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To investigate whether serum urate levels, number of gout flares, and tophi burden are related to death from cardiovascular (CV) causes after treatment with febuxostat or allopurinol in patients with gout from the Cardiovascular Safety of Febuxostat or Allopurinol in Patients With Gout and Cardiovascular Comorbidities (CARES) trial.Patients were randomly assigned to receive febuxostat (40 mg or 80 mg once daily, according to serum urate levels at week 2) or allopurinol titrated in 100-mg increments from 200-400 mg or 300-600 mg (with dose determined according to kidney function). Changes from baseline in serum urate level, gout flares, and tophus resolution were key exploratory efficacy parameters in the overall population and in subgroups of patients who died and those who did not die from a CV-related cause. The latter subgroup included patients who died due to non-CV causes and those who did not die due to any cause.Patients received treatment with febuxostat (n = 3,098) or allopurinol (n = 3,092) for a median follow-up period of 32 months (for a maximum of 85 months). In the overall population, mean serum urate levels were lower in those receiving febuxostat compared with those receiving allopurinol at most study visits. There were no associations between serum urate levels and death from CV causes with febuxostat. The number of gout flares requiring treatment was higher within 1 year of treatment with febuxostat compared with allopurinol (mean incidence of gout flares per patient-years of exposure 1.33 versus 1.20), but was comparable thereafter and decreased overall throughout the study period (mean incidence of gout flares per patient-years of exposure 0.35 versus 0.34 after 1 year of treatment; overall mean incidence 0.68 versus 0.63) irrespective of whether the patient died from a CV-related cause. Overall, 20.8% of patients had ≥1 tophus at baseline; tophus resolution rates were similar between treatment groups, with cumulative resolution rates of50%.In the CARES trial, febuxostat and allopurinol (≤600 mg doses) had comparable efficacy in patients with gout and CV disease, and there was no evidence of a relationship between death from CV causes and serum urate levels, number of gout flares, or tophus resolution among the patients receiving febuxostat.

Objective To assess the efficacy and safety of febuxostat extended release (XR) and immediate release (IR) in patients with gout and normal or impaired renal function. Methods This was a 3‐month, phase III, multicenter, double‐blind, placebo‐controlled study. Patients (n = 1,790) with a history of gout and normal or impaired (mild‐to‐severe) renal function were randomized to receive placebo, febuxostat IR 40 or 80 mg, or febuxostat XR 40 or 80 mg once daily (1:1:1:1:1 ratio). End points included proportions of patients with a serum urate (UA) level of

The xanthine oxidase (XO) system is a significant source of vascular oxidative stress, which is believed to impair endothelial function, an important contributor to atherosclerotic disease. We tested whether febuxostat, a potent XO inhibitor, improves coronary endothelial function (CEF) in patients with stable coronary artery disease (CAD) in a single-center, randomized, placebo-controlled, double-blind crossover trial.CEF was measured using noninvasive magnetic resonance imaging (MRI) assessment of changes in 30 patients with stable CAD and baseline impaired CEF. Patients received either febuxostat or placebo for 6 weeks and then were crossed over to the alternative for an additional 6 weeks. MRI-detected changes in coronary flow and in coronary cross-sectional area from rest to isometric handgrip exercise, a known endothelial-dependent stressor, were measured at the end of each 6 week period.Mean serum urate levels were lower at the end of the 6-week febuxostat period (2.9±0.8mg/dL) than at the end of the 6-week placebo period (5.9±0.04, P.001). However, there were no significant differences in any of the CEF parameters measured at the end of the febuxostat and placebo periods.In summary, although XO inhibition with febuxostat was well tolerated and lowered serum urate, it did not improve the primary end point of the study, CEF measured using MRI after 6 weeks of treatment. In conclusion, these findings suggest that short-term inhibition of XO does not significantly improve impaired CEF in patients with stable CAD.

Background/Aims: This post-marketing observational study assessed the long-term safety of lanthanum carbonate (LaC) in US patients with end-stage renal disease (NCT00567723). Methods: Patients (≥18 years old) undergoing dialysis, who had Medicare as their primary healthcare payer, and records in the United States Renal Data System were followed-up for 5 years. Patients who had received LaC for at least 12 consecutive weeks formed the exposed cohort. During the same time period, patients who had undergone dialysis for at least 12 consecutive weeks and had been treated with any other phosphate binder formed the primary comparator cohort. A historical cohort was also evaluated. Primary outcomes were all-cause mortality, and time to and incidence of first bone-fracture event requiring hospitalization. Secondary outcomes were time to first occurrence of and incidence of specific gastrointestinal (GI) disease, liver disease, malignancy, and major infectious episode requiring hospitalization. ­Results: 2,026 and 8,094 patients were included in the exposed and primary comparator cohorts, respectively. A Cox proportional hazards model showed that patients receiving LaC were not at increased risk of all-cause mortality (adjusted hazard ratio 0.94; 95% CI 0.88–1.01; p = 0.078), bone fractures (0.86; 0.71–1.05; p = 0.130), specific GI disease (0.86; 0.76–0.97; p = 0.015), liver disease (0.88; 0.70–1.09; p = 0.236), malignancy (0.85; 0.54–1.34; p = 0.496), or major infectious episodes (0.87; 0.80–0.94; p < 0.001) requiring hospitalization compared with primary comparator patients. Conclusions: LaC was not associated with increased risk of mortality, bone fractures, or any secondary outcome.

Objective Renal impairment is a risk factor for gout and a barrier to optimal gout management. We undertook this exploratory study to obtain data that have been heretofore limited regarding the safety and efficacy of febuxostat in patients with moderate-to-severe renal impairment (estimated glomerular filtration rate [GFR] 15–50 ml/minute/1.73 m2). Methods Ninety-six gout patients with moderate-to-severe renal impairment were enrolled in a 12-month multicenter, randomized, double-blind, placebo-controlled study. Patients were randomly assigned at a 1:1:1 ratio to receive 30 mg febuxostat twice daily, 40/80 mg febuxostat once daily, or placebo. The primary efficacy end point was the change in serum creatinine (Cr) level from baseline to month 12. Secondary end points included the change in estimated GFR from baseline to month 12 and the proportion of patients with a serum uric acid (UA) level of

Cardiovascular risk is increased in patients with gout. We compared cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with those associated with allopurinol, a purine base analogue xanthine oxidase inhibitor, in patients with gout and cardiovascular disease.We conducted a multicenter, double-blind, noninferiority trial involving patients with gout and cardiovascular disease; patients were randomly assigned to receive febuxostat or allopurinol and were stratified according to kidney function. The trial had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization).In total, 6190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up. In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P=0.002 for noninferiority). All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all-cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention-to-treat analysis.In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials.gov number, NCT01101035 .).

Background Febuxostat immediate release (IR), a xanthine oxidase inhibitor, is indicated for the management of hyperuricemia in patients with gout by lowering urate levels. An extended release (XR) formulation of febuxostat was developed to provide equal or superior efficacy on urate lowering compared with the IR formulation and potentially lower the risk of treatment-initiated gout flares due to an altered pattern of drug exposure. The present study evaluated the efficacy and safety of febuxostat XR and IR formulations in patients with gout and moderate renal impairment (estimated glomerular filtrate rate ≥ 30 and

Background Hyperuricemia is associated with hypertension, with elevated serum uric acid levels postulated to have a causal role in the development of hypertension. Consequently, serum uric acid reduction may help lower blood pressure ( BP ). A Phase 2, double‐blind, placebo‐controlled trial was conducted to assess the potential BP ‐lowering effects of the xanthine oxidase inhibitor febuxostat in subjects with hypertension and hyperuricemia (serum uric acid ≥0.42 mmol/L [≥7.0 mg/dL]). Methods and Results Subjects (n=121) were randomized 1:1 to febuxostat 80 mg once daily or to placebo. The primary end point was change from baseline to Week 6 in 24‐hour mean ambulatory systolic BP ( SBP ). Additional end points included the following: change from baseline to Week 3 in 24‐hour mean SBP and changes from baseline to Weeks 3 and 6 in 24‐hour mean ambulatory diastolic BP , serum uric acid, mean daytime and nighttime ambulatory SBP /diastolic BP , and clinic SBP /diastolic BP . For the overall study population, there were no significant differences between febuxostat and placebo for changes from baseline to Weeks 3 or 6 in ambulatory, daytime or nighttime, or clinic SBP or diastolic BP . However, in a preplanned subgroup analysis, there was a significant decrease in SBP from baseline to Week 6 in subjects with normal renal function (estimated glomerular filtration rate ≥90 mL/min) treated with febuxostat versus placebo; least squares mean difference, −6.7; 95% confidence interval −13.3 to −0.0; P =0.049. Conclusions This study suggests that febuxostat may lower BP in hyperuricemic patients with hypertension and normal renal function; further studies should be conducted to confirm this finding. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01496469.

Hyperuricemia can accelerate renal decline associated with aging. Chronic kidney disease is frequently seen in patients with hyperuricemia and gout.Assess the impact of urate-lowering therapy on renal function in subjects with gout who were treated with febuxostat for ≤ 48 months.Subjects from 2 phase 3 clinical studies were enrolled in the phase 3, long-term, open-label Febuxostat/Allopurinol Comparative Extension Long-Term (EXCEL) study. In the EXCEL study, 1086 subjects initially were treated with febuxostat 80 or 120 mg daily, or allopurinol 300 mg daily. The subjects were permitted to switch between doses of febuxostat and/or allopurinol during the first 6 months of treatment to achieve and maintain a serum uric acid (SUA) level ≥ 3 to6 mg/dL. For the analysis presented in this article, data from 551 subjects who received only febuxostat throughout the duration of both the phase 3 and EXCEL studies (≤ 48 months) were used to determine the impact of SUA reduction on estimated glomerular filtration rates (eGFRs).At baseline of the 2 original phase 3 studies, subjects' mean SUA level was 9.8 mg/dL. Greater sustained decreases in subjects' SUA levels were associated with less renal function decline (P0.001) by statistical modeling. The study data predicted that for every 1 mg/dL of chronic reduction of SUA level in subjects with gout, there would be a preservation of 1.15 mL/min of eGFR.Sustained urate-lowering therapy with febuxostat appears to impede renal decline in patients with gout. The results discussed in this article support similar observations previously reported in 116 hyperuricemic subjects with gout who received febuxostat for ≤ 5 years.

Individuals with osteoarthritis face an increased risk of cardiovascular (CV) disease compared with age-matched control subjects. Both conditions share some common risk factors (eg, age, obesity, and hypertension) and the consequences or treatment of osteoarthritis may increase CV risk by impairing physical activity and exacerbating CV risk factors. Nonsteroidal anti-inflammatory drugs may have prothrombotic and/or hypertensive effects and a negative impact on renal function, all of which contribute to the increased risk of CV disease associated with these agents. The magnitude of these effects differs between agents and is, in part, determined by the relative balance of cyclo-oxygenase-1 or cyclo-oxygenase-2 inhibition. To minimize risk of CV disease in patients with osteoarthritis taking nonsteroidal anti-inflammatory drugs, physicians need to 1) monitor blood pressure and the new appearance or exacerbation of edema; 2) encourage lifestyle changes/nonpharmacologic treatments for pain/risk factor management; 3) choose the lowest effective dose of appropriate drug therapy to achieve adequate pain relief while minimizing CV risk; 4) change nonsteroidal anti-inflammatory drugs as needed to one with lower propensity to aggravate CV risk; and 5) modulate antihypertensive therapy and diuretic management as needed to maintain target blood pressure and weight.

The incidence of gout and the clinical manifestation of hyperuricemia continue to rise. In addition to painful acute attacks, chronic gout can lead to the development of crystal arthropathy, tophi, and renal lithiasis, coincidental with declines in quality of life. As a greater appreciation for the associations between hyperuricemia, gout, and certain comorbidities, such as renal impairment and cardiovascular diseases, grows, so does the search for new therapeutic options to both alleviate the painful symptoms of acute gout attacks and reduce the underlying hyperuricemia. This manuscript reviews the pathophysiology of hyperuricemia and gout, and associated comorbidities, and then discusses traditional therapeutic options, newly available agents, and future targets for pharmacologic management.

Selective cyclooxygenase (COX)-2 inhibitors have been associated with an increased risk of thromboembolic cardiovascular (CV) events. Prior studies have found that rofecoxib has a destabilizing effect on blood pressure; however, whether this translates to an increased risk of thromboembolic CV events is unknown. The objective of this study was to evaluate risk of thromboembolic CV events among hypertensive and nonhypertensive patients treated with rofecoxib or celecoxib, nonselective nonsteroidal anti-inflammatory drugs (ns-NSAIDs), or no NSAIDs (nonusers). This was a retrospective cohort study of 31,743 adult arthritis patients enrolled in a Blue Cross/Blue Shield health insurance plan in the northeastern United States. The main outcome measure was incident acute myocardial infarction and stroke. A clinically significant channeling effect was observed where selective COX-2 inhibitor users had a more severe CV risk profile. Among normotensive patients, the hazard ratio (HR) of CV events for ns-NSAIDs, rofecoxib, or celecoxib versus nonusers was 0.91 (95% confidence interval, 0.68-1.21), 1.05 (0.61-1.80), and 1.19 (0.86-1.66), respectively. Among hypertensive patients, the risk of CV events for ns-NSAIDs users was not significantly different versus nonusers (HR = 1.21; 0.88-1.67). However, rofecoxib was associated with a significant 2-fold increase in CV risk versus nonusers of NSAIDs (HR = 2.16; 1.51-3.09), whereas celecoxib was not (HR = 1.18; 0.89-1.57). These data support the hypothesis that elevated CV risk is not a drug class effect of selective COX-2 inhibitors. That this effect was specific to hypertensive patients indicates that blood pressure destabilization is likely an important contributing mechanism.

Rofecoxib and celecoxib were the first cyclooxygenase-2 (COX-2)-specific inhibitors to be marketed as effective anti inflammatory agents. The results of several recent trials and a meta analysis of currently available studies all demonstrate a greater incidence of increased blood pressure, edema, and cardiovascular events in subjects treated with rofecoxib compared with celecoxib. As an approach to the assessment of molecular mechanisms that may contribute to these cardiorenal differences, this study investigated the inhibitory effects of celecoxib on renal carbonic anhydrase enzyme activity in human hypertensive subjects because in vitro enzyme studies demonstrate such an effect. Ten subjects with stable, treated hypertension were randomized to 1 of 3 treatment sequences, which included, in differing order, 200 mg celecoxib twice a day, 250 mg acetazolamide twice a day, or placebo twice a day. Whereas acetazolamide caused a bicarbonate diuresis and a hyperchloremic metabolic acidosis, celecoxib appeared to have no detectable effect on renal carbonic anhydrase or acid-base homeostasis. Thus, in this short-term study of human subjects, therapeutic doses of celecoxib did not appear to have a clinically significant inhibitory action on renal carbonic anhydrase.

Background Valdecoxib and its intravenous prodrug parecoxib are reported to increase thromboembolic risk after coronary artery bypass grafting. The authors conducted a randomized trial to examine their safety and analgesic efficacy in patients recovering from major noncardiac surgical procedures. Methods The trial was randomized and double-blind, with 10 days of treatment and 30 days of follow-up. Patients (n = 1,062) received either parenteral parecoxib for 3 days and oral valdecoxib for the rest of the treatment period or placebo medications throughout. The frequency of predefined adjudicated postrandomization adverse events, including cardiovascular thromboembolism, renal dysfunction, gastroduodenal ulceration, and wound-healing complications, was assessed in each group. Secondary efficacy endpoints included patients' pain ratings, opioid analgesic consumption (recorded as morphine equivalents), and reports of opioid-related adverse effects. Results Predefined adjudicated adverse events had similar frequencies among patients who received parecoxib and valdecoxib (2.7%) and placebo patients (3.2%) (P = 0.58), including cardiovascular thromboembolic events (1.0% in each group; P = 1.0). Placebo patients consumed more morphine equivalents (66.2 +/- 92.4 mg) than did patients receiving parecoxib and valdecoxib (43.2 +/- 65.7 mg) (P < 0.001). Placebo patients had higher mean pain ratings on each of study days 2-10 (P < 0.01) and reported more opioid-related symptom distress on days 2-6 (P < 0.01). Conclusions Parecoxib and valdecoxib are useful adjuncts to opioids for the treatment of postoperative pain in noncardiac surgical patients. Further study will be required to determine the safety profile of parecoxib and valdecoxib administered to patients with known atherosclerotic disease after noncardiac surgery.

An investigation of the fabrication of microporous silicon (MPS) layers as a material for the development of an electrolyte insulator semiconductor (EIS) capacitance sensor has been performed. The goal was to create a high surface area substrate for the immobilisation of biorecognition elements. Structural analysis of MPS layers as a function of key etch parameters, namely implant type (p or n), implant dose, hydrofluoric acid (HF) etch concentration and current density has been performed using scanning electron microscopy (SEM). It was possible to image porous layers with average pore diameter as low as 4 nm. n-type silicon samples had larger pore networks than p-type samples and reducing the silicon resistivity led to a reduction in the pores per μm 2 . It was found that increasing the HF etch concentration reduced the average pore diameter and increased the pores per μm 2 . Increasing the current density at which the etch was performed has the same effect. Understanding the effect of these parameters allows the MPS layer to be tuned to match specifications for optimum biocapacity. Different MPS layers were electrically characterised using capacitance–voltage and capacitance–frequency sweeps, in order to determine the effect of porosity on increases in surface area. The measured capacitance increased with increasing pores per μm 2 . p-type silicon with a boron implant in the back of the wafer, which had been etched in 25% HF in ethanol at a current density of 75 mA/cm 2 yielded the highest capacitance signal per unit area. The effect of porosity and pore size on the biocapacity of the samples was also determined. For avidin immobilisation, with pores sizes above 5 nm, as the porosity increased the biocapacity increased. MPS fabricated in p-type silicon with a front and back implant etched in 25% HF at a current density of 25 mA/cm 2 was used for the capacitance detection of synthetic oligonucleotides.

background Valdecoxib and its intravenous prodrug parecoxib are used to treat postoperative pain but may involve risk after coronary-artery bypass grafting (CABG). We conducted a randomized trial to assess the safety of these drugs after CABG. methods In this randomized, double-blind study involving 10 days of treatment and 30 days of follow-up, 1671 patients were randomly assigned to receive intravenous parecoxib for at least 3 days, followed by oral valdecoxib through day 10; intravenous placebo followed by oral valdecoxib; or placebo for 10 days. All patients had access to standard opioid medications. The primary end point was the frequency of predefined adverse events, including cardiovascular events, renal failure or dysfunction, gastroduodenal ulceration, and wound-healing complications. results As compared with the group given placebo alone, both the group given parecoxib and valdecoxib and the group given placebo and valdecoxib had a higher proportion of patients with at least one confirmed adverse event (7.4 percent in each of these two groups vs. 4.0 percent in the placebo group; risk ratio for each comparison, 1.9; 95 percent confidence interval, 1.1 to 3.2; P=0.02 for each comparison with the placebo group). In particular, cardiovascular events (including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism) were more frequent among the patients given parecoxib and valdecoxib than among those given placebo (2.0 percent vs. 0.5 percent; risk ratio, 3.7; 95 percent confidence interval, 1.0 to 13.5; P=0.03). conclusions The use of parecoxib and valdecoxib after CABG was associated with an increased incidence of cardiovascular events, arousing serious concern about the use of these drugs in such circumstances.

Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), including the cyclooxygenase-2 (COX-2) specific inhibitors, with antihypertensive medication is common practice for many patients with arthritis. This study evaluated the effects of celecoxib 200 mg/day and rofecoxib 25 mg/day on blood pressure (BP) and edema in a 6-week, randomized, parallel-group, double-blind study in patientsor =65 years of age with osteoarthritis who were treated with fixed antihypertensive regimens. One thousand ninety-two patients received study medication (celecoxib, n = 549; rofecoxib, n = 543). Significantly more patients in the rofecoxib group compared with the celecoxib group developed increased systolic BP (change20 mm Hg plus absolute valueor =140 mm Hg) at any time point (14.9% vs 6.9%, p0.01). Rofecoxib caused the greatest increase in systolic BP in patients receiving angiotensin-converting enzyme inhibitors or beta blockers, whereas those on calcium channel antagonists or diuretic monotherapy receiving either celecoxib or rofecoxib showed no significant increases in BP. Clinically significant new-onset or worsening edema associated with weight gain developed in a greater percentage of patients in the rofecoxib group (7.7%) compared with the celecoxib group (4.7%) (p0.05). Thus, in patients with controlled hypertension on a fixed antihypertensive regimen, careful monitoring of BP is warranted after the initiation of celecoxib or rofecoxib therapy.

Background: The addition of a nonsteroidal anti-inflammatory drug to the regimen of a patient with treated hypertension can cause a destabilization of blood pressure. Objective: The aim of this study was to describe physician-reported management of clinically significant edema and/or destabilized blood pressure in patients with osteoarthritis (OA) and hypertension when initiating therapy with rofecoxib or celecoxib. Methods: A cross-sectional survey was administered to physicians who attended one of several arthritis consultant programs sponsored by Pharmacia Corporation, with attendees selected by local sales representatives. Each program included a clinical presentation by a physician concerning the cardiorenal safety of celecoxib, followed by a consultative presentation and session led by a Pharmacia Clinical Education Manager. Results: A total of 828 physicians in the following specialties completed the survey: family practice (33.0%), internal medicine (25.0%), orthopedics (15.2%), and rheumatology (11.4%). Responding physicians expected that the majority of patients who experienced edema would contact them (68.4%). They reported that they schedule follow-up visits for blood pressure monitoring 65.6% of the time after initiating a cyclooxygenase-2 (COX-2)-specific inhibitor, with family practitioners and internists most likely to indicate that they would do so and orthopedists least likely. Responding physicians indicated that the presence of edema and destabilized blood pressure generally led to discontinuation of the COX-2-specific inhibitor (58%–82% of the time). Internists and family practitioners were most likely to report that they treat edema by initiating or modifying diuretic therapy (33%–51% of the time). For destabilized blood pressure, an antihypertensive drug was reported to be initiated or modified 40% to 55% of the time by family practitioners and internists, whereas orthopedists indicated that they referred patients to the primary care provider. The COX-2-specific inhibitor prescribed resulted in management differences: physicians indicated that they were more likely to switch from rofecoxib to celecoxib in the event of edema or destabilized blood pressure, whereas they were more likely to adjust the celecoxib dose than the rofecoxib dose. Because the data were captured from convenience samples of physicians attending sponsored meetings, it is possible that respondents provided the answers they thought the sponsor would want. Because this was a cross-sectional survey, reported behavior was not compared with actual behavior. Conclusions: A significant percentage of physicians reported that they monitor patients with OA and hypertension for the occurrence of destabilized blood pressure and edema after initiation of a COX-2-specific inhibitor. Physicians indicated that they would nearly always intervene when either event is identified.

Renal impairment is a risk factor for gout and a barrier to optimal gout management. We undertook this exploratory study to obtain data that have been heretofore limited regarding the safety and efficacy of febuxostat in patients with moderate-to-severe renal impairment (estimated glomerular filtration rate [GFR] 15-50 ml/minute/1.73 m(2) ).Ninety-six gout patients with moderate-to-severe renal impairment were enrolled in a 12-month multicenter, randomized, double-blind, placebo-controlled study. Patients were randomly assigned at a 1:1:1 ratio to receive 30 mg febuxostat twice daily, 40/80 mg febuxostat once daily, or placebo. The primary efficacy end point was the change in serum creatinine (Cr) level from baseline to month 12. Secondary end points included the change in estimated GFR from baseline to month 12 and the proportion of patients with a serum uric acid (UA) level of6.0 mg/dl at month 12.At month 12, there were no significant differences in the change in serum Cr level from baseline, or in the change in estimated GFR from baseline, in either febuxostat group compared to the placebo group. The proportion of patients with a serum UA level of6.0 mg/dl at month 12 was significantly greater in both febuxostat groups compared to the placebo group (both P 0.001). At least 1 treatment-emergent adverse event (TEAE) occurred in 78.1% of patients receiving 30 mg febuxostat twice daily, 87.5% of patients receiving 40/80 mg febuxostat once daily, and 78.1% of patients receiving placebo. TEAEs most frequently involved the categories of renal failure and impairment and renal function analyses.Febuxostat proved to be efficacious in serum UA reduction and was well tolerated in gout patients with moderate-to-severe renal impairment. Patients randomly assigned to receive febuxostat demonstrated significantly lower serum UA levels and no significant deterioration in renal function.

Two isoforms of cyclooxygenase (COX) have been identified, both of them inhibited by traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX-2 has been associated with the therapeutic effects of NSAIDs, whereas inhibition of COX-1 is believed to be the cause of the adverse gastrointestinal effects associated with NSAID therapy. When administered at therapeutic doses, new COX-2-specific inhibitors inhibit only the COX-2 isoform.This study sought to compare renal safety signals between the COX-2-specific inhibitors rofecoxib and celecoxib, based on spontaneous reports of adverse drug reactions (ADRs) in the World Health Organization/Uppsala Monitoring Centre (WHO/UMC) safety database through the end of the second quarter 2000.Disproportionality in the association between a particular drug and renal-related ADR was evaluated using a bayesian confidence propagation neural network method in which a statistical parameter, the information component (IC) value, was calculated for each drug-ADR combination. In this method, an IC value significantly greater than 0 implies that the association of a drug-ADR pair is stronger than background; the higher the IC value, the more the combination stands out from the background. The ratio of actual to expected numbers of ADRs was also used to assess disproportionality.As with traditional NSAIDs, both COX-2-specific inhibitors were associated with renal-related ADRs. However, the adverse renal impact of rofecoxib was significantly greater than that of celecoxib. IC values were significantly different for the following comparisons: water retention (1.97 rofecoxib vs 1.18 celecoxib; P0.01); abnormal renal function (2.38 vs 0.70; P0.01); renal failure (2.22 vs 1.09; P0.01); cardiac failure (2.39 vs 0.48; P0.01); and hypertension (2.15 vs 1.33; P0.01). In an additional analysis, celecoxib was shown to have a similar renal safety profile to that of diclofenac and ibuprofen.Based on spontaneous ADR reports in the WHO/UMC safety database at the end of the second quarter 2000, this analysis indicates that rofecoxib has significantly greater renal toxicity than celecoxib or traditional NSAIDs. This negative renal impact may have the potential to increase the risk for serious cardiac and/or cerebrovascular events.

Preexisting renal impairment is an all-encompassing risk factor for radiocontrast-associated nephrotoxicity. Renal impairment appears to be associated with the inadequate production of renal prostaglandins at the critical time of radiocontrast administration and for a variable time period afterward. We prospectively studied 130 patients with chronic renal insufficiency (serum creatinine > or =1.5 mg/dL) who were undergoing radiocontrast administration. Using a double-blind, randomized, prospective technique, patients were assigned to either placebo or one of three prostaglandin E1 (PGE1) treatment groups (10, 20, or 40 ng/kg/min). Infusion was started 60 +/- 30 minutes before the administration of radiocontrast and was continued for a total of 6 hours. In the placebo group, radiocontrast administration resulted in a mean increase (+/- SD) in serum creatinine of 0.72 +/- 1.15 mg/dL at 48 hours. This increase was less in each of the PGE1 treatment groups after 48 hours, with a significant difference between placebo and the 20 ng/kg/min PGE1 group (P = 0.01). Using baseline adjusted means, analysis of covariance with baseline serum creatinine as the covariable demonstrated significant differences between the placebo and 20 ng/kg/min PGE1 group (P = 0.03) and between the placebo and 10 ng/kg/min PGE1 group P = 0.047). In a subgroup analysis of the diabetic patients, the increase in serum creatinine was less pronounced in the three PGE1 groups versus the placebo group, and the 20 ng/kg/min PGE1 group had the most favorable outcome. The parenteral administration of PGE1 immediately before radiocontrast exposure and continued for a period of 5 to 5.5 hours significantly reduced the elevation of serum creatinine poststudy. The most effective of the three PGE1 dosing regimens was 20 ng/kg/min.

In the clinical setting of reduced renal perfusion, as seen in patients with renal, cardiac, or liver disease, dehydration, or aging kidneys, renal prostaglandin production (mediated primarily by cyclooxygenase [COX]-1 and possibly by COX-2) plays a major role in compensatory renal hemodynamics. Inhibition of the synthesis of renal prostaglandins by conventional nonsteroidal anti-inflammatory drugs (NSAIDs) may result in several nephrotoxic syndromes, including fluid and electrolyte abnormalities, acute renal failure, nephrotic syndrome, and renal papillary necrosis. Moreover, NSAIDs may adversely influence blood pressure control in treated hypertensive individuals and also may decompensate the clinical stability of diuretic-treated patients with chronic heart failure. The recently approved COX-2–specific inhibitors celecoxib and rofecoxib offer the potential for sparing homeostatic COX-1 activity in the kidney while inhibiting COX-2–mediated pain and inflammation. Emerging clinical data are helping to quantify the renal and related cardiovascular risks associated with the use of COX-2–specific versus conventional NSAIDs. Although the risk of serious toxicity associated with the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) is relatively low, nonetheless, up to approximately 5% of individuals exposed to NSAIDs may develop one or more forms of diverse “nephrotoxic” renal side effect syndromes. The number of at-risk individuals is high as a consequence of the fast consumption of these compounds either used at prescription strength or at over-the-counter dosing regimens. Hence, 500,000 to 2,500,000 individuals in the United States are estimated, on an annual basis, to potentially manifest an NSAID-related renal side-effect syndrome. The relevance of these clinical problems is particularly important in those NSAID users who become particularly “at risk” for nephrotoxic effects as a result of the clinical presence of volume-contracted states, low cardiac output, or other conditions that tend to compromise renal perfusion. The various NSAID-related renal syndromes that may become clinically apparent, after as little drug use as a single ingestion through to several weeks or months of drug consumption, will vary from the commonly encountered problems of edema formation through to the development of acute renal failure and the rare complication of acute papillary necrosis. –10 On the other hand, there are frequently encountered clinical NSAID-induced side effects that represent drug– drug– disease interactions and are manifest in treated hypertensive patients as an increase in blood pressure or seen in otherwise stable diuretic-treated individuals with chronic heart failure as a destabilization of their cardiac function. This review will summarize the known information defining the mechanisms by which these renal syndromes and related cardiovascular NSAID-induced side effects evolve and will characterize the “at-risk” NSAID consumer populations, together with approaches to the prevention and management of these diverse NSAID-related side effects. It will also summarize the currently available clinical information contrasting the development of renal and related cardiovascular NSAID-induced side effects in conventional versus COX-2–specific NSAID exposed individuals. It is clear that in conventional NSAID-treated individuals most of the nephrotoxic and related cardiovascular side effects are mediated as a result of the inhibition of renal prostaglandin synthesis.

Objective: To provide a review of the renal toxicity of disease-modifying antirheumatic drugs (DMARDs) currently used for the treatment of rheumatoid arthritis. Methods: Papers in American and European medical journals related to renal toxicity of DMARDs used for the treatment of rheumatoid arthritis were reviewed. Specific DMARDs reviewed were cyclosporine, gold, D-penicillamine, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, infliximab, and DMARD combination therapy. Results: The renal toxicity of DMARDs varies widely. Cyclosporine, gold, and D-penicillamine all have a serious potential for renal side effects, particularly in the elderly or in patients with compromised renal function. Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the potential for renal damage. In contrast, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, and infliximab have relatively little renal toxicity. Conclusions: The potential for renal toxicity should always be considered when determining which DMARD to use for RA therapy. DMARDs that combine efficacy with negligible renal adverse effects should be used for the treatment of patients susceptible to DMARD-associated renal damage. Semin Arthritis Rheum 30:196-208. Copyright © 2000 by W.B. Saunders Company

The novel cyclooxygenase- (COX)-2 inhibitor celecoxib is an effective treatment for the signs and symptoms of osteoarthritis and rheumatoid arthritis. Conventional treatment for these debilitating conditions routinely involves the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs), which are nonspecific inhibitors of COX-1 and COX-2. Numerous studies suggest that inhibition of renal prostaglandin synthesis by NSAIDs is deleterious to kidney function, particularly in high-risk patients. As celecoxib inhibits COX-2 and spares COX-1 at therapeutic doses, we hypothesized that it may offer an improved renal safety profile in patients at risk for NSAID-induced renal toxicity. This article represents a post hoc analysis of the renal safety of celecoxib, using the safety database generated during its clinical development program. This analysis includes data from more than 50 clinical studies involving more than 13,000 subjects. Most subjects were enrolled in randomized, controlled trials (of up to 12 weeks' duration); however, more than 5000 subjects received celecoxib for as long as 2 years in a long-term, open-label study at as much as twice the maximum recommended dosage. The overall incidence of renal adverse events after celecoxib was greater than that after placebo but similar to that after NSAIDs. The most common events reported after celecoxib, namely, peripheral edema (2.1%), hypertension (0.8%), and exacerbation of preexisting hypertension (0.6%), were not time- or dose-related. Peripheral edema was not associated with increased weight or blood pressure. Furthermore, there was no evidence of drug-drug interactions between celecoxib and concomitant angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, calcium channel blockers, or diuretics. We conclude that celecoxib is well tolerated by patients who may be at risk for NSAID-induced renal toxicity, such as the elderly and those with hypertension or preexisting chronic heart disease.

See related article, pp 1148–1156 Rarely in clinical medicine is it possible to define a distinct laboratory abnormality associated, for unknown reasons, with a specific disease entity and to have one group of tenacious investigators resolve the conundrum of contributing mechanisms. Nonetheless, in this issue of Hypertension such is the case as presented in the investigations of Soletsky and Feig.1 These investigators have now contributed to a decade or more of animal and human investigation by Feig and Johnson and their coworkers by unraveling the major mechanism that links hyperuricemia to hypertension. This has been a long-standing clinical and basic science quest.2 Gout, as the long-term manifestation of hyperuricemia, is a metabolic disease process that has been known from antiquity. Egyptian physicians described the disease some 5000 years ago followed by the astute clinical characterization of the disease, in the fifth century BC, by the Greek physician Hippocrates, as “the unwalkable disease.”3 By the mid-1800s AD Sir Alfred Baring Garod identified that uric acid was the cause of gout and not a consequence of the disease. In addition, this also coincided with the time framework in which several investigators speculated on the linkage of hyperuricemia to the presence of hypertension. However, it was not until the contemporary studies of Feig and Johnson and colleagues that we learned that, in animal models, acute elevation of serum urate induces a prompt elevation of blood pressure and that chronic elevation sustains the abnormal pressure and induces irreversible vascular and glomerular changes that lead to a form of salt-sensitive hypertension.4,5 Hence, the lesson learned from the animal investigations suggested that, in humans, early treatment to reduce hyperuricemia associated with increases in blood pressure might be successful, whereas the years of hyperuricemia attendant with the emergence of gout and …

In this double-blind, 6-week study comparing once-daily oral betaxolol and atenolol, the study design allowed the effects of simulated drug noncompliance to be examined. Overall similar blood pressure and heart rate responses were seen in 114 patients with mild-to-moderate hypertension. Similarly, there was no statistically significant difference in percentage of patients achieving goal diastolic blood pressure reductions at the end of 6 weeks of active therapy (betaxolol, 87%, 46/53; atenolol, 82%, 44/54), and safety results overall were similar. However, when patients randomly received placebo for two consecutive treatment days in either the fifth or sixth week of the study to simulate the effect of missing doses, magnitude and duration of effect on systolic blood pressure (p = 0.006), diastolic blood pressure (p = 0.02) and heart rate (p = 0.001) were significantly greater for betaxolol than atenolol as calculated from 28-h ambulatory blood pressure monitoring data. Although betaxolol and atenolol monotherapy are equally effective in controlling blood pressure when taken consistently, the blood pressure and heart rate response with betaxolol is significantly superior for at least 24 h after missing a dose, an important consideration related to patient noncompliance. These results are compatible with the different elimination half-lives of each drug.

Background: Desirudin, a bivalent direct thrombin inhibitor (DTI), is approved by the US Food and Drug Administration for the prevention of deep vein thrombosis, which may lead to pulmonary embolism, in patients undergoing elective hip replacement surgery. It became available in the United States in March 2010. Objective: The goal of the present article was to provide an overview of the rationale and design of the PREVENT-HIT study, a randomized, prospective, openlabel, active drug-controlled, exploratory trial comparing the clinical and economic utility of desirudin versus argatroban in patients with suspected heparin-induced thrombocytopenia (HIT), with or without thrombosis. Summary: The PREVENT-HIT study was designed to enroll ∼120 patients from 20 to 25 US centers. All eligible patients were required to be aged ≥18 years. Patients with suspected HIT with or without thrombosis were divided into 2 treatment arms and randomized to receive treatment with desirudin or argatroban in a 1:1 ratio using a block randomization method. Arm A comprised patients who were naive to DTI therapy; arm B included patients whose condition was previously stabilized with intravenous argatroban. Desirudin was administered as a fixed-dose injection (15 or 30 mg SC q12h in patients without or with thrombosis, respectively). Argatroban was administered by continuous intravenous infusion in accordance with approved prescribing information or institutional prescribing guidelines at each study site. The primary efficacy outcome measure included the occurrence of any of the following up to 30 days after study drug discontinuation: new-onset or worsening thrombosis requiring discontinuation of study drug; amputation; or all-cause mortality. Other outcomes that were assessed included platelet recovery, bleeding, and pharmacoeconomic parameters. In addition, adverse events and other safety parameters were evaluated. Study enrollment began in November 2008 and ended in December 2009 due to slow enrollment (N = 16). The study results will be published separately. Conclusion: The results from the PREVENT-HIT study should enhance understanding of the comparative clinical and economic utility of desirudin and argatroban in patients with HIT with or without thrombosis.

A new polymeric matrix technology provides a sustained-release formulation of diltiazem hydrochloride (diltiazem SR) suitable for once-daily therapy. The efficacy and safety of diltiazem SR were evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. After a single-blind, placebo lead-in period, 275 patients with mild to moderate essential hypertension were assigned to receive placebo or diltiazem SR 120, 240, 360, or 480 mg once daily for 4 weeks. The efficacy evaluation was based on office and 24-hour ambulatory blood pressure monitoring. Twenty-four hours after the last dose in the 4-week, double-blind treatment period, the mean reduction from baseline in supine diastolic blood pressure ranged from 5.1 to 10.6 mm Hg in the diltiazem SR 120- to 480-mg groups, resulting in a significant linear trend across all treatments (P less than .001). Reductions in systolic blood pressure were similar. Ambulatory blood pressure monitoring, performed in 138 patients, confirmed the dose-response relationship and showed consistent antihypertensive activity throughout the 24-hour dosing interval. The percentage of patients reporting adverse events was similar in the placebo- and active-treated groups. The results of this study indicate that diltiazem SR is well tolerated, lowers blood pressure in a dose-related manner, and provides sustained activity throughout the 24-hour dosing interval.

Introduction ___________________________________________________________ 419 Prostaglandins and renal function __________________________________________ 420 The prostaglandin pathway 420 Renal prostanoid receptors 421 Cyclooxygenase isoforms _________________________________________________ 422 Factors regulating isoform expression 422 Distribution within the kidney 422 Mechanism of action of NSAIDs ____________________________________________ 422 Renal syndromes associated with NSAIDs ____________________________________ 423 Acute deterioration of renal function 424 Salt and water retention 428 The concept of “renal sparing” NSAIDs 430 Nephrotic syndrome with interstitial nephritis 431 Chronic renal failure/papillary necrosis 432 Other NSAID-induced renal syndromes 434 Renal effects of COX-2 inhibitors ___________________________________________ 435 Effects on renal function: GFR/urinary sodium excretion 435 Incidence of adverse cardio-renal events 436 Concurrent use of an oral synthetic prostaglandin analog with a NSAID ___________ 444 Conclusions and future challenges _________________________________________ 445 References _____________________________________________________________ 449

Le suivi du rythme circadien des parametres cardiovasculaires peut se faire a l'aide de methodes invasives et non invasives. Les avantages et les inconvenients des deux types d'approche sont presentes. Ces etudes mettent en evidence des periodes a risques durant la journee et devrait permettre d'optimiser les traitements de l'hypertension

Background and objectives This study was design to compare the diuretic and natriuretic effects of the 2 parenteral formulations of metolazone and the combination of these 2 formulations of metolazone with the parenteral administration of furosemide. Metolazone is an anthracrene acid derivate and manifests a dual diuretic effect on the proximal and distal tubule with a minimal kaluretic effect. It is currently only marketed in an orally administrable formulation, and this has limited its utility in critically ill patients. Metolazone given orally and furosemide given orally or parenterally are frequently administrated together when furosemide alone is clinically inadequate at producing a desired diuresis. Methods Sprague Dawley male rats (400 to 450 g) were divided into groups to receive a parenteral formulation of metolazone or furosemide administrated separately intraperitoneally (IP) or administrated IP in combination with one another. Tris buffer-administered IP was used as a control vehicle comparator. The urine volume voided over the following 24 hours was collected, measured and analyzed for sodium content. Results Vehicle (Tris buffer) caused 9 +/- 1 mL/d output of urine with a sodium [Na+] concentration of 194 +/- 41 micromol/L (n=6 per group). Metolazone 2 mg/kg resulted in 16 +/- 3 mL/d urine output and sodium [Na+] of 278 +/- 76 micromol/L (n=6 per group). Furosemide 2, 4, and 6 mg/kg resulted in a volume of urine 9 +/- 1, 14 +/- 2 and 17 +/- 2 mL/d and [Na+] micromol/L of 194 +/- 41, 206 +/- 108, and 229 +/- 91, respectively. Metolazone 4 mg/kg combined with furosemide 4 mg/kg resulted in a urine volume of 21 +/- 1 mL/d and [Na+] of 326 +/- 108 micromol/L. Conclusion Combining metolazone and furosemide can cause an increase in urine volume and sodium excretion. Metolazone administrated parenterally in combination with the parenteral administration of furosemide appears to have an important clinical potential.

The cardiorenal safety database from the Celecoxib Long-term Arthritis Safety Study (CLASS) was analyzed to examine whether supratherapeutic doses of celecoxib are associated with decreased renal function and blood pressure (BP) effects compared with standard doses of diclofenac and ibuprofen in osteoarthritis (OA) and rheumatoid arthritis (RA) patients.In total, 8059 patients were enrolled; 7968 received at least one dose of study drug (RA: N = 2183; OA: N = 5785). Patients received celecoxib, 400 mg twice a day (b.i.d.). (N = 3987); ibuprofen, 800 mg three times a day. (N = 1985); or diclofenac, 75 mg b.i.d. (N = 1996). Effects measured included: investigator-reported hypertension, edema or congestive heart failure, clinically important BP elevations, incidence of patients starting new antihypertensive medication, and increases in serum creatinine or reductions in creatinine clearance. Celecoxib was associated with a similar incidence of hypertension or edema to diclofenac but significantly lower than ibuprofen. The celecoxib group had significantly fewer initiations of antihypertensives versus ibuprofen. Systolic BP increases of20 mmHg and above 140 mmHg occurred significantly less often with celecoxib compared with ibuprofen or diclofenac. Changes in serum creatinine or estimated creatinine clearance occurred in a similar percentage of patients taking celecoxib or ibuprofen; modest differences were evident against diclofenac. In patients with mild prerenal azotemia, significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.7%), compared with diclofenac (7.3%; P0.05) and ibuprofen (7.3%; P0.05). A supratherapeutic dose of celecoxib was associated with an improved cardiorenal safety profile compared with standard doses of either ibuprofen or diclofenac.

Nonopioid analgesics, which include acetaminophen, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2)–specific inhibitors (coxibs), are frequently used for the relief of mild-to-moderate pain. Although all of these agents are effective at controlling pain, inhibition of prostaglandins (PGs) by NSAIDs may result in untoward cardiorenal effects, including hypertension, fluid and electrolyte abnormalities, congestive heart failure, acute renal failure, and nephrotic syndrome. Individuals with an increased risk for cardiorenal effects from NSAIDs (eg, the elderly, and those with hypertension, cardiac disease, or gouty nephropathy) should be monitored for early onset of edema, destabilization of blood pressure control, and/or onset of congestive heart failure when started on NSAID therapy. Because acetaminophen has a different mechanism of action from the conventional NSAIDs, it does not inhibit peripheral PGs at recommended dosing and therefore appears to have a more favorable cardiovascular and gastrointestinal safety profile. This review discusses the effects of acetaminophen, traditional NSAIDs, and coxibs on fluid and electrolytes, blood pressure, congestive heart failure, and renal function, as well as their consequences in patients with or at risk for cardiovascular disease (CVD). It also summarizes information on the mechanisms by which NSAID-induced cardiovascular adverse events develop, and it provides recommendations for the use of nonopioid analgesics for relief of mild-to-moderate pain in patients with or at risk for CVD.

There have been concerns that the risk of cardiovascular thrombotic events may be higher with cyclooxygenase (COX)-2-specific inhibitors than nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We evaluated cardiovascular event data for valdecoxib, a new COX-2-specific inhibitor in approximately 8000 patients with osteoarthritis and rheumatoid arthritis treated with this agent in randomized clinical trials. The incidence of cardiovascular thrombotic events (cardiac, cerebrovascular and peripheral vascular, or arterial thrombotic) was determined by analyzing pooled valdecoxib (10-80 mg daily), nonselective NSAID (diclofenac 75 mg bid, ibuprofen 800 mg tid, or naproxen 500 mg bid) and placebo data from 10 randomized osteoarthritis and rheumatoid arthritis trials that were 6-52 weeks in duration. The incidence rates of events were determined in all patients (n = 7934) and in users of low-dose (or =325 mg daily) aspirin (n = 1051) and nonusers of aspirin (n = 6883). Crude and exposure-adjusted incidences of thrombotic events were similar for valdecoxib, NSAIDs, and placebo. The risk of serious thrombotic events was also similar for each valdecoxib dose. Thrombotic risk was consistently higher for users of aspirin users than nonusers of aspirin (placebo, 1.4% vs. 0%; valdecoxib, 1.7% vs. 0.2%; NSAIDs, 1.9% vs. 0.5%). The rates of events in users of aspirin were similar for all 3 treatment groups and across valdecoxib doses. Short- and intermediate-term treatment with therapeutic (10 or 20 mg daily) and supratherapeutic (40 or 80 mg daily) valdecoxib doses was not associated with an increased incidence of thrombotic events relative to nonselective NSAIDs or placebo in osteoarthritis and rheumatoid arthritis patients in controlled clinical trials.

Recent studies have investigated the renal and cardiovascular safety of celecoxib and rofecoxib. Both agents have been studied in long-term safety trials: the Celecoxib Long-Term Safety Study (CLASS) and Vioxx Gastrointestinal Outcomes Research Study (VIGOR). Renal safety was investigated in CLASS and the results indicated that celecoxib (even at the supratherapeutic 800 mg daily doses used in CLASS) is associated with lower rates of renal side effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). The renal safety of celecoxib was also assessed in healthy elderly subjects. In these subjects, celecoxib administration was associated with minimal effects on glomerular filtration rate compared with naproxen, while urinary sodium and prostaglandin E2 excretion were similar. Celecoxib and rofecoxib were compared with each other in two studies of elderly hypertensive patients with osteoarthritis (OA). These patients were treated with usual therapeutic doses of celecoxib (200 mg daily) or rofecoxib (25 mg daily). In the first study, celecoxib treatment had a significantly lower incidence of peripheral oedema than rofecoxib (4.9% versus 9.5%, P = 0.014). The second study confirmed the results of the initial study: the incidence of oedema was again lower with celecoxib than with rofecoxib (4.7% versus 7.7%, P0.05). Rofecoxib use was also associated with significantly greater mean and clinically relevant increases in systolic blood pressure than celecoxib. The CLASS study, which evaluated cardiovascular safety, showed that celecoxib treatment was not associated with an increase in myocardial infarction (MI) compared with non-selective NSAIDs (incidence in all patients was 0.3% for celecoxib and 0.3% for conventional NSAIDs). In a 12-week study of celecoxib (the Successive Celecoxib Efficacy and Safety Studies, SUCCESS-1) in more than 13000 patients with OA, combined doses of celecoxib (200 mg and 400 mg daily) and conventional NSAIDs (naproxen 1000 mg daily and diclofenac 100 mg daily) were again associated with similar rates of cardiovascular adverse events, including MI. However, in the VIGOR trial, treatment with rofecoxib was associated with a significantly higher rate of MI compared with naproxen (0.4% compared with 0.1% in the naproxen group, P0.05). In summary, celecoxib may have safety and tolerability advantages compared with non-selective NSAIDs studied and may have some cardiorenal benefits compared with rofecoxib.

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).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.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.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.

To determine the costs of heart failure in hypertensive patients receiving celecoxib, rofecoxib, and nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs) in clinical practice.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.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.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.

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.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.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.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.