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Intravenous idarucizumab, an antibody fragment of a human antibody specific for dabigatran, produced rapid reversal of the anticoagulant effect in patients with bleeding or an urgent surgical indication with no apparent toxic effects or rebound hypercoagulable state. A non–vitamin K antagonist oral anticoagulant, dabigatran etexilate (dabigatran) is an oral thrombin inhibitor that is licensed for the prevention of stroke in patients with nonvalvular atrial fibrillation and for the prevention and treatment of venous thromboembolism. Although dabigatran is associated with less serious bleeding than warfarin, 1 – 3 life-threatening bleeding can occur; in addition, dabigatran-treated patients may require urgent surgery or intervention, and dabigatran can increase the risk of perioperative bleeding. To improve the treatment of such patients, a specific dabigatran-reversal agent would be beneficial. Idarucizumab, a monoclonal antibody fragment, binds dabigatran with an affinity that is 350 times as . . .

Patients with venous thromboembolism who had received initial anticoagulant therapy were studied in two trials of dabigatran. Dabigatran was effective in preventing recurrent venous thromboembolism and carried a lower risk of bleeding than warfarin but a higher risk than placebo. Anticoagulant treatment with vitamin K antagonists is recommended for patients with venous thromboembolism. 1 Most patients receive at least 3 months of treatment. Long-term treatment is recommended if there are risk factors for recurrence, such as multiple thrombotic episodes. 1 In the absence of clear contraindications to anticoagulant therapy, the risk of major bleeding is approximately 1% per year with extended vitamin K antagonist therapy after venous thromboembolism. 2 The risk of major bleeding, together with the need for frequent laboratory monitoring and dose adjustments, makes long-term treatment problematic. Dabigatran, a direct thrombin inhibitor, does not require frequent monitoring and dose adjustments. At . . .

In a phase 2 trial, patients with mechanical heart valves were randomly assigned to receive either dabigatran or warfarin for anticoagulation. Dabigatran was associated with higher rates of ischemic stroke (5%, vs. 0% with warfarin) and major bleeding (4% vs. 2%). Prosthetic heart-valve replacement is recommended for many patients with severe valvular heart disease and is performed in several hundred thousand patients worldwide each year. 1 Mechanical valves are more durable than bioprosthetic valves 2 but typically require lifelong anticoagulant therapy. The use of vitamin K antagonists provides excellent protection against thromboembolic complications in patients with mechanical heart valves 3 but requires restrictions on food, alcohol, and drugs and lifelong coagulation monitoring. Because of the limitations of vitamin K antagonists, many patients opt for a bioprosthesis rather than a mechanical valve, despite the higher risk of premature valve failure requiring repeat valve-replacement surgery with . . .

Background/aimsTo evaluate the ocular hypotensive efficacy of fixed-dose combinations of the Rho kinase inhibitor and norepinephrine transport inhibitor AR-13324 (0.01% and 0.02%) and latanoprost (PG324 Ophthalmic Solution) relative to the active components AR-13324 0.02% and latanoprost 0.005%, used bilaterally at night.MethodsThis was a double-masked, randomised, parallel comparison study in patients with open-angle glaucoma or ocular hypertension. After washout, patients were randomised to one of four treatment arms and treated for 28 days. The primary efficacy variable was mean diurnal intraocular pressure (IOP) at day 29.ResultsWe randomised 298 patients, of whom 292 (98%) completed the study. Mean unmedicated diurnal IOPs (study eye) was 25.1, 25.1, 26.0 and 25.4 in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. On day 29, mean diurnal IOP decreased to 17.3, 16.5, 18.4 and 19.1 mm Hg, respectively. For the primary efficacy variable of mean diurnal IOP at day 29, PG324 0.02% met the criterion for statistical superiority relative to both latanoprost and AR-13324 0.02% (p<0.0001), providing additional IOP lowering of 1.9 and 2.6 mm Hg, respectively. PG324 0.01% also met the criterion for superiority. The most frequently reported adverse event was conjunctival hyperaemia with an incidence of 41% (30/73), 40% (29/73), 14% (10/73) and 40% (31/78) in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively.ConclusionsIn this short-term study, the fixed-dose combination of AR-13324 0.02% and latanoprost 0.005% in PG324 Ophthalmic Solution provides clinically and statistically superior ocular hypotensive efficacy relative to its individual active components at the same concentrations. The only safety finding of note was transient asymptomatic conjunctival hyperaemia which was typically of mild severity.Trial registration numberNCT02207491.

Apixaban (5 mg BID), dabigatran (available as 150 mg and 110 mg BID in Europe), and rivaroxaban (20 mg once daily) are 3 novel oral anticoagulants (NOACs) currently approved for stroke prevention in patients with atrial fibrillation (AF). The objective of this study was to evaluate the cost-effectiveness of apixaban against other NOACs from the perspective of the United Kingdom National Health Services. A Markov model was developed to evaluate the pharmacoeconomic impact of apixaban versus other NOACs over a lifetime. Pair-wise indirect treatment comparisons were conducted against other NOACs by using ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), and ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial results for the following end points: ischemic stroke, hemorrhagic stroke, intracranial hemorrhage, other major bleeds, clinically relevant nonmajor bleeds, myocardial infarction, and treatment discontinuations. Outcomes were life-years, quality-adjusted life years gained, direct health care costs, and incremental cost-effectiveness ratios. Apixaban was projected to increase life expectancy versus other NOACs, including dabigatran (both doses) and rivaroxaban. A small increase in therapeutic management costs was observed with apixaban due to projected gains in life expectancy and lower discontinuation rates anticipated on apixaban versus other NOACs through lifetime. The estimated incremental cost-effectiveness ratio was £9611, £4497, and £5305 per quality-adjusted life-year gained with apixaban compared with dabigatran 150 mg BID, dabigatran 110 mg BID, and rivaroxaban 20 mg once daily, respectively. Sensitivity analyses indicated that results were robust over a wide range of inputs. Although our analysis was limited by the absence of head-to-head trials, based on the indirect comparison data available, our model projects that apixaban may be a cost-effective alternative to dabigatran 150 mg BID, dabigatran 110 mg BID, and rivaroxaban 20 mg once daily for stroke prevention in AF patients from the perspective of the United Kingdom National Health Services.

Purpose    To compare the efficacy and safety of the fixed-dose combination (FDC) of netarsudil 0.02%/latanoprost 0.005% ophthalmic solution (NET/LAT; Roclanda ® ) with bimatoprost 0.03%/timolol maleate 0.5% (BIM/TIM; Ganfort ® ) ophthalmic solution in the treatment of open-angle glaucoma (OAG) and ocular hypertension (OHT). Methods MERCURY-3 was a 6-month prospective, double–masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study. Patients (≥ 18 years) with a diagnosis of OAG or OHT in both eyes that was insufficiently controlled with topical medication (IOP ≥ 17 mmHg in ≥ 1 eye and < 28 mmHg in both eyes) were included. Following washout, patients were randomized to once-daily NET/LAT or BIM/TIM for up to 6 months; efficacy was assessed at Week 2, Week 4, and Month 3; safety was evaluated for 6 months. Comparison of NET/LAT relative to BIM/TIM for mean IOP at 08:00, 10:00, and 16:00 h was assessed at Week 2, Week 6, and Month 3. Non-inferiority of NET/LAT to BIM/TIM was defined as a difference of ≤ 1.5 mmHg at all nine time points through Month 3 and ≤ 1.0 mmHg at five or more of nine time points through Month 3. Results Overall, 430 patients were randomized (NET/LAT, n  = 218; BIM/TIM, n  = 212), and all received at least one dose of study medication. Efficacy analyses were performed at Month 3 on 388 patients (NET/LAT, n  = 184; BIM/TIM, n  = 204). NET/LAT demonstrated non-inferiority to BIM/TIM, with a between-treatment difference in IOP of ≤ 1.5 mmHg achieved at all time points and ≤ 1.0 mmHg at the majority of time points (six of nine) through Month 3. Mean diurnal IOP during the study ranged from 15.4 to 15.6 mmHg and 15.2 to 15.6 mmHg in the NET/LAT and BIM/TIM groups respectively, with no between-group statistically significant difference. No significant differences were observed in key secondary endpoints. No serious, treatment-related adverse events (AEs) were observed, and AEs were typically mild/moderate in severity. The most common treatment-related AEs were conjunctival hyperemia (NET/LAT, 30.7%; BIM/TIM, 9.0%) and cornea verticillata (NET/LAT, 11.0%; BIM/TIM, 0%). Conclusions Once-daily NET/LAT was non-inferior to BIM/TIM in IOP reduction in OAG and OHT, with AEs consistent with previous findings. NET/LAT offers a compelling alternative FDC treatment option for OAG and OHT.

This study evaluated the tolerability and efficacy of the topical rho-kinase inhibitor netarsudil for canine primary corneal endothelial degeneration (PCED). Twenty-six eyes of 21 client-owned dogs with PCED were enrolled in a prospective, randomized, vehicle control clinical trial and received topical netarsudil 0.02% (Rhopressa®) or vehicle control twice daily (BID) for the first 4 months. Then, all patients received netarsudil for the next 4 or 8 months. Complete ophthalmic examination, ultrasonic pachymetry , Fourier-domain optical coherence tomography, and in vivo confocal microscopy were performed at baseline and 1, 2, 4, 6, 8 and 12 months. Effect of netarsudil on central corneal thickness (CCT), percentage of cornea with edema, and endothelial cell density (ECD) were evaluated by repeated measures ANOVA. Kaplan–Meier curves and log-rank test were used to compare corneal edema and clinical progression of eyes in netarsudil versus vehicle control groups. All dogs developed conjunctival hyperemia in at least one eye while receiving netarsudil. Unilateral transient reticulated intraepithelial bullae and stromal hemorrhage were observed respectively in 2 dogs in the netarsudil group. Two dogs showed persistently decreased tear production while receiving netarsudil, requiring topical immunomodulatory treatment. No significant differences in CCT, ECD, corneal edema or clinical progression were observed between netarsudil or vehicle treated eyes. When comparing efficacy of topical netarsudil BID and topical ripasudil 0.4% administered four times daily from our previous study, dogs receiving ripasudil had significantly less progression than those receiving netarsudil.

Insect-borne diseases are a major cause of illness and death worldwide. Insect repellents can reduce the risk of being bitten. In this study, volunteers inserted their arms into standardized mosquito-containing cages, and investigators calculated the elapsed time until the first bite in order to evaluate which repellent products available to consumers in the United States offered the most complete, reliable protection. Products containing high concentrations of N,N -diethyl-3-methylbenzamide (DEET) were most effective, with other products containing IR3535 or botanicals offering far less protection. This study in volunteers finds that only DEET-based repellents provide adequate protection. Insect-transmitted disease remains a major source of illness and death worldwide. Mosquitoes alone transmit disease to more than 700 million persons annually. 1 Malaria kills 3 million persons each year, including 1 child every 30 seconds. 2 , 3 Although insect-borne diseases currently represent a greater health problem in tropical and subtropical climates, no part of the world is immune to their risks. In the United States, arboviruses transmitted by mosquitoes continue to cause sporadic outbreaks of eastern equine encephalitis, western equine encephalitis, St. Louis encephalitis, and La Crosse encephalitis. 4 , 5 In the fall of 1999, West Nile virus, transmitted by mosquitoes, was . . .

Warfarin and aspirin are used to prevent stroke in patients with atrial fibrillation (AF). There are inherent challenges with both treatments, including variable and inconsistent benefit and increased bleeding risks. The availability of new anticoagulants offers some alternatives. A mixed treatment comparison meta-analysis to evaluate direct and indirect treatment data including aspirin, warfarin apixaban, dabigatran, edoxaban, and rivaroxaban for the prevention of primary or secondary stroke in patients with AF. A comprehensive, systematic literature search was conducted to identify randomized trials comparing aspirin, warfarin, apixaban, dabigatran, edoxaban, and rivaroxaban in patients with AF requiring treatment for stroke prevention. Open-label and blinded designs were included if they evaluated any stroke or any bleeding event. Data on stroke and bleeding events were abstracted, verified, evaluated, scored, and entered into Aggregate Data Drug Information System version 1.16 to generate a mixed treatment comparison meta-analysis. Direct and indirect comparisons were evaluated, and we looked for inconsistency in closed loop structures. Data are reported as rate ratios with 95% credible intervals. In addition, we reviewed variance statistics and explored variance with node-splitting models. Our literature search yielded 30 articles, 21 of which were included. All treatments except aspirin reduced the risk of any stroke compared with placebo. Warfarin (0.43 [0.33–0.57]), apixaban (0.37 [0.27–0.54]), dabigatran (0.34 [0.21–0.57]), rivaroxaban (0.36 [0.22–0.60]), and aspirin with clopidogrel (0.73 [0.53–0.99]) were more protective than aspirin alone. Warfarin and the new anticoagulants were similar in the reduction of stroke, vascular death, and mortality. There was no difference in major bleeding between any treatment group. There were more nonmajor bleeding events when comparing warfarin and apixaban (1.83 [1.05–4.03]); no other differences between warfarin and the other new anticoagulants were found. This mixed treatment comparison meta-analysis found similarity between warfarin and the new anticoagulants with the exception of one comparison, in which warfarin was associated with more non-major bleeding than apixaban. Thus, the new anticoagulants are therapeutically comparable when warfarin is inappropriate.