Amarjot Kaur

Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison

BACKGROUND Cyclo-oxygenase-2 (COX-2) selective inhibitors have been associated with an increased risk of thrombotic cardiovascular events in placebo-controlled trials, but no clinical trial has been reported with the primary aim of assessing relative cardiovascular risk of these drugs compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs). The MEDAL programme was designed to provide a precise estimate of thrombotic cardiovascular events with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac. METHODS We designed a prespecified pooled analysis of data from three trials in which patients with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac (150 mg daily). The primary hypothesis stated that etoricoxib is not inferior to diclofenac, defined as an upper boundary of less than 1.30 for the 95% CI of the hazard ratio for thrombotic cardiovascular events in the per-protocol analysis. Intention-to-treat analyses were also done to assess consistency of results. These trials are registered at http://www.clinicaltrials.gov with the numbers NCT00092703, NCT00092742, and NCT00250445. FINDINGS 34 701 patients (24 913 with osteoarthritis and 9 787 with rheumatoid arthritis) were enrolled. Average treatment duration was 18 months (SD 11.8). 320 patients in the etoricoxib group and 323 in the diclofenac group had thrombotic cardiovascular events, yielding event rates of 1.24 and 1.30 per 100 patient-years and a hazard ratio of 0.95 (95% CI 0.81-1.11) for etoricoxib compared with diclofenac. Rates of upper gastrointestinal clinical events (perforation, bleeding, obstruction, ulcer) were lower with etoricoxib than with diclofenac (0.67 vs 0.97 per 100 patient-years; hazard ratio 0.69 [0.57-0.83]), but the rates of complicated upper gastrointestinal events were similar for etoricoxib (0.30) and diclofenac (0.32). INTERPRETATION Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs.

Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison

BACKGROUND Upper gastrointestinal safety of cyclo-oxygenase (COX)-2 selective inhibitors versus traditional non-steroidal anti-inflammatory drugs (NSAIDs) has not been assessed in trials that simulate standard clinical practice. Our aim was to assess the effects of these drugs on gastrointestinal outcomes in a population that includes patients taking gastrointestinal protective therapy. METHODS A prespecified pooled intent-to-treat analysis of three double-blind randomised comparisons of etoricoxib (60 or 90 mg daily) and diclofenac (150 mg daily) in 34 701 patients with osteoarthritis or rheumatoid arthritis was done for upper gastrointestinal clinical events (bleeding, perforation, obstruction, or ulcer) and the subset of complicated events (perforation, obstruction, witnessed ulcer bleeding, or significant bleeding). We also assessed such outcomes in patients who were taking concomitant proton pump inhibitors (PPIs) or low-dose aspirin. These trials are registered with , with the numbers , , and . FINDINGS Overall upper gastrointestinal clinical events were significantly less common with etoricoxib than with diclofenac (hazard ratio [HR] 0.69, 95% CI 0.57-0.83; p=0.0001). There were significantly fewer uncomplicated gastrointestinal events with etoricoxib than there were with diclofenac (0.57, 0.45-0.74; p<0.0001); there was no difference in complicated events (0.91, 0.67-1.24; p=0.561). PPIs were used concomitantly for at least 75% of the study period by 13 862 (40%) and low-dose aspirin by 11 418 (33%) patients; treatment effects did not differ significantly in these individuals. INTERPRETATION There were significantly fewer upper gastrointestinal clinical events with the COX-2 selective inhibitor etoricoxib than with the traditional NSAID diclofenac due to a decrease in uncomplicated events, but not in the more serious complicated events. The reduction in uncomplicated events with etoricoxib is maintained in patients treated with PPIs and is also observed with regular low-dose aspirin use.

Significant Differential Effects of Alendronate, Estrogen, or Combination Therapy on the Rate of Bone Loss after Discontinuation of Treatment of Postmenopausal Osteoporosis: A Randomized, Double-Blind, Placebo-Controlled Trial

Context Alendronate and conjugated estrogen therapy both increase bone mineral density in postmenopausal women, but is the rate of bone loss greater when alendronate or estrogen therapy is discontinued? Contribution The discontinuation phase of this double-blind, placebo-controlled trial showed loss of spine and trochanter bone mass in postmenopausal women 1 year after withdrawal of estrogen and no such loss after withdrawal of either alendronate or combination therapy with alendronate and estrogen therapy. Cautions The study was not large or long enough to show whether discontinuation of estrogen therapy is associated with more fractures than discontinuation of either alendronate or combination therapy. The Editors Several antiresorptive agents have been shown to increase bone mass and reduce osteoporotic fractures (1-3). Because greater improvements in bone mass in women using therapy are associated with greater reductions in fracture (4, 5), investigators have begun to examine combinations of antiresorptive therapies to achieve more substantial gains in bone mass. Lindsay and colleagues demonstrated that addition of alendronate to hormone replacement therapy in postmenopausal women resulted in greater increases in bone mass than did maintenance of estrogen therapy alone (6). We previously showed that administration of alendronate and estrogen for 2 years in postmenopausal women with low bone mass resulted in statistically significantly greater increases in bone mass at the lumbar spine and femoral neck than those seen in women taking either agent alone (7). Furthermore, combination therapy was safe and resulted in normal findings on histologic examination of bone. In clinical practice, a key concern is the potential for accelerated bone loss when antiresorptive therapy is discontinued. Approximately one third of women discontinue hormone replacement therapy within 1 year of initiation (8). Older studies have demonstrated significant losses in bone mass after discontinuation of hormone replacement therapy (9-11). In contrast, when therapy with oral alendronate, 10 mg/d, is discontinued after osteoporosis treatment, bone mass at the hip and spine are maintained for 1 year (12). However, no head-to-head comparison of hormone replacement therapy and alendronate or the combination of antiresorptive therapy after discontinuation has been done. In addition, future losses in bone mass when patients discontinue therapy must be considered in management of osteoporosis in postmenopausal women. We therefore sought to examine the rate of bone loss after discontinuation of 2 years of alendronate therapy, hormone replacement therapy, or combination therapy. A subset of participants continued to take combination therapy for a third year to determine whether prolonged therapy remained beneficial. Methods Study Participants Four hundred twenty-five postmenopausal women 42 to 82 years of age who had low bone mass were enrolled in a 2-year randomized, double-blind, placebo-controlled clinical trial conducted at 18 centers in the United States (7). Participants were recruited from clinics, private practices, newspaper advertisements, and targeted mailings. All participants who completed the initial study were asked to enroll in the 1-year extension. Participants were told that if they were taking active treatment, they might be randomly allocated to receive placebo or treatment for the third year and that if they were taking placebo, they would continue to do so. Entry criteria for the initial study are described elsewhere (7). All women had had hysterectomy and had a bone mineral density at the lumbar spine that was less than or equal to a T score of 2.0 SDs below the peak bone mass in young adults. Data on presence or absence of ovaries were not collected. Exclusion criteria were metabolic bone disease, a low serum 25-hydroxyvitamin D level, use of medications known to affect bone turnover, renal insufficiency, severe cardiac disease, and recent major upper gastrointestinal disease. The institutional review board at each clinical site approved the extension protocol. After signing the extension consent form and undergoing baseline evaluation for the extension, participants were allocated to blinded treatment on the basis of their original treatment in the first 2 years of the study. The randomization process was centrally determined by a statistician; as in the initial study, treatment allocation was concealed. Design As described for the initial study at each center, patients were randomly allocated to one of four treatment groups: placebo (n = 50); alendronate, 10 mg/d (n = 92); conjugated estrogen, 0.625 mg/d (n = 143); or alendronate, 10 mg/d, plus conjugated estrogen, 0.625 mg/d (n = 140) (Figure 1). The conjugated estrogen used was Premarin (Wyeth-Ayerst, Philadelphia, Pennsylvania). All women received calcium carbonate to provide 500 mg of elemental calcium daily. Figure 1. Design of original 2-year study and reallocation to extension phase for year 3. At the end of the second year, 244 of the 425 women (57%) continued in a 1-year extension of the study (Figure 1). Of these women, 28 who previously received placebo continued to do so. Women who were taking combination therapy were reallocated to continue taking combination therapy (n = 44) or switch to placebo (n = 41). In addition, 50 participants taking alendronate alone and 81 participants taking conjugated estrogen alone for the first 2 years were assigned to placebo for the third year. All patients and investigators remained blinded to medication allocation. Patients continued to receive calcium supplementation during the third year. Outcome Measures Women were examined at month 24 (baseline of the 1-year extension), month 30, and month 36. Bone mineral density of the lumbar spine, hip (femoral neck, trochanter, total hip), and total body were assessed by using dual-energy x-ray absorptiometry with QDR-1000W, QDR-1500, or QDR-2000 series bone densitometers (Hologic, Inc., Bedford, Massachusetts). A standard phantom was used for cross-calibration at all sites. Serum and urine samples were also obtained at months 24, 30, and 36 for assessment of biochemical markers of bone turnover, namely bone-specific alkaline phosphatase and urinary N-telopeptide cross-links of collagen type I, corrected for creatinine. Statistical Analysis We used SAS software, version 6.12, TSLevel 0060, PROCedureGLM (SAS Institute, Inc., Cary, North Carolina) to analyze the data. The primary efficacy end point was the mean difference between groups in the percentage change in bone mineral density at the lumbar spine from month 24 to month 36. Secondary efficacy end points were the mean percentage changes in bone mineral density of the hip and total body and biochemical markers of bone turnover. Overall percentage changes from month 0 to 36 in spine, hip, and total-body bone mineral density were also analyzed. The prespecified analysis was based on an intention-to-treat approach. At study design, we prespecified that all patients who had a baseline measurement and at least one measurement during treatment would be included in the analysis according to the group to which they were randomly allocated. The missing data were approximated by carrying forward the last available value on treatment forward to the missing time point. No data from the original 2-year study were carried forward to the extension period for any assessment of change. Women who violated the protocol were excluded from analysis of biochemical markers, as previously reported (7). Between-group comparisons of bone mineral density and biochemical measures were made by using analysis of variance techniques, with treatment, center, and treatment-by-center as factors. The assumption of homoscedasticity for the analysis of variance model was assessed by using the Levene test, and the normality assumption was assessed by using the ShapiroWilk test (13). If the assumptions were violated, a nonparametric method was used to corroborate the parametric results. The Fisher exact test was used to compare treatment groups for the proportion of participants who exceeded predefined limits of change in laboratory safety variables (13). Power calculations based on estimated sample sizes of 56 and 84 participants in the alendronate/placebo and estrogen/placebo treatment groups, respectively, yielded an estimate of 92% power to detect a 1.5% difference between mean percentage changes from month 24 to month 36 in bone mineral density at the lumbar spine ( = 0.05, two-tailed test). As requested by the journal editors, data on bone mineral density were also analyzed by using a mixed-model analysis, and results of this analysis are presented. An appropriate curvilinear function was fitted to the actual data, and the function was estimated by using all data available across time points for each participant. A model that regressed bone mineral density versus log (month + 1) provided the appropriate fit for the 3-year data and was used to analyze these data. The variable log (month + 1) was used because log (month) is undefined when month is 0, and log (month + 1) yields the value 0 at baseline. The fitted values from the model were used to obtain the percentage change during the period of interest. Data on bone mineral density from the mixed-model analyses are presented unless otherwise specified. Role of the Funding Source Data were collected by investigators at each study site with the support of Merck Research Laboratories, Rahway, New Jersey. Analyses were performed by statisticians at Merck & Co., Inc. Data were interpreted by the authors, who submitted the manuscript for publication. Results Patient Characteristics and Retention Baseline randomization characteristics did not differ between participants who entered the extension phase and those who did not. Baseline demographic characteristics of the 244 women who entered the extension phase were s

Alendronate and Estrogen–Progestin in the Long-Term Prevention of Bone Loss: Four-Year Results from the Early Postmenopausal Intervention Cohort Study: A Randomized, Controlled Trial

Osteoporosis is a serious disease that develops slowly over many years and results in fractures and associated health care costs (1-3). Available treatments increase bone mineral density and reduce the risk for fractures but do not fully restore bone mass or microarchitecture (4). Alendronate, a bisphosphonate that inhibits bone resorption but not bone mineralization (5), prevents bone loss, increases bone mineral density (6-10), and reduces the incidence of fractures at the spine and hip by 30% to 50% in postmenopausal women with osteoporosis (7, 11, 12). Because alendronate prevents bone loss, it can be used as an alternative to estrogenprogestin in the prevention of postmenopausal osteoporosis (13, 14). The optimal length and regimen of alendronate treatment, however, have not yet been determined. Long-term treatment is probably needed to substantially affect bone mass and achieve lasting prevention of bone loss. However, clinical trials must be done to address the continuing efficacy and safety of agents used for prevention of osteoporosis, including alendronate. We compared the effects of 4 years of alendronate treatment or placebo on bone mass and bone turnover. We also evaluated the residual effects of alendronate after treatment was discontinued. A small comparison group of participants who received estrogenprogestin was included. Results of the first 2 years of the study were published elsewhere (13). Methods The Early Postmenopausal Intervention Cohort Study is a clinical trial of oral alendronate in 1609 postmenopausal women who were randomly assigned in a double-blind manner to receive alendronate, placebo, or open-label estrogenprogestin (13). Four study centers (two in the United States [Portland, Oregon, and Honolulu, Hawaii] and two in Europe [Nottingham, England, United Kingdom, and Copenhagen, Denmark]) are involved in this trial. Women in the alendronate groups received alendronate during the first 2 years of the study. Treatment was then continued without change or was discontinued and replaced with placebo for the last 2 years of the study (Table 1). All women treated with estrogenprogestin followed the same regimen for 4 years. The randomization schedule for the duration of the study was predetermined at baseline. The study was approved by the local ethics committees and institutional review boards. Table 1. Demographic Characteristics of the Study Sample at Year 2 and Distribution of Study Groups at Different Time Points Participants We selected healthy women 45 to 59 years of age who were at least 6 months past menopause at study entry. Bone mineral density at the spine at baseline was 0.8 g/cm2 or greater in approximately 90% of participants (13). Treatment Treatment was distributed across two strata. In stratum 1, women were assigned to receive 5 mg of oral alendronate per day, 2.5 mg of oral alendronate per day, placebo (Merck Research Laboratories, Rahway, New Jersey), or open-label estrogenprogestin. Dosages of alendronate were selected on the basis of results from previous dose-finding studies (10, 14). Prevention of bone loss or a slight increase in bone mineral density was the desired outcome. Participants in whom estrogenprogestin was contraindicated or unacceptable were enrolled in stratum 2, which did not include an estrogenprogestin group. In the United States, estrogenprogestin was given in a continuous combined regimen of conjugated equine estrogens, 0.625 mg/d (Premarin, Wyeth-Ayerst, Philadelphia, Pennsylvania), plus medroxyprogesterone acetate, 5 mg/d (Provera, Upjohn, Kalamazoo, Michigan). In Europe, estrogenprogestin was given in a cyclic combined regimen of micronized 17-estradiol, 2 mg/d, for 22 days; norethisterone acetate, 1 mg/d, on days 13 to 22; and estradiol, 1 mg/d, on days 23 to 28 (Trisequens, Novo Nordisk, Lyngby, Denmark). Dietary calcium intake was estimated at baseline and at annual visits (13). All women whose calcium intake was lower than that dictated by the local standard of care were advised to increase their intake by changing their diet or by taking supplements. Measurements of Bone Mineral Density and Biochemical Markers of Bone Turnover Bone mineral density was measured at baseline and annually thereafter (QDR-2000, Hologic, Waltham, Massachusetts) (13). Fasting blood and urine samples (second morning void) were collected every 6 months. Bone resorption and formation were estimated by using urine N-telopeptide cross-links of type I collagen (Osteomark, Ostex, Seattle, Washington) corrected for creatinine excretion and serum osteocalcin (Human Osteocalcin Kit, Nichols Institute, San Juan Capistrano, California), respectively. In addition, the serum level of bone-specific alkaline phosphatase (Ostase, Hybritech, San Diego, California) was measured at baseline and at months 12, 24, and 36 in a random sample of 550 women. Assessment of Treatment Safety Participants were clinically evaluated every 3 months (13). All unfavorable and unintended clinical events, including fractures and abnormal laboratory values, were considered to be adverse events and were evaluated for severity, duration, and probable causal relation to study drug and outcome. Statistical Analysis Bone mineral density was analyzed by using an intention-to-treat approach in the 1404 participants who received the same treatment for 4 years and had a baseline measurement and at least one follow-up measurement and in participants who switched from alendronate to placebo and had at least one measurement during years 3 and 4. No data from years 1 and 2 were included in later analyses of participants whose treatment did not remain constant during the study. Treatment effects were evaluated by using analysis of variance that included treatment, study center, stratum, and treatment-by-center interaction terms as factors. Interaction terms that were nonsignificant (P>0.10) or nonqualitative were removed from the model. Between-treatment comparisons of least-squares means (adjusted for stratum and study center) were performed by using analysis of variance. Within-group changes were evaluated by using the pairwise t-test to examine whether the mean percentage changes differed significantly from 0. In the groups that received alendronate for 4 years, the progressiveness of the response with an increasing dose of alendronate was assessed by using the stepwise Tukey trend test, adjusted for multiplicity. In addition, subgroup analyses were performed according to years since menopause (<3 years, 3 to 9 years, and 10 years) and baseline bone mineral density at the spine (in all women and in women with osteopenia). All statistical tests were two-sided. All between-group comparisons of placebo or alendronate and estrogenprogestin were performed within stratum 1. estrogenprogestin regimens differed in U.S. and European centers; therefore, estrogenprogestin and alendronate were compared separately in each group by location of study center (United States or Europe). For graphical presentation, data from the groups receiving 4 years of alendronate or 2 years of alendronate followed by 2 years of placebo were pooled by dose during the first 2 years of the study because they were similar with respect to effect of treatment on bone mineral density and biochemical markers until that time. In the groups that received alendronate followed by placebo, a stepwise multiple regression analysis was used to compare cumulative bone loss in years 3 and 4 (after withdrawal of alendronate) with bone loss in years 1 and 2 in the group that continuously received placebo. Treatment, study center, stratum, bone mineral density at year 2, age, years since menopause, and body mass index were covariates of interest, and the least significant difference interval method was used to compare rates of cumulative bone loss. Role of the Funding Source Employees of Merck & Co., Inc., participated in the study as co-investigators. After designing the study with the input of the other study investigators, these employees implemented the protocol and coordinated data collection and statistical analyses. They also contributed to the writing of this paper, but data interpretation and decisions about the content of the paper and submission for publication resided with the entire group of investigators. Results All study groups had similar demographic characteristics at baseline; however, women in the estrogenprogestin group had experienced menopause more recently (Table 1). By the end of year 4, the relative proportion across treatment groups of women who had continued to participate in the study was similar to that at baseline (Table 1). Eighty-five percent of participants were white, 10% were Oriental (persons of Chinese, Japanese, and Korean descent), 1.4% were Asian (persons of Indian and Philippine descent), and less than 1% were from other ethnic groups. Bone Mineral Density Groups That Received the Same Treatment for 4 Years In the placebo group, bone mineral density decreased at all skeletal sites (Figure 1, Table 2). Bone loss usually decreased as years since menopause increased. In contrast, 4 years of treatment with 5 mg of alendronate per day increased bone mineral density at the spine, hip, and total body and attenuated bone loss at the forearm (Figure 1, Table 2). Five mg of alendronate per day had a more pronounced effect on bone mineral density than did 2.5 mg of alendronate per day (P<0.01). In both alendronate groups, bone mineral density at the spine, hip, and total body increased or remained unchanged during years 3 and 4 compared with year 2. Figure 1. Mean percentage change (SE) from baseline in bone mineral density at the lumbar spine, total hip, total body, and one-third distal forearm. Table 2. Mean Percentage Change in Bone Mineral Density at Subregions of the Hip Compared with 4 years of treatment with 5 mg of alendronate per day, treatment with estrogen-medroxyprogesterone acetate resulted in greater increases in

Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults

BACKGROUND In North America and Europe, millions of patients experience symptoms of allergic rhinitis with or without conjunctivitis (AR/C) on exposure to ragweed pollen. The disease burden can be significant, with most patients relying on symptomatic medications without disease-modifying potential. However, novel sublingual immunomodulatory treatment options may potentially play an important role if efficacy and side effect profiles allow the convenience of self-administration. OBJECTIVES This study evaluated an allergy immunotherapy tablet (AIT; SCH 39641/MK-3641) for treatment of ragweed-induced AR/C in the first large randomized, double-blind multinational trial of this therapeutic modality for ragweed allergy. METHODS Adults (n = 784) with short ragweed-induced AR/C were randomly assigned to approximately 52 weeks of daily self-administered ragweed AIT of 1.5, 6, or 12 units of Ambrosia artemisiifolia major allergen 1 (Amb a 1-U) or placebo. Subjects could use as-needed allergy rescue medication. Symptoms and medications were recorded daily. The primary efficacy end point was total combined daily symptom/medication score (TCS) during peak ragweed season. Safety was monitored through adverse event diaries maintained through study duration. RESULTS During peak ragweed season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 9% (-0.76; P = .22), 19% (-1.58; P = .01), and 24% (-2.04; P = .002) compared with placebo. During the entire season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 12% (-0.88; P = .09), 18% (-1.28; P = .01), and 27% (-1.92; P < .001) compared with placebo. Treatment was well tolerated; no systemic allergic reactions occurred. CONCLUSIONS In this trial, ragweed AIT of 12 Amb a 1-U was effective and tolerable with a safety profile that permitted daily self-administration of ragweed allergen immunotherapy.

Lower Gastrointestinal Events in a Double-Blind Trial of the Cyclo-Oxygenase-2 Selective Inhibitor Etoricoxib and the Traditional Nonsteroidal Anti-Inflammatory Drug Diclofenac

BACKGROUND & AIMS Nonsteroidal anti-inflammatory drugs (NSAIDs) cause lower gastrointestinal (GI) clinical events such as bleeding. Cyclo-oxygenase (COX)-2 selective inhibitors decrease upper GI events, but no prospective trial has prespecified assessment of lower GI clinical events. METHODS Patients >or=50 years old with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 or 90 mg qd) or diclofenac (150 mg qd). Lower GI clinical events, confirmed by a blinded adjudication committee, included perforation or obstruction requiring hospitalization or bleeding (gross or occult rectal bleeding without upper GI cause associated with hypotension, orthostatic changes in heart rate [>20 beats per minute] or blood pressure [>20 mmHg systolic or >10 mmHg diastolic], hemoglobin drop >or=2 g/dl, or transfusion; or observed active bleeding or stigmata of hemorrhage). RESULTS We enrolled 34,701 patients with mean duration of therapy of 18 months. Rates were 0.32 and 0.38 lower GI clinical events per 100 patient-years for etoricoxib and diclofenac (hazard ratio [HR] = 0.84; 95% confidence interval [CI], 0.63-1.13). Bleeding was the most common event (rates of 0.19 and 0.23 per 100 patient-years, respectively). Multivariable analysis revealed significant risk factors to be prior lower GI event (HR = 4.06; 95% CI, 2.93-5.62) and age >or=65 years (HR = 1.98; 95% CI, 1.45-2.71). CONCLUSIONS A statistically significant decrease in lower GI clinical events was not seen with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac. The risk of a lower GI clinical event with NSAID use seems to be constant over time, and the major risk factors are a prior lower GI event and older age.

Randomized controlled trial of ragweed allergy immunotherapy tablet efficacy and safety in North American adults.

BACKGROUND Ragweed is an important cause of allergic rhinitis with or without conjunctivitis (AR/C) in North America and elsewhere. Allergen immunotherapy enabling safe patient self-administration is considered an unmet clinical need. Allergy immunotherapy tablet (AIT) treatment has shown promising efficacy and safety for grass allergy but has not been assessed for ragweed allergy. OBJECTIVE To evaluate efficacy and safety of 2 short ragweed AIT doses in patients with AR/C. METHODS Adults with ragweed pollen-induced AR/C were randomized 1:1:1 to daily ragweed AIT (6 or 12 Amb a 1 units) or placebo before, throughout, and after ragweed season (approximately 52 weeks). Patients could use predefined allergy rescue medications in season. Efficacy end points included peak and entire season total combined score (TCS) and its components daily symptom score (DSS), and daily medication score (DMS). Safety assessments included adverse events. RESULTS A total of 565 patients were randomized. During peak season, the 6- and 12-Amb a 1 unit ragweed AIT doses showed 21% (-1.76 score) and 27% (-2.24 score) improvement in TCS vs placebo (P < .05). The 6- and 12-Amb a 1 unit AIT doses significantly improved DSS and DMS vs placebo (P < .05). Peak and entire season efficacy were comparable. The 12-Amb a 1 unit AIT dose reduced peak-season TCS vs placebo by 21% and 25% in subgroups with and without local application-site reactions, respectively. Most treatment-related adverse events were mild, oral reactions; no systemic allergic reactions were reported. One patient in the 6-Amb a 1 unit group received epinephrine at an emergency facility for sensation of localized pharyngeal edema. CONCLUSION In this trial, ragweed AIT was effective and well tolerated in ragweed-allergic North American adults. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00783198.

Cardiovascular safety and gastrointestinal tolerability of etoricoxib vs diclofenac in a randomized controlled clinical trial (The MEDAL study)

OBJECTIVE To compare cardiovascular (CV) and other safety and efficacy parameters of etoricoxib 60 and 90 mg, and diclofenac 150 mg. METHODS This double-blind study randomized OA patients to etoricoxib 90 mg, then to 60 mg once daily vs diclofenac 75 mg twice daily; RA patients were randomized to etoricoxib 90 mg once daily or diclofenac 75 mg twice daily. The primary endpoint was non-inferiority of etoricoxib vs diclofenac for thrombotic CV events (95% CI upper bound of hazard ratio <1.30). Other safety and efficacy parameters were evaluated in cohorts of patients based on etoricoxib dose and disease. RESULTS A total of 23 504 patients were randomized with mean treatment duration from 19.4 to 20.8 months. The thrombotic CV risk hazard ratio (HR) (etoricoxib to diclofenac) was 0.96 (95% CI 0.81, 1.15), consistent with non-inferiority of etoricoxib to diclofenac. The cumulative gastrointestinal (GI)/liver adverse events (AEs) discontinuation rate was significantly lower for etoricoxib than diclofenac in each patient cohort; HR (95% CI) of 0.46 (0.39, 0.54), 0.52 (0.42, 0.63) and 0.49 (0.39, 0.62) for the 60 mg OA, 90 mg OA and RA cohorts. The maximum average change in systolic blood pressure (BP) with etoricoxib was 3.4-3.6 mmHg (diastolic BP: 1.0-1.5 mmHg), while diclofenac produced a maximum average change of 0.9-1.9 mmHg (diastolic BP: 0.0-0.5 mmHg). Both agents resulted in similar efficacy regardless of etoricoxib dose. CONCLUSION Long-term etoricoxib use is associated with a risk of thrombotic CV events comparable with that of diclofenac. Compared with diclofenac, etoricoxib demonstrated a greater risk of renovascular AEs, but a more favourable GI/liver tolerability profile.

Risk factors for NSAID-associated upper GI clinical events in a long-term prospective study of 34 701 arthritis patients

Aliment Pharmacol Ther 2010; 32: 1240–1248

Prescription rates of protective co-therapy for NSAID users at high GI risk and results of attempts to improve adherence to guidelines.

Background  Protective co‐therapy is recommended in NSAID users with GI risk factors, but adherence is poor.