolic disorders represents a paradigm shift from oral VKAs. The DOACs provide similar efficacy and improved safety in selected patients as compared with VKAs. Clinicians treating VTE need to be familiar with the intricacies involved in using these agents, including the appropriate dose selection for the relevant indication, avoidance of drug-drug and drug-disease interactions, and consideration of dose adjustments in specific clinical situations, such as organ dysfunction.

Clinical use of rivaroxaban: pharmacokinetic and pharmacodynamic rationale for dosing regimens in different indications.

Target-specific oral anticoagulants have become increasingly available as alternatives to traditional agents for the management of a number of thromboembolic disorders. To date, the direct Factor Xa inhibitor rivaroxaban is the most widely approved of the new agents. The dosing of rivaroxaban varies and adheres to specific schedules in each of the clinical settings in which it has been investigated. These regimens were devised based on the results of phase II dose-finding studies and/or pharmacokinetic modeling, and were demonstrated to be successful in randomized, phase III studies. In most cases, the pharmacodynamic profile of rivaroxaban permits once-daily dosing. A once-daily dose is indicated for the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery, the long-term prevention of stroke in patients with non-valvular atrial fibrillation, and the long-term secondary prevention of recurrent VTE. Twice-daily dosing is required in the acute phase of treatment in patients with VTE and in the combination of rivaroxaban with standard single or dual antiplatelet therapy for secondary prevention after acute coronary syndrome events. This article reviews the empirical and clinical rationale supporting the dose regimens of rivaroxaban in each clinical setting.

Key articles related to complementary and alternative medicine in cardiovascular disease: part 1.

Complementary and alternative medicine (CAM) therapy has gained popularity in America over the past several years, reflected in the increased utilization of these agents. Given the abundance of nontraditional products available to the public, clinicians should be made aware of the existing evidence relating to CAM therapy to better provide patient care in a meaningful manner. This bibliography article compiled key articles specific to CAM therapy and cardiovascular disease, which include primary literature, review articles, consensus statements, and abstracts of landmark studies. Based on the numerous published reports available on this topic, this bibliography, as part 1 of 2, focuses on the efficacy of CAM therapy in cardiovascular disease.

Advances in the management of stable angina.

OBJECTIVE: To describe the approved uses, pharmacology, pharmacodynamics, pharmacokinetics, efficacy, safety, and place in therapy of ranolazine, the first new antianginal drug therapy introduced in more than 20 years for the treatment of chronic angina. SUMMARY: The mechanism of action of ranolazine is unknown, but it may involve inhibition of the late sodium current in the myocardium, thereby preventing sodium-induced intracellular calcium overload during ischemia. This mechanism differs from that of other antianginal agents, which primarily affect myocardial oxygen supply or demand through hemodynamic effects. Ranolazine undergoes extensive metabolism, primarily by cytochrome P-450 (CYP) 3A4, so interactions with drugs that are moderate to potent inhibitors of CYP3A4 need to be considered. Ranolazine is also a P-glycoprotein (P-gp) substrate and inhibitor, and it may interact with other P-gp substrates and inhibitors. In patients with an inadequate response to other antianginal agents, the addition of ranolazine to existing antianginal therapy increases exercise duration and the time to angina on an exercise treadmill test, and it decreases the frequency of angina attacks and nitroglycerin use. The drug produces antianginal effects without significantly affecting either heart rate or blood pressure. Ranolazine prolongs the QT interval on the electrocardiogram, but the overall electrophysiologic effects of the drug suggest that it is not expected to cause torsades de pointes. CONCLUSION: Ranolazine has a unique mechanism of action that may be complementary to that of conventional antianginal agents in the treatment of chronic angina. An understanding of the potential for drug interactions, disease interactions, and contraindications is needed to ensure safe and effective use of the drug.