Javier Borja

COPD severity score as a predictor of failure in exacerbations of COPD. The ESFERA study

BACKGROUND Exacerbations are a frequent cause of morbidity and mortality in COPD. It is crucial to identify risk factors for failure after treatment of exacerbations of COPD. This study evaluates the COPD severity score (COPDSS) as a predictor of clinical failure, together with other severity, activity and quality of life measurements, in patients with exacerbated COPD. METHOD Multicenter, prospective, observational study in ambulatory patients with exacerbation of COPD. The patients completed the COPDSS, the London Chest Activities of Daily Living (LCADL) and the EuroQol 5D (EQ-5D). A follow-up visit was scheduled one month after presentation with the exacerbation to assess the clinical evolution. RESULTS A total of 346 patients were included (mean age 68.5 years (SD=9.5 years and 90.7% male) and mean FEV(1)(% predicted) 46.9% (SD=17)). After one month, 28.2% of episodes were classified as failures, with half of them requiring hospital admission. Patients who failed were more frequently active smokers, with more severe dyspnoea at presentation and worse lung function. They had significantly worse scores of COPDSS, LCADL, EQ-5D index and EQ-5D visual analogue score (VAS) and shorter mean time walking per day. ROC analysis of relationship between COPDSS and failure gave AUC 0.72, which improved only to 0.77 when the other significant variables in univariate analysis were considered. CONCLUSIONS Clinical failure after ambulatory treatment of exacerbation of COPD is frequent. Usual markers of severity (impaired lung function, active smoking and severe dyspnoea) are associated with failure; however, a short severity questionnaire (COPDSS) provides better predictive value than the usual variables.

Safety of Rupatadine Administered Over a Period of 1 Year in the Treatment of Persistent Allergic Rhinitis

AbstractBackground: Rupatadine (Rupafin®), a novel antihistamine approved recently in Europe for the treatment of allergic rhinitis (AR) and chronic idiopathic urticaria in patients aged ≥12 years, has been shown to be highly efficacious, and as safe and well tolerated as other commonly employed antihistamines in the treatment of allergic disease. There are, however, few data on the long-term safety of these antihistamines derived in accordance with the clinical safety recommendations of the European Agency for the Evaluation of Medicinal Products (EMEA) and the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline. Objective: To assess the safety and tolerability of treatment with rupatadine 10 mg/day for 12 months in subjects with persistent AR (PER). Methods: A multicentre, open-label, phase IV study in patients recruited from 33 centres in Spain, from September 2002 to November 2005. The study enrolled 324 male and female patients (aged 12–70 years) with a medical history of PER for at least 12 months and a documented positive skin-prick test to an appropriate allergen. On 4 of the 7 days prior to start of treatment, the patients were required to have a minimum total nasal symptom score (TNSS [for sneezing, rhinorrhoea, nasal obstruction/congestion and nasal itching]) of ≥5. Of the 324 eligible patients starting treatment, 120 needed to be treated for more than 6 months and were followed up until the end of 12 months. All patients received rupatadine 10 mg/day and were allowed to continue their normal concomitant medication for all conditions, other than rhinitis, for up to 6 or 12 months. Safety was assessed by means of adverse events (AEs) reported by patients or detected by investigators, scheduled centralized ECG with special attention to Bazzet corrected QT interval (QTcB) and standard laboratory investigations. Results: Assessment of treatment compliance rates indicated 90% and 83% of patients to be compliant during the 1–6 months and 1–12 months treatment periods, respectively, with compliance rates >80% being associated with the majority of the study population reporting at least one AE. Overall, 74.1% and 65.8% of the patients reported at least one AE during the 1–6 months and 1–12 months treatment periods, respectively, compared with 20.4% and 10.8% of patients reporting at least one treatment-related AE during these periods. Disorders of the nervous system and respiratory thoracic and media-stinal system, in particular headache, somnolence and catarrh, were the three most common AEs reported by >5% of the patients during both treatment periods. Detailed ECG assessments demonstrated no clinically relevant abnormal ECG findings, nor any QTcB increases >60 msec or QTcB values >470 msec for any patient at any time during treatment. Serious AEs were reported in seven patients, of whom six were considered as unlikely to be related to rupatadine treatment, whereas one involving increased blood enzyme levels was considered as possibly related to rupatadine treatment. Conclusion: This study confirmed the good long-term safety and tolerability of rupatadine at the therapeutic dose of 10 mg/day in patients with PER.

Triflusal versus Aspirin for the Prevention of Stroke

ABSTRACT Antiplatelet agents represent an important part of the therapeutic armamentarium in the prevention of stroke. Triflusal is an antiplatelet agent structurally related to salicylates but not derived from acetylsalicylic acid. Like aspirin, triflusal irreversibly acetylates cyclo-oxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. Triflusal is rapidly absorbed after oral administration, with an absorption half life of 0.44 hours. Evidence of the efficacy and safety of triflusal is derived from clinical trials performed in patients with unstable angina, acute myocardial infarction, stroke, aortocoronary by-pass, atrial fibrillation, valve replacement, and asthmatic patients intolerant to aspirin and/or non-steroidal antiinflamatory drugs (NSAID). The Triflusal versus Aspirin for the Prevention of Infarction: A Randomized Stroke Study (TAPIRSS) study was performed to explore the efficacy and safety of triflusal versus aspirin in the prevention of vascular complications in patients with a previous TIA or ischemic stroke in a Latin American population. In this pilot study differences between triflusal and aspirin in the prevention of vascular complications after TIA or ischemic stroke were not observed. Hemorrhagic risk was lower with triflusal than with aspirin. The TAPIRSS study contributed evidence on the efficacy and safety of triflusal as a valid alternative to aspirin in the prevention of vascular events in patients with ischemic stroke or TIA.

Comparative bioavailability study of triflusal oral solution vs. triflusal capsules in healthy subjects. A single, randomized, two-way cross-over, open-label phase I study.

Triflusal (CAS 322-79-2) is an antiplatelet agent that irreversibly acetylates cyclooxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), possesses also antiaggregant activity. Recently a new oral 600 mg (10 ml) solution form of triflusal has been developed. The purpose of this clinical trial was to study the relative bioavailability of the new oral solution of triflusal versus the capsules formulation, both administered as a single dose. This was a randomized, two-way, cross-over, open-label, single-site phase I clinical trial, in 24 healthy volunteers who received triflusal as 600 mg oral solution and as two 300 mg capsules in a single administration separated by a washout period of at least 17 days. Blood samples were collected and plasma concentrations of HTB were measured. Pharmacokinetic parameters used for bioequivalence assessment included AUC(0-t), AUC(0-inf) and Cmax. The formulations were considered bioequivalent if the geometric mean ratios of AUC(0-t), AUC(0-inf) and Cmax were within the predetermined equivalence range (80% to 125%). Tolerability was based on the recording of adverse events (AEs), physical examination, electrocardiogram (ECG) and laboratory tests. The parameters for bioequivalence, mean [SD] values were as follows: AUC(0-t) (microg x h/ml): 3574.08 [628.17] for triflusal oral solution and 3901.78 [698.43] for triflusal capsules; AUC(0-infinity) (microg x h/ml): 4089.21 [842.54] for triflusal oral solution and 4471.33 [905.93] for triflusal capsules; Cmax, (microg/ml): 91.24 [12.88] for triflusal oral solution and 88.61 [13.46] for triflusal capsules; Cmax/AUC(0-infinity) (h(-1)): 0.03 (0.00) for triflusal oral solution and 0.02 (0.00) for triflusal capsules. The 90% confidence intervals for the ratio experimental/control by analysis of variance after log transformed AUC(0-infinity), AUC(0-t), and Cmax were within 80% to 125%. Similar results were found for the data without log transformation. All adverse events were of mild or moderate intensity and all subjects recovered. Nine and 12 subjects reported at least one adverse event during treatment with triflusal oral solution and with triflusal capsules, respectively. The most frequently reported adverse events were headache and dizziness. It was concluded that the 600-mg solution of triflusal appeared to be bioequivalent to the reference formulation capsules. Both formulations were well tolerated.

Antithrombotic treatment in atrial fibrillation: Response to: BEREZNICKI LR, PETERSON GM, JACKSON SL, JEFFREY EC: The risks of warfarin use in the elderly. Expert Opin. Drug Saf. (2006) 5(3):417-431.

Concerning the article of Dr Bereznicki and co-workers [1] about the risk of warfarin in the elderly, the authors of this letter would like to comment on the results of the National Study for Prevention of Embolism in Atrial Fibrillation (NASPEAF) [2], performed with triflusal, an antiplatelet agent structurally related to salicylates, but not derived from acetylsalicylic acid. Briefly, it was a prospective, multi-centre, randomised clinical trial, performed in 1209 patients with atrial fibrillation, that were divided into two groups based on risk for thromboembolism: the high-risk group included nonvalvular plus prior embolism and patients with mitral stenosis with and without prior embolism. All others were included in the intermediate-risk group. Patients in the intermediate-risk group were randomised to one of the three arms: oral anticoagulation with acenocoumarol (a vitamin K antagonist commonly used in Europe) to a target international normalised ratio (INR) of 2 – 3, triflusal 600 mg daily, or a combination of both with a target INR of 1.25 – 2. In the high-risk group, the triflusal-only arm was omitted and subjects were assigned to anticoagulation with a target INR of 2 – 3 or the combination therapy with a target INR of 1.4 – 2.4. Primary outcome was a composite of vascular death, transient ischaemic attack and nonfatal stroke or systemic embolism, whichever came first. In the intermediate-risk group, patients’ age (years ± standard deviation) was 69.9 ± 8, 69.6 ± 7 and 69.8 ± 7 in the triflusal, anticoagulant and combined arms, respectively, whereas in the high-risk group patients’ age was 66.6 ± 9 and 67.3 ± 10 in the anticoagulant and combined arms, respectively. After a median follow-up of 2.76 years, primary outcome was lower in the combined therapy than in the anticoagulant arm in both the intermediate (hazard ratio [HR]: 0.33 [95% CI: 0.12 – 0.91]; p = 0.02) and the high-risk group (HR: 0.51 [95% CI: 0.27 – 0.96]; p = 0.03). Bleeding risk was not increased in the combined arms and, moreover, primary outcome plus severe bleeding was lower with combined therapy in the intermediate-risk group. Compared with anticoagulant alone therapy, combined therapy reduced the risk of vascular events by 58.3% in mitral stenosis patients [3]. In conclusion, the NASPEAF study [2] evidenced that the addition of triflusal to reduced-intensity anticoagulation improves the benefit–risk relationship over anticoagulation alone. We believe that due to the age of the patients included, their results are valuable to elderly patients with atrial fibrillation.

Letter by Borja and García-Rafanell Regarding Article, “Guidelines for the Prevention of Stroke in Patients With Stroke or Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association”

To the Editor: In “Guidelines for the Prevention of Stroke in Patients With Stroke or Transient Ischemic Attack,”1 the authors mention that “triflusal has been examined only in a pilot trial.” This information is not correct and is misleading for the reader. Neither the Triflusal versus Aspirin in Cerebral Infarction Prevention (TACIP) study,2 nor a meta analysis of 4 clinical trials comparing triflusal with aspirin in patients with stroke or transient ischemic attack3 were mentioned. The TACIP study, the most important study of triflusal in this kind of patient, was a randomized, double …

Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack

To the Editor: In the Guidelines for Prevention of Stroke in Patients with Ischemic Stroke or Transient Ischemic Attack,1 the authors did not include a mention of 3 important clinical trials: the Triflusal versus Aspirin in Cerebral Infarction Prevention (TACIP)2, Triflusal versus Aspirin for Prevention of Infarction: a Randomized Stroke Study (TAPIRSS),3 and the National Study for Prevention of Embolism in Atrial Fibrillation (NASPEAF)4 studies. The TACIP2 and Triflusal versus Aspirin for Prevention of Infarction: a Randomized Stroke Study (TAPIRSS)3 studies, performed in 2107 and 431 patients, …