Dabigatran in atrial fibrillation: pharmacology and clinical trials

The central pharmacologic approach to stroke prevention in atrial fibrillation has recently changed with the approval of dabigatran by the US Food and Drug Administration (FDA). Dabigatran is an oral anticoagulant that belongs to the class of direct thrombin inhibitors. Dabigatran has predictable pharmacokinetics, without significant drug and food interactions, rapid onset, and requires twice-daily administration without the need for monitoring. The only drug contraindicated with dabigatran is rifampin. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, dabigatran at a dose of 150 mg bid is statistically superior to warfarin in preventing strokes and systemic embolism in patients with atrial fibrillation and has a lower non-statistically significant rate of major bleeding. There is significantly lower rate of intracranial bleeding. The FDA recently approved the 150-mg bid dose for patients with a creatinine clearance above 30 mL/min and 75 mg bid for use in patients with a creatinine clearance of 15 to 30 mL/min. A prespecified subanalysis in both warfarin-experienced and warfarin-naive subgroups mirrored the main results. For cardioversions, a post hoc analysis showed that the rate of thromboembolism and major bleeding within 30 days of cardioversion for dabigatran 150 mg bid was low and comparable to that of warfarin, with or without transesophageal echocardiography guidance. Dabigatran, therefore, is the first novel anticoagulant to offer an alternative to warfarin.     

Diastolic dysfunction and atrial fibrillation

INTRODUCTION: Isolated diastolic heart failure (DHF) is defined as heart failure with preserved left ventricular (LV) systolic function in the absence of valve disease. DHF is a clinical diagnosis confirmed by echocardiography and is presumed to be due to diastolic dysfunction (DD). DD is characterized by abnormalities in relaxation and/or distensibility (restriction) of the left ventricle (LV). DHF accounts for 30% to 50% of patients with heart failure and is an independent predictor of atrial fibrillation (AF) in the elderly. AIM: This paper will describe the diagnosis of DD in both sinus rhythm and AF as well report on agents used in the treatment of DHF and prevention of AF in DHF. DIAGNOSIS IN SINUS RHYTHM: Early DD is identified by Doppler determined mitral inflow measurements: The ratio of the peak velocity of the early filling (E) wave to the atrial contraction (A) wave, E/A is <1, the deceleration time (DT) is slow (>240 ms), the isovolumic relaxation period (IRP) is prolonged (>110 ms). In Moderate DD, the LV stiffens with elevated left atrial pressure resulting in "pseudonormal" filling pattern with E/A ratio >1. This is unmasked by pulmonary vein measurements with the systolic forward flow (S) being less than (approximately 50%) diastolic forward flow wave (D). Retrograde flow wave (A (R)) is increased >0.25 m/s. As the LV stiffens, restrictive features develop resulting in rapid early filling with E/A ratio >2, shortened DT <150 ms and IRP <60 ms. The A (R) wave is increased in amplitude >0.35 m/s and duration >30 ms. Early diastolic filling reflected by tissue Doppler determination of mitral annulus motion velocity (E') is reduced in DD. The E/E' ratio correlates well with filling pressures. DIAGNOSIS IN AF: Atrial contraction is absent and therefore measurements independent of atrial influence such as DT, IRP, E/E' ratio and S wave are used. THERAPY FOR DHF AND AF PREVENTION: While not well established, Treatment with ACE-inhibitors, angiotensin receptor blockers (ARBs) and aldosterone antagonists have shown objective improvement in DHF and ARBs have been found to decrease the incidence of AF. Candesartan decreases the incidence of AF in patients with symptomatic heart failure and preserved LV systolic function. There are ongoing studies of Irbesartan and spironolactone to evaluate their effect on DHF treatment. CONCLUSION: Diagnosis of DD is made by echocardiography in patients with sinus rhythm or in patients with AF. Randomized controlled trials in patients with DHF are under way. The treatment of DHF and AF prevention will continue to evolve.     

Knowledge, attitude and practice towards periodontal diseases among gynaecologists: a pilot study

Disorders relating to short gestation and low birth weight are among the leading causes of death and disability in infants. About 25% of pre-term low birth weight (PLBW) cases occur without even a suspected risk factor. Of all PLBW cases, 18.2% may be attributable to periodontitis (Offenbacher et al. 1996 ). Therefore, this study was conducted to assess the views and knowledge of gynaecologist's on association between periodontal disease and pre-term low birth weight and their willingness to advise their patients to seek dental treatment.     

Is Minocycline an Antiviral Agent? A Review of Current Literature

Minocycline is a second‐generation semi‐synthetic derivative of tetracycline and has well‐known anti‐bacterial effects. The drug possesses anti‐inflammatory, anti‐oxidant, anti‐apoptotic and immunomodulatory effects. The drug is widely used in bacterial infections and non‐infectious conditions such as acne, dermatitis, periodontitis and neurodegenerative conditions. Minocycline was shown to have antiviral activity in vitro and also against different viruses in some animal models. Some studies have been done on human patients infected with Human Immunodeficiency Virus. We have review the available data regarding minocycline activity as an antiviral agent.     

Hygiene hypothesis and periodontitis – A possible association

Hygiene hypothesis has been proposed more than two decades back to explain an increasing prevalence of allergic diseases and atopy. It states that, a lack of early childhood exposure to infectious agents increases susceptibility to allergic diseases and atopy later in life. The evidence in relation to hygiene hypothesis is controversial and inconclusive. Moreover, its underlying mechanisms are elusive and remain to be elucidated. Periodontitis is an inflammatory disease initiated by microorganisms present in the plaque biofilm. Association between periodontitis and various systemic diseases has already been established and is currently an area of interest particularly in periodontal research. Consistent with hygiene hypothesis, some researchers believed that pathogens associated with periodontal diseases might have a protective role in the development of asthma and other allergic diseases.     

A randomized trial of budiodarone in paroxysmal atrial fibrillation

Objective

The aim of this study was to investigate the preliminary safety and efficacy of three doses of budiodarone in patients with paroxysmal atrial fibrillation.

Background

Budiodarone is a chemical analogue of amiodarone and shares its mixed ion channel electrophysiological properties. It has a shorter half-life than amiodarone.

Methods

Patients with paroxysmal atrial fibrillation and a previously implanted dual-chamber pacemaker capable of storing electrograms for at least 4?weeks were enrolled. Pacemaker memories were used to quantify atrial tachycardia/atrial fibrillation burden (AT/AFB). All antiarrhythmic drugs were stopped for greater than five half-lives and amiodarone greater than 3?months prior to enrollment. Following a 4-week baseline period to assess AT/AFB off antiarrhythmic drugs, patients with AT/AFB between 3% and 70% were blindly randomized to placebo, 200, 400, or 600?mg BID of budiodarone for 12?weeks followed by a 4-week washout period. Pacemakers were interrogated and safety assessed every 4?weeks. Pacemaker-derived electrograms were adjudicated blinded to treatment assignment. The primary study endpoint was percent change from baseline AT/AFB over 12?weeks of treatment compared to placebo.

Results

Of 72 randomized patients, 61 completed the study. The median reduction of AT/AFB for the 400 and 600?mg BID groups vs. placebo was 54% and 74% (p?=?0.01 and 0.001), respectively. The budiodarone dose?Cresponse was statistically significant (p?Conclusions In this preliminary study, budiodarone at both higher doses significantly reduced AT/AFB. The study is novel because dual-chamber pacemakers, previously placed for standard clinical indications, were successfully used to monitor AT/AFB.     

Dabigatran in Clinical Practice

BackgroundStroke and systemic thromboembolism remain critical causes of mortality and morbidity in patients with paroxysmal or persistent atrial fibrillation. Dabigatran etexilate is a novel oral direct thrombin inhibitor, which provides stroke risk reduction for patients with nonvalvular atrial fibrillation. Randomized clinical data demonstrate dabigatran to be an alternative oral anticoagulant with an improved efficacy profile compared with oral warfarin dose adjusted to an INR (international normalized ratio) target of 2.0 to 3.0.ObjectivesOur aim was to review the pharmacology, mechanism of action, drug metabolism, and clinical trial data supporting dabigatran use.MethodsWe reviewed all the major published clinical studies of dabigatran and analyzed data regarding practical applications in selected clinical scenarios.ResultsThis review provides recommendations for clinicians regarding dosing during invasive surgical procedures, transitioning off alternative anticoagulants, and a discussion of storage and handling of the drug.ConclusionsOur effort should facilitate the safe and effective use of dabigatran in atrial fibrillation.