Psychopharmacologic Agents in the Prevention of Psychiatric Disorders

The success of psychoactive agents in management of psychoses has directed attention to prevention of psychiatric disorders. A number of substances are said to be effective in prophylaxis, but the claims await substantiation in controlled studies and preventive pharmacotherapy in general awaits a clearer understanding of etiology.     

Direct Oral Anticoagulants: New Drugs and New Concepts

Direct oral anticoagulants (DOACs) are approved for multiple thromboembolic disorders and provide advantages over existing agents. As with all anticoagulants, management protocols for the eventuality of bleeding are important. Randomized phase III studies generally show that DOACs have a similar risk of clinically relevant bleeding compared with standard anticoagulants, with reductions in major bleeding in some cases. This may be particularly important in patients with atrial fibrillation, for whom the rate of intracranial hemorrhage was approximately halved with DOACs compared with warfarin. Conversely, the risk of gastrointestinal bleeding may be increased. Specific patient characteristics, such as renal impairment, comedications, and particular aspects of each drug, including the proportion eliminated by the kidneys, must be taken into account when assessing the risk of bleeding. Although routine coagulation monitoring of DOACs is not required, it may be useful under some circumstances. Of the traditional clotting assays, a sensitive and calibrated prothrombin time may be useful for detecting the presence or absence of clinically relevant factor Xa inhibitor concentrations (rivaroxaban or apixaban), but specific anti–factor Xa assays can measure drug levels quantitatively. For dabigatran, the results of an activated partial thromboplastin time test may exclude a clinically relevant pharmacodynamic effect, but a calibrated dilute thrombin time assay can be used for quantification of drug levels. In the event of mild or moderate bleeding, normal hemostatic support measures are recommended. For life-threatening bleeding, use of nonspecific prohemostatic agents may be considered, although clinical evidence is scarce. Specific antidotes are in development.     

Newer oral anticoagulant agents: a new era in medicine

After a gap of almost 60 years following the development of warfarin, 2 new categories of oral anticoagulant agents have been approved for clinical use - the direct thrombin inhibitors and factor Xa inhibitors. These agents promise to be more convenient to administer with fixed dosing but still have equivalent efficacy and improved bleeding risk compared to warfarin. The clinical community is looking forward to the widespread usage of these agents but there is also some apprehension regarding bleeding risks, non-availability of specific reversal strategies and lack of specific monitoring parameters. This review article will attempt to educate the reader about three representative drugs from these classes: Dabigatran, Rivaroxaban and Apixaban. We will discuss the historical perspective to the development of these drugs, available research data and pharmacology of these agents. The best strategies for monitoring and reversal of these drugs in special situations will also be touched upon.     

Cost-Utility Analysis of Apixaban versus Warfarin in Atrial Fibrillation Patients with Chronic Kidney Disease

Background

Warfarin use for stroke prevention in atrial fibrillation (AF) patients with chronic kidney disease is debated. Apixaban was shown to be safer than warfarin, with superior reduction in the risk of stroke, systemic embolism, mortality, and major bleeding irrespective of kidney function.

A Prospective Cohort Comparative Study of Rivaroxaban,Dabigatran, and Apixaban Oral Thromboprophylaxis in 2431 Hip and Knee Arthroplasty Patients: Primary Efficacy Outcomes and Safety Profile

BackgroundDirect oral anticoagulants (DOACs) have promised superior efficacy to low molecular weight heparins in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty. However, there are concerns about raised associated bleeding and wound problems with these agents. This study aims to evaluate and compare the efficacy and safety of the 3 DOAC drugs: rivaroxaban, dabigatran and apixaban.MethodsThe primary outcome measures were rate of symptomatic VTE and major bleeding. Secondary outcome measures were wound healing problems and requirement for return to theater. A total of 2431 patients received one of the DOAC drugs as thromboprophylaxis following total hip arthroplasty (35 days) or total knee arthroplasty (14 days) between 2011 and 2015. Binary variables were compared between the 3 groups by using the chi-squared test or Fisher’s exact test. Relative risks of selected primary and secondary end points were also calculated for the prespecified pairwise comparison.ResultsThe overall symptomatic VTE rate was 2%. Rivaroxaban had a statistically significant superior efficacy for overall VTE prevention (0.8% vs 2.6%) compared with dabigatran (P < .01) and apixaban (P < .01), and deep vein thrombosis prevention (0.3% vs 2.2%) over dabigatran (P < .01). The overall rate of major bleeding was 1.2% with no significant difference observed between the 3 studied drugs.ConclusionAll 3 drugs had symptomatic VTE rates comparable with low molecular weight heparin from the published literature. Rivaroxaban appears to have superior efficacy in VTE prevention over apixaban and dabigatran. No statistical difference was observed for major bleeding with any of the 3 agents.     

Comprehensive review of the impact of direct oral anticoagulants on thrombophilia diagnostic tests: Practical recommendations for the laboratory

There is a laboratory and clinical need to know the impact of direct oral anticoagulants (DOACs) on diagnostic tests to avoid misinterpretation of results. Although the regulatory labelling documents provide some information about the influences of each DOAC on diagnostic tests, these are usually limited to some of the most common tests and no head to head comparison is available. In this paper, we report the impact of DOACs on several thrombophilia tests, including assessment of antithrombin, protein S and protein C activity assays, detection of activated protein C resistance and assays used for lupus anticoagulant. Results are compared and discussed with data obtained from literature. The final goal of this comprehensive review is to provide practical recommendations for laboratories to avoid misdiagnosis due to oral direct factor Xa (FXa) or IIa (FIIa) inhibitors. Overall, oral direct FXa (apixaban, betrixaban, edoxaban and rivaroxaban) and FIIa (dabigatran) antagonists may affect clot-based thrombophilia diagnostic tests resulting in false-positive or false-negative results. An effect on FIIa-based thrombophilia diagnostic tests is observed with dabigatran but not with anti-FXa DOACs and conversely for FXa-based thrombophilia diagnostic tests. No impact was observed with antigenic/chromogenic methods for the assessment of protein S and C activity. In conclusion, interpretation of thrombophilia diagnostic tests results should be done with caution in patients on DOACs. The use of a device/chemical compound able to remove or antagonize the effect of DOACs or the development of new diagnostic tests insensitive to DOACs should be considered to minimize the risk of false results.     

Potential Role of Direct Oral Anticoagulants in the Management of Heparin-induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a rare, potentially life-threatening condition secondary to unfractionated heparin or low molecular weight heparin exposure. This immune-mediated drug reaction manifests as thrombocytopenia with a paradoxical hypercoagulable state that can result in life-threatening thrombosis. It is imperative to ensure cessation of heparin-based products as soon as HIT is identified. Traditional treatment options include argatroban, bivalirudin, fondaparinux, and danaparoid with a transition to warfarin upon platelet recovery. These anticoagulants are notwithstanding limitations including parenteral administration and routine laboratory monitoring leading to prolonged hospitalizations, emphasizing the need for new therapies. Direct oral anticoagulants (DOACs) have been increasingly investigated for the management of HIT and may overcome the aforementioned challenges of current therapies. The objective of this narrative review is to summarize the current HIT guidelines, discuss limitations to contemporary treatment options, provide insight into the emerging evidence for the DOACs rivaroxaban, apixaban, and dabigatran, and conclude with a clinical summary for their use in this setting. The PubMed, Google Scholar, and MEDLINE databases were searched for peer-reviewed literature from January 1, 2012, to June 31, 2018. Twenty-seven articles met inclusion criteria for review: 1 prospective trial, 5 retrospective cohort studies, and 21 case reports totaling 104 patients treated with a DOAC for HIT. The DOACs prevented new and recurrent thrombosis in 98% (n=102) of cases, and bleeding complications occurred in 3% (n=3). While current literature remains limited, it is suggestive of a potential role of DOACs for HIT, which has led to their integration into the 2018 American Society Hematology Guidelines with a conditional recommendation.