Alpha blockers do not increase the risk for falls, fractures, or death in the hemodialysis population, a new observational study concludes.

In phases 4 to 6 of the Japan Dialysis Outcomes and Practice Patterns (J-DOPPS) Study, 5149 patients on hemodialysis (mean age 65 years, 68% men) received anti-hypertensive drugs, including 717 patients (14%) prescribed alpha blockers such as doxazosin, bunazosin, prazosin, or urapidil. During a mean 2 years of follow-up, 247 fractures, 525 falls, and 498 deaths occurred in the overall cohort.

Multivariable analysis of the intent-to-treat population showed that patients prescribed alpha blockers had no higher risks of falls or fractures than patients not prescribed these agents, Ken Iseri, MD, PhD, of Showa University School of Medicine in Tokyo, Japan, and colleagues reported in Kidney Medicine. This result included patients at greater risk for falls due to advanced age, systolic blood pressure less than 140 mmHg, anemia, low body mass index, or large fluid removal volume.

“The face-to-face meeting with nephrologists three times per week may permit avoidance of undesirable events through achievement of optimal blood pressure management,” Dr Iseri’s team suggested. Pre-dialysis blood pressure levels were significantly higher in alpha blocker users, indicating that these agents were commonly prescribed for resistant or refractory hypertension.

Alpha blockers also conferred no higher risk for all-cause mortality in the total hemodialysis population, the investigators reported. Alpha blockers were significantly associated with a decreased risk of death among older patients (by 29%), women (32%), patients with a cardiovascular disease history (33%), and those with a pre-dialysis systolic blood pressure of 140 mmHg or greater (31%).

“We could not fully explain why this favorable effect was found only in specific hemodialysis populations, but not in total populations,” Dr Iseri’s team wrote. “However, recent studies have shown that alpha blockers may prevent cardiac remodeling and the development and progression of heart failure and have protective benefits against hyperinflammation and cytokine storm syndrome.”

Since this was an observational study of a single ethnicity and lacked data on patient strength, frailty, history of hypotension, bone mineral density, medication adherence, and other factors, more research is needed.

Ana Marques, MD, PhD, from Université Clermont-Auvergne in France and colleagues enrolled adult patients with essential or isolated head tremor in a multicenter trial. A total of 117 patients were randomly assigned to receive botulinum toxin type A or placebo (62 and 55 patients, respectively) injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12, and were included in the intention-to-treat analysis.

The researchers found that improvement of at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18) occurred in 31 and 9 percent of patients in the botulinum toxin and placebo groups, respectively (relative risk, 3.37). At six and 12, but not 24 weeks, analyses of secondary outcomes were generally supportive of the primary outcome analysis. About half of the patients in the botulinum toxin group had adverse events, including head and neck pain, posterior cervical weakness, and dysphagia.

“The percentage of patients with improvement in head tremor, prespecified as improvement by at least two points on the CGI scale at week 18 (primary outcome), was higher in the botulinum toxin group than in the placebo group,” the authors write.

Several authors disclosed ties to the pharmaceutical industry.

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HealthDay News — For patients with chronic coronary artery disease, colchicine is associated with a reduced incidence of total knee replacement (TKR) and total hip replacement (THR) vs placebo, according to a study published online May 30 in the Annals of Internal Medicine.

Michelle W.J. Heijman, PhD, from Radboud University Medical Center in Nijmegen, Netherlands, and colleagues examined whether colchicine reduces TKRs and THRs in an exploratory analysis of the Low-Dose Colchicine 2 randomized trial involving 5522 patients with chronic coronary artery disease at 43 centers in Australia and the Netherlands. Participants were randomly assigned to 0.5mg colchicine or placebo once daily (2762 and 2760 patients) during a median follow-up of 28.6 months.

The researchers found that TKR or THR was performed in 2.5 and 3.5% of patients in the colchicine and placebo groups, respectively, during the trial (incidence rate, 0.90 vs 1.30 per 100 person-years; hazard ratio, 0.69). Similar results were obtained in sensitivity analyses when patients with gout at baseline were excluded and when joint replacements that occurred in the first three and six months of follow-up were not included.

“We showed that colchicine, 0.5mg daily, was associated with a lower incidence of TKR and THR compared with placebo in patients with chronic coronary artery disease,” the authors write. “This suggests that colchicine may slow the progression of osteoarthritis, but this needs to be confirmed in an appropriately designed prospective placebo-controlled trial.”

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HealthDay News — For patients with acute low back pain, the comparative effectiveness and safety of analgesic medications is unclear, according to a systematic review and meta-analysis published online March 22 in The BMJ.

Michael A. Wewege, from the University of New South Wales in Sydney, and colleagues conducted a systematic review and network meta-analysis to assess the comparative effectiveness and safety of analgesic medicines for acute nonspecific low back pain. Data were reviewed from 98 randomized controlled trials (15,134 participants), which included 69 medicines and combinations.

The researchers observed low or very low confidence in evidence for reduced pain intensity after treatment with tolperisone, aceclofenac plus tizanidine, pregabalin (mean differences, −26.1, −26.1, and −24.7, respectively), and 14 other medicines vs placebo. There was low or very low confidence seen for no difference between the effects of several of these medications. There was moderate to very low confidence noted for increased adverse events with tramadol, acetaminophen plus sustained-release tramadol, baclofen, and acetaminophen plus tramadol compared with placebo (risk ratio, 2.6, 2.4, 2.3, and 2.1, respectively). There was moderate-to-low confidence for these medicines increasing the risk for adverse events compared with other medicines. For secondary outcomes and a secondary analysis of medicine classes, moderate-to-low confidence was also noted.

“Despite nearly 60 years of research involving more than 15,000 patients, high quality evidence to guide clinical decisions on analgesic medicines for acute nonspecific low back pain remains limited,” the authors write.

The Sydney Pharmacy School receives funding from GlaxoSmithKline for a postgraduate scholarship supporting a research student supervised by one of the authors.

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The Food and Drug Administration (FDA) has approved Daxxify^® (daxibotulinumtoxinA- lanm) for the treatment of cervical dystonia in adults.

DaxibotulinumtoxinA-lanm is an acetylcholine release inhibitor and neuromuscular blocking agent. The approval was based on data from a double-blind, placebo-controlled trial (ASPEN-1; ClinicalTrials.gov Identifier: NCT03608397) that included patients with a clinical diagnosis of cervical dystonia with baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score of at least 20, TWSTRS severity score of at least 15, TWSTRS disability score of 3 or greater, and TWSTRS pain score of 1 or greater (N=301). Eighty-four percent of these patients had previously received botulinum toxin as a treatment for cervical dystonia.

Study participants were randomly assigned to receive a single administration of 2.5mL of Daxxify 125 Units (n=125), Daxxify 250 Units (n=130), or placebo (n=46), divided amongst the affected muscles. The primary endpoint was the mean change in the TWSTRS total score from baseline averaged over weeks 4 and 6.

Compared with placebo, the mean change from baseline in the total TWSTRS score was significantly greater in the Daxxify 125U group (least squares mean [LSM] difference from placebo, -8.4 [95% CI, -12.2, -4.6]; P <.0001) and the Daxxify 250U group (LSM difference from placebo, -6.6 [95% CI, -10.4, -2.8]; P =.0007).

Median duration of effect (defined as time from treatment until loss of ≥80% of the peak effect) was reported to be 24 and 20.3 weeks in the Daxxify 125U and Daxxify 250U groups, respectively. Significant improvement with both dosages was also observed in the clinician global impression of change and patient global impression of change scales.

The most common adverse reactions reported were headache, injection site pain, injection site erythema, muscular weakness, and upper respiratory tract infection.

Daxxify is supplied as a lyophilized powder for reconstitution in single-dose 50 Unit and 100 Unit vials. The recommended dose for cervical dystonia ranges from 125 Units to 250 Units. Treatment is administered intramuscularly as a divided dose among affected muscles.

The Food and Drug Administration (FDA) has approved Duvyzat (givinostat) for the treatment of patients 6 years of age and older with Duchenne muscular dystrophy (DMD).

The approval was based on data from the randomized, double-blind, placebo-controlled phase 3 EPIDYS study (ClinicalTrials.gov Identifier: NCT02851797). The study assessed the efficacy and safety of givinostat, a histone deacetylase inhibitor, in male patients 6 years of age and older with DMD who were ambulatory and on a stable dosage of corticosteroids. Study participants were randomly assigned to receive either givinostat (n=118) or placebo (n=61).

The primary endpoint was the change from baseline to month 18 in 4-stair climb time, a measure of muscle function that tests the time it takes to climb 4 stairs. The primary analysis population included 81 patients in the Duvyzat arm and 39 patients in the placebo arm.

Results showed treatment with givinostat was associated with statistically significant less decline in the 4-stair climb time compared with placebo (treatment difference from placebo, -1.78 seconds [95% CI, -3.46, -0.11]; P =.037). 

While not statistically significant, patients treated with givinostat experienced less worsening than those in the placebo group on the North Star Ambulatory Assessment, a 17-item rating scale used to measure functional motor abilities in ambulant children with DMD.

“There is a tremendous unmet need for novel therapies in DMD that can achieve meaningful benefits for a broad range of patients,” said Craig M. McDonald, MD, Professor at the Department of Pediatrics and Physical Medicine Rehabilitation at the University of California Davis Health and investigator for the EPIDYS trial. “Duvyzat’s unique mechanism of action has shown a positive risk/benefit profile and the ability to delay disease progression, supporting its potential to become a key component of the standard of care for people living with DMD.”

The most common adverse reactions reported with Duvyzat were diarrhea, abdominal pain, thrombocytopenia, nausea/vomiting, hypertriglyceridemia, and pyrexia. 

Prior to initiating treatment, baseline platelet counts and triglycerides should be obtained and monitoring during treatment is recommended. Additionally, for patients with underlying cardiac disease or those on concomitant medications that prolong the QTc interval, an ECG should be performed and repeated as clinically indicated.

The recommended dosage of Duvyzat is based on body weight and administered orally twice daily with food. Dosage modification may be required for decreased platelet counts, diarrhea, increased triglycerides, or QTc prolongation.

Duvyzat is supplied as an oral suspension containing 8.86mg of givinostat per mL in a 140mL bottle. The product is expected to be available in the third quarter of 2024.

Anoush Kalachian, DNP, from Englewood Health in New Jersey, and colleagues conducted a retrospective chart review to examine an institution’s current postoperative pain protocol and assess whether elimination of ER opioids in the multimodal medication regimen could improve TKR patient outcomes.

Sixty patients (mean age, 70 years) were reviewed preprotocol and postprotocol (36 and 34 patients, respectively). The researchers identified reductions in antiemetic use and length of stay, and an increase in discharges to home vs rehabilitation facility (67% in the postprotocol group vs 53% in the preprotocol group). Upon discharge, all patients received 30 tablets of only one opioid prescription, with no refill; these included oxycodone-immediate release, hydromorphone, and tramadol (82, 5, and 12%, respectively).

“Studies have shown that extended-release or long-acting opioids increase the risk of opioid dependence and possible addiction because of the greater concentration of the drug and the longer time that they remain in the body,” coauthor Judith Barberio, PhD, from Rutgers Biomedical and Health Science in Newark, New Jersey, said in a statement. “If you can move from long-acting to immediate-release opioids without increased pain or other adverse effects, that’s a win. This quality improvement project suggests it’s possible to do that when recovering from a total knee replacement.”

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HealthDay News — Individuals with statin-associated muscle symptoms do not have worse exercise-induced muscle injury after prolonged moderate-intensity exercise, according to a study published in the April 11 issue of the Journal of the American College of Cardiology.

Neeltje A.E. Allard, MD, from the Radboud University Medical Center in Nijmegen, Netherlands, and colleagues examined the effect of prolonged moderate-intensity exercise on markers of muscle injury in statin users with and without statin-associated muscle symptoms (35 and 34 participants, respectively) and in 31 controls. Participants walked 30, 40, or 50km/day for 4 consecutive days. Markers of muscle injury, muscle performance, and reported muscle symptoms were examined at baseline and after exercise.

The researchers found that at baseline, all muscle injury markers were comparable and they increased following exercise, with no difference between the groups observed in terms of the magnitude of exercise-induced elevations. Symptomatic statin users had higher muscle pain scores at baseline, but scores increased similarly in all groups following exercise. Compared with control participants, symptomatic statin users had a greater increase in muscle relaxation time following exercise. Symptomatic and asymptomatic statin users and control participants had no difference in leukocyte coenzyme Q10 levels, which were measured at baseline; levels were not related to muscle injury markers, fatigue resistance, or reported muscle symptoms.

“This study demonstrated that habitually active statin users can engage in prolonged moderate-intensity exercise without exacerbating skeletal muscle injury and reinforces the recommendation to combine statin therapy with a physically active lifestyle,” the authors write.

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The first generic version of Keveyis^® (dichlorphenamide) tablets has been made available by Torrent Pharma.

Dichlorphenamide is a carbonic anhydrase inhibitor approved for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants. Primary periodic paralysis is a rare hereditary condition characterized by episodic attacks that affect the muscles resulting in muscle weakness or temporary paralysis.

Keveyis was the first drug approved by the FDA for this condition in 2015. The approval was based on data from 2 trials that showed treatment with dichlorphenamide resulted in fewer attacks of muscle weakness in both patients with hyperkalemic and hypokalemic periodic paralysis.

Torrent’s dichlorphenamide tablets are supplied as 50mg tablets in 30- and 100-count bottles. The Company is distributing the product through select specialty pharmacies.

MG is a rare, autoimmune disease characterized by muscle weakness and fatigue that is caused by disrupted communication between motor neurons and muscle fibers at the neuromuscular junction. Symptoms tend to be the most severe and progressive during the first few years after diagnosis. Therefore, gaining adequate control of disease symptoms to prevent further deterioration or progression is a critical goal for initial MG treatments that are provided during the first few years.

An international team of researchers conducted a retrospective, nationwide, population-based study, collecting relevant patient data from 4 Swedish registries on 554 patients (45.7% women; average age, 62) with primary MG diagnosis codes documented at least twice within 12 or more months apart. A neurologist was required to have recorded at least 1 of these documentations that pertained to a diagnosis of MG between January 1, 2010 and December 31, 2017. Participants were followed-up for at least 24 months or longer.

During the first year after diagnosis, individuals with MG demonstrated significantly higher rates of corticosteroid use (60% vs 48%), increased MG-related hospitalization rates (62.5% vs 15.9%), increased all-cause hospitalization rates (70.9% vs 34.7%), and increased rate of thymectomy procedures (12.1% vs 2.7%) compared to the second year after diagnosis (all P <.01).

Correspondingly, compared with the second year, the first year following MG diagnosis included higher health care costs due to increased health care resource use. The difference in health care costs between the first and second years totaled €7,294 (approximately $7,701 US dollars) for all causes and €6629 (approximately $7,000 US dollars) for MG-related causes (both P <.01).

“More treatments and/or surgeries are performed in the first year after diagnosis than later in the disease course, leading to higher costs immediately after diagnosis,” the researchers concluded. “Findings highlight the need for use of more efficacious treatments early in the disease course.”

Disclosures: Several study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see original source for full list of disclosures.

HealthDay News — Hormone preparations increase lumbar spine bone mineral density (BMD) in postmenopausal women, according to a study published online May 2 in Menopause.

Yiran Wang, MD, and Chao Sun, MD, from the First Affiliated Hospital of Xi’an Jiaotong University in China, evaluated the associations between hormone preparations with lumbar spine BMD, osteopenia, and osteoporosis in 6031 postmenopausal women.

The researchers found a positive association between combined oral contraceptive pills, estrogen-only pills, estrogen/progestin combo pills, estrogen-only patches, or the use of more than 2 kinds of hormone preparations with lumbar spine BMD. Other hormone preparations also had a protective effect against osteopenia (all odds ratios less than 1.0), except for estrogen-only patches, but none of them were associated with osteoporosis prevalence. In the current and past users groups, BMD increased by 0.10 and 0.04g/cm², respectively, vs nonusers. The risk for osteopenia was reduced in both current and past user groups (odds ratios, 0.34 and 0.57, respectively).

“This large cross-sectional study showed that current and prior use of multiple types of hormone therapies, including combined hormone contraception used in premenopausal women and menopause hormone therapies, were linked with bone protection in postmenopausal women and that these effects persisted after discontinuation of treatment,” Stephanie Faubion, MD, medical director of the North American Menopause Society, said in a statement. “Additional study is needed to investigate the influence of time since stopping hormone therapy as well as the differential effects of various doses and formulations on bone health, including fracture risk.”

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This month’s case focuses on how a physician handled continuing a patient’s medication after she was released from a hospital stay. It’s a reminder that when a Boxed Warning is involved, extra care should be taken when prescribing that particular medication.

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The patient, Ms B, 73, had been seeing a rheumatologist since the early 2000’s, and had been diagnosed with rheumatoid arthritis. As of 2016, Ms B was taking the corticosteroid prednisone to compensate for the effects of a pituitary tumor that had caused adrenal insufficiency.

Starting in 2012, Ms B began seeing an internist, Dr R. Over the next 4 years, Dr R treated the patient for a variety of issues, including an earache, cat bite, cough, pre-operative clearance for hand surgery, and hip pain.

In late November 2016, Ms B contacted Dr R with complaints of high fever, weakness, and difficulty moving. The physician recommended that she go to a hospital emergency department, which she did. The emergency department physician diagnosed the patient with severe community-acquired pneumonia, sepsis secondary to pneumonia, and effusion. The hospital physician consulted with an intensive care unit physician and pulmonologist who recommended treating the patient with levofloxacin.

Ms B was admitted to the hospital as an inpatient for 5 days, with Dr R listed as the admitting physician. During this time, the patient was administered 750mg of levofloxacin every 48 hours for 5 days, and continued on her existing medications, including prednisone. Dr R examined Ms B in the hospital between November 24 and November 26, 2016.

The hospital physicians adjusted Ms B’s prednisone dose after noting findings consistent with an inflammatory response to poorly controlled rheumatoid arthritis. The plaintiff’s arthritis was improved after that, and she was discharged from the hospital on November 28, 2016, in stable condition, with a prescription for prednisone, and instructions to follow up with Dr R, her internist.

She saw Dr R the day after she was discharged, November 29, and he provided her with a continuation prescription for levofloxacin, one 750mg tablet every 48 hours for 6 days. She filled the prescription and took the medication. Within a month, Ms B suffered from an acute rupture of the gluteus medius tendon, requiring her to undergo 2 major surgeries leaving her unable to walk without assistance, and suffering from numerous disabilities.

Tendon rupture is a known risk of fluoroquinolones such as levofloxacin, and the risk is increased in patients over the age of 60 and in those taking corticosteroids, such as prednisone. This information has been the subject of a Boxed Warning which was added to the dispensing information in 2008.

Researchers conducted the randomized, double blind, parallel group, phase 3 INVIGORATE-1 trial (ClinicalTrials.gov Identifier: NCT04156620). They reported on the long-term efficacy, safety, and tolerability of IV SEC among adult patients with active axSpA. 

Patients were equally divided into two groups, one receiving IV SEC at a dose of 6 mg/kg initially, followed by 3 mg/kg every 4 weeks, and the other receiving a placebo for the first 16 weeks. 

Following the 16-week mark, patients initially assigned to the placebo group were transitioned to IV SEC at a dose of 3 mg/kg every 4 weeks, while those initially assigned to treatment with SEC continued until week 52.

The primary study endpoint was defined as the Assessment of SpondyloArthritis international Society-40 (ASAS40) response rate at week 16.

Efficacy was further evaluated until week 52 by examining the percentage of patients achieving an ASAS40 response, a major improvement in the Ankylosing Spondylitis Disease Activity Score with C-reactive protein, achievement of an ASAS5/6 response, and changes from baseline in Bath Ankylosing Spondylitis Disease Activity Index scores, Bath Ankylosing Spondylitis Functional Index scores, and Short Form 36 Physical Component Summary scores. 

Safety data were monitored through 60 weeks. A total of 264 patients were randomly assigned to the IV SEC group and 262 patients to the placebo/IV SEC group; 86% and 88.9% of participants completed the full study period, respectively. 

Among the participants, 413 patients had radiographic axSpA and 113 patients had nonradiographic axSpA. Demographics and baseline characteristics were evenly distributed between the treatment groups. Patients initially treated with SEC demonstrated rapid improvements in ASAS40 response rates. 

Patients originally treated with placebo who switched to SEC at week 16 achieved ASAS40 response rates comparable to those of patients initially treated with SEC by week 24. Response rates were maintained through week 52, with a rate of 66.8% among the SEC group and 74.9% among the placebo/SEC group.

Patients treated with SEC demonstrated sustained improvement among all other efficacy measures through week 52. In terms of safety, the incidence of adverse events (AEs) through week 16 was similar between patients receiving SEC vs placebo/SEC (38.6% vs 39.1%).

Comparable rates were also observed for serious AEs (2.7% vs 1.1%) and AEs leading to treatment discontinuation (1.9% vs 0.4%) between the SEC and placebo/SEC groups, respectively. 

Among patients who received IV SEC at any time during the study, 63.2% reported any AE, 6% experienced serious AEs, and 3.5% had AEs leading to treatment discontinuation. One death unrelated to treatment occurred during SEC therapy.

The study authors noted, “The safety profile of IV SEC for patients with axSpA was consistent with that of previous reports for subcutaneous SEC, and no new safety signals were observed.”

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. 

Sheila Sprague, PhD, from McMaster University in Hamilton, Ontario, Canada, and colleagues conducted a cluster-randomized, crossover trial at 25 hospitals in the US and Canada to compare use of alcohol solutions containing iodine povacrylex or chlorhexidine gluconate as skin antisepsis before surgery to repair a fractured limb. Hospitals were randomly assigned to use 0.7% iodine povacrylex in 74% isopropyl alcohol (iodine group) or 2% chlorhexidine gluconate in 70% isopropyl alcohol (chlorhexidine group) as preoperative antisepsis. The hospitals alternated interventions every 2 months. The trial included 6785 patients with a closed fracture and 1700 with an open fracture.

The researchers found that surgical-site infection occurred in 2.4 and 3.3% of patients in the iodine and chlorhexidine groups, respectively, in the closed-fracture population (odds ratio, 0.74; 95% CI, 0.55 to 1.00; P =.049) and in 6.5 and 7.3%, respectively, in the open-fracture population (odds ratio, 0.86; 95% CI, 0.58 to 1.27; P =.45). The 2 groups had similar frequencies of unplanned reoperation, one-year outcomes, and serious adverse events.

“The interventions that we compared in this trial are similar in price, availability, and directions for use,” the authors write. “Our findings suggest that the use of iodine povacrylex in alcohol as preoperative skin antisepsis could prevent surgical-site infection in thousands of patients with closed fractures, but such use is unlikely to improve the outcomes in patients with open fractures.”

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