Treatment patterns and healthcare resource utilization among patients with hereditary angioedema in the United States.

BACKGROUND: Real-world data on usage and associated outcomes with hereditary angioedema (HAE)-specific medications introduced to the United States (US) market since 2009 are very limited. The purpose of this retrospective study was to evaluate real-world treatment patterns of HAE-specific medications in the US and to assess their impact on healthcare resource utilization (HCRU). This analysis used IMS PharMetrics PlusTM database records (2006-2014) of patients with HAE, ≥1 insurance claim for an HAE-specific medication, and continuous insurance enrollment for ≥3 months following the first HAE prescription claim. RESULTS: Of 631 total patients, 434 (68.8%) reported C1-INH(IV) use; 396 (62.8%) reported using ecallantide and/or icatibant. There were 306 episodes of prophylactic use of C1-INH(IV) (defined by continuous refills averaging ≥1500 IU/week for ≥13 weeks) in 155 patients; use of ≥1 on-demand rescue medication was implicated during 53% (163/306) of those episodes. Sixty-eight (20.2%) of 336 C1-INH(IV) users eligible for the HCRU analysis were hospitalized at least once, and 191 (56.8%) visited the emergency department (ED). Eighteen patients (5.4%) had a central venous access device (CVAD); of these, 5 (27.7%) required hospitalization and 14 (77.7%) had an ED visit. The adjusted relative risk of hospitalization and/or ED visits for patients with a CVAD was 2.6 (95% CI: 0.17, 39.23) compared to C1-INH(IV) users without a CVAD. CONCLUSIONS: Despite widespread availability of modern HAE medications in the US, we identified a subset of patients requiring long-term prophylaxis who continue to be burdened by frequent rescue medication usage and/or complications related to the use of CVADs for intravenous HAE medication.

Health-Related Quality of Life with Subcutaneous C1-Inhibitor for Prevention of Attacks of Hereditary Angioedema.

BACKGROUND: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) impairs health-related quality of life (HRQoL). OBJECTIVE: The objective of this study was to assess HRQoL outcomes in patients self-administering subcutaneous C1-INH (C1-INH[SC]; HAEGARDA) for routine prevention of HAE attacks. METHODS: Post hoc analysis of data from the placebo-controlled, crossover phase III COMPACT study (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy). Ninety patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH(SC) 40 or 60 IU/kg twice weekly for 16 weeks, preceded or followed by 16 weeks of twice weekly placebo injections. All HAE attacks were treated with open-label on-demand treatment as necessary. HRQoL assessments at week 14 (last visit) included the European Quality of Life-5 Dimensions Questionnaire (EQ-5D-3L), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication (TSQM). RESULTS: Compared with placebo (on-demand treatment alone), treatment with twice weekly C1-INH(SC) (both doses combined) was associated with better EQ-5D visual analog scale general health, less HADS anxiety, less WPAI presenteeism, work productivity loss, and activity impairment, and greater TSQM effectiveness and overall treatment satisfaction. More patients self-reported a "good/excellent" response during routine prevention with C1-INH(SC) compared with on-demand only (placebo prophylaxis) management. For each HRQoL measure, a greater proportion of patients had a clinically meaningful improvement during C1-INH(SC) treatment compared with placebo. CONCLUSIONS: In patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on-demand treatment alone (placebo prophylaxis).

Patient satisfaction and experience with intravenously administered C1-inhibitor concentrates in the United States.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disorder with substantial morbidity and mortality. Despite expanded choices for effective acute treatment, prophylactic options are more limited. Intravenous C1 esterase inhibitor (C1-INH[IV]) is licensed and used to prevent HAE symptoms. OBJECTIVE: To better understand patient experiences with using C1-INH(IV), including level of satisfaction and types and frequency of complications. METHODS: Fifty adult members (≥18 years of age) of the US HAE Association who had HAE type I or II completed a self-administered internet survey. Eligible participants were experiencing at least 1 HAE attack per month and must have been receiving treatment with C1-INH(IV) as prophylaxis or acute therapy. RESULTS: Almost all respondents (n = 47; 94%) were using C1-INH(IV) for HAE prophylaxis. Most patients reported administration of C1-INH(IV) through a peripheral vein (n = 34) and 19 were currently (n = 17) or previously (n = 2) using a central venous port. Most respondents (62%) who used a peripheral vein to administer treatment reported having difficulty finding a usable vein or getting the infusion to work properly at least some of the time. Issues accessing veins, exhausted veins, and frequency of attacks were the main reasons physicians recommended ports to respondents. Although ports allow easier administration of therapy, 47% of respondents with ports experienced problems such as occlusion, thrombosis, and infection. Respondents using C1-INH prophylaxis reported a mean of 2.3 attacks per month during the previous 6 months. CONCLUSION: The survey results identified clinical challenges with IV HAE medication use, including venous access issues and ongoing monthly attack occurrence despite prophylactic C1-INH(IV) administration.

Application of the OMERACT filter to measures of core outcome domains in recent clinical studies of acute gout.

OBJECTIVE: To determine the extent to which instruments that measure core outcome domains in acute gout fulfill the Outcome Measures in Rheumatology (OMERACT) filter requirements of truth, discrimination, and feasibility. METHODS: Patient-level data from 4 randomized controlled trials of agents designed to treat acute gout and 1 observational study of acute gout were analyzed. For each available measure, construct validity, test-retest reliability, within-group change using effect size, between-group change using the Kruskall-Wallis statistic, and repeated measures generalized estimating equations were assessed. Floor and ceiling effects were also assessed and minimal clinically important difference was estimated. These analyses were presented to participants at OMERACT 11 to help inform voting for possible endorsement. RESULTS: There was evidence for construct validity and discriminative ability for 3 measures of pain [0 to 4 Likert, 0 to 10 numeric rating scale (NRS), 0 to 100 mm visual analog scale (VAS)]. Likewise, there appears to be sufficient evidence for a 4-point Likert scale to possess construct validity and discriminative ability for physician assessment of joint swelling and joint tenderness. There was some evidence for construct validity and within-group discriminative ability for the Health Assessment Questionnaire as a measure of activity limitations, but not for discrimination between groups allocated to different treatment. CONCLUSION: There is sufficient evidence to support measures of pain (using Likert, NRS, or VAS), joint tenderness, and swelling (using Likert scale) as fulfilling the requirements of the OMERACT filter. Further research on a measure of activity limitations in acute gout clinical trials is required.

A measure of treatment response: patient and physician satisfaction with traditional NSAIDs for osteoarthritis control.

PURPOSE: The clinical response to traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) varies substantially. The objective of this study was to describe physicians' and patients' perceptions of response to tNSAIDs as measured by satisfaction with control of patients' osteoarthritis (OA). PATIENTS AND METHODS: A cross-sectional survey was undertaken in 2009 in Germany, Spain, and the UK. Linked physician and patient questionnaires collected data on OA management, degree of pain and disability, and satisfaction with OA control. RESULTS: The study included 363 treating physicians and 713 patients receiving tNSAIDs. Patient mean (standard deviation) age was 65.5 (11.0) years (range 36-94 years); 60% were women; 86% were white; and one-quarter were obese. Dissatisfaction with control of patients' OA was expressed by physicians or their patients, or both, for 51% of patients, including 208 patients (31%) with mild OA and 478 patients (60%) with moderate or severe OA. Overall, 37% of patients reported dissatisfaction and 34% had a physician who reported dissatisfaction. Patient and physician assessments were the same in 70% of cases; Cohen's κ coefficient was 0.34 (95% confidence interval 0.26-0.41), indicating fair agreement. Of those reporting dissatisfaction, most physicians (79%) and patients (64%) believed that the current control was the best that could be achieved. The most common reasons for which physicians reported dissatisfaction were inadequate response (56%), side effects (11.1%), and poor tolerance (7.8%). CONCLUSION: One-half of patients or their treating physicians were dissatisfied with the control of OA provided by tNSAID therapy; moreover, most believed it was the best control that could be achieved.

An algorithm to identify medical practices common to both the General Practice Research Database and The Health Improvement Network database.

PURPOSE: To identify practices common to both the General Practice Research Database and The Health Improvement Network database for purposes of combining the databases for analysis without duplicate records. METHODS: We developed two independent algorithms to identify practices common to the two databases. The first used the total number of patients in the therapy and clinical data sets and the total number of etoricoxib and celecoxib users each year during the study period. The second used the total number of patients stratified by gender and four different categories of birth year. Further checking of potential matched practice pairs identified by the two algorithms was performed by comparing the patient-level medical records by birth year, dates of clinical visits, and diagnosis codes. RESULTS: Three hundred twelve potential matched pairs of practices were found by both algorithms. Fifteen additional potential pairs were matched by only one algorithm: 13 by algorithm 1 (A1) only and 2 by algorithm 2 (A2) only. The examination of the patient-level visit dates and diagnosis codes for the matches revealed that all of the 327 potential pairs of duplicate practices were in fact the same practice in the two databases. CONCLUSIONS: The two algorithms successfully found the practices common to the two different databases without de-identifying the practices. The identification of the common practices allows for combining the two databases without duplicate records to create a larger data set for analysis, with 168 more practices than when using the General Practice Research Database alone, or with 268 more practices than when using The Health Improvement Network alone. Copyright © 2012 John Wiley & Sons, Ltd.

How do physicians weigh benefits and risks associated with treatments in patients with osteoarthritis in the United Kingdom?

OBJECTIVE: To quantify the relative importance that UK physicians attach to the benefits and risks of current drugs when making treatment decisions for patients with osteoarthritis (OA). METHODS: Physicians treating at least 10 patients with OA per month completed an online discrete-choice experiment survey and answered 12 treatment-choice questions comparing medication profiles. Medication profiles were defined by 4 benefits (reduction in ambulatory pain, resting pain, stiffness, and difficulty doing daily activities) and 3 treatment-related risks [bleeding ulcer, stroke, and myocardial infarction (MI)]. Each physician made medication choices for 3 of 9 hypothetical patients (varied by age, history of MI, hypertension, and history of gastrointestinal bleeding). Importance weights were estimated using a random-parameters logit model. Treatment-related risks physicians were willing to accept in exchange for various reductions in ambulatory and resting pain also were calculated. RESULTS: The final sample was 475. A reduction in ambulatory pain from 75 mm to 25 mm (1.6 units) was 1.1 times as important as an increase in MI risk from 0% to 1.5% (1.5 units). The greatest importance was for eliminating a 3% treatment-related risk of MI or stroke. On average, physicians were willing to accept an increase in bleeding ulcer risk of 0.7% (95% CI 0.4%-1.7%) for a reduction in ambulatory pain of 75 mm to 50 mm. CONCLUSION: When presented with well-known benefits and risks of OA treatments, physicians placed greater importance on the risks than on the analgesic properties of the drug. This has implications for the reporting of the results of clinical research to physicians.

Definition of nonresponse to analgesic treatment of arthritic pain: an analytical literature review of the smallest detectable difference, the minimal detectable change, and the minimal clinically important difference on the pain visual analog scale.

Our objective was to develop a working definition of nonresponse to analgesic treatment of arthritis, focusing on the measurement of pain on the 0-100 mm pain visual analog scale (VAS). We reviewed the literature to assess the smallest detectable difference (SDD), the minimal detectable change (MDC), and the minimal clinically important difference (MCID). The SDD for improvement reported in three studies of rheumatoid arthritis was 18.6, 19.0, and 20.0. The median MDC was 25.4 for 7 studies of osteoarthritis and 5 studies of rheumatoid arthritis (calculated for a reliability coefficient of 0.85). The MCID increased with increasing baseline pain score. For baseline VAS tertiles defined by scores of 30-49, 50-65, and >65, the MCID for improvement was, respectively, 7-11 units, 19-27 units, and 29-37 units. Nonresponse can thus be defined in terms of the MDC for low baseline pain scores and in terms of the MCID for high baseline scores.

Recommendations for safety planning, data collection, evaluation and reporting during drug, biologic and vaccine development: a report of the safety planning, evaluation, and reporting team.

BACKGROUND: The Safety Planning, Evaluation and Reporting Team (SPERT) was formed in 2006 by the Pharmaceutical Research and Manufacturers of America. PURPOSE: SPERT's goal was to propose a pharmaceutical industry standard for safety planning, data collection, evaluation, and reporting, beginning with planning first-in-human studies and continuing through the planning of the post-product-approval period. METHODS: SPERT's recommendations are based on our review of relevant literature and on consensus reached in our discussions. RESULTS: An important recommendation is that sponsors create a Program Safety Analysis Plan early in development. We also give recommendations for the planning of repeated, cumulative meta-analyses of the safety data obtained from the studies conducted within the development program. These include clear definitions of adverse events of special interest and standardization of many aspects of data collection and study design. We describe a 3-tier system for signal detection and analysis of adverse events and highlight proposals for reducing "false positive" safety findings. We recommend that sponsors review the aggregated safety data on a regular and ongoing basis throughout the development program, rather than waiting until the time of submission. LIMITATIONS: We recognize that there may be other valid approaches. CONCLUSIONS: The proactive approach we advocate has the potential to benefit patients and health care providers by providing more comprehensive safety information at the time of new product marketing and beyond.

Effects of increasing high-density lipoprotein cholesterol and decreasing low-density lipoprotein cholesterol on the incidence of first acute coronary events (from the Air Force/Texas Coronary Atherosclerosis Prevention Study).

Reducing low-density lipoprotein (LDL) cholesterol with statins reduces cardiovascular risk, but the associations between increases in high-density lipoprotein (HDL) cholesterol and cardiovascular risk at different LDL levels have been less well characterized. To evaluate the associations between the 1-year changes in HDL cholesterol and LDL cholesterol with lovastatin and subsequent acute major coronary events (AMCEs), we studied 2,928 patients in the lovastatin arm who were followed for 5.2 years in a post-hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). The percentage of HDL cholesterol increase and apolipoproteins at year 1 and the incidence of AMCEs thereafter were assessed stratified by the LDL cholesterol levels. With lovastatin, LDL cholesterol was reduced by 25% on average to 115 mg/dl at year 1, and HDL cholesterol increased 6.0%. Patients with both an increase in HDL cholesterol of > or =7.5% and LDL cholesterol of <115 mg/dl at year 1 had the lowest event rate (3.53/1,000 person-years; p = 0.028). Similar results were found for an increase in HDL cholesterol of > or =7.5% and a decrease in LDL cholesterol of >25%, as well as for apolipoproteins A-I and B. The 1-year percent increase in HDL cholesterol appeared to be associated with a reduction in AMCEs in subsequent follow-up (p = 0.07 with the percentage of HDL cholesterol increase analyzed continuously). Patients with an HDL cholesterol increase of > or =7.5% had an AMCE rate of 5.18 compared with 7.66/1,000 person-years in patients with a lower HDL cholesterol increase (p = 0.08). In conclusion, lovastatin therapy was associated with a greater risk reduction of AMCEs when LDL cholesterol was substantially reduced and the HDL cholesterol increased by > or =7.5%.

Serum urate during acute gout.

OBJECTIVE: To study the frequency of normal serum urate (SU) levels during acute gout in the largest studies of acute gout treatment to date. METHODS: Data collected from 2 randomized controlled clinical trials assessing the efficacy of etoricoxib or indomethacin for 7 days in acute gout were used to assess SU levels during acute gouty attacks. Efficacy was similar with both agents, so both groups were combined for analysis. RESULTS: A total of 339 patients were enrolled in the 2 studies; 94% were male; mean age was 50.5 years. At baseline, 14% of patients had a "true" normal SU (

Patients' experiences of niacin-induced flushing in clinical practice: a structured telephone interview.

BACKGROUND: Niacin is highly effective at raising high-density lipoprotein cholesterol but remains underused because of the adverse event of flushing. OBJECTIVE: The objective of this study was to determine the incidence and severity of niacin-induced flushing and their relationship to niacin discontinuation and skipping or delaying niacin doses in clinical practice. The use of aspirin to avoid niacin-induced flushing was also assessed. METHODS: Structured telephone interviews were performed with patients identified from administrative claims data as having newly initiated niacin. The main outcome measures were rate and severity of flushing, association between flushing and niacin discontinuation, and rate of prophylactic aspirin use to avoid flushing. Flushing was evaluated on a scale of none, mild, moderate, severe, and extreme. RESULTS: Telephone interviews were conducted with 500 patients who had newly initiated niacin. The patients interviewed were predominantly white men with at least some college education and a mean (SD) age of 55.0 (10.9) years. The mean (SD) time between therapy initiation and interview was 9.3 (3.3) months. At the time of the interview, 27.2% of respondents reported having discontinued niacin ("discontinuers"; n = 136), with a mean duration of niacin use of 4.3 months, and 72.8% continued taking niacin ("continuers"; n = 364). Approximately 91.2% (124/136) of niacin discontinuers and 82.1% (299/364) of continues reported experiencing flushing symptoms (P = 0.013), and 54.4% of discontinuers versus 20.9% of continuers experienced severe or extreme flushing (P < 0.001). Significantly more discontinuers (79.4%) than continuers (58.0%) reported that the greatest degree of flushing they could tolerate was "mild" or "moderate" (P < 0.001). Multivariate logistic regression indicated that flushing symptom severity was a strong predictor of discontinuation as compared with no flushing symptoms (severe: odds ratio [OR], 3.19; 95% CI, 1.43-7.15; extreme: OR, 11.29; 95% CI, 4.20-30.39). Similar percentages of discontinuers and continuers reported both receiving a physician's advice to take prophylactic aspirin (42.0% vs 49.5%, respectively; P = NS) and actually taking aspirin regardless of what their physicians advised (36.0% vs 43.7%; P = NS). CONCLUSIONS: Severe or extreme symptoms of flushing, which occurred in about one third of patients newly treated with niacin, were associated with discontinuation of this otherwise highly effective therapy. Less than half of patients reported being advised by their physician to take prophylactic aspirin or took aspirin regardless of their physician's recommendation to avoid niacin-induced flushing symptoms.

Dosage, titration, and gaps in treatment with extended release niacin in clinical practice.

OBJECTIVE: To examine the dosage, titration patterns, and gaps in treatment of newly-initiated ER niacin in clinical practice. RESEARCH DESIGN AND METHODS: Historical cohort study using the Ingenix Lab/Rx database. Patients were at least 20 years old, received an initial, index ER niacin prescription between January 1, 2001 and June 30, 2003, and had no ER niacin use in the preceding 12 months. Follow-up data were collected for at least 6 months after the index date. MAIN OUTCOME MEASURES: Average daily dosage (ADD) and titration patterns of ER niacin therapy at defined time points after the index prescription, and the incidence and timing of continuous gaps of >/=30 days in ER niacin therapy. RESULTS: A total of 14 386 patients initiating ER niacin were followed for a mean of 6.5 months after the index prescription. The ADD of the initial ER niacin prescription was 750 mg. Forty percent of patients experienced a >/=30-day gap in therapy immediately after the first prescription. Almost 80% had at least one >/=30-day gap in therapy during the post-index period, and the ADD of the last prescription prior to discontinuation was /=1000 mg and only 7.6% reached the dose of 2000 mg. CONCLUSIONS: A considerable proportion of new ER niacin users failed to reach recommended daily maintenance dosages in clinical practice. The main limitations of the study include its reliance on administrative data, inability to capture over-the-counter niacin use, and evaluation of reasons for suboptimal titration. Future research should determine the extent to which gaps in ER niacin therapy and failure to titrate to optimal dosages are due to poor tolerability, physician practice, or other factors.

Hepatic effects of lovastatin exposure in patients with liver disease: a retrospective cohort study.

BACKGROUND: Little is known about the potential adverse hepatic effects of HMG-CoA reductase inhibitors ('statins') in patients with existing liver disease; therefore, we examined the risk of liver toxicity with lovastatin exposure in these patients. METHODS: A retrospective cohort study was performed using data from a large integrated health plan in Northern California, USA. Patients with laboratory or clinical evidence of liver disease were identified and their exposure to lovastatin was determined. The primary outcome was a pattern of liver-test abnormalities associated with a poor prognosis among patients with drug-induced liver disease, based on Hy's Rule. Secondary outcomes included liver injury (defined as moderate or severe, depending on the degree of ALT level elevations) or the development of either clinical cirrhosis or liver failure. Incidence rate ratios (IRRs) were calculated and multivariate analyses conducted using extended Cox models. RESULTS: A total of 93 106 patients met the entry criteria. Lovastatin exposure was associated with a lower incidence of all endpoints, including the primary outcome (IRR = 0.28, 95% CI 0.12, 0.55), moderate liver injury (IRR = 0.56, 95% CI 0.47, 0.65), severe liver injury (IRR = 0.50, 95% CI 0.29, 0.81) and the occurrence of either cirrhosis or liver failure (IRR = 0.29, 95% CI 0.21, 0.38); adjustment for age and sex resulted in some attenuation of this reduction in incidence. The observed effects were generally consistent across a range of baseline liver-disease diagnoses and greater cumulative lovastatin exposure was associated with fewer outcome events for some endpoints. CONCLUSIONS: In this retrospective analysis, exposure to lovastatin was not associated with an increased risk of adverse hepatic outcomes. These results do not support concern regarding lovastatin-related hepatotoxicity in patients with existing liver disease.

Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia.

Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D(2), which leads to poor patient compliance and suboptimal dosing. This phase II dose-ranging study was designed to assess whether the prostaglandin D(2) receptor 1 antagonist laropiprant (LRPT; MK-0524) would (1) reduce extended-release niacin (ERN)-induced flushing in dyslipidemic patients and (2) support a novel accelerated ERN dosing paradigm: initiating ERN at 1 g and advancing rapidly to 2 g. In part A of the study, 154 dyslipidemic patients were randomized to LRPT 150 mg/day or placebo in a 9-week, 2-period crossover study. Patients who completed part A (n = 122) entered part B (after a 2-week washout), together with additional patients who entered part B directly (n = 290). Part B patients were randomized to placebo, ERN 1 g (Niaspan, no previous titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling of the respective doses for the remaining 4 weeks. Patients treated with LRPT plus ERN experienced significantly less ERN-induced flushing than those treated with ERN alone during the initiation of treatment (ERN 1 g, week 1) and the maintenance treatment (ERN 1 to 2 g, weeks 2 to 8). All doses of LRPT were maximally effective in inhibiting niacin-induced flushing. LRPT did not alter the beneficial lipid effects of ERN. LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERN-induced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients.

Systematic review of trials of the effect of continued use of oral non-selective NSAIDs on blood pressure and hypertension.

OBJECTIVE: To investigate the effects of continued use of non-selective NSAIDs (nsNSAIDs) on blood pressure and hypertension. RESEARCH DESIGN AND METHODS: This was a systematic review of randomized clinical trials of oral nsNSAIDs used for at least a 4-week duration. Searches were conducted of PubMed and the Cochrane Database of Systematic Reviews, using key terms for nsNSAIDs and blood pressure or hypertension, to identify articles published in the English language peer-reviewed literature through March 2007. MAIN OUTCOME MEASURES: Change from baseline to end of study in systolic blood pressure (SBP) and diastolic blood pressure (DBP), and the incidence of hypertension. Pooled statistics were computed using fixed and random-effects analyses. RESULTS: Thirty-two articles were included. The mean change (95% confidence interval [CI]) in blood pressure (in mmHg) from baseline to end of study for five trials of ibuprofen was 3.54 (2.70, 4.39) for SBP and 1.16 (0.68, 1.64) for DBP (p < 0.001 for both changes). Results of four trials of indomethacin were similar to those for ibuprofen: 2.90 (-0.28, 6.08) for SBP (p = 0.07) and 1.58 (0.29, 2.87) for DBP (p = 0.02). Mean changes from baseline for two trials of diclofenac were -0.46 (-1.48, 0.56) for SBP (p = 0.38) and -0.56 (-1.19, 0.07) for DBP (p = 0.08) and were similar to those for placebo. Changes from baseline in SBP were positive but not statistically significant for naproxen, sulindac, and nabumetone. Compared with placebo, the risk ratio (95% CI) for hypertension was 2.85 (1.44, 5.65; p = 0.003) in two ibuprofen trials. CONCLUSIONS: Continued use of ibuprofen increases blood pressure and raises the incidence of hypertension. There appears to be heterogeneity in such effects with continued use of other nsNSAIDs but, due to limitations in the data, results for naproxen, sulindac, and nabumetone are inconclusive.

Validation of a questionnaire to assess niacin-induced cutaneous flushing.

BACKGROUND: Niacin is currently the most effective approved agent for raising high-density lipoprotein cholesterol. However, niacin-induced cutaneous flushing (redness, warmth, tingling and/or itching) significantly limits patient acceptance. To further characterize flushing, a patient-reported Flushing Symptom Questionnaire (FSQ) was developed and validated. METHODS: The FSQ was validated in an 8-week, randomized, double-blind, placebo-controlled trial of extended-release (ER) niacin and placebo. The primary flushing endpoint of the study was based on the single Global Flushing Severity Score (GFSS), an item within the FSQ, which assesses overall flushing severity on a 0-10 discretized analog scale. RESULTS: A total of 175 patients were randomized to one of four treatment groups (sequences of placebo and ER niacin [given as niacin (NIASPAN) 1 g (N1) and 2g (N2)]. Test-retest reliability and reproducibility coefficients for the single-item GFSS were all above 0.75. Construct validity was supported by moderate to strong correlations (r > 0.5) with other FSQ items. All FSQ item scores and specifically the GFSS discriminated between treatment groups and demonstrated expected relationships with predefined known groups. The GFSS demonstrated high responsiveness in patients who switched from ER niacin to placebo. The ability of the GFSS and GFBS to discriminate changes in flushing symptoms in patients who increased drug dose was less than expected possibly due to accommodation to the flushing effects of niacin over time; differential drop-out due to flushing; and/or FSQ items not being sensitive enough to detect a change that was present. CONCLUSIONS: The FSQ items and specifically the Global Flushing Severity Score (GFSS), are reliable and valid measures to assess niacin-induced flushing.

Association between nonnaproxen NSAIDs, COX-2 inhibitors and hospitalization for acute myocardial infarction among the elderly: a retrospective cohort study.

PURPOSE: To evaluate the association between rofecoxib, celecoxib, diclofenac, and ibuprofen and the risk of hospitalization for acute myocardial infarction (AMI) in an elderly population. METHODS: We conducted a retrospective cohort study, using data from the government of Quebec health insurance agency databases, among patients 65-80 years of age who filled a prescription for any of the study drugs during 1999-2002. Cox regression models with time-dependent exposure were used to compare the incidence rates of hospitalization for AMI adjusting for patients' baseline characteristics. Analyses stratified by dose and number of supplied days were also conducted. RESULTS: At the index date, a total of 91 062 patients were taking rofecoxib, 127 928 celecoxib, 49 193 diclofenac, and 15 601 ibuprofen. The adjusted hazard ratio (HR) (95%CI) of hospitalization for AMI were: celecoxib versus rofecoxib: 0.90 (0.79, 1.01); ibuprofen versus rofecoxib: 0.95 (0.65, 1.37); diclofenac versus rofecoxib: 1.01 (0.84, 1.22). In secondary analyses based on intended duration of use, neither COX-2 selective inhibitor was associated with a higher risk than ibuprofen or diclofenac. The unadjusted risk of AMI for all NSAIDs increased with dose. In the direct two way adjusted comparison of each NSAID stratified by dose, the only statistically significant difference was with rofecoxib >25 mg/day versus celecoxib >200 mg/day. CONCLUSION: In this study there was no difference between AMI occurrence in elderly patients taking rofecoxib or celecoxib at recommended doses for chronic indications versus those taking ibuprofen/diclofenac. However, the risk of AMI was higher among patients using higher doses of rofecoxib (>25 mg/day) compared to patients using higher doses of celecoxib (>200 mg/day).