Jordi Castellsague

Hormone replacement therapy and risk of venous thromboembolism: population based case-control study

Abstract Objective: To evaluate the association between use of hormone replacement therapy and the risk of idiopathic venous thromboembolism. Design: Population based case-control study. Setting: Population enrolled in the General Practice Research Database, United Kingdom. Subjects: A cohort of 347 253 women aged 50 to 79 without major risk factors for venous thromboembolism was identified. Cases were 292 women admitted to hospital for a first episode of pulmonary embolism or deep venous thrombosis; 10 000 controls were randomly selected from the source cohort. Main outcome measures: Adjusted relative risks estimated from unconditional logistic regression. Results: The adjusted odds ratio of venous thromboembolism for current use of hormone replacement therapy compared with non-users was 2.1 (95% confidence interval 1.4 to 3.2). This increased risk was restricted to first year users, with odds ratios of 4.6 (2.5 to 8.4) during the first six months and 3.0 (1.4 to 6.5) 6-12 months after starting treatment. No major risk differences were observed between users of low and high doses of oestrogens, unopposed and opposed treatment, and oral and transdermal preparations. The risk of idiopathic venous thromboembolism among non-users of replacement therapy was estimated to be 1.3 per 10 000 women per year. Among current users, idiopathic venous thromboembolism occurs at two to three times the rate in non-users, resulting in one to two additional cases per 10 000 women per year. Conclusions: Current use of hormone replacement therapy was associated with a higher risk of venous thromboembolism, although the risk seemed to be restricted to the first year of use.

Individual NSAIDs and Upper Gastrointestinal Complications A Systematic Review and Meta-Analysis of Observational Studies (the SOS Project)

AbstractBackground: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community’s Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. Objective: The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. Methods: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. Results: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4–5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses. Conclusions: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.

Efficacy of Omalizumab, an Anti-immunoglobulin E Antibody, in Patients with Allergic Asthma at High Risk of Serious Asthma-related Morbidity and Mortality

Summary Aim: Add-on therapy with omalizumab, an anti-immunoglobulin E antibody, is effective in improving disease control in patients with allergic asthma of varying severity. The aim of the present study was to determine the efficacy of omalizumab in a subgroup of patients at high risk of serious asthma-related morbidity and mortality. Methods: A meta-analysis was performed of three randomised, double-blind, placebo-controlled studies (studies 1, 2 and 3) that enrolled 1412 patients with moderate or severe allergic asthma, all requiring daily treatment with inhaled corticosteroids (ICS). Omalizumab was administered subcutaneously every 2 or 4 weeks at a total 4-weekly dose of at least 0.016mg/kg/IgE [IU/ml]. Each study consisted of a 16-week steroid-stable phase and a 12-16-week steroid-reduction phase, followed by a 24-week extension phase (studies 1 and 2 only). The primary outcome measure was the annualised rate of significant asthma exacerbation episodes (sAEEs) during the steroid-stable phase for the pooled subgroup of 254 high-risk patients (omalizumab, n = 135; placebo, n = 119). sAEEs were those requiring a doubling of baseline ICS dose (studies 1 and 2 only) or use of systemic steroids (all three studies). Results: Overall, the number of patients with at least one sAEE during the steroid-stable phase was reduced from 35% (42/119) with placebo to 18% (24/135) with omalizumab. Mean sAEE rates were 1.56 and 0.69 per patient-year, respectively, a reduction of 56% with omalizumab (p = 0.007). Similar reductions in exacerbations in favour of omalizumab were observed for the whole study period and for all AEEs. In those with a history of hospitalisation in the last year, 6/49 (12%) on placebo vs. 2/44 (4.5%) on omalizumab were re-hospitalised during the study period. Patients treated with omalizumab also showed significantly greater improvements from baseline in PEFR (p = 0.026), overall AQoL (p = 0.042) and mean nocturnal (p = 0.007) and mean total (p = 0.011) asthma symptom scores compared with placebo. Conclusions: In patients at high risk of serious asthma-related morbidity and mortality, treatment with omalizumab offers the potential to halve the rate of asthma exacerbations and improve disease control.

Myocardial infarction and individual nonsteroidal anti-inflammatory drugs meta-analysis of observational studies

To conduct a systematic review of observational studies on the risk of acute myocardial infarction (AMI) with use of individual nonsteroidal anti‐inflammatory drugs (NSAIDs).

One-year efficacy and safety of inhaled formoterol dry powder in children with persistent asthma

BACKGROUND The long-term efficacy and safety of formoterol dry powder capsules for inhalation in pediatric asthma have not previously been evaluated. OBJECTIVE We examined the effectiveness of inhaled formoterol over a period of 12 months in asthmatic children who were still symptomatic despite anti-inflammatory treatment. METHODS After a run-in period, 518 patients (5 to 12 years old) were randomized in a double-blind manner to receive 12 or 24 microg formoterol dry powder (Foradil, Novartis Pharma AG, Basel, Switzerland) or placebo twice daily for 12 months. The drug was administered by inhaler (Aerolizer, Novartis Pharma AG) and was given in addition to their anti-inflammatory treatment. The primary variable was the area under the curve for forced expiratory volume in 1 second measured over 12 hours after the morning dose of study medication. RESULTS The area under the curve for forced expiratory volume in 1 second after the first dose of treatment and after 3 and 12 months of treatment was significantly greater for patients receiving formoterol 12 microg and 24 microg than for patients receiving placebo (all P < or = 0.0062). Compared with placebo, both doses of formoterol significantly improved morning and evening premedication peak expiratory flow rate (all P < 0.001). In the group treated with formoterol 24 microg, median symptom score and median dose of rescue medication at night were lower than during the run-in period, whereas the opposite occurred in the placebo group. The incidence of hospitalizations for asthma was higher in the formoterol groups than in the placebo group. CONCLUSION Our results indicate that, in asthmatic children who are still symptomatic despite anti-inflammatory therapy, the addition of formoterol consistently improves airflow obstruction and nocturnal symptoms and reduces the use of rescue medication. However, this treatment requires close disease monitoring to detect early signs of acute exacerbation.

Recent epidemiological studies of the association between hormone replacement therapy and venous thromboembolism : A review

SummaryThe association between use of hormone replacement therapy (HRT) and the risk of venous thromboembolism (VTE) has been assessed in relatively few epidemiological studies. Evidence from the earliest studies did not support an increased risk of VTE among HRT users. However, methodological limitations in most studies, including small sample size and inadequate control of confounding, did not allow firm conclusions to be made.Most of these limitations have been overcome in 5 recent studies which consistently show that the risk of VTE among women currently using HRT is 2 to 3 times higher than among women not using HRT. The overall relative risk of VTE for women currently using HRT obtained from these studies was 2.6 (95% confidence interval 1.6 to 4.2). This association is unlikely to be explained by confounding or other potential biases affecting observational studies. The risk appears to be more prominent during the first year of HRT use, and in 2 studies the risk disappeared after the first year of therapy. A dose-response relationship, with a doubling of risk among users of high doses of estrogens, was shown in 2 of these studies. No major differences were observed with the different types of therapy, but users of unopposed estrogen therapy and transdermal therapy might be at lower risk than users of opposed regimens and oral preparations.Evidence from these new studies indicates that, among healthy post-menopausal women, between 1 and 2 additional cases of VTE per 10 000 women can be annually attributed to current use of HRT. The Committee on Safety of Medicines in the UK evaluated this risk as small and considered that it does not change the overall benefit-risk profile of HRT for most women.

Acute pain: a multifaceted challenge – the role of nimesulide

Abstract Background: This article summarizes the outcome from an international consensus meeting, which took place in Vienna on 4 November 2014. Scope: The aim of the meeting was to provide the state of the art on the pathophysiology and treatment of acute pain with special emphasis on nimesulide, a non-steroidal anti-inflammatory drug (NSAID) indicated for the treatment of acute pain and primary dysmenorrhea. Besides the data on the mechanisms of acute inflammatory pain and on the efficacy and safety of nimesulide in patients affected by different forms of acute pain, the clinical experience of attending experts was discussed based on selected case reports. Results: The members of this consensus group recognized that nimesulide is a NSAID highly effective in the treatment of several painful situations with an acute inflammatory component including primary dysmenorrhea. Although safety concerns regarding nimesulide have emerged in recent years, both robust new epidemiological data and clinical experience confirm a positive benefit/risk profile of nimesulide in the treatment of several forms of acute pain. Conclusions: The members of this international consensus group concluded that nimesulide, when used appropriately, remains a particularly valuable and safe option for the treatment of several conditions characterized by the presence of acute inflammatory pain because of the rapid onset of the analgesic action, and the positive evidence-based benefit/risk profile.

Risk of serious skin disorders among users of oral antifungals: a population-based study

BackgroundSerious skin disorders have been associated with the use of oral antifungals in a number of case reports and series of cases. However the incidence of these disorders remains unknown.MethodsWe estimated the risk of serious skin disorders in a cohort of users of oral antifungals identified in the general population of the General Practice Research Database in the UK. The cohort included 61,858 patients, 20 to 79 years old, who had received at least one prescription for either oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine.ResultsThe background rate of serious cutaneous adverse reactions (the one corresponding to non use of oral antifungals) was 3.9 per 10,000 person-years (95% CI 2.9–5.2). Incidence rates for current use were 15.4 per 10,000 person-years (1.9–55.7) for itraconazole, 11.1 (3.0–28.5) for terbinafine, 10.4 (1.3–37.5) for fluconazole, and 4.6 (0.1–25.8) for griseofulvin. Itraconazole was the antifungal associated with the highest relative risk, 3.9 (0.5–15.0), when compared to the risk among non users, followed by terbinafine and fluconazole, with relative risks of 2.8 (0.7–7.8) and 2.6 (0.3–10.1), respectively.ConclusionsWe conclude that cutaneous disorders associated with the use of oral antifungals in this study were all of mild severity and that the risk associated with the use of oral antifungals was slightly higher than the risk in non-users. The safety profile of terbinafine regarding cutaneous disorders is similar to other antifungals and in the very low range of risks associated with other drugs.

Risk of Acute Liver Injury Associated with the Use of Moxifloxacin and Other Oral Antimicrobials: A Retrospective, Population-Based Cohort Study

To estimate the incidence and relative risk of a hospitalization or emergency visit for noninfectious liver injury in users of eight oral antimicrobials—amoxicillin, amoxicillin‐clavulanic acid, clarithromycin, cefuroxime, doxycycline, levofloxacin, moxifloxacin, telithromycin—compared with nonusers of these antimicrobials.

Validation of Acute Liver Injury Cases in a Population-Based Cohort Study of Oral Antimicrobial Users

We conducted a cohort study of acute, noninfectious liver injury among oral antimicrobial users. Potential cases were identified in the HealthCore Integrated Research Database (HIRD(SM)) population between July 1, 2001, and March 31, 2009, using ICD-9-CM codes primarily for acute and subacute necrosis of the liver, hepatic coma, and unspecified hepatitis. Liver test results were used to confirm case status according to published criteria. Two physician reviewers experienced in studying acute liver injury (blinded to study drug exposures) evaluated data abstracted from hospital and emergency department records to validate potential cases. Of 715 potential cases having claims associated with any of the primary screening codes, 312 (44%) were valid cases, 108 (15%) were not cases, and 295 (41%) were of uncertain status (records inadequate for validation). Among potential cases with adequate medical records, the PPV for presence of any of the primary codes was 74% (95% CI, 70%-78%). The highest PPV for a single code was for acute and subacute necrosis of the liver (84%; 95% CI, 77%-90%). Evaluation of cases of noninfectious liver injury using hospital and emergency department medical records continues to represent the preferred approach in studies using insurance claims data.