Allopurinol and febuxostat are similarly effective in controlling flares in patients with gout, including those with stage 3 chronic kidney disease (CKD), according to trial results published in the New England Journal of Medicine.

In double-blind CSP594 Comparative Effectiveness in Gout: Allopurinol vs Febuxostat trial (ClinicalTrials.gov identifier: NCT02579096), investigators randomly assigned 940 patients with hyperuricemia to receive allopurinol or febuxostat at titrated doses to achieve a serum urate target of 6mg/dL or lower (or 5mg/dL or lower if tophi were present). Approximately a third of patients in both groups had stage 3 CKD (30-59 mL/min/1.73 m² using the Modification of Diet in Renal Disease study formula for estimated glomerular filtration rate). The allopurinol and febuxostat groups received daily doses of 100 and 40mg, respectively, to start, then therapies were titrated until attainment of target uric acid levels or maximal dose. Patients also received guideline-directed anti-inflammatory prophylaxis with colchicine, nonsteroidal anti-inflammatory drugs, or glucocorticoids. After the maintenance phase, no study drug dose adjustments were allowed, and all anti-inflammatory treatments were discontinued except in the event of gout flare.

Results showed that 36.5% of the allopurinol group and 43.5% of the febuxostat group experienced the primary outcome of 1 or more gout flares during the observation phase; a 7% difference that met a criterion for noninferiority, James R. O’Dell, MD, of Veterans Affairs (VA) Nebraska-Western Iowa Health Care System in Omaha, Nebraska, and colleagues reported. Among patients with stage 3 CKD, allopurinol also proved noninferior to febuxostat with 31.9% vs 45.3% experiencing a gout flare, respectively, the investigators reported.

In both the allopurinol and febuxostat groups, 80% of patients, including those with stage 3 CKD, achieved and maintained target serum urate levels at 1 year.

“Our randomized double-blind trial demonstrates that allopurinol, when dosed appropriately as part of a titrate-to-target strategy, is noninferior to febuxostat with respect to flares of gout,” Dr O’Dell’s team wrote.

In 2019, the FDA issued a boxed warning concerning the cardiovascular safety of febuxostat based on results of the CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout) trial. The 2020 FAST trial (Febuxostat versus Allopurinol Streamlined Trial), however, showed no increased risk for cardiovascular events. In the current study, the investigators found no evidence that febuxostat increases cardiovascular morbidity or overall mortality compared with allopurinol. Serious adverse events (26.7% vs 26.1%), including cardiovascular events (8.1% vs 6.8%) and death (8 patients in each group), occurred in comparable proportions of the allopurinol and febuxostat arms, respectively. Dr O’Dell and colleagues suggested that the nearly ubiquitous use of colchicine in the early phases of the trial might have mitigated cardiovascular risks.

Dr O’Dell’s team made other observations that also warrant additional research. Hospitalization for heart failure was numerically higher among patients treated with allopurinol (23 vs 10 hospitalizations). A post hoc analysis showed that acute kidney injury occurred in 15 allopurinol-treated patients compared with 4 febuxostat-treated patients who had stage 3 CKD. Most AKI events were related to volume depletion or congestive heart failure, the investigators noted. All but 3 AKI events were transient.

Reference

O’Dell JR, Brophy MT, Pillinger MH, et al. Comparative effectiveness of allopurinol and febuxostat in gout management. N Engl J Med. Published online February 3, 2022. doi:10.1056/EVIDoa2100028

The storms “hampered our ability to boost critically low blood supply levels,” said Red Cross spokesman Daniel Parra. “Since the beginning of the year, blood drives have been cancelled in nearly every state where the Red Cross collects blood, causing thousands of units of blood and platelets to go uncollected.”

Parra explained that to bring blood supplies back up to normal levels, the agency needs to collect an extra 8000 donations each week during the next few weeks.

Already, the US has the lowest number of people giving blood observed over the past 20 years, according to the Red Cross. When supplies are stretched thin, events such as storms can “have a huge effect on the availability of blood products,” Parra noted.

“Donors in areas unaffected by severe weather are vital to ensuring those in need of transfusions have access to lifesaving care across the Red Cross network,” he said.

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Laura Samples, MD, from the Fred Hutchinson Cancer Center in Seattle, and colleagues examined the optimal treatment of BTKi-associated HTN in a study involving randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drugs with at least 3 months of follow-up data. Participants were classified as those diagnosed with HTN prior to BTKi initiation (prior HTN; 118 patients) and those diagnosed after BTKi initiation (de novo HTN; 78 patients).

The researchers found that patients with prior HTN who took beta blockers with hydrochlorothiazide and patients diagnosed with de novo HTN who took either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker with hydrochlorothiazide had significant mean arterial pressure (MAP) reductions (−5.05 and −5.47 mm Hg, respectively). The greatest percentages of normotensive MAPs were also seen in correlation with these regimens.

“Given that increased blood pressure is a ‘class effect’ of treatment with BTKis, both doctors and patients need to be aware of this risk and patients’ blood pressure should be monitored regularly so that treatment can begin immediately when an increase is detected,” Samples said in a statement.

The study was funded by AstraZeneca.

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HealthDay News — Apixaban has a lower bleeding risk than warfarin or rivaroxaban during initial treatment for patients with venous thromboembolism (VTE), according to a study published online August 28 in the Journal of Internal Medicine.

Katarina Glise Sandblad, from the University of Gothenburg in Sweden, and colleagues compared major bleeding rates by choice of anticoagulation during the initial 6 months of treatment and extended treatment (up to 5 years) for VTE. The analysis included cancer-free patients with a first-time VTE between 2014 and 2020.

The researchers found that during initial treatment, major bleeding rates were 3.86 per 100 patient-years for warfarin, 2.93 for rivaroxaban, and 1.95 for apixaban, yielding adjusted hazard ratios (aHRs) of 0.89 (95% CI, 0.71 to 1.12) for rivaroxaban vs warfarin, 0.55 (95% CI, 0.43 to 0.71) for apixaban vs warfarin, and 0.62 (95% CI, 0.50 to 0.76) for apixaban vs rivaroxaban. Major bleeding rates during extended treatment were 1.55 per 100 patient-years for warfarin, 1.05 for rivaroxaban, and 0.96 for apixaban, with aHRs of 0.72 (95% CI, 0.53 to 0.99) for rivaroxaban versus warfarin, 0.60 (95% CI, 0.44 to 0.82) for apixaban versus warfarin, and 0.85 (95 percent CI, 0.64 to 1.12) for apixaban vs rivaroxaban. During both initial and extended treatment, previous bleeding and increasing age were risk factors for bleeding.

“It is important to keep in mind that patients included in the analysis on extended treatment were free of major bleeding during initial treatment, which could contribute to the low bleeding incidence,” the authors write.

Several authors disclosed ties to the pharmaceutical industry.

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Kevin N. Sheth, MD, from the Yale University School of Medicine in New Haven, Connecticut, and colleagues examined whether DTT time is associated with outcome among patients with anticoagulation-associated ICH treated with reversal interventions in a cohort study using data from the American Heart Association Get With The Guidelines-Stroke quality improvement registry. Data were included for 9492 patients with anticoagulation-associated ICH and documented reversal intervention status.

Overall, 7469 patients received reversal therapy, including 85.0% of the 5429 patients taking warfarin and 70.2% of the 2069 taking a non-vitamin K antagonist oral anticoagulant. The researchers found that the median onset-to-treatment time was 232 minutes and median DTT time was 82 minutes among the 5224 patients taking a reversal intervention with documented workflow times. Overall, 27.7% had a DTT time of 60 minutes or less, which was associated with reduced mortality and discharge to hospital, but no difference in functional outcome. White race, higher systolic blood pressure, and lower stroke severity were seen in association with DTT time of 60 minutes or less.

“These findings support intensive efforts to accelerate evaluation and treatment for patients with this devastating form of stroke,” the authors write.

Several authors disclosed ties to biopharmaceutical companies, including AstraZeneca, which partially funded the study.

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Researchers conducted the randomized, active-controlled, parallel-group, 52-week, double-blind MANDARA trial (ClinicalTrials.gov Identifier: NCT04157348). They reported on the safety and efficacy profiles of benralizumab and mepolizumab for the treatment of patients with EGPA.

During the 52-week study duration, patients were administered either 30 mg monthly benralizumab or a 3-times-monthly dose of 100 mg mepolizumab through subcutaneous injections. Oral glucocorticoid dosage was reduced to a maximum of 4 mg per day if disease progression was under control.

The primary endpoint was defined as the percentage of patients achieving remission (Birmingham Vasculitis Activity Score = 0; OGC dose ≤4 mg/day) at weeks 36 and 48. 

Secondary endpoints encompassed evaluating sustained remission, OGC usage, clinical improvements, time to the first relapse, and safety monitoring. A total of 140 patients were included in the analysis and randomly assigned to the benralizumab (n=70) and mepolizumab (n=70) groups. The mean patient age was 52.3 years and 60% were women.

At both weeks 36 and 48, the benralizumab group exhibited an adjusted remission rate of 59.2%, while the mepolizumab group demonstrated a rate of 56.5% (difference, 2.71%; 95% CI, -12.54 to 17.96; P =.7278), thereby validating the noninferiority of benralizumab.

Both groups experienced a relapse rate of 30%. At baseline, the average OGC dose was 11.02±5.25 mg per day. By weeks 48 to 52, 86.1% of the benralizumab group had successfully reduced their OGC dose by at least 50% from baseline, with an additional 41.4% completely tapering off OGCs. 

Adverse events (AEs) were reported by 90% of patients treated with benralizumab and 95.7% of those treated with mepolizumab. The most commonly observed AEs included COVID-19 (21.4% vs 27.1%), headache (17.1% vs 15.7%), and arthralgia (17.1% vs 11.4%) among the benralizumab vs mepolizumab groups, respectively. 

Serious AEs occurred among 5.7% of patients taking benralizumab and 12.9% of patients taking mepolizumab. The study authors noted, “No benralizumab and 2 mepolizumab recipients experienced AEs leading to discontinuation of treatment.”

Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

HealthDay News — Patients with hemophilia A or B with inhibitors have a lower annualized bleeding rate with concizumab than with no prophylaxis, according to a phase 3 study published online August 31 in the New England Journal of Medicine.

Tadashi Matsushita, MD, PhD, from Nagoya University Hospital in Japan, and colleagues evaluated the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. As part of the explorer7 phase 3 trial, participants were randomly assigned to receive no prophylaxis for at least 24 weeks (group 1; 19 patients) or to receive concizumab prophylaxis for at least 32 weeks (group 2; 33 patients), or they were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4; 81 patients).

The researchers found that the estimated mean annualized bleeding rate in group 1 was 11.8 episodes vs 1.7 episodes in group 2 (rate ratio, 0.14; P <.001). For patients receiving concizumab (groups 2, 3, and 4), the overall median annualized bleeding rate was zero episodes. After concizumab therapy was restarted, no thromboembolic events were reported. Plasma concentrations of concizumab were stable over time.

“Concizumab represents a novel, subcutaneous treatment option in patients with hemophilia A or B with inhibitors that can potentially improve long-term outcomes,” the authors write.

The study was funded by Novo Nordisk.

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Hannah K. Peng, from the University of Michigan in Ann Arbor, and colleagues assessed COVID-19 immunization coverage among 3424 Michigan residents with SCD (5 years of age and older) vs 9.4 million residents without SCD.

The researchers found that COVID-19 immunization coverage for people with SCD was 33.5%, vs 61.3% for people without SCD (relative risk, 0.55). Immunization completion increased with age for people with SCD (range, 17 to 74%) and without SCD (range, 25 to 87%). By age group, relative risks were 0.68 for 5 to 11 years, 0.75 for 12 to 17 years, 0.58 for 18 to 64 years, and 0.84 for 65 years and older.

“These results are consistent with findings from health system-based studies in which fewer than half of patients with SCD completed the vaccination series,” the authors write. “Misinformation and mistrust are reasons frequently associated with low COVID-19 immunization completion in the SCD community, which are also common throughout the Black population in the United States.”

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Terri Victoria Newman, PharmD, from the University of Pittsburgh, and colleagues examined characteristics that may be associated with DMT use among patients with SCD and described patterns of annual use from 2014 to 2021.

Sample A included 5022 patients with SCD (2.9, 5.5, 17.8, and 73.9% inconsistent users, incident users, consistent users, and non-DMT users, respectively). The researchers found that compared with other use groups, inconsistent users had a higher prevalence of vaso-occlusive crises, splenic complications, pulmonary complications, kidney disease, acute chest syndrome, and health care visits. The prevalence of vaso-occlusive crises, acute chest syndrome, and inpatient and emergency department visits was lowest for non-DMT users; this group also had the highest proportion of adults aged 65 years and older. The use of hydroxyurea increased in sample B (6287 beneficiaries with SCD), from 19.6 to 24.3% in 2014 and 2021, respectively. There was a brief increase seen in L-glutamine use, followed by a gradual decrease throughout the study period. Overall, total DMT use increased from 2014 to 2021, from 19.6 to 28.3%.

“Ultimately, increasing access to and use of DMTs has the potential to improve outcomes and quality of life for individuals with SCD,” the authors write.

Two authors disclosed ties to the pharmaceutical industry.

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HealthDay News — Patients with sickle cell disease may soon have 2 new treatments to try. On Tuesday, a US Food and Drug Administration advisory committee will weigh the merits of a new gene therapy for the painful, inherited condition. The agency is expected to make a decision on that therapy in early December, and it also plans to decide on a second new treatment before year’s end, the Associated Press reported.

The treatment being reviewed Tuesday is based on CRISPR technology, a gene-editing tool. The inventors of that tool won the Nobel Prize in 2020 for their work, the AP reported. A one-time treatment, “exa-cel” is made by Vertex Pharmaceuticals and CRISPR Therapeutics, and it permanently changes DNA in a patient’s blood cells.

On Tuesday, FDA advisers will consider whether more research is needed into potential unintended consequences of the new gene therapy.

In briefing documents filed with the advisory committee, Vertex said that 46 people got the treatment in its study. Among the 30 who had 18 months of follow-up, 29 were free of pain crises for at least a year and all 30 avoided being hospitalized for pain crises. Still, the FDA advisory panel is asking outside gene therapy experts to discuss the possibility of “off-target effects” (i.e., unexpected changes to a person’s genome). The FDA would like to determine whether company research on these possible effects has been adequate or whether more studies are needed, the AP reported. The company has proposed a postapproval safety study and product labeling that notes potential risks.

The second gene therapy for sickle cell disease that the FDA will consider is intended to work by making functional copies of a modified gene, the AP reported. This helps red blood cells produce hemoglobin that is not misshapen. That treatment is made by Bluebird Bio.

Prices for the 2 gene therapies have not been released, the AP reported. However, a price tag of around $2 million would be considered cost-effective because the existing treatments cost about $1.6 million for women and $1.7 million for men from birth to age 65 years, according to recent research.

Associated Press Article

The Food and Administration (FDA) has extended the review period for the Biologics License Application (BLA) for valoctocogene roxaparvovec, an investigational adeno-associated virus (AAV) gene therapy, for the treatment of hemophilia A in adults.

The new Prescription Drug User Fee Act target date is June 30, 2023. The FDA determined that the 3-year data analysis from the ongoing phase 3 GENEr8-1 study (ClinicalTrials.gov Identifier: NCT03370913) constituted a major amendment due to the substantial amount of additional data.

Valoctocogene roxaparvovec is administered as a single infusion to produce clotting factor VIII. In December 2019, the BLA was originally submitted based on interim analysis from the phase 3 GENEr8-1 study (ClinicalTrials.gov Identifier: NCT03370913) and 3-year phase 1/2 data (ClinicalTrials.gov Identifier: NCT02576795).

The FDA subsequently issued a Complete Response Letter (CRL) in August 2020, requesting the Company provide substantial evidence from its phase 3 study demonstrating durable effect using annualized bleeding rate (ABR) as the primary endpoint. 

To address the issues raised in the CRL, the BLA was resubmitted in October 2022, which included 2-year outcome data from the GENEr8-1 study and supportive data from 5 years of follow-up from the 6e13 vg/kg dose cohort in the ongoing phase 1/2 dose escalation study. 

“We are continuing to work closely with FDA and appreciate the agency’s active engagement as we seek to deliver this important therapy to patients with severe hemophilia A,” said Hank Fuchs, MD, president of Worldwide Research and Development of BioMarin. 

Reference

BioMarin provides update on FDA review of Roctavian (valoctocogene roxaparvovec) gene therapy for adults with severe hemophilia A. News release. BioMarin. March 6, 2023. Accessed March 7, 2023. https://www.prnewswire.com/news-releases/biomarin-provides-update-on-fda-review-of-roctavian-valoctocogene-roxaparvovec-gene-therapy-for-adults-with-severe-hemophilia-a-301763924.html.