Dose-response relationship between opioid use and adverse effects after ambulatory surgery.

This health outcomes analysis based on data from a randomized, double-blind, placebo-controlled trial determined dose-response relationship between opioid use and related symptoms. All patients received intravenous fentanyl on demand for pain predischarge, and oral acetaminophen 500 mg/hydrocodone 5 mg every 4-6 hours as needed postdischarge for up to 7 days postsurgery. Patients completed an opioid-related Symptom Distress Scale (SDS) questionnaire every 24 hours postdischarge for 7 days, which assessed 12 opioid-related symptoms by 3 ordinal measures: frequency, severity, and bothersomeness. Clinically meaningful events (CMEs) were defined based on the responses to this questionnaire. Opioid use was converted to morphine equivalent dose (MED). The dose-response relationship between composite SDS scores and MED on Day 1, on Days 0 and 1, and on Days 1-4, was assessed. SDS scores for all 12 symptoms within the 3 dimensions were significantly associated with MED on Day 1 (F-value=1.56; P=0.04), as well as cumulative MED used on Days 0 and 1 (F-value=1.85; P<0.01). Patients with a specific CME used a higher MED than those without a CME on Day 1 (P<0.001). Between Days 1 and 4, patients with a higher number of patient-CME-days used a significantly higher MED. Regression analyses suggested that once the MED reached a threshold, approximately every 4 mg increase in MED was related to 1 additional patient-CME-day (P<0.01). A dose-response relationship empirically exists between MED and directly assessed opioid-related CMEs after ambulatory laparoscopic cholecystectomy. Once daily MED reaches a threshold, every 3-4 mg increase will be associated with 1 additional clinically meaningful opioid-related symptom, or 1 additional patient-day with an opioid-related CME.

Drug switching patterns among patients with rheumatoid arthritis and osteoarthritis using COX-2 specific inhibitors and non-specific NSAIDs.

PURPOSE: To compare RA and OA patients' time-to-switch after newly initiating treatment with three most commonly used non-specific (NS)-NSAIDs and two COX-2 inhibitors, celecoxib and rofecoxib. METHODS: Managed care enrollees newly prescribed celecoxib, rofecoxib, ibuprofen, naproxen or diclofenac were identified. Time to switch to a different NS-NSAID or COX-2 specific inhibitor was determined using time-to-event analysis and Cox proportional hazards models were used to estimate the odds ratio (OR) after controlling for potential confounders. RESULTS: The time to 25% of the cohort switching was longer for rofecoxib and celecoxib (159 and 205 days respectively) compared to the three NS-NSAIDs (49-78 days). Patients were at the highest risk of switching within the first 100 days of therapy. After adjusting for potential confounding factors, the OR for switching to another NS-NSAID or COX-2 specific inhibitor ranged from 1.74 to 2.35 for the three NS-NSAIDs compared to celecoxib (all comparisons, p < 0.01). Similar findings were obtained when comparing rofecoxib to each of the three NS-NSAIDS (all comparisons, p < 0.01). When COX-2 inhibitors combined were compared to NS-NSAIDS combined, the OR for switching was 1.53 (95% confidence interval = 1.42-1.65; p < 0.01) after adjusting for potential confounders. CONCLUSIONS: Patients on the COX-2 specific inhibitors (celecoxib and rofecoxib) were significantly less likely to switch their therapy than patients on NS-NSAIDS (ibuprofen, naproxen and diclofenac). These results suggest that COX-2 specific inhibitors may be a more effective treatment option when compared with NS-NSAIDs in usual clinical practice.

Longer use of COX-2-specific inhibitors compared to nonspecific nonsteroidal antiinflammatory drugs: a longitudinal study of 3639 patients in community practice.

OBJECTIVE: To compare COX-2-specific inhibitor therapy with conventional nonspecific nonsteroidal antiinflammatory drugs (NS NSAID), and investigate the effect of demographic and disease factors on NSAID duration of use. METHODS: A total of 3639 patients with rheumatoid arthritis (RA), osteoarthritis, and fibromyalgia starting therapy of celecoxib, rofecoxib, naproxen, or ibuprofen were surveyed at 6-month intervals for up to 2.5 years. Detailed demographic and disease severity variables were also measured. Time to discontinuation, discontinuation rates, and effect of covariates were determined by Weibull parametric survival analyses, controlling for a wide variety of demographic and disease severity factors. RESULTS: The median duration of use for celecoxib, rofecoxib, naproxen, and ibuprofen was 15, 13, 10, and 10 months, respectively. Duration of use of celecoxib and rofecoxib, as measured by survival times, was significantly longer than those of naproxen and ibuprofen. The celecoxib survival time was significantly longer than the rofecoxib survival time (p = 0.005). Disease severity was not associated with survival times, but survival was related to younger age and male sex. In addition, ulcer diagnosis was a strong predictor of early termination. After adjustment for severity, survival times for RA and non-RA patients were the same. CONCLUSION: COX-2-specific inhibitors have a longer duration of use than NS NSAID. Among the COX-2-specific inhibitors, celecoxib has a longer survival time than rofecoxib. In addition, COX-2-specific inhibitors also have longer survival times than noted in the literature of NS NSAID in RA community practice. Duration of use can be an indicator of treatment effectiveness and/or drug acceptability, and provides additional interpretation beyond the results of clinical trials.

Incidence of outpatient physician claims for upper gastrointestinal symptoms among new users of celecoxib, ibuprofen, and naproxen in an insured population in the United States.

OBJECTIVE: The aim of this study was to compare the risk of outpatient medical claims for UGI symptoms among new users of celecoxib versus ibuprofen, and naproxen. METHODS: The study was conducted using LifeLink, an insurance claims database of approximately 1.8 million employees, dependents, and retirees in the United States. Patients newly treated with a prescription of celecoxib, ibuprofen, or naproxen between June 1, 1999, and June 30, 2001, were included. A patient with an upper GI (UGI) symptom was any individual with an outpatient physician claim for dyspepsia (ICD-9 = 536.8), abdominal pain (789.0), or nausea/vomiting (787.0). Incidence was determined using person-time analysis. Multivariate analyses were conducted using Poisson and Cox regression models. RESULTS: The cohort consisted of patients prescribed celecoxib (n = 68,939), ibuprofen (n = 71,456), or naproxen (n = 50,014). At baseline, celecoxib users were older and more likely to have a history of UGI or cardiovascular conditions. The incidence rate of any UGI symptom was 0.46 per 1,000 patient-days for celecoxib, 0.70 for ibuprofen, and 0.62 for naproxen. After adjusting for confounding factors using Poisson regression, the ibuprofen rate was 48% higher than the celecoxib rate (incidence rate ratio (IRR) = 1.48; 95% CI = 1.39-1.58; p < 0.001), whereas the naproxen rate was 40% higher (IRR = 1.40; 95% CI = 1.31-1.49; p < 0.001). The association between drug use and UGI symptoms was confirmed by Cox regression analysis; the hazard ratios were 1.21 (95% CI = 1.13-1.29; p < 0.001) for ibuprofen and 1.15 (95% CI = 1.07-1.23; p < 0.001) for naproxen relative to celecoxib. Younger age, female sex, medical history of UGI, cardiovascular and renal conditions, and higher baseline average healthcare expenditures for the 12-month period preceding the index prescription were also significantly associated with an increased incidence of UGI symptoms. CONCLUSIONS: Celecoxib use is associated with a significantly decreased risk of outpatient physician claims for UGI symptoms compared with commonly used prescription nonspecific nonsteroidal anti-inflammatory drugs.

Patient perception of the burden of weight gain and blood pressure increase among RA patients using celecoxib, rofecoxib, and non-specific NSAIDs.

Nonsteroidal anti-inflammatory medications (NSAIDs) may be accompanied by clinically important renal side effects. We compared the rate of reported side effects from celecoxib, rofecoxib, and nonspecific (NS) NSAIDs and their burden in RA patients. Patients on rofecoxib were more likely to report a problem with weight gain (P < 0.05) and an increase in blood pressure (P < 0.001). In addition, rofecoxib users were 28% more likely to be in a more severe category for being bothered by unintentional weight gain (OR = 1.28, P < 0.05) and 53% more likely to state that they were in a more severe category for blood pressure increase (OR = 1.53, P < 0.000), compared with patients receiving celecoxib. Weight gain and blood pressure were also increased by coexisting cardiovascular disease. Clinicians should be aware that patient-reported weight gain and increases in blood pressure can occur with all NSAIDs, and may be particularly increased with rofecoxib. Existing cardiovascular disease is also an independent predictor of weight gain and increased blood pressure.

Comparison of the baseline cardiovascular risk profile among hypertensive patients prescribed COX-2-specific inhibitors or nonspecific NSAIDs: data from real-life practice.

OBJECTIVE: To evaluate the baseline cardiovascular (CV) risk of hypertensive patients newly starting cyclooxygenase (COX)-2-specific inhibitors (celecoxib or rofecoxib) or nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: Cross-sectional analysis was performed based on real-life practice data contained in the LifeLink Integrated Claims Solutions employer claims database. Patients who newly received treatment of celecoxib, rofecoxib, ibuprofen, naproxen, or diclofenac between January 1, 1999, and September 30, 2000, were identified from the database. Among them, only those who had a stable hypertensive condition for at least 3 consecutive months before the index prescription were included. Baseline characteristics were determined from claims data at the time of the index prescription. RESULTS: A total of 55 396 index prescriptions were identified, which consisted of 20,915 (37.8%) prescriptions for celecoxib, 12,952 (23.4%) for rofecoxib, 10 789 (19.5%) for ibuprofen, 8,840 (16.0%) for naproxen, and 1,900 (3.4%) for diclofenac. Both univariate and multivariate analyses showed that the patients prescribed COX-2-specific inhibitors were older and more likely to be female than those given nonspecific NSAIDs. Patients prescribed COX-2-specific inhibitors had a significantly higher baseline history of and/or current CV conditions, including ischemic heart disease, heart failure, other forms of heart disease, and cerebrovascular diseases or disorders, than patients prescribed nonspecific NSAIDs. The baseline proportion of patients with rheumatoid arthritis was also higher among COX-2-specific inhibitor users. In addition, COX-2-specific inhibitor users at baseline had higher prescription rates for medications that influence blood pressure, including estrogens, certain types of antidepressants, and corticosteroids. CONCLUSION: COX-2-specific inhibitors were prescribed preferentially to patients who, at the time of their index COX-2-specific inhibitor prescription, were at an increased baseline risk of CV events compared with patients prescribed nonspecific NSAIDs. Researchers aiming to compare the incidence of CV events between COX-2-specific inhibitors and nonspecific NSAIDs using observational study designs should take into account the underlying baseline CV risk of the populations being compared.

Blood pressure destabilization and related healthcare utilization among hypertensive patients using nonspecific NSAIDs and COX-2-specific inhibitors.

OBJECTIVE: To determine the incremental cost of blood pressure (BP) destabilization among patients with stable hypertension who newly initiate therapy with celecoxib, rofecoxib, or 3 commonly used nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen, diclofenac, or naproxen, based on incidence rates of BP destabilization and costs of BP destabilization events obtained from a single observational data source. METHODS: Historical cohort observational analysis was performed based on real-life practice data that are contained in the LifeLink Integrated Claims Solutions employer claims databases. Patients with stable hypertension who had newly initiated therapy with rofecoxib, celecoxib, ibuprofen, diclofenac, or naproxen between January 1, 1999, and September 30, 2000, were identified from the database. The study consists of 3 components. First, the incidence rate of BP destabilization, based on patients' time of exposure to studied drugs, was estimated. Then, the cost of a BP destabilization event was determined by matching all BP destabilization cases with non-BP destabilization cases and following them for 90 days. The differences in the total costs between cases and controls were considered an estimate of the costs associated with managing the BP destabilization event. Last, the drug-specific incremental costs of BP destabilization of using each treatment were estimated in comparison with celecoxib. Incremental costs of BP destabilization were determined by multiplying the specific excess incidence rate of BP destabilization for each of the specific drugs, relative to celecoxib, by the cost of a BP destabilization event. RESULTS: The adjusted incidence rate of outpatient BP destabilization for celecoxib was 2.27 per 1000 patient-days vs 2.66 for rofecoxib (P < .001) or 2.65 for nonspecific NSAIDs (P < .001). The incremental cost of BP destabilization per patient per day of drug utilization for the study drugs compared with celecoxib were $0.18 for rofecoxib and $0.17 for nonspecific NSAIDs. The higher costs of BP destabilization relative to celecoxib were due to the higher incidence of outpatient BP destabilization associated with the other study drugs. The average incremental healthcare cost for an outpatient BP destabilization event within the first 90 days of the event was $459. The incidence of inpatient BP destabilization among rofecoxib users was significantly higher than among celecoxib users (risk rate = 4.17; 95% Cl, 1.86-9.26; P< .001). Incremental cost was not estimated for inpatient BP destabilization because the sample size was too small to provide a stable result. CONCLUSION: The costs of managing BP destabilization were significantly lower for celecoxib compared with rofecoxib and nonspecific NSAIDs. The observed differences among these anti-inflammatory drugs in the costs of BP destabilization will have a significant impact on the total cost of therapy in patients with stable hypertension. In addition to the monetary cost of BP destabilization, the physical cost to the patient regarding development or exacerbation of this serious medical condition should be considered when choosing cyclooxygenase-2-specific inhibitor and nonspecific NSAID therapies.

Cost of heart failure among hypertensive users of nonspecific NSAIDs and COX-2-specific inhibitors.

OBJECTIVE: To determine the costs of heart failure in hypertensive patients receiving celecoxib, rofecoxib, and nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs) in clinical practice. METHODS: Stable hypertensive patients without a history of heart failure and newly treated with celecoxib, rofecoxib, ibuprofen, naproxen, or diclofenac between January 1, 1999, and September 30, 2000, were identified from the LifeLink Integrated Claims Solutions employer database. The incidence rate of inpatient and outpatient heart failure claims was determined based on patients' time of exposure to study drugs after adjusting for confounding factors. The heart failure costs of managing inpatient and outpatient events were estimated as the total healthcare costs for patients with heart failure claims minus the total healthcare costs among matched control groups without heart failure claims. Healthcare costs were computed for the 0 to 30 days and 31 to 90 days following the initial outpatient or inpatient claim. Finally, the excess incidence rate of patients with inpatient and outpatient heart failure claims, relative to celecoxib, were multiplied by the heart failure cost of an inpatient and outpatient event to determine the incremental costs of heart failure associated with each of the study drugs relative to celecoxib. RESULTS: Among 50 940 patients, 707 patients had outpatient heart failure claims and 229 patients had inpatient heart failure claims. In this study, rofecoxib-treated patients were 26% more likely to have an outpatient claim (rate ratio [RR] = 1.26; 95% confidence interval [CI], 1.06-1.48; P= .007) and 52% more likely to have an inpatient claim (RR = 1.52; 95% Cl, 1.15-2.02; P = .003) for heart failure than celecoxib-treated patients. The adjusted RR of heart failure claims was similar between celecoxib and NSAIDs. The average cost of outpatient heart failure was $1054 within 30 days and $221 for the period 31 to 90 days after the initial claim (total 90-day cost of $1275). The cost for a patient with inpatient heart failure was $5966 during the hospitalization. The 90-day posthospitalization heart failure cost was $245 (total 90-day cost of $6,211 for hospitalization and follow-up). The total heart failure-related incremental cost per patient per day of use was $0.15 for rofecoxib and $0.04 for nonspecific NSAIDs relative to celecoxib. CONCLUSION: The additional heart failure costs associated with the use of rofecoxib significantly add to its cost in patients with stable hypertension, relative to celecoxib and nonspecific NSAIDs. The higher heart failure costs of rofecoxib were attributable to the higher incidence of patients with inpatient and outpatient heart failure claims relative to celecoxib and nonspecific NSAID populations being compared.

Risk of acute liver injury in patients with diabetes.

STUDY OBJECTIVES: To estimate the incidence of acute liver injury in patients with diabetes and compare it with the corresponding incidence in the general population, and to examine the association between occurrence of acute liver injury and administration of antidiabetic drugs in patients with diabetes. DESIGN: Retrospective cohort study. SETTING: United Kingdom General Practice Research Database. PATIENTS: A total of 34,328 patients with adult-onset (type 2) diabetes and a random sample of 50,000 patients with no recorded diagnosis of diabetes; all were aged 20-79 years from 1994-1998 and free of risk factors for hepatic disease. INTERVENTION: Using the United Kingdom General Practice Research Database as our resource, we followed the two cohorts to identify patients with a recorded diagnosis compatible with acute liver injury Medical records of all patients identified as potentially having liver injury were requested from the general practitioners to validate the diagnosis. MEASUREMENT AND MAIN RESULTS: After validation, 27 patients met our definition for having acute liver injury: 14 in the diabetes cohort and 13 in the general population cohort. Overall annual incidence was 14.2 and 8.8/100,000 patient-years in the diabetes and general population cohorts, respectively. The adjusted relative risk of acute liver injury in the diabetes cohort compared with that of the general population cohort was 1.0 (95% confidence interval [CI] 0.2-3.7). Patients with diabetes taking antidiabetic drugs had a relative risk of 2.8 (95% CI 0.6-12.5) compared with those not taking these drugs. CONCLUSION: Our findings suggest that diabetes itself does not constitute a major risk for acute liver injury and that a small increased risk could be associated with use of antidiabetic drugs. However, due to the low number of cases detected, the estimates of risk with individual drugs are not conclusive.

Length of hospital stay and cost of Staphylococcus and Streptococcus infections among hospitalized patients.

BACKGROUND: Staphylococcus (Staph) and Streptococcus (Strep) infections are important causes of morbidity and mortality worldwide. The economic burden of these infections is also significant, especially among hospitalized patients. OBJECTIVE: The aim of this study was to estimate length of hospital stay (LOS) and total payments for hospital admissions for patients with Staph or Strep infection as a first (primary) or second or higher (comorbid) diagnosis. METHODS: From the 1994-1997 MarketScan inpatient database, admissions with Staph (n = 2,042) or Strep (n = 1,401) infection (905 as primary and 2,538 as comorbid diagnosis) and 89,899 control admissions without a diagnosis of gram-positive infection were identified. Crude and category-specific mean LOS and anti-log mean total payments were compared between admissions with Staph or Strep infection and admissions without a diagnosis of any gram-positive infection within major diagnostic categories and principal surgical procedures (SPs). RESULTS: For admissions with Staph or Strep infection as first (primary) diagnosis (n = 905), the mean LOS was 4.68 days (95% CI, 4.44-4.93) and 4.78 days (95% CI, 4.35-5.26), respectively. The mean total payments were $6,445 (95% CI, $6,045-$6,870) and $6,821 (95% CI, $6,149-$7,566), respectively. In contrast, the average LOS and total payment for the control group were 2.99 days (95% CI, 2.98-3.01) and $6,325 (95% CI, $6,284-$6,365). For admissions with infection as the comorbid diagnosis (n = 2,538), mean LOS and total payment were 4 days longer and $6,000 higher for Staph infections and 1.2 days longer and $1,200 higher for Strep infections than the control group. Within each SP, LOS and total payments were substantially higher for patients with Staph and Strep infections. CONCLUSIONS: The results of this study indicate that infections with the pathogens Staph and Strep substantially increase LOS and total payments among hospitalized patients.

Urinary antispasmodic use and the risks of ventricular arrhythmia and sudden death in older patients.

OBJECTIVES: The introduction of new medications to treat overactive bladder has resulted in a significant increase in the number of individuals with this condition who use medications for symptoms. Formal epidemiological studies of the safety of these medications in typical patient populations are lacking, particularly studies of serious events. We sought to determine whether the use of urinary antispasmodics increases the risk of ventricular arrhythmias or sudden death. DESIGN: Retrospective cohort study. SETTING: Retrospective analysis of data of participants in community, hospital or nursing home setting. PARTICIPANTS: Fourteen thousand six hundred thirty-eight subjects with a diagnosis of urinary incontinence made between January 1, 1991, and June 30, 1995; all were aged 65 and older and enrolled in Medicare and Medicaid or the Pharmacy Assistance for the Aged and Disabled programs of New Jersey. MEASUREMENTS: Filled prescriptions for oxybutynin (Ditropan), flavoxate (Urispas), hyoscyamine (Cystospas), and hyoscyamine sulfate (Cystospas-M) were used to define days of exposure to these drugs. We also identified all use of nonsedating antihistamines and cytochrome P450 3A4 inhibitors, and their concurrent use, to serve as a positive control exposure. Two outcomes were then defined: a new diagnosis of ventricular arrhythmia combined with initiation of an antiarrhythmic medication and sudden death. Other covariates, including clinical, demographic, medication use, and healthcare utilization variables, were also assessed. Adjusted risk ratios of ventricular arrhythmia and sudden death were derived from multivariable Cox proportional hazards models. RESULTS: There was no significant association between periods of use of urinary antispasmodics and the development of ventricular arrhythmias (adjusted risk ratio (RR) = 1.23, 95 confidence interval (CI) = 0.87-1.75) or sudden death (adjusted RR = 0.70, 95% CI = 0.28-1.74). A significantly increased risk of ventricular arrhythmia was observed for the positive control regimen, concurrent use of nonsedating antihistamines and cytochrome P450 3A4 inhibitors (adjusted RR = 5.47; 95% CI = 1.34-22.26), but not for use of either drug group alone. Concurrent use of nonsedating antihistamines and cytochrome P450 3A4 inhibitors was also associated with a significant increase in the risk of sudden death (adjusted RR = 21.50, 95% CI = 5.23-88.37). Other variables significantly associated with ventricular arrhythmia included ischemic heart disease and congestive heart failure, whereas nursing home use before the index date was associated with a decreased likelihood of receiving a diagnosis of and treatment for ventricular arrhythmia. Other variables significantly associated with sudden death included male gender, black race, and congestive heart failure. CONCLUSIONS: Antimuscarinic urinary antispasmodics available before 1996 were not associated with an increased risk of ventricular arrhythmias and sudden death. Additional study will be required to confirm these results, exclude the possibility of unmeasured confounders contributing to any lack of an observed relationship, and extend these findings to newer agents such as tolterodine.