Risk Factors for Major Adverse Cardiovascular Events in Phase III and Long-Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis.

OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). This study was undertaken to evaluate the risk of major adverse cardiovascular events (MACE) in patients with RA receiving tofacitinib. METHODS: Data were pooled from patients with moderately to severely active RA receiving ≥1 tofacitinib dose in 6 phase III and 2 long-term extension studies over 7 years. MACE (myocardial infarction, stroke, cardiovascular death) were independently adjudicated. Cox regression models were used to evaluate associations between baseline variables and time to first MACE. Following 24 weeks of tofacitinib, changes in variables and time to future MACE were evaluated after adjusment for age, baseline values, and time-varying tofacitinib dose. Hazard ratios and 95% confidence intervals were calculated. RESULTS: Fifty-two MACE occurred in 4,076 patients over 12,873 patient-years of exposure (incidence rate 0.4 patients with events per 100 patient-years). In univariable analyses of baseline variables, traditional cardiovascular risk factors and glucocorticoid and statin use were associated with MACE risk; disease activity and inflammation measures were not. In subsequent multivariable analyses, baseline age, hypertension, and the total cholesterol to high-density lipoprotein (HDL) cholesterol ratio remained significantly associated with risk of MACE. After 24 weeks of treatment, an increase in HDL cholesterol and a decrease in the total to HDL cholesterol were associated with decreased MACE risk; changes in total cholesterol, low-density lipoprotein (LDL) cholesterol, and disease activity measures were not. Increased erythrocyte sedimentation rates trended with increased future MACE risk. CONCLUSION: In this post hoc analysis, after 24 weeks of tofacitinib treatment, increased HDL cholesterol, but not increased LDL cholesterol or total cholesterol, appeared to be associated with lower future MACE risk. Further data are needed to test the cardiovascular safety of tofacitinib.

Efficacy and Safety of Tofacitinib in Chinese Patients with Rheumatoid Arthritis.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies. METHODS: ORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout. RESULTS: ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population. CONCLUSIONS: Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population. CLINICAL TRIAL IDENTIFIER: NCT00856544 and NCT00413699.

Sildenafil improves renal function in patients with pulmonary arterial hypertension.

AIM: Elevated serum creatinine (sCr) and low estimated glomerular filtration rate (eGFR) are associated with poor outcomes in patients with pulmonary arterial hypertension (PAH) whereas sildenafil treatment improves PAH outcomes. This post hoc analysis assessed the effect of sildenafil on kidney function and links with clinical outcomes including 6-min walk distance, functional class, time to clinical worsening and survival. METHODS: Patients with PAH received placebo or sildenafil 20, 40 or 80 mg three times daily in the SUPER-1 study and open-label sildenafil titrated to 80 mg three times daily (as tolerated) in the extension study. RESULTS: Baseline characteristics were similar among groups (n = 277). PAH was mostly idiopathic (63%) and functional class II (39%) or III (58%). From baseline to week 12, kidney function improved (increased eGFR, decreased sCr) with sildenafil and worsened with placebo. In univariate logistic regression, improved kidney function was associated with significantly improved exercise and functional class (odds ratios 1.17 [95% CI 1.01, 1.36] and 1.21 [95% CI 1.03, 1.41], respectively, for sCr and 0.97 [95% CI 0.94, 0.99] and 0.97 [95% CI 0.94, 0.99] for eGFR, all P < 0.05). In patients who maintained or improved kidney function, time to worsening was significantly delayed (P < 0.02 for both kidney parameters). Observed trends towards improved survival were not significant. Patients with eGFR <60 (vs. ≥60) ml min(-1) 1.73 m(-2) appeared to have worse survival. CONCLUSIONS: Sildenafil treatment was associated with improved kidney function in patients with PAH, which was in turn associated with improved exercise capacity and functional class, a reduced risk of clinical worsening, and a trend towards reduced mortality.

Endothelin antagonism and uric acid levels in pulmonary arterial hypertension: clinical associations.

BACKGROUND: Elevated serum uric acid is detected in pulmonary arterial hypertension (PAH) and is associated with poor patient outcomes. High serum uric acid is an independent risk factor for cardiovascular disease and renal impairment. We analyzed the effects of endothelin receptor antagonism on serum uric acid in PAH patients participating in the Sitaxentan to Relieve Impaired Exercise (STRIDE)-2/2X trial, and the impact of uric acid on 6-minute walk distance (6MWD), time to clinical worsening (TtCW) and survival. METHODS: In the 18-week, double-blind, placebo-controlled STRIDE-2 trial, 246 PAH patients were randomized and received matched placebo, sitaxentan 50 or 100 mg orally once daily, or open-label bosentan 125 mg twice daily. STRIDE-2X was a 1-year, open-label extension of STRIDE-2. RESULTS: Baseline serum uric acid was similar between groups. Increased serum uric acid was a significant risk factor for 1-year mortality and TtCW. Compared with placebo, sitaxentan 50 and 100 mg and bosentan all reduced serum uric acid (p < 0.05). Reduced serum uric acid correlated with increased 6MWD (p = 0.0037). CONCLUSIONS: Endothelin receptor antagonism reduces serum uric acid in PAH patients, and this reduction is associated with improved survival and longer TtCW. Further prospective studies are needed to investigate the pathogenic role of serum uric acid in PAH and its prognostic potential.

Assessment of measurement properties of peak VO(2) in children with pulmonary arterial hypertension.

BACKGROUND: The 6-minute walk test evaluates the effect of pharmacologic intervention in adults with pulmonary arterial hypertension (PAH) but, for reasons of compliance or reliability, may not be appropriate for children at all ages. Thus, peak oxygen consumption (VO2, maximal exercise test) was used instead in a pediatric PAH trial (STARTS-1) to evaluate pharmacologic intervention with sildenafil. This was the first large placebo-controlled trial to use the peak VO2 endpoint in this population. Our working hypothesis was that, as with other populations, percentage changes in peak VO2 in pediatric patients with PAH are reliable and are associated with changes in other clinical endpoints. METHODS: Using data from the subpopulation of 106 patients who were developmentally and physically able to perform exercise testing, all of whom were World Health Organization Functional Class (WHO FC) I, II, or III, reliability was assessed using the intraclass correlation coefficient and Bland-Altman plot on screening and baseline data. Relationships between percentage change in peak VO2 from baseline to end of treatment and other endpoints were evaluated using correlation coefficients and regression analyses. RESULTS: The intraclass correlation was 0.79 between screening and baseline peak VO2, an agreement that was supported by the Bland-Altman plot. Percentage change in peak VO2 correlated well (r ≥0.40) and showed responsiveness to a physician global assessment of change and with change in WHO FC (for baseline classes I and III). Percentage change in peak VO2 did not correlate with change in the Family Cohesion of the Child Health Questionnaire (r = 0.04) or with a subject global assessment of change (r = 0.12). The latter may have been influenced by child and parental-proxy response and instrument administration. CONCLUSION: In pediatric PAH patients who are developmentally and physically able to perform exercise testing, peak VO2 measurements exhibited good reliability and improvements that were associated with improvements in certain other clinical endpoints, such as the WHO FC and a physician global assessment. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00159913.

Ocular safety of sildenafil citrate when administered chronically for pulmonary arterial hypertension: results from phase III, randomised, double masked, placebo controlled trial and open label extension.

OBJECTIVE: To assess the ocular effects and safety profile of chronic sildenafil oral dosing in patients with pulmonary arterial hypertension. DESIGN: 12 week, double masked, randomised, placebo controlled, phase III trial with open label extension. SETTING: 53 institutions worldwide. PARTICIPANTS: 277 adults with idiopathic pulmonary arterial hypertension or pulmonary arterial hypertension associated with connective tissue disease or after congenital heart disease repair (mean pulmonary artery pressure ≥25 mm Hg; pulmonary capillary wedge pressure ≤15 mm Hg at rest). INTERVENTIONS: During the double masked study, oral sildenafil 20 mg, 40 mg, or 80 mg or placebo (1:1:1:1) three times daily for 12 weeks was added to baseline drug treatment. In the extension study, the placebo, 20 mg and 40 mg groups received 40 mg three times daily titrated to 80 mg three times daily at week 6. After unmasking, the dose was titrated according to clinical need. MAIN OUTCOME MEASURE: Ocular safety (ocular examinations, visual function tests, participants' reports of adverse events, and visual disturbance questionnaire completed by investigators) by treatment group at 12 weeks, 24 weeks, 18 months, and yearly. RESULTS: Findings of the objective assessments-that is, intraocular pressure and visual function tests (visual acuity, colour vision, and visual field)-were similar across groups (20 mg, n=69; 40 mg, n=67; 80 mg, n=71; placebo, n=70). No clinically significant changes occurred between baseline and 12 weeks, except for an efficacy signal in contrast sensitivity for the sildenafil 40 mg three times daily group. In right eyes, changes in intraocular pressure from baseline to week 12 ranged from a mean of -0.5 (95% confidence interval -1.3 to 0.2) mm Hg with placebo, -0.2 (-0.9 to 0.5) mm Hg with sildenafil 40 mg, and -0.1 (-0.7 to 0.5) mm Hg with 80 mg to 0.3 (-0.4 to 0.9) mm Hg with sildenafil 20 mg (the approved dose for pulmonary arterial hypertension). Mean changes from baseline to week 12 in contrast sensitivity in right eyes were -0.02 (SD 0.12) in the sildenafil 20 mg three times daily group compared with -0.05 (0.18) in the placebo group (P=0.044). Percentages of participants with deterioration in visual acuity (Snellen) from baseline to week 12 ranged from 10% (n=7) in the placebo group to 3% (n=2) in the sildenafil 20 mg three times daily group; the same percentages had visual field changes from normal to abnormal during the period in these two groups. The investigators did not deem any findings on colour vision assessment to be clinically significant. Findings of the objective assessments in the 40 mg and 80 mg three times daily sildenafil treatment groups and in left eyes were not substantially different, nor were any measures different throughout the open label extension compared with week 12. However, objective data were limited after month 18, as most participants had missing data or visual parameters were no longer collected by investigators. Incidence of ocular adverse events reported on the case report forms and assessed by the investigator was low with all doses, but a modest, dose related incidence of chromatopsia, cyanopsia, photophobia, and visual disturbance was reported with 80 mg three times daily consistent with the indicated dosing for erectile dysfunction. Retinal haemorrhages, captured on funduscopy, occurred in 2% (4/207) of sildenafil treated participants and none in the placebo group during the double masked study and in 4% (10/259) during the open label extension. CONCLUSIONS: Sildenafil dosing up to 80 mg three times daily is safe and well tolerated from an ocular perspective in patients with pulmonary arterial hypertension. Daily chronic dosing in this patient population was not associated with visual change and had no detrimental effect on best corrected visual acuity, contrast sensitivity, colour vision, or visual field, or on slit lamp examinations, funduscopy, or intraocular pressure during the duration of this study. TRIAL REGISTRATION: Clinical trials NCT00644605 and NCT00159887.

Safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension.

OBJECTIVE: To assess safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension (PAH). BACKGROUND: Sitaxsentan is a highly selective endothelin-A receptor antagonist that was recently withdrawn by the manufacturer because of a pattern of idiosyncratic liver injury. METHODS: Before sitaxsentan withdrawal, this 18-week double-blind, placebo-controlled study randomized patients with PAH to receive placebo or sitaxsentan 50 or 100 mg once daily. The primary efficacy endpoint was change from baseline in 6-min walk distance (6MWD) at week 18. Changes in World Health Organization (WHO) functional class and time to clinical worsening (TTCW) were secondary endpoints. The primary efficacy analysis was powered for sitaxsentan 100 mg versus placebo. RESULTS: Of 98 randomized patients, 61% were WHO functional class II at baseline. Improvement from baseline to week 18 in 6MWD occurred with sitaxsentan 100 but not 50 mg; a strong placebo effect was observed. At week 18, WHO functional class was improved or maintained in more patients receiving sitaxsentan 100 mg than placebo (P = 0.038); 0% versus 12% of patients deteriorated, respectively. TTCW was not significantly different for 100-mg sitaxsentan patients than placebo (P = 0.090). Adverse events (AEs) occurring more frequently with sitaxsentan (50 or 100 mg) included headache, peripheral edema, dizziness, nausea, extremity pain, and fatigue; most AEs were of mild or moderate severity. CONCLUSION: Sitaxsentan 100 mg improved functional class but not 6MWD in PAH patients who were mostly WHO functional class II at baseline. No patient receiving sitaxsentan 100 mg experienced clinical worsening; sitaxsentan was well tolerated.

The role of benzalkonium chloride in the occurrence of punctate keratitis: a meta-analysis of randomized, controlled clinical trials.

BACKGROUND: Benzalkonium chloride (BAK), the most commonly used preservative in topical ophthalmic solutions, has undergone considerable criticism in recent years, principally based on in vitro and in vivo studies. Relevance to the clinical setting has not been confirmed. OBJECTIVE: To determine whether administration of twice the amount of BAK was associated with an increased incidence of punctate keratitis in long-term, double-masked trials comparing latanoprost ophthalmic solution and vehicle with timolol ophthalmic solution in patients with glaucoma or ocular hypertension. METHODS: A meta-analysis of the double-masked phases of 7 prospective, controlled clinical trials compared the incidence of punctate keratitis among patients assigned to treatment with latanoprost or timolol. In all studies, the amount of BAK administered daily in the latanoprost arms was approximately twice the amount used in the timolol arms. All reports of punctate keratitis either as a finding or an adverse event were included. A fixed-effect model was used because the heterogeneity was small and not statistically significant. Sensitivity analyses were conducted. Funnel plots were provided to address potential publication bias. RESULTS: Of the 1694 patients enrolled in the double-masked portion of the trials (latanoprost, n = 892; timolol, n = 802), the overall incidence of punctate keratitis was 6.3% (106/1694). The incidence in latanoprost-treated patients was 6.5% and in timolol-treated patients was 6.0%. The risk difference for punctate keratitis of latanoprost versus timolol was 0.005 (95% CI -0.011 to 0.020; p = 0.574), and the risk ratio of latanoprost versus timolol was 1.084 (95% CI 0.739 to 1.589; p = 0.680). CONCLUSIONS: These results indicate that BAK does not produce significant corneal toxicity in the vast majority of patients with glaucoma or ocular hypertension at the concentrations used in these studies.

Assessing the efficacy of latanoprost vs timolol using an alternate efficacy parameter: the intervisit intraocular pressure range.

PURPOSE: To compare latanoprost and timolol with regard to changes in the intervisit intraocular pressure (IOP) range, a measure of long-term IOP fluctuation. DESIGN: Post hoc analysis of three 6-month, multicenter, randomized (1:1), double-masked registration trials of latanoprost (n = 313) vs timolol (n = 318). METHODS: Analyses included patients with glaucoma or ocular hypertension who instilled latanoprost once daily in the evening and vehicle in the morning and those instilling timolol twice daily. Pretreatment intervisit IOP range: highest IOP minus lowest IOP of 4 measurements obtained at screening and baseline. Posttreatment intervisit IOP range: highest IOP minus lowest IOP of 4 measurements obtained at weeks 18 and 26. Ranges were dichotomized to high (> 6 mm Hg) and low (< or = 6 mm Hg). RESULTS: Both treatments resulted in significant reductions in mean intervisit IOP range during 26 weeks. Pretreatment, comparable proportions of patients treated with latanoprost and timolol had high intervisit IOP ranges (22% [70/313] and 23% [72/318], respectively; P = .934). After treatment, 6% (19/313) and 11% (35/318) of patients in the latanoprost and timolol groups, respectively, had high intervisit IOP ranges (P = .026). Significant risk factors for high posttreatment intervisit range (multivariate logistic regression) were high pretreatment intervisit IOP range, treatment with timolol, Black race, longer time since diagnosis, and higher mean pretreatment IOP. CONCLUSIONS: Compared with timolol, treatment with latanoprost results in significantly fewer patients with a high IOP fluctuation. The impact of reducing high IOP fluctuation on progressive glaucomatous damage deserves further investigation in prospective studies.

Inter-visit intraocular pressure range: an alternative parameter for assessing intraocular pressure control in clinical trials.

PURPOSE: To evaluate whether inter-visit intraocular pressure (IOP) range, which reflects extreme and potentially damaging IOP fluctuations, provides additional information on IOP control compared to mean IOP. DESIGN: Post hoc analysis of Xalatan/Lumigan/Travatan study data, a masked-evaluator, randomized, parallel-group comparison of 12-week efficacy of latanoprost, bimatoprost, and travoprost in open-angle glaucoma/ocular hypertension patients. METHODS: Pretreatment inter-visit IOP range defined as highest IOP minus lowest IOP at screening, safety check, and baseline (six measurements); posttreatment inter-visit IOP range defined as highest IOP minus lowest IOP at weeks two, six, and 12 or early termination (nine measurements). Ranges dichotomized as "high" (>6 mm Hg) vs "low" (< or =6 mm Hg). RESULTS: Included were 410 patients (latanoprost, 136; bimatoprost, 136; travoprost, 138). Each resulted in significant mean IOP range reductions during 12 weeks. Pretreatment inter-visit IOP range was associated with African-American race, male gender, and presence of visual field defect (P < .05 for all). Percentages with high pretreatment inter-visit IOP ranges were comparable across treatments (63% to 64%). High posttreatment inter-visit IOP range was seen in 21% (28/136), 28% (38/136), and 36% (50/138) of latanoprost, bimatoprost, and travoprost groups, respectively (P = .016, overall; P = .005, latanoprost vs travoprost). High posttreatment inter-visit IOP range was associated with African-American race, high pretreatment inter-visit IOP range, and treatment with travoprost vs latanoprost (P < .05 for all). CONCLUSIONS: Given that high inter-visit IOP range is associated with risk factors for glaucomatous damage and that such differences cannot be evaluated using mean IOPs, inter-visit IOP range may be another useful approach to assessing IOP control in clinical trials.