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Allan D Struthers - One of the best experts on this subject based on the ideXlab platform.

  • Allopurinol reduces left ventricular mass in patients with type 2 diabetes and left ventricular hypertrophy
    Journal of the American College of Cardiology, 2013
    Co-Authors: Benjamin R Szwejkowski, Jacob George, Chim C Lang, Sushma Rekhraj, Stephen J Gandy, J G Houston, Andrew D Morris, Allan D Struthers
    Abstract:

    Objectives This study sought to ascertain whether high-dose Allopurinol causes regression of left ventricular mass (LVM) in patients with type 2 diabetes mellitus (T2DM). Background Left ventricular hypertrophy (LVH) is common in T2DM and contributes to patients9 high cardiovascular (CV) event rate. Oxidative stress (OS) has been implicated in LVH development, and Allopurinol has been previously shown to reduce vascular OS. We therefore investigated whether Allopurinol causes regression of LVH in patients with T2DM. Methods We conducted a randomized, double-blind, placebo-controlled study of 66 optimally-treated T2DM patients with echocardiographic evidence of LVH. Allopurinol, 600 mg/day, or placebo was given over the study period of 9 months. The primary outcome was reduction in LVM as calculated by cardiac magnetic resonance imaging at baseline and at 9 months9 follow-up. Secondary endpoints were change in flow-mediated dilation and augmentation index. Results Allopurinol significantly reduced absolute LVM (−2.65 ± 5.91 g vs. placebo group +1.21 ± 5.10 g [p = 0.012]) and LVM indexed to body surface area (−1.32 ± 2.84 g/m2 vs. placebo group +0.65 ± 3.07 g/m2 [p = 0.017]). No significant changes were seen in either flow-mediated dilation or augmentation index. Conclusions Allopurinol causes regression of LVM in patients with T2DM and LVH. Regression of LVH has been shown previously to improve CV mortality and morbidity. Therefore, Allopurinol therapy may become useful to reduce CV events in T2DM patients with LVH. (Allopurinol in Patients with Diabetes and LVH; UKCRN 8766)

  • high dose Allopurinol reduces left ventricular mass in patients with ischemic heart disease
    Journal of the American College of Cardiology, 2013
    Co-Authors: Sushma Rekhraj, Jacob George, Chim C Lang, Stephen J Gandy, Benjamin R Szwejkowski, Adnan M Nadir, Awsan Noman, Graeme J Houston, Allan D Struthers
    Abstract:

    Objectives This study sought to ascertain if high-dose Allopurinol regresses left ventricular mass (LVM) in patients with ischemic heart disease (IHD). Background LV hypertrophy (LVH) is common in patients with IHD including normotensive patients. Allopurinol, a xanthine oxidase inhibitor, has been shown to reduce LV afterload in IHD and may therefore also regress LVH. Methods A randomized, double-blind, placebo-controlled, parallel group study was conducted in 66 patients with IHD and LVH, comparing 600 mg/day Allopurinol versus placebo therapy for 9 months. The primary outcome measure was change in LVM, assessed by cardiac magnetic resonance imaging (CMR). Secondary outcome measures were changes in LV volumes by CMR, changes in endothelial function by flow-mediated dilation (FMD), and arterial stiffness by applanation tonometry. Results Compared to placebo, Allopurinol significantly reduced LVM (Allopurinol −5.2 ± 5.8 g vs. placebo −1.3 ± 4.48 g; p = 0.007) and LVM index (LVMI) (Allopurinol −2.2 ± 2.78 g/m2 vs. placebo −0.53 ± 2.5 g/m2; p = 0.023). The absolute mean difference between groups for change in LVM and LVMI was −3.89 g (95% confidence interval: −1.1 to −6.7) and −1.67 g/m2 (95% confidence interval: −0.23 to −3.1), respectively. Allopurinol also reduced LV end-systolic volume (Allopurinol −2.81 ± 7.8 mls vs. placebo +1.3 ± 7.22 mls; p = 0.047), improved FMD (Allopurinol +0.82 ± 1.8% vs. placebo −0.69 ± 2.8%; p = 0.017) and augmentation index (Allopurinol −2.8 ± 5.1% vs. placebo +0.9 ± 7%; p = 0.02). Conclusions High-dose Allopurinol regresses LVH, reduces LV end-systolic volume, and improves endothelial function in patients with IHD and LVH. This raises the possibility that Allopurinol might reduce future cardiovascular events and mortality in these patients. (Does a Drug Allopurinol Reduce Heart Muscle Mass and Improve Blood Vessel Function in Patients With Normal Blood Pressure and Stable Angina?; ISRCTN73579730)

  • mechanistic insights into the therapeutic use of high dose Allopurinol in angina pectoris
    Journal of the American College of Cardiology, 2011
    Co-Authors: Narasimharajapura S Rajendra, Sheila Ireland, Jacob George, J J F Belch, Chim C Lang, Allan D Struthers
    Abstract:

    Objectives The aim of this study was to evaluate the effect of high-dose Allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD). Background Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether Allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of Allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether Allopurinol really does reduce vascular tissue OS in CAD patients. Methods A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing Allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine. Results Compared with placebo, Allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 ± 67% vs. 145 ± 106%, p = 0.006) and flow-mediated dilation (4.2 ± 1.8% vs. 5.4 ± 1.7%, p Conclusions Our study demonstrates that, in optimally treated CAD patients, high-dose Allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of Allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose Allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor Allopurinol in angina; ISRCTN15253766)

  • impact of Allopurinol use on urate concentration and cardiovascular outcome
    British Journal of Clinical Pharmacology, 2011
    Co-Authors: Li Wei, Allan D Struthers, Isla S Mackenzie, Yang Chen, Thomas M Macdonald
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Guidelines recommend that the therapeutic goal of urate-lowering therapy (ULT) is to achieve a urate concentration of ≤6 mg dl−1. • High-dose Allopurinol is associated with reduced cardiovascular events and mortality in heart failure patients. WHAT THIS STUDY ADDS • Less than 50% of patients taking Allopurinol reached target urate concentration. • Higher doses of Allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality in all patients on Allopurinol treatment. AIMS To characterize patients with urate measurements by urate-lowering therapy (ULT) use and to study the impact of Allopurinol treatment on cardiovascular and mortality outcomes. METHODS A cohort study using a record-linkage database. The study included 7135 patients aged ≥60 years with urate measurements between 2000 and 2002 followed up until 2007. A Cox regression model was used. The association between urate levels, dispensed Allopurinol and cardiovascular hospitalization and mortality was determined. RESULTS Six thousand and forty-two patients were not taking ULT and 45.9% of those (2774 of 6042) had urate concentrations ≤6 mg dl−1. Among 1035 Allopurinol users, 44.7% (45.6% for men and 43.3% for women) reached target urate concentration. There was no significant increased risk of cardiovascular events for Allopurinol users when compared with non-ULT users [adjusted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.95–1.26] and the non-ULT group with urate >6 mg dl−1 (adjusted HR 1.07, 95% CI 0.89–1.28). Within the Allopurinol use cohort, cardiovascular event rates were 74.0 (95% CI 61.9–86.1) per 1000 person years for the 100 mg group, 69.7 (49.6–89.8) for the 200 mg group and 47.6 (38.4–56.9) for the ≥300 mg group. Compared with low-dose (100 mg) users, high-dose (≥300 mg) users had significant reductions in the risk of cardiovascular events (adjusted HR 0.69, 95% CI 0.50–0.94) and mortality (adjusted HR 0.75, 95% CI 0.59–0.94). CONCLUSIONS Less than 50% of patients taking Allopurinol reached target urate concentration. Higher doses of Allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality.

  • high dose Allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid
    Circulation, 2006
    Co-Authors: Jacob George, J J F Belch, Elaine Carr, Justine Davies, Allan D Struthers
    Abstract:

    Background— Allopurinol has been shown to improve endothelial function in chronic heart failure. This study aimed to establish its mechanism of action and to construct a dose–response curve for the effect of Allopurinol. Methods and Results— Two randomized, placebo-controlled, double-blind, crossover studies were performed for 1 month on patients with New York Heart Association Class II–III chronic heart failure, comparing 300 mg Allopurinol, 600 mg Allopurinol, and placebo for the first study and 1000 mg probenecid versus placebo in the second study. Endothelial function was assessed by standard forearm venous occlusion plethysmography. Allopurinol 600 mg/d significantly increased forearm blood flow response to acetylcholine compared with both Allopurinol 300 mg/d and placebo (% change in forearm blood flow [mean±SEM]: 240.31±38.19% versus 152.10±18.21% versus 73.96±10.29%, P<0.001). For similar levels of urate lowering, the uricosuric agent probenecid had no effect on endothelial function. Sodium nitrop...

J B Singh - One of the best experts on this subject based on the ideXlab platform.

  • comparative effectiveness of Allopurinol and febuxostat for the risk of atrial fibrillation in the elderly a propensity matched analysis of medicare claims data
    European Heart Journal, 2019
    Co-Authors: J B Singh, John D Cleveland
    Abstract:

    AIMS Gout is associated with a higher risk of atrial fibrillation (AF). Comparative effectiveness of Allopurinol or febuxostat for reducing the AF risk is unknown, which was our study's main objective. METHODS AND RESULTS We used the 5% Medicare Beneficiary cohort (≥65 years) from 2006 to 2012 to identify people with a new filled prescription for Allopurinol or febuxostat, with a baseline period of 365 days without respective medication and without AF. We used 5:1 propensity-matched Cox regression analyses to assess whether Allopurinol use differed from febuxostat use regarding the hazard ratio (HR) of incident AF. We found 25 732 eligible episodes in 23 135 beneficiaries. Of these, 2311 incident Allopurinol or febuxostat use episodes (9%) ended in incident AF with crude incidence rates of 8.0 and 10.5 per 100 person-years, respectively. In propensity-matched analyses, compared with Allopurinol, febuxostat was associated with higher HR of AF, 1.25 [95% confidence interval (CI) 1.05-1.48]. Compared with Allopurinol <200 mg/day, febuxostat 80 mg/day was associated with significantly higher HR of AF, 1.62 (95% CI 1.16-2.27), but not febuxostat 40 mg/day or higher Allopurinol doses. Compared with 1-180 days of Allopurinol use, febuxostat use for 1-180 days was associated with significantly higher HR of AF, 1.36 (95% CI 1.10-1.67), but longer durations were not. CONCLUSION Febuxostat was associated with a higher risk of AF compared with Allopurinol in older adults. Increased AF risk was noted with febuxostat 80 mg/day dose and was most evident in the first 6 months of use. These findings need replication.

  • comparative effectiveness of Allopurinol versus febuxostat for preventing incident dementia in older adults a propensity matched analysis
    Arthritis Research & Therapy, 2018
    Co-Authors: J B Singh, John D Cleveland
    Abstract:

    The purpose of this study was to assess the comparative effectiveness of Allopurinol versus febuxostat for preventing incident dementia in older adults. In a retrospective cohort study using Medicare claims data, we included patients newly treated with Allopurinol or febuxostat (baseline period of 365 days without either medication). We used 5:1 propensity-matched Cox regression analyses to compare the hazard ratio (HR) of incident dementia with Allopurinol versus febuxostat use and with Allopurinol/febuxostat dose and duration. Crude rates of incident dementia per 100,000 person-days were lower with higher daily dose: Allopurinol less than 200, 200 to 299, and at least 300 mg/day with 12, 9, and 8 and febuxostat 40 and 80 mg/day with 9 and 8, respectively. In propensity-matched analyses, compared with Allopurinol use, febuxostat use was not significantly different, and the HR of incident dementia was 0.79 (95% confidence interval (CI) 0.61, 1.03). Compared with Allopurinol less than 200 mg/day, higher Allopurinol doses (200 to 299 and at least 300 mg/day) and the febuxostat 40 mg/day dose were each associated with lower HRs of dementia: 0.80 (95% CI 0.64, 0.98), 0.59 (95% CI 0.50, 0.71), and 0.64 (95% CI 0.47, 0.86), respectively. Compared with Allopurinol use for 1 to 180 days, longer Allopurinol or febuxostat use durations were not significantly associated with differences in HR of dementia (range of 0.76 to 1.14). A dose-related reduction in the risk of dementia in older adults was noted with higher Allopurinol dose and with febuxostat 40 mg daily dose. Future studies need to examine the mechanism of this benefit.

  • Allopurinol use and the risk of acute cardiovascular events in patients with gout and diabetes
    BMC Cardiovascular Disorders, 2017
    Co-Authors: J B Singh, Rekha Ramachandaran, Jeffrey R Curtis
    Abstract:

    Few studies, if any, have examined cardiovascular outcomes in patients with diabetes and gout. Both diabetes and gout are risk factors for cardiovascular disease. The objective of this study was to examine the effect of Allopurinol on the risk of incident acute cardiovascular events in patients with gout and diabetes. We used the 2007–2010 Multi-Payer Claims Database (MPCD) that linked health plan data from national commercial and governmental insurances, representing beneficiaries with United Healthcare, Medicare, or Medicaid coverage. In patients with gout and diabetes, we assessed the current Allopurinol use, defined as a new filled prescription for Allopurinol, as the main predictor of interest. Our outcome of interest was the occurrence of the first Incident hospitalized myocardial infarction (MI) or stroke (composite acute cardiovascular event), after which observations were censored. We employed multivariable-adjusted Cox proportional hazards models that simultaneously adjusted for patient demographics, cardiovascular risk factors and other medical comorbidities. We calculated hazard ratios [HR] (95% confidence intervals [CI]) for incident composite (MI or stroke) acute cardiovascular events. We performed sensitivity analyses that additionally adjusted for the presence of immune diseases and colchicine use, as potential confounders. There were 2,053,185 person days (5621.3 person years) of current Allopurinol use and 1,671,583 person days (4576.5 person years) of prior Allopurinol use. There were 158 incident MIs or strokes in current and 151 in prior Allopurinol users, respectively. Compared to previous Allopurinol users, current Allopurinol users had significantly lower adjusted hazard of incident acute cardiovascular events (incident stroke or MI), with an HR of 0.67 (95% CI, 0.53, 0.84). Sensitivity analyses, additionally adjusted for immune diseases or colchicine use, confirmed this association. Current Allopurinol use protected against the occurrence of acute cardiovascular events in patients with gout and diabetes. The underlying mechanisms for this potential cardio-protective effect of Allopurinol need further exploration.

  • are Allopurinol dose and duration of use nephroprotective in the elderly a medicare claims study of Allopurinol use and incident renal failure
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: J B Singh
    Abstract:

    Objective To assess the effect of Allopurinol dose/duration on the risk of renal failure in the elderly with Allopurinol use. Methods We used the 5% random Medicare claims data from 2006 to 2012. Multivariable-adjusted Cox regression analyses assessed the association of Allopurinol dose/duration with subsequent risk of developing incident renal failure or end-stage renal disease (ESRD) (no prior diagnosis in last 183 days) in Allopurinol users, controlling for age, sex, race and Charlson–Romano comorbidity index. HRs with 95% CIs were calculated. Sensitivity analyses considered a longer baseline period (365 days), controlled for gout or used more specific codes. Results Among the 30 022 Allopurinol treatment episodes, 8314 incident renal failure episodes occurred. Compared with 1–199 mg/day, Allopurinol dose of 200–299 mg/day (HR 0.81; 95% CI 0.75 to 0.87) and ≥300 mg/day, 0.71 (0.67 to 0.76), had significantly lower hazard of renal failure in multivariable-adjustment model, confirmed in multiple sensitivity analyses. Longer Allopurinol use duration was significantly associated with lower hazards in sensitivity analyses (365-day look-back; reference, 1–2 years, 0.85 (0.73 to 0.99); and >2 years, 0.81 (0.67 to 0.98). Allopurinol ≥300 mg/day was also associated with significantly lower risk of acute renal failure and ESRD with HR of 0.89 (0.83 to 0.94) and 0.57 (0.46 to 0.71), respectively. Conclusions Higher Allopurinol dose is independently protective against incident renal failure in the elderly Allopurinol users. A longer duration of Allopurinol use may be associated with lower risk of incident renal failure. Potential mechanisms of these effects need to be examined.

  • Allopurinol and the risk of atrial fibrillation in the elderly a study using medicare data
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: J B Singh
    Abstract:

    Objective To assess the effect of Allopurinol use on the risk of incident atrial fibrillation (AF) in the elderly. Methods We used the 5% random Medicare Claims data from 2006 to 2012 to examine the association of Allopurinol use and incident AF in a cohort of patients with an absence of AF at baseline (at least 365 days). Multivariable-adjusted Cox regression analyses compared Allopurinol exposed and non-exposed periods for the risk of AF, controlling for age, sex, race, Charlson–Romano comorbidity index and use of statins, diuretics, ACE inhibitors and β-blockers. HR with 95% CIs was calculated. Sensitivity analyses considered a longer baseline period (365 days vs 183 days) and individual comorbidities. Results There were 9244 episodes of incident Allopurinol use in 8569 beneficiaries, of which 1366 episodes (14.8%) had incident AF. In multivariable-adjusted analyses, Allopurinol use was associated with an HR of 0.83 (95% CI 0.74 to 0.93) for incident AF. In a separate multivariable-adjusted model, compared with no Allopurinol use, longer Allopurinol use durations were associated with a lower HR of AF: 180 days–2 years, 0.85 (95% CI 0.73 to 0.99) and >2 years, 0.65 (95% CI 0.52 to 0.82). Other factors significantly associated with a higher hazard of AF were: age 75– Conclusions Allopurinol use was associated with a reduced risk of incident AF in the elderly, especially its use for >6 months duration. Future studies should assess the mechanisms underlying this beneficial effect of Allopurinol.

C. Storgard - One of the best experts on this subject based on the ideXlab platform.

  • lesinurad in combination with Allopurinol a randomised double blind placebo controlled study in patients with gout with inadequate response to standard of care the multinational clear 2 study
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, Scott Adler, N Bhakta, Scott Baumgartner, Robert T Keenan, Puja P Khanna, Alexander So
    Abstract:

    Objectives Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to Allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. Methods Patients on Allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of Results Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to Allopurinol, significantly increased proportions of patients achieving sUA target versus Allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p Conclusion Lesinurad added to Allopurinol demonstrated superior sUA lowering versus Allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy. Trial registration number NCT01493531.

  • lesinurad combined with Allopurinol a randomized double blind placebo controlled study in gout patients with an inadequate response to standard of care Allopurinol a us based study
    Arthritis & Rheumatism, 2017
    Co-Authors: Kenneth G Saag, C. Storgard, Maple Fung, Scott Adler, N Bhakta, Scott Baumgartner, David Fitzpatrick, Michael Becker
    Abstract:

    Objective Lesinurad is a selective uric acid reabsorption inhibitor used for the treatment of gout in combination with a xanthine oxidase inhibitor. The Combining Lesinurad with Allopurinol Standard of Care in Inadequate Responders (CLEAR 1) study, a 12-month, multicenter, randomized, double-blind, placebo-controlled phase III trial, was conducted to investigate daily lesinurad (200 mg or 400 mg orally) added to Allopurinol versus placebo plus Allopurinol in patients with serum urate (UA) levels above a target of <6.0 mg/dl. Methods Patients receiving ≥300 mg of Allopurinol (≥200 mg in those with moderate renal impairment) who had serum UA levels ≥6.5 mg/dl at screening and ≥2 gout flares during the previous year were studied. The primary end point was the proportion of patients achieving a serum UA level of <6.0 mg/dl at month 6. Key secondary end points were the mean gout flare rate requiring treatment (months 7–12) and the proportions of patients with complete resolution of ≥1 target tophus (month 12). Safety assessments included adverse events and laboratory data. Results The study patients (n = 603) were predominantly male and had a mean ± SD age of 51.9 ± 11.3 years, a gout duration of 11.8 ± 9.4 years, a baseline serum UA level of 6.94 ± 1.27 mg/dl, and were receiving an Allopurinol dosage of 306.6 ± 59.58 mg/day. Lesinurad at doses of 200 mg or 400 mg added to Allopurinol therapy significantly increased the proportions of patients who achieved serum UA target levels by month 6 as compared with those receiving Allopurinol alone (54.2%, 59.2%, and 27.9%, respectively, P < 0.0001). Lesinurad was not significantly superior to Allopurinol alone in terms of the secondary end points: rates of gout flares and complete resolution of tophi. Lesinurad was generally well-tolerated; the safety profile of the 200-mg dose was comparable to that of Allopurinol alone, except for higher incidences of predominantly reversible elevations of serum creatinine levels. Conclusion Lesinurad added to Allopurinol provided benefit as compared with Allopurinol alone in reducing serum UA levels and represents a new treatment option for patients needing additional urate-lowering therapy.

  • lesinurad in combination with Allopurinol results of a phase 2 randomised double blind study in patients with gout with an inadequate response to Allopurinol
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Fernando Perezruiz, Jeffrey N. Miner, John S Sundy, M Cravets, C. Storgard
    Abstract:

    Objectives To assess the efficacy and tolerability of lesinurad, an oral selective uric acid reabsorption inhibitor, in combination with Allopurinol versus Allopurinol alone in patients with gout and an inadequate response to Allopurinol. Methods Patients (N=227) with an inadequate response to Allopurinol, defined as serum urate (sUA) ≥6 mg/dL on ≥2 occasions ≥2 weeks apart despite ≥6 weeks of Allopurinol, were randomised 2:1 to 4 weeks of double-blind treatment with lesinurad (200, 400 or 600 mg/day) or matching placebo in combination with their prestudy Allopurinol dose (200–600 mg/day). Colchicine prophylaxis for gout flares was required. The primary end point was percent reduction from baseline sUA levels at 4 weeks. A pharmacokinetic substudy was also conducted. Safety was assessed throughout. Results Patients (n=208) received ≥1 dose of blinded medication. Lesinurad 200, 400 and 600 mg in combination with Allopurinol produced significant mean percent reductions from baseline sUA of 16%, 22% and 30%, respectively, versus a mean 3% increase with placebo (p Conclusions Lesinurad achieves clinically relevant and statistically significant reductions in sUA in combination with Allopurinol in patients who warrant additional therapy on Allopurinol alone. Trial registration number NCT01001338.

  • an open label 6 month study of Allopurinol safety in gout the lasso study
    Seminars in Arthritis and Rheumatism, 2015
    Co-Authors: Michael Becker, C. Storgard, David Fitzpatrick, M Cravets, Nicola Dalbeth, Hyon K Choi, Scott Baumgartner
    Abstract:

    Abstract Objectives Allopurinol is the most widely prescribed serum uric acid-lowering therapy (ULT) in gout. To achieve serum uric acid (sUA) concentrations associated with clinical benefit, Allopurinol is serially uptitrated with sUA monitoring. Suboptimal dosing is a key contributor to poor clinical outcomes, but few data are available on the safety and efficacy of dose-titrated Allopurinol, particularly at doses >300mg/d. The objective of this open-label study was to investigate the safety and efficacy of Allopurinol under conditions where investigators were encouraged to titrate to optimal, medically appropriate doses. Methods Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) was a large, 6-month, multicenter study of Allopurinol (NCT01391325). Adults meeting American Rheumatism Association Criteria for Classification of Acute Arthritis of Primary Gout and ≥2 gout flares in the previous year were eligible. Investigators were encouraged (but not required) to titrate Allopurinol doses to achieve target sUA Results Of 1735 patients enrolled, 1732 received ≥1 Allopurinol doses. The maximal daily Allopurinol dose during study was 300mg in 20.2% of patients; dosing duration was 115.5, 152.0, and 159.7 days, respectively. Overall, baseline demographic characteristics and comorbidity rates were similar across these three categories, but patients receiving >300-mg maximal dose had more severe gout. Treatment-emergent adverse events possibly related to Allopurinol occurred in 15.2%, 9.5%, and 11.4% of patients in the 300-mg categories, respectively. Rash incidence was low (1.5%) and Allopurinol hypersensitivity syndrome was not reported. No clinically meaningful changes occurred in laboratory values. sUA 300mg, respectively. Conclusions This large multicenter study found that the Allopurinol dose-titration strategy was well tolerated, without new safety signals emerging over 6 months. However, despite encouragement to treat to target, significant proportions of patients did not achieve target sUA.

Michael Becker - One of the best experts on this subject based on the ideXlab platform.

  • lesinurad combined with Allopurinol a randomized double blind placebo controlled study in gout patients with an inadequate response to standard of care Allopurinol a us based study
    Arthritis & Rheumatism, 2017
    Co-Authors: Kenneth G Saag, C. Storgard, Maple Fung, Scott Adler, N Bhakta, Scott Baumgartner, David Fitzpatrick, Michael Becker
    Abstract:

    Objective Lesinurad is a selective uric acid reabsorption inhibitor used for the treatment of gout in combination with a xanthine oxidase inhibitor. The Combining Lesinurad with Allopurinol Standard of Care in Inadequate Responders (CLEAR 1) study, a 12-month, multicenter, randomized, double-blind, placebo-controlled phase III trial, was conducted to investigate daily lesinurad (200 mg or 400 mg orally) added to Allopurinol versus placebo plus Allopurinol in patients with serum urate (UA) levels above a target of <6.0 mg/dl. Methods Patients receiving ≥300 mg of Allopurinol (≥200 mg in those with moderate renal impairment) who had serum UA levels ≥6.5 mg/dl at screening and ≥2 gout flares during the previous year were studied. The primary end point was the proportion of patients achieving a serum UA level of <6.0 mg/dl at month 6. Key secondary end points were the mean gout flare rate requiring treatment (months 7–12) and the proportions of patients with complete resolution of ≥1 target tophus (month 12). Safety assessments included adverse events and laboratory data. Results The study patients (n = 603) were predominantly male and had a mean ± SD age of 51.9 ± 11.3 years, a gout duration of 11.8 ± 9.4 years, a baseline serum UA level of 6.94 ± 1.27 mg/dl, and were receiving an Allopurinol dosage of 306.6 ± 59.58 mg/day. Lesinurad at doses of 200 mg or 400 mg added to Allopurinol therapy significantly increased the proportions of patients who achieved serum UA target levels by month 6 as compared with those receiving Allopurinol alone (54.2%, 59.2%, and 27.9%, respectively, P < 0.0001). Lesinurad was not significantly superior to Allopurinol alone in terms of the secondary end points: rates of gout flares and complete resolution of tophi. Lesinurad was generally well-tolerated; the safety profile of the 200-mg dose was comparable to that of Allopurinol alone, except for higher incidences of predominantly reversible elevations of serum creatinine levels. Conclusion Lesinurad added to Allopurinol provided benefit as compared with Allopurinol alone in reducing serum UA levels and represents a new treatment option for patients needing additional urate-lowering therapy.

  • an open label 6 month study of Allopurinol safety in gout the lasso study
    Seminars in Arthritis and Rheumatism, 2015
    Co-Authors: Michael Becker, C. Storgard, David Fitzpatrick, M Cravets, Nicola Dalbeth, Hyon K Choi, Scott Baumgartner
    Abstract:

    Abstract Objectives Allopurinol is the most widely prescribed serum uric acid-lowering therapy (ULT) in gout. To achieve serum uric acid (sUA) concentrations associated with clinical benefit, Allopurinol is serially uptitrated with sUA monitoring. Suboptimal dosing is a key contributor to poor clinical outcomes, but few data are available on the safety and efficacy of dose-titrated Allopurinol, particularly at doses >300mg/d. The objective of this open-label study was to investigate the safety and efficacy of Allopurinol under conditions where investigators were encouraged to titrate to optimal, medically appropriate doses. Methods Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) was a large, 6-month, multicenter study of Allopurinol (NCT01391325). Adults meeting American Rheumatism Association Criteria for Classification of Acute Arthritis of Primary Gout and ≥2 gout flares in the previous year were eligible. Investigators were encouraged (but not required) to titrate Allopurinol doses to achieve target sUA Results Of 1735 patients enrolled, 1732 received ≥1 Allopurinol doses. The maximal daily Allopurinol dose during study was 300mg in 20.2% of patients; dosing duration was 115.5, 152.0, and 159.7 days, respectively. Overall, baseline demographic characteristics and comorbidity rates were similar across these three categories, but patients receiving >300-mg maximal dose had more severe gout. Treatment-emergent adverse events possibly related to Allopurinol occurred in 15.2%, 9.5%, and 11.4% of patients in the 300-mg categories, respectively. Rash incidence was low (1.5%) and Allopurinol hypersensitivity syndrome was not reported. No clinically meaningful changes occurred in laboratory values. sUA 300mg, respectively. Conclusions This large multicenter study found that the Allopurinol dose-titration strategy was well tolerated, without new safety signals emerging over 6 months. However, despite encouragement to treat to target, significant proportions of patients did not achieve target sUA.

  • the urate lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout the confirms trial
    Arthritis Research & Therapy, 2010
    Co-Authors: Michael Becker, Ralph H Schumacher, Luis R Espinoza, Alvin F Wells, Patricia A Macdonald, Eric E Lloyd, Christopher Lademacher
    Abstract:

    The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and Allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial. Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or Allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death. Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and Allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to Allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or Allopurinol (42%), but febuxostat 40 mg showed greater efficacy than Allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40 mg and 0.4% for both febuxostat 80 mg and Allopurinol. One death occurred in each febuxostat group and three in the Allopurinol group. Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and Allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than Allopurinol and equally safe. At the doses tested, safety of febuxostat and Allopurinol was comparable. NCT00430248

  • febuxostat compared with Allopurinol in patients with hyperuricemia and gout
    The New England Journal of Medicine, 2005
    Co-Authors: Michael Becker, Ralph H Schumacher, Patricia A Macdonald, Robert L Wortmann, Denise Eustace, William A Palo, Janet Streit, Nancy Josephridge
    Abstract:

    background Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to Allopurinol for patients with hyperuricemia and gout. methods We randomly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter (480 µmol per liter) to receive either febuxostat (80 mg or 120 mg) or Allopurinol (300 mg) once daily for 52 weeks; 760 received the study drug. Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter (360 µmol per liter) at the last three monthly measurements. The secondary end points included reduction in the incidence of gout flares and in tophus area. results The primary end point was reached in 53 percent of patients receiving 80 mg of febuxostat, 62 percent of those receiving 120 mg of febuxostat, and 21 percent of those receiving Allopurinol (P<0.001 for the comparison of each febuxostat group with the Allopurinol group). Although the incidence of gout flares diminished with continued treatment, the overall incidence during weeks 9 through 52 was similar in all groups: 64 percent of patients receiving 80 mg of febuxostat, 70 percent of those receiving 120 mg of febuxostat, and 64 percent of those receiving Allopurinol (P=0.99 for 80 mg of febuxostat vs. Allopurinol; P = 0.23 for 120 mg of febuxostat vs. Allopurinol). The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat, as compared with 50 percent in those receiving Allopurinol (P=0.08 for 80 mg of febuxostat vs. Allopurinol; P=0.16 for 120 mg of febuxostat vs. Allopurinol). More patients in the high-dose febuxostat group than in the Allopurinol group (P=0.003) or the low-dose febuxostat group discontinued the study. Four of the 507 patients in the two febuxostat groups (0.8 percent) and none of the 253 patients in the Allopurinol group died; all deaths were from causes that the investigators (while still blinded to treatment) judged to be unrelated to the study drugs (P=0.31 for the comparison between the combined febuxostat groups and the Allopurinol group). conclusions Febuxostat, at a daily dose of 80 mg or 120 mg, was more effective than Allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate. Similar reductions in gout flares and tophus area occurred in all treatment groups.

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  • Allopurinol reduces left ventricular mass in patients with type 2 diabetes and left ventricular hypertrophy
    Journal of the American College of Cardiology, 2013
    Co-Authors: Benjamin R Szwejkowski, Jacob George, Chim C Lang, Sushma Rekhraj, Stephen J Gandy, J G Houston, Andrew D Morris, Allan D Struthers
    Abstract:

    Objectives This study sought to ascertain whether high-dose Allopurinol causes regression of left ventricular mass (LVM) in patients with type 2 diabetes mellitus (T2DM). Background Left ventricular hypertrophy (LVH) is common in T2DM and contributes to patients9 high cardiovascular (CV) event rate. Oxidative stress (OS) has been implicated in LVH development, and Allopurinol has been previously shown to reduce vascular OS. We therefore investigated whether Allopurinol causes regression of LVH in patients with T2DM. Methods We conducted a randomized, double-blind, placebo-controlled study of 66 optimally-treated T2DM patients with echocardiographic evidence of LVH. Allopurinol, 600 mg/day, or placebo was given over the study period of 9 months. The primary outcome was reduction in LVM as calculated by cardiac magnetic resonance imaging at baseline and at 9 months9 follow-up. Secondary endpoints were change in flow-mediated dilation and augmentation index. Results Allopurinol significantly reduced absolute LVM (−2.65 ± 5.91 g vs. placebo group +1.21 ± 5.10 g [p = 0.012]) and LVM indexed to body surface area (−1.32 ± 2.84 g/m2 vs. placebo group +0.65 ± 3.07 g/m2 [p = 0.017]). No significant changes were seen in either flow-mediated dilation or augmentation index. Conclusions Allopurinol causes regression of LVM in patients with T2DM and LVH. Regression of LVH has been shown previously to improve CV mortality and morbidity. Therefore, Allopurinol therapy may become useful to reduce CV events in T2DM patients with LVH. (Allopurinol in Patients with Diabetes and LVH; UKCRN 8766)

  • high dose Allopurinol reduces left ventricular mass in patients with ischemic heart disease
    Journal of the American College of Cardiology, 2013
    Co-Authors: Sushma Rekhraj, Jacob George, Chim C Lang, Stephen J Gandy, Benjamin R Szwejkowski, Adnan M Nadir, Awsan Noman, Graeme J Houston, Allan D Struthers
    Abstract:

    Objectives This study sought to ascertain if high-dose Allopurinol regresses left ventricular mass (LVM) in patients with ischemic heart disease (IHD). Background LV hypertrophy (LVH) is common in patients with IHD including normotensive patients. Allopurinol, a xanthine oxidase inhibitor, has been shown to reduce LV afterload in IHD and may therefore also regress LVH. Methods A randomized, double-blind, placebo-controlled, parallel group study was conducted in 66 patients with IHD and LVH, comparing 600 mg/day Allopurinol versus placebo therapy for 9 months. The primary outcome measure was change in LVM, assessed by cardiac magnetic resonance imaging (CMR). Secondary outcome measures were changes in LV volumes by CMR, changes in endothelial function by flow-mediated dilation (FMD), and arterial stiffness by applanation tonometry. Results Compared to placebo, Allopurinol significantly reduced LVM (Allopurinol −5.2 ± 5.8 g vs. placebo −1.3 ± 4.48 g; p = 0.007) and LVM index (LVMI) (Allopurinol −2.2 ± 2.78 g/m2 vs. placebo −0.53 ± 2.5 g/m2; p = 0.023). The absolute mean difference between groups for change in LVM and LVMI was −3.89 g (95% confidence interval: −1.1 to −6.7) and −1.67 g/m2 (95% confidence interval: −0.23 to −3.1), respectively. Allopurinol also reduced LV end-systolic volume (Allopurinol −2.81 ± 7.8 mls vs. placebo +1.3 ± 7.22 mls; p = 0.047), improved FMD (Allopurinol +0.82 ± 1.8% vs. placebo −0.69 ± 2.8%; p = 0.017) and augmentation index (Allopurinol −2.8 ± 5.1% vs. placebo +0.9 ± 7%; p = 0.02). Conclusions High-dose Allopurinol regresses LVH, reduces LV end-systolic volume, and improves endothelial function in patients with IHD and LVH. This raises the possibility that Allopurinol might reduce future cardiovascular events and mortality in these patients. (Does a Drug Allopurinol Reduce Heart Muscle Mass and Improve Blood Vessel Function in Patients With Normal Blood Pressure and Stable Angina?; ISRCTN73579730)

  • mechanistic insights into the therapeutic use of high dose Allopurinol in angina pectoris
    Journal of the American College of Cardiology, 2011
    Co-Authors: Narasimharajapura S Rajendra, Sheila Ireland, Jacob George, J J F Belch, Chim C Lang, Allan D Struthers
    Abstract:

    Objectives The aim of this study was to evaluate the effect of high-dose Allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD). Background Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether Allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of Allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether Allopurinol really does reduce vascular tissue OS in CAD patients. Methods A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing Allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine. Results Compared with placebo, Allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 ± 67% vs. 145 ± 106%, p = 0.006) and flow-mediated dilation (4.2 ± 1.8% vs. 5.4 ± 1.7%, p Conclusions Our study demonstrates that, in optimally treated CAD patients, high-dose Allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of Allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose Allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor Allopurinol in angina; ISRCTN15253766)

  • high dose Allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid
    Circulation, 2006
    Co-Authors: Jacob George, J J F Belch, Elaine Carr, Justine Davies, Allan D Struthers
    Abstract:

    Background— Allopurinol has been shown to improve endothelial function in chronic heart failure. This study aimed to establish its mechanism of action and to construct a dose–response curve for the effect of Allopurinol. Methods and Results— Two randomized, placebo-controlled, double-blind, crossover studies were performed for 1 month on patients with New York Heart Association Class II–III chronic heart failure, comparing 300 mg Allopurinol, 600 mg Allopurinol, and placebo for the first study and 1000 mg probenecid versus placebo in the second study. Endothelial function was assessed by standard forearm venous occlusion plethysmography. Allopurinol 600 mg/d significantly increased forearm blood flow response to acetylcholine compared with both Allopurinol 300 mg/d and placebo (% change in forearm blood flow [mean±SEM]: 240.31±38.19% versus 152.10±18.21% versus 73.96±10.29%, P<0.001). For similar levels of urate lowering, the uricosuric agent probenecid had no effect on endothelial function. Sodium nitrop...