Safety and efficacy of non-vitamin K oral anticoagulants in non-valvular atrial fibrillation: a Bayesian meta-analysis approach

Introduction: Choosing between different non-vitamin K antagonist oral anticoagulants (NOACs) in non-valvular atrial fibrillation (NVAF) is difficult due to the absence of head to head comparative studies. We performed a Bayesian meta-analysis to explore similarities and differences between different NOACs and to rank treatments overall for safety and efficacy outcomes.

Areas covered: Through a systematic literature search we identified randomized controlled Phase III trials of dabigatran, rivaroxaban, apixaban, and edoxaban versus adjusted-dose warfarin in patients with NVAF.

Expert opinion: Warfarin ranked worst for all-cause mortality and intracranial bleedings and had a nil probability of ranking first for any outcome. The risk of major bleeding versus warfarin was lower with apixaban, dabigatran 110 mg, and both doses of edoxaban. All agents reduced the risk of intracranial bleeding versus warfarin. Edoxaban 30 mg was the best among the treatments being compared for major and gastrointestinal bleeding. Dabigatran 150 mg was the best for stroke and systemic embolism. This study suggests that NOACs are generally preferable to warfarin in patients with NVAF. However, safety and efficacy differences do exist among NOACs, which might drive their use in specific subsets of AF patients, allowing prescribers to tailor treatment to distinct patient profiles.     

Dose tailoring of dabigatran etexilate: obvious or excessive?

Introduction: Dabigatran etexilate is used for preventing blood clots and tends to replace older anticoagulants in many of their indications. However, the ‘one dose fits all’ policy is subject to criticism. Recent findings assert the anxiety of the scientific community concerning the pharmacokinetic properties of dabigatran etexilate, that is, an important interindividual variability including an important genetic variant with a significant dependence of the renal function as route of elimination.

Areas covered: This meta-opinion provides an overview of the current knowledge and evidence on the dose tailoring of dabigatran etexilate. It also discusses the remaining challenges to benefit from this perspective strategy to enhance the benefit–risk balance of dabigatran etexilate. Data were searched in the published literature and on regulatory agencies’ websites. Additionally, unpublished data were searched and discussed.

Expert opinion: Causality between dabigatran exposure and bleeding risk is now established and recommendations on how to best estimate the drug exposure are published. Additionally, simulating studies revealed that a dose adaptation based on dabigatran plasma concentration estimations could improve the benefit–risk profile of the drug. This accumulating evidence suggests that some patients under dabigatran etexilate may benefit from a tailoring of the dose beyond the ones already proposed by the manufacturer.     

Edoxaban for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation

Introduction: Oral anticoagulation is central to the management of patients with atrial fibrillation (AF) and at least one additional stroke risk factor. For decades, the vitamin K antagonists (e.g. warfarin) remained the only oral anticoagulant available for stroke prevention in AF. The non-vitamin K oral anticoagulants (NOACs) are now available, and these drugs include the direct thrombin inhibitors and factor Xa inhibitors. The latter class includes edoxaban, which has recently been approved for stroke prevention in AF by the United States Food and Drug Administration and the European Medicine Agency. In line with other NOACs, edoxaban avoids the many limitations of warfarin associated with variability of anticoagulation effect and multiple food and drug interactions.

Areas covered: In this review, the currently available evidence on edoxaban in patients with non-valvular AF is discussed. The pharmacology, efficacy and safety, and current aspects of use of edoxaban in patients with non-valvular AF for stroke and thromboembolism prevention are reviewed.

Expert opinion: Phase III trials on edoxaban for stroke prevention in non-valvular AF confirms non-inferiority of edoxaban compared to well-managed warfarin both in terms of efficacy and safety. Currently ongoing and future trials as well as real-world data are warranted to confirm its effectiveness and safety for chronic anticoagulation and improve evidence in other areas which are lacking evidence where NOAC use remains controversial.     

The safety of edoxaban for treating atrial fibrillation

Introduction: Atrial Fibrillation (AF) has a worldwide increasing incidence and prevalence, putting patients at risk for atrial thrombus formation and consecutive thromboembolic events. Morbidity and mortality have become a significant global public health care burden. Thus, there is increasing need for safe and effective medical prophylaxis of thromboembolic events. Edoxaban is the fourth approved non-vitamin K oral anticoagulant (NOAC) that has been introduced into the market for the prophylaxis of stroke or systemic embolism in non valvulär AF patients after dabigatran, rivaroxaban, and apixaban. The pivotal phase III clinical trial evaluating safety and efficacy of edoxaban included more than 21,000 patients.

Areas covered: The aim of this expert opinion drug safety review is to introduce edoxaban as a compound, to discuss its development, and its pharmacologic properties. Furthermore, efficacy and safety data of edoxaban – with emphasis on a comparison to oral anticoagulation with warfarin and the other currently available NOACs – are discussed. Ongoing studies that further evaluate edoxaban in special patient populations and disease entities are summarized.

Expert opinion: Concerning safety and efficacy, medical compliance, adherence and concomitant diseases like renal impairment are of utmost importance in daily clinical practice, why in the expert opinion part of this review emphasis is put on that issue.     

Strategies for improving dabigatran adherence for stroke prevention in patients with non-valvular atrial fibrillation: education and drug intake reminders (FACILITA study)

Objective To assess the efficacy of a mixed intervention, educational, and reminder calendar of the intake, as a strategy to improve therapeutic adherence with dabigatran in patients with non-valvular atrial fibrillation (NVAF).

Methods This was a prospective, longitudinal, multi-center study, carried out in 110 specialized healthcare centers in Spain. Seven hundred and twenty-six patients treated with dabigatran prescribed for stroke prevention were included. A cluster randomization was performed based on two groups: (1) Control Group (CG) as usual clinical practice, and (2) Intervention Group (IG) with a mixed strategy: (a) Healthcare education, and (b) Use of a reminder calendar for taking the anticoagulant medication. Three visits took place: baseline and follow-up at 6 and 12 months. Compliance was measured by using electronic monitors (MEMS). Average adherence percentage (%; Average AP) and daily compliance (%; Daily AP) was calculated. A patient was considered adherent when AP was 80–100%.

Results Six hundred and twenty-five patients completed the study (315 in the IG and 310 in the CG). Daily AP was 91.97% at 6 months and 91.05% after 12 months in the IG and 82.26% and 82.63% in the CG. Average adherence was 90.79% and 89.20% in the IG and 64.51% and 63.22% in the CG at 6 and 12 months, respectively. Significant differences were observed in the Daily AP and Average AP, with higher percentages in the IG. In the non-adherents group, the number of concomitant drugs, baseline, and 6 months SBP values, 6 and 12 months DBP values, and weight, total cholesterol, and LDL cholesterol were significantly higher. The number needed to treat (NNT) was 3.84 patients to prevent one non-adherence.

Conclusions A mixed intervention, consisting of patient education and a simple calendar reminder of drug intake, is an effective strategy to improve dabigatran therapeutic adherence in patients with NVAF. The percentage of adherence with dabigatran was high.     

A rapid evidence assessment of bleed-related healthcare resource utilization in publications reporting the use of direct oral anticoagulants for non-valvular atrial fibrillation

Objective: Non-valvular atrial fibrillation (NVAF), a common cardiac arrhythmia, is associated with high morbidity and carries a substantial economic burden. Historically, vitamin K antagonists (VKAs; e.g. warfarin) have been used for therapy of NVAF, but recently several direct oral anticoagulants (DOACs) have been approved for prevention of stroke in patients with NVAF. This review summarizes the real-world evidence (RWE) for healthcare resource utilization (HRU) in patients receiving oral anticoagulants (VKAs and/or DOACs) for therapy of NVAF.

Methods: A PRISMA-compliant literature search assessed Medline^® and Embase^® databases from 1 January 2011 to 4 May 2017, and the National Health Service Economic Evaluation Database from 1 January 2011 to 31 December 2015. Publications were included if they reported observational data from real-world use of one or more anticoagulant therapies. Outcomes of interest included hospitalizations, length of stay (LOS), mortality and costs.

Results: Twenty-eight publications were included. Apixaban and dabigatran were associated with fewer bleed-related hospitalizations than warfarin. Bleed-related LOS were generally longer for warfarin than for DOACs. Bleed-related treatment costs were lower for patients receiving apixaban or receiving dabigatran than patients receiving rivaroxaban or receiving warfarin. Bleed-related mortality in patients receiving oral anticoagulation for treatment of NVAF were low across all DOACs and warfarin.

Conclusions: The limited available evidence for HRU burden among patients receiving oral anticoagulation for NVAF suggests that DOACs (particularly apixaban and dabigatran) offer some degree of benefit in terms of HRU outcomes, compared with warfarin. Further work is required to understand HRU outcomes in patients receiving DOACs.     

Considerations and treatment options for patients with comorbid atrial fibrillation and diabetes mellitus

Introduction: Atrial fibrillation (AF) and diabetes mellitus (DM) are common worldwide and their incidence is increasing, representing a significant public health and economic burden as well as an increase in individual increased morbidity and mortality risk profiles. Both conditions are closely related, as patients with DM are at increased risk of incident AF, and AF patients with DM are at higher risk of cardiovascular events compared to non-AF patients.

Areas covered: This review article aims to provide an overview of the current evidence linking DM and AF, as well as the impact of obesity, weight loss and stroke on these coexisting conditions. Second, the effects of new oral anti hyperglycaemic medications on cardiovascular risk will be considered.

Expert opinion: In conclusion, coexisting AF and DM represent a high risk population of patients requiring aggressive risk factor identification and treatment optimisation. The multifactorial interplay between these conditions requires individual assessment of patient risk profiles with the aim of minimising the impact of each modifiable risk factor.     

Anticoagulant and antiplatelet therapy choices for patients with atrial fibrillation one year after coronary stenting or acute coronary syndrome

Introduction: Guidelines recommend a combined anticoagulant and antiplatelet approach for patients with atrial fibrillation (AF) after coronary stenting (CS) or acute coronary syndrome (ACS). Finding the optimal balance of reducing ischemic risk and minimizing bleeding risk is challenging. Recent trials have evaluated a variety of regimens for up to one year for AF patients after CS/ACS. Little empiric evidence exists about the best antithrombotic strategy beyond one year.

Areas covered: In this review two key areas are covered. First, a summary of the overall risk and benefits of anticoagulant and antiplatelet therapy in patients with AF and CS or ACS is provided. Second, despite limited empiric evidence to guide therapeutic decisions for combined anticoagulant and antiplatelet therapy in patients with AF one year after CS/ACS we provide guidance for shared patient-physician decision making.

Expert opinion: The evidence is limited. For all patients with AF and stable CAD (≥1 year after CS or ACS) the risk for thromboembolism, cardiovascular events and bleeding should be assessed individually. For patients with low bleeding risk and high risk for cardiovascular events, antiplatelet therapy might be added to anticoagulant therapy.     

Effects of CYP2C11 gene knockout on the pharmacokinetics and pharmacodynamics of warfarin in rats

1. CYP2C11 is the most abundant isoform of cytochrome P450s (CYPs) in male rats and is considered the main enzyme for warfarin metabolism.

2. To further access the in vivo function of CYP2C11 in warfarin metabolism and efficacy, a CYP2C11-null rat model was used to study warfarin metabolism with both in vitro and in vivo approaches. Prothrombin time (PT) of warfarin was also determined.

3. The maximum rate of metabolism (V_max) and intrinsic clearance (CL_int) of liver microsomes from CYP2C11-null males were reduced by 37 and 64%, respectively, compared to those in Sprague Dawley (S-D) rats. The K_m of liver microsomes from CYP2C11-null males was increased by 73% compared to that of S-D rats. The time to reach the maximum plasma concentration (T_max) of warfarin in CYP2C11-null males was significantly delayed compared to that in S-D males, and the CL rate was also reduced. The PT of CYP2C11-null rats was moderately longer than that of S-D rats.

4. In conclusion, the clearance rate of warfarin was mildly decreased and its anticoagulant effect was moderately increased in male rats following CYP2C11 gene knockout. CYP2C11 played a certain role in the clearance and efficacy of warfarin, while it did not seem to be essential.     

Risk of gastrointestinal bleeding during anticoagulant treatment

Introduction: Gastrointestinal bleeding (GIB) is a major problem in patients on oral anticoagulation therapy. This issue has become even more pressing since the introduction of direct oral anticoagulants (DOACs) in 2009.

Areas covered: Here we review current evidence related to GIB associated with oral anticoagulants, focusing on randomized controlled trials, meta-analyses, and post-marketing observational studies. Dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily increase the risk of GIB compared to warfarin. The risk increase with edoxaban is dose-dependent, while apixaban shows apparently, no increased risk. We summarize what is known about GIB risk factors for individual anticoagulants, the location of GIB in patients taking these compounds, and prevention strategies that lower the risk of GIB.

Expert opinion: Recently there has been an important shift in the clinical presentation of GIB. Specifically, upper GIB has decreased with the decreased incidence of peptic ulcers due to the broad use of proton pump inhibitors and the decreased prevalence of H. pylori infections. In contrast, the incidence of lower GIB has increased, due in part to colonic diverticular bleeding and angiodysplasia in the elderly. In this population, the addition of oral anticoagulation therapy, especially DOACs, seems to increase the risk of lower GIB.     

Thromboembolic and bleeding risks in patients undergoing atrial fibrillation ablation: oral anticoagulation perspectives

Introduction: Atrial fibrillation (AF) is a cause of significant morbidity and mortality. Catheter ablation for AF (CAAF) has emerged as an effective treatment option of rhythm control for patients with symptomatic AF. However, the risk of thromboembolism and bleeding in the periprocedural period represent a worrisome complication of this therapy. The reported incidence of thromboembolic and bleeding events associated with CAAF varies from 0.9% to 5% depending on the CAAF strategy and the anticoagulation regimen used in the periprocedural period.

Areas covered: The different anticoagulation regimens used prior to, during, and after CAAF to minimize the risk of thromboembolic and bleeding events are reviewed. The use of uninterrupted oral anticoagulation and appropriate heparin dosing to achieve safe activated clotting time levels are also detailed. A comprehensive approach with assessment of individual risk for thromboembolic and bleeding complications, and understanding the pharmacokinetics of the anticoagulant agents available is also reviewed.

Expert opinion: The key advances done in the periprocedural anticoagulation field include the use of uninterrupted anticoagulation strategies in patients undergoing AF ablation and efforts to simplify the selection of patients who need LAA thrombus screening prior to ablation.     

Clinical relevance of pharmacokinetic and pharmacodynamic properties of edoxaban when treating patients with atrial fibrillation and heart failure

Introduction: Atrial fibrillation (AF) is an independent risk factor for stroke. It is most prevalent in the elderly and frequently coexists with heart failure (HF). The joint occurrence of AF and HF further worsens prognosis. The prevention of thromboembolism is crucial in the management of AF. In recent years, new oral anticoagulants (NOACs) have been licensed for the prevention of stroke and systemic embolism in patients with AF.

Areas covered: This article reviews the key published studies on the pharmacology, clinical efficacy and safety of edoxaban, the latest NOAC to receive approval for the AF indication. This potent and selective inhibitor of factor Xa shows predictable pharmacokinetic and pharmacodynamic profiles. Its efficacy and safety have been demonstrated in the pivotal, phase III, warfarin-controlled ENGAGE AF-TIMI 48 trial in 21,105 AF patients.

Expert opinion: NOACs will likely improve the management of AF, with or without HF. Edoxaban has a favorable pharmacokinetic profile that supports its use in special patient populations, including patients aged ≥75 years, with HF, renal impairment, poor adherence, and on polypharmacy. Proven strategies of edoxaban dose-reduction for optimal use in the presence of moderate renal impairment, and/or use of strong P-gp inhibitors are available.     

Non-vitamin K antagonist oral anticoagulants: impact of non-adherence and discontinuation

Introduction: Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) are at least as effective as vitamin K antagonists (VKAs) reducing thromboembolism and mortality in atrial fibrillation (AF). These ‘fixed-dose regimen’ drugs are characterized by not requiring routine monitoring or dosage adjustment. Stroke prevention with OAC is indicated in AF patients with CHA₂DS₂-VASc ≥2 (≥3 in females) and NOACs are recommended in preference to VKAs. However, underuse, premature discontinuation of treatment and non-adherence to guidelines is common, and independently associated with higher stroke risk and all-cause mortality.

Areas covered: In this review, we provide an overview of the impact of under or overdosing NOACs in AF patients. We debate the current adherence to AF-guidelines, the reasons involved in non-adherence and discontinuation, as well as the limitations found by patients and physicians about the use of NOACs.

Expert opinion: The more convenient non-monitored and fixed-dose regimen of NOACs might improve patients’ adherence but may hinder the identification of patients with poor adherence or discontinuation. Since there are several reasons for OAC underuse, future strategies to improve adherence should be implemented, that include more and better education about AF and stroke risk, as well as and specific information about the potential consequences of non-adherence to OAC.     

Pharmacokinetic drug evaluation of bucindolol for the treatment of atrial fibrillation in heart failure patients

Introduction: Atrial fibrillation (AF) and heart failure (HF) often coexist. When AF and HF are both present, they are associated with negative outcomes, increased hospitalizations and mortality. As β-blockade is effective inF and may be useful in presence of AF, bucindolol, a non-selective β-blocker with α-1 vasodilatory effect, may be used.

Area covered: This review evaluates the efficacy and safety of bucindolol in HF patients with AF. The largest amount of data comes from BEST trial which evaluated the efficacy of bucindolol in HF patients. Since bucindolol’s effects are genetically modulated by β1 and α2c-adrenergic receptor polymorphisms BEST genetic substudy arose.

Expert opinion: In the BEST Trial, bucindolol demonstrated efficacy in HF patients showing a 74% reduction in new-onset atrial fibrillation events particularly in β1 389 Arg/Arg homozygous. GENETIC-AF study was designed to determine whether bucindolol therapy is superior to metoprolol in preventing recurrent AF in a genetically targeted population of HF patients. Furthermore, this drug is safe, but presents the same side effects as all β-blockers and has showed no clear benefits in African-Americans and in class IV NYHA patients. Further studies are needed to confirm and validate the role of bucindolol and its economic implications.     

Conventional- versus high-dose vancomycin regimen in patients with acute bacterial meningitis: a randomized clinical trial

Objective: Efficacy of the conventional- versus high-dose vancomycin regimen in patients with acute bacterial meningitis was compared.

Methods: In a randomized clinical trial 44 patients with acute bacterial meningitis were randomly assigned to the conventional- or high-dose vancomycin groups. Clinical and laboratory parameters were used for evaluation of response to the treatment regimens.

Results: In the high-dose group, leukocytosis and fever resolved significantly faster than those in the conventional group. Furthermore, the length of hospitalization was shorter and Glasgow Coma Scale at the end of 10th day was significantly lower in the high dose compared to the conventional group. Trend of creatinine clearance changes did not differ significantly between the two groups.

Conclusion: In comparison to the conventional-dose regimen, the high-dose vancomycin regimen was associated with significantly more favorable clinical response without increase in the incidence of nephrotoxicity in patients with acute bacterial meningitis.     

Efficacy of fulvestrant 500 mg in Japanese postmenopausal advanced/recurrent breast cancer patients and factors associated with prolonged time-to-treatment failure

Objective: We aimed to confirm the efficacy of fulvestrant in Japanese postmenopausal advanced/recurrent breast cancer (ABC) patients, and investigate factors contributing to time-to-treatment failure (TTF) prolongation.

Research design and methods: This retrospective study included 194 ABC patients who received fulvestrant (500 mg) from January 2012 to December 2014.

Main outcome measures: TTF (efficacy measure), overall survival (OS), factors prolonging TTF and adverse events were evaluated.

Results: The median age was 65 (42 – 90) years. Overall, TTF was 5.48 months. In patients without prior chemotherapy (n = 59), OS was significantly longer (p = 0.0131) than in patients with prior chemotherapy (n = 135). There was no strong correlation between TTF with fulvestrant and other endocrine therapies, total duration of endocrine therapy and maximum duration of endocrine therapy. TTF was significantly longer in patients with less than two prior chemotherapy regimens (p = 0.0093), de novo metastatic disease (p = 0.0124) and without liver metastasis (p = 0.0024). We observed one case each of pulmonary infarction and psychiatric disorder.

Conclusions: Fulvestrant is effective for ABC patients and may show greater efficacy in patients with few prior chemotherapy regimens, de novo metastatic disease and absence of liver metastasis. Prior endocrine therapy duration might not be a predictive factor for fulvestrant TTF in heavily treated ABC patients.     

Inhibitors of α-glucosidase and α-amylase from Cyperus rotundus

Context: A methanol extract of Cyperus rotundus L. (Cyperaceae) rhizomes showed inhibitory activity against α-glucosidase and α-amylase, two enzymes involve in carbohydrate digestion.

Objective: Identification of compounds from C. rotundus rhizomes responsible for the inhibition of α-glucosidase and α-amylase.

Materials and methods: Compounds were identified by a phytochemical investigation using combined chromatographic and spectroscopic methods. α-glucosidase and α-amylase inhibitory activities were evaluated by in vitro enzyme inhibition assays.

Results: A new (2RS,3SR)-3,4′,5,6,7,8-hexahydroxyflavane (1), together with three known stilbene dimers cassigarol E (2), scirpusin A (3) and B (4) were isolated. Compound 2 inhibited both α-glucosidase and α-amylase activities while the flavane 1 only showed effect on α-amylase, and compounds 3 and 4 were active on α-glucosidase. All four compounds showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity.

Discussion: The inhibitory activities against α-amylase and α-glucosidase of the C. rotundus rhizomes were reported for the first time. Stilbene dimers are considered as potent inhibitors of α-glucosidase and promising antihyperglycemic agents.

Conclusion: The isolated compounds may contribute to the antidiabetic property of C. rotundus.