Overactive bladder treatment using antimuscarinic drugs increases the risks for urinary tract infection (UTI) and lower urinary tract symptoms (LUTS), a new study finds.

Nobuhiro Haga, MD, PhD, of Fukuoka University in Japan, and colleagues performed a meta-analysis of 29 placebo-controlled trials of antimuscarinic agents and 9 placebo-controlled trials of beta 3-adrenoceptor agonists involving 35,939 patients with overactive bladder, published during 2002 to 2021. All trials had low risk of bias.

At 1-3 months after treatment, UTI risk was a significant 23% higher among patients receiving antimuscarinic drugs compared with placebo, the investigators reported in The Journal of Urology. The broad UTI outcome encompassed upper UTI, acute cystitis requiring treatment, as well as febrile UTI. Use of antimuscarinic drugs also was significantly associated with a 2.9-fold increased risk for urinary retention (few patients required catheterization), dysuria, and/or increased residual urine volume, factors involved in UTI pathogenesis. Antimuscarinic drugs included imidafenacin, solifenacin, tolterodine, fesoterodine, darifenacin, and trospium of various doses.

Use of beta 3-adrenoceptor agonists was not associated with any of these risks, the investigators reported. Drugs in this class included solabegron, mirabegron, and vibegron.

“To prevent urinary tract infection emergence, beta 3-adrenoceptor agonists might be safer than antimuscarinic agents,” according to Dr Haga’s team. The investigators noted that UTI causes not only LUTS, but pyelonephritis, which can lead to kidney dysfunction. They suggested that older adults and patients with diabetes might be good candidates for beta 3-adrenoceptor agonists due to their increased risks for UTI. Women with strong overactive bladder symptoms and men without bladder outlet obstruction due to benign prostatic hyperplasia or other conditions might be good candidates for antimuscarinic agents.

The investigators acknowledged that a direct comparison between antimuscarinics and beta 3-adrenoreceptor antagonists in a randomized trial would be more reliable and informative than a meta-analysis.

Reference

Tsubouchi K, Arima H, Abe M, et al. Effect of pharmacotherapy for overactive bladder on the incidence of and factors related to urinary tract infection: a systematic review and meta-analysis. J Urol. 209(4):665-674. doi:10.1097/JU.0000000000003209

Treatment with aspirin might reduce mortality risk in patients with sepsis-associated acute kidney injury (SA-AKI) admitted to the ICU, investigators report.

In a propensity score analysis of 7694 adults with SA-AKI, the risk of dying within 90 days was 27.8% lower among those who received aspirin compared with those who did not, Fanna Liu, MD, and colleagues from The First Affiliated Hospital of Jinan University, in Guangzhou, China, reported in the Frontiers of Pharmacology. The median survival time was significantly longer for patients treated with vs without aspirin: 46.47 vs 24.26 days.

Hypertension, diabetes, and prior cardiac surgery are common in this population and each factor increases cardiovascular-related mortality. Aspirin use was associated with greater benefits in these patients. Aspirin significantly reduced the risk for early mortality by 33.3% in patients with prior cardiac surgery patients compared with 19.7% in patients without cardiac surgery. Patients with hypertension and diabetes had 24.2% and 28.2% lower mortality risk with aspirin use, respectively. Patients without these conditions had 24.1% and 21.2% reduced risks for early mortality, respectively.

Aspirin might exert beneficial effects on the cardiovascular system, the investigators suggested. In sepsis-associated AKI, aspirin may exert anti-inflammatory and anti-platelet effects. By AKI stage, patients with stage 3 AKI had the greatest 90-day mortality risk reduction (32.6%).

Dr Lui’s team also found a dose-dependent response. High-dose aspirin of more than 300 mg/d was significantly associated with a 14.8% reduced risk for early mortality compared with lower-dose aspirin. Enteric-coated aspirin appeared less effective than plain aspirin. High-dose aspirin inhibits both cyclooxygenase 1 and 2, whereas lower dose aspirin inhibits only 1 form of the enzyme.

ICU length of stay was significantly shorter for the aspirin than non-aspirin group: 5.19 vs 5.58 days. Gastrointestinal hemorrhage rates did not differ between patients taking vs not taking aspirin. “Aspirin may be an effective drug for SA-AKI,” according to Dr Liu’s team.

HealthDay News — Cannabidiol (CBD) oil is safe but not effective for pain control or reducing opioid use in patients undergoing ureteroscopy with stent placement for urinary stone disease, according to a study published in the April issue of The Journal of Urology.

Gopal Narang, MD, from the University of North Carolina in Chapel Hill, and colleagues examined the effect of a US Food and Drug Administration-approved CBD oil (Epidiolex) on pain control and opioid use after ureteroscopy in a prospective double-blind trial. In total, 90 patients (median age, 64 years; 61% female) undergoing ureteroscopy with stent placement for urinary stone disease were randomly assigned to placebo or 20mg CBD oil for 3 days postoperatively in a 1:1 ratio.

The researchers found that the groups did not differ in pain scores or opioid usage postoperatively. When comparing physical activity, sleep, urination, and activities of daily life, the level of discomfort with ureteral stents was also not different between the groups. The groups did not differ in preoperative or perioperative characteristics.

“Postoperative CBD was safe but ineffective when compared to placebo in minimizing postureteroscopy stent discomfort or opioid usage,” the authors write. “Despite the availability of numerous analgesic agents, stent-related symptoms and bother continue to be a factor in patient care. Further translational research into the presence of endocannabinoid receptors in the ureter and studies evaluating CBD oil with dose escalation could help to better understand the role of CBD oil in the postureteroscopy setting.”

Several authors disclosed financial ties to the biopharmaceutical industry.

Abstract/Full Text

Paul Piedras, from the University of California at Irvine, and colleagues analyzed 5 commercially available alkaline waters to assess their potential to increase urinary pH compared to potassium citrate, the gold standard for urinary alkalinization.

The researchers found that the pH levels of the bottled alkaline water ranged from 9.69 to 10.15. For all brands, electrolyte content was minimal and the physiologic alkali content was below 1 mEq/L. Compared with potassium citrate, the alkali content of alkaline water is minimal. Other organic beverages, synthetic beverages, and supplements contain more alkali content than alkaline water and can achieve the American Urological Association and European Association of Urology alkali recommendation of 30 to 60 mEq per day with no more than 3 servings per day.

“Commercially available alkaline water has negligible alkali content and thus provides no added benefit over tap water for patients with uric acid and cystine urolithiasis,” the authors write.

One author disclosed employment with Litholink, a subsidiary of LabCorp.

Abstract/Full Text

A harsh cocktail of chemotherapy, radiation and immunotherapy for his advanced lung cancer had permanently destroyed his lungs and caused irreparable damage to his liver.

But Gibbon, a 69-year-old resident of Santa Monica, California, remains alive thanks to a groundbreaking, combined lung-liver transplant, according to his doctors at Northwestern Medicine in Chicago.

“I’ve been a physician for decades, and we tend to be conservative at times with our treatment plans, which is why the enormity of the science that went into this procedure is awe-inspiring to me,” Gibbon, a pulmonologist-allergist-immunologist, said in a Northwestern news release.

Gibbon calls the landmark surgery his “Triple L”; 2 lungs and a liver.

“To our knowledge, this is the first known case in the nation where a patient with advanced lung cancer has successfully received a combined lung-liver transplant,” said Dr Ankit Bharat, chief of thoracic surgery and director of the Northwestern Medicine Canning Thoracic Institute. Bharat performed Gibbon’s lung transplant.

Gibbon was born in Cape Town, South Africa, but spent the last 33 years in private practice in Santa Monica before he fell ill.

In March 2023, Gibbon started coughing and losing weight. A chest X-ray revealed stage 3 lung cancer.

Doctors went after the cancer hard, subjecting Gibbon to brutal rounds of chemo, radiation and immunotherapy.

By mid-July, Gibbon was hospitalized with septic shock, pneumonia and multiple organ failure. His lungs were irreversibly scarred by the immunotherapy, and he would need them replaced.

“As a pulmonologist, I never imagined I’d ever need a lung transplant, let alone for lung cancer,” Gibbon said.

Northwestern University offers a first-of-its-kind clinical program called Double Lung Replacement and Multidisciplinary Care (DREAM), and Gibbon turned to doctors there to save his life.

While evaluating Gibbon, Northwestern doctors found the immunotherapy had also caused liver cirrhosis.

A 4-hour medical flight delivered Gibbon to Chicago on September 10, where he awaited donor organs in the ICU at Northwestern Memorial Hospital.

After 12 days on the transplant wait list, Gibbon received his new lungs and liver from the same donor during a 10-hour surgical procedure.

Surgeons implanted the new lungs first, while the donor liver was kept alive outside the body thanks to a machine that pumps warm, oxygenated and nutrient-enriched blood through the organ, a technology the docs call “liver in a box.”

The liver-sustaining technology gave Bharat sufficient time to meticulously remove Gibbon’s damaged lungs as well as all the cancer.

Bharat had to remove both cancer-ridden lungs, and then wash out the airways and the chest cavity before transplanting in the new lungs.

During this process, Gibbon was on full heart and lung bypass, Bharat said.

“These patients can have billions of cancer cells in the lungs, so we must be extremely meticulous to not let a single cell spill into the patient’s chest cavity or blood stream,” Bharat said. “We believe this technique can help reduce the risk of recurrence, which we learned through our experience with pioneering COVID-19 lung transplants.”

Six months after surgery, Gibbon has no signs of cancer in his body and does not require any further treatment, his doctors said.

Gibbon will remain in Chicago through the summer so his transplant team can closely monitor him.

“This DREAM program is new territory for transplantation and the fact that I could experience it and have a wonderful outcome makes me feel so blessed,” Gibbon said. “I wouldn’t be here today without Northwestern Medicine.”

More information

The American Cancer Society has more about lung cancer.

SOURCE: Northwestern University, news release, March 28, 2024

Phosphodiesterase-5 inhibitors (PDE5i) reduce the likelihood of major adverse cardiovascular events in men with both coronary artery disease (CAD) and erectile dysfunction (ED), according to study findings presented at the American Urological Association’s 2023 annual meeting in Chicago, Illinois.

In addition, investigators found that the cardiac benefit of PDE5i is more pronounced with tadalafil than sildenafil.

In a retrospective study of 41,287 men with CAD (but not pulmonary hypertension) and ED, Albert Ha, MD, of Columbia University’s Irving Medical Center in New York, New York, and colleagues found that men who took tadalafil and sildenafil had a significant 33% and 22% lower 5-year risk for heart failure, respectively, compared with men who received no PDE5i treatment after propensity-score matching. Tadalafil and sildenafil recipients had 25% and 12% lower 5-year risks for myocardial infarction and 41% and 35% lower 5-year risks for overall mortality, respectively.

Further, compared with sildenafil recipients, tadalafil-treated patients had significant 15%, 14%, and 15%, lower 5-year risks forheart failure, myocardial infarction, and overall mortality, respectively.

“I think our study is the first to tease out specific differences among individual PDE5i in relation to cardiac outcomes, with our preliminary results suggesting that tadalafil may be superior to other PDE5i like sildenafil in relation to heart failure, myocardial infarction, and mortality, ” Dr Ha said in an interview. “Since erectile dysfunction is a common harbinger for cardiac disease later in life, it is important for patients to understand what drugs may best address their medical issues, especially in a time when medical care may be siloed in different (and oftentimes disconnected) specialties. “

As for the greater cardiac benefit observed with tadalafil, Dr Ha said, “We speculate that this may be due to differences in pharmacokinetics, with tadalafil offering more specific inhibition of PDE5 enzymes with less cross reactivity, as well as a longer duration of efficacy. As such, this may promote medication compliance, particularly in patients with both ED and CAD. However, our results are preliminary, and as such, we cannot definitely conclude that clinicians should preferentially prescribe tadalafil until additional research is performed.”

The study population included 12,214 sildenafil users, 6751 tadalafil users, and 22,321 men who received no treatment. Dr Ha’s team performed propensity-score matching using baseline comorbidities of hypertension, ischemic heart disease, cerebral infarction, diabetes, and hyperlipidemia.

Reference

Ha H, Wayne G, Jacobs M, Kalogeropoulos A, Alukal J. Phosphodiesterase-5 inhibitor use and progression to heart failure in men with coronary artery disease and erectile dysfunction. Presented at: AUA 2023, Chicago, Illinois, April 28-May 1. Presentation PD11-10.

Investigators performed a meta-analysis of 3 cohorts including 50,832 patients with and 1,028,825 without kidney stones. Genetic proxies of thiazide diuretics were significantly associated with 15% decreased odds of kidney stones, Adriana M. Hung, MD, MPH, of Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues reported in JAMA Network Open.

Genetic proxies of thiazide diuretics also were associated with significantly higher serum calcium and total cholesterol levels, but lower serum potassium.

The genetic proxies of thiazide diuretics were naturally occurring genetic variants in the thiazide-sensitive sodium chloride cotransporter gene, which is associated with systolic blood pressure. These proxies are not affected by diet or environment as drugs would be. As negative controls, genetic proxies of β-blockers and systolic blood pressure showed no association with stone risk.

“In this genetic association study, genetic proxies of thiazide diuretics were associated with reduced kidney stone risk,” Dr Hung’s team wrote. “This finding reflects a drug effect over the course of a lifetime, unconstrained by the limited follow-up period of clinical trials.”

This past March, investigators reported findings from the NOSTONE randomized trial demonstrating that hydrochlorothiazide had no effect on recurrence of calcium-containing kidney stones over nearly 3 years of follow-up.

Dr Hung and colleagues noted that although Mendelian randomization does not supersede evidence from a randomized clinical trial, it “provides an additional level of evidence for the preventive potential of thiazide diuretics in kidney stone disease.”

The International Consortium for Blood Pressure, UK Biobank, and the FinnGen study included mostly European adults. The Million Veteran Program included mostly male veterans. The results of this study might not apply to women and other ethnicities.

Although a recent meta-analysis suggested that gonadotropin-releasing hormone (GnRH) antagonists lead to fewer major adverse cardiovascular events (MACE) compared with luteinizing hormone-releasing hormone (LHRH) agonists, a new real-world study finds the opposite: higher MACE risk with GnRH antagonist use. Investigators presented the findings at the Society of Urologic Oncology 24th Annual Meeting in Washington, DC.

“Our analysis of data from [approximately] 45,000 PCa patients collected over the most recent decade likely reflects real-world outcome patterns,” according to Tanya Dorff, MD, of the City of Hope National Medical Center, Duarte, California, and colleagues.

The investigators examined MACE and all-cause mortality risk among men receiving at least 1 dose of an GnRH antagonist or LHRH agonist (99% from 2010-2020) from the Decision Resources Group database.

Based on data from 40,753 men, MACE risk was a significant 1.6-fold higher for GnRH antagonist recipients vs LHRH agonist recipients in an adjusted analysis, Dr Dorff reported on behalf of her team. Based on data from 41,765 men, all-cause mortality risk was a significant 1.8-fold higher for GnRH antagonist vs LHRH agonist users in an adjusted analysis.

Adjusted analyses accounted for age, body mass index, personal and family MACE history, statin use, tobacco history, history of diabetes and/or hypertension, antagonist vs agonist use, baseline PSA, oncology vs urology setting, and race and ethnicity. 

“In this real-world claims database, overall MACE and mortality risk both increased consistently by 4-5% per year during the first 4 years after ADT initiation,” Dr Dorff and colleagues reported. Due to the inherent limitations of retrospective observational studies, further detailed studies are needed to explain any differences in these risks for GnRH antagonist vs LHRH agonist users. ADT duration and concomitant use of androgen receptor pathway inhibitors are important factors.

The median age of the cohort was 75 years. Black and Asian men accounted for 12.7% and 1.3% of patients, respectively. The antagonist and agonist groups had comparable proportions of patients with MACE history (3.4% vs 3.0%). MACE incidence was higher among White than Black and Asian patients initiating androgen deprivation therapy (ADT): 4.0% vs. 2.4% vs 2.2%, respectively, at 1 year after ADT initiation and 21.0% vs 13.3% vs 11.7%, respectively, at 4 years.

“As patients initiating ADT likely have a high burden of underassessed and untreated CV risk factors, clinicians should focus on monitoring and treating comorbidities to reduce mortality risk in PCa patients on ADT,” the authors concluded in a poster presentation.

Disclosure: This research was supported by Tolmar inc. Please see the original reference for a full list of disclosures.

Nithya Krishnamurthy, from the Icahn School of Medicine at Mount Sinai in New York City, and colleagues examined the effect of using exogenous testosterone as GAHT on hematocrit in 6670 patients who were prescribed testosterone through Plume.

Of the patients, 8.4, 2.7, and 0.9% had a hematocrit 50% or greater, 52% or greater, and 54% or greater, respectively. The researchers found that hematocrit varied significantly between different clinically relevant testosterone thresholds (T <50 vs 50 to 299 vs 300 to 999 vs ≥1,000ng/dL) and on comparison of serum testosterone in increments of 50ng/dL within the target range for males (300 to 1000ng/dL). The range of mean hematocrit was from 41.84% (T <50 ng/dL) to 45.68% (T 900 to 949ng/dL). Higher mean hematocrit was seen for patients on intramuscular testosterone vs transdermal testosterone (44.96 vs 43.41%). When controlling for each other, both route of administration and testosterone level had significant associations with hematocrit.

“It’s noteworthy that in the largest North American cohort reported to date, less than 1% of transmasculine individuals had a hematocrit level where medical interventions might be required,” Krishnamurthy said in a statement. “These results should help providers feel more comfortable prescribing testosterone as part of GAHT.”

Abstract/Full Text (subscription or payment may be required)

Previous research has indicated that among patients with NAFLD, those with comorbid T2D are at increased risk for fibrosis progression. However, there has been little data about T2D-specific risk for hepatic decompensation or HCC in NAFLD.

To evaluate these relationships, investigators from the University of California San Diego searched publication databases for relevant studies to be included in a systematic review and meta-analysis. Study data were sourced from 6 well-characterized cohorts of patients with NAFLD, who were recruited from the United States, Japan, and Turkey.

The pooled sample size was 2,016 patients. Study participants had a mean [SD] age of 57.8[14] years, 53% were women, they had a BMI of 31.32 (SD, 7.43) kg/m², and 1,280 had T2D.

Among a subset of 1,732 patients who did not have hepatic decompensation at baseline, 112 progressed to hepatic decompensation during a median follow-up of 3 years.

The cumulative incidence of hepatic decompensation among the T2D and control cohorts were 3.3% and 1.0% at 1 year, 6.9% and 2.3% at 3 years, and 9.7% and 2.7% at 5 years (P <.001), respectively.

Similarly, the cumulative incidence of HCC was higher among patients with T2D at 1 (1.3% vs 0.1%), 3 (2.0% vs 0.2%), and 5 (2.7% vs 0.3%) years compared with control individuals (P <.001), respectively.

After adjusting for age, gender, race and ethnicity, and BMI, compared with control individuals, T2D was associated with increased risk for hepatic decompensation (adjusted hazard ratio [aHR], 2.10; 95% CI, 1.38-3.20; P = .0006) and HCC (aHR, 5.10; 95% CI, 1.67-15.67; P = .004).

This study may have been limited by the small sample size of patients who did not have T2D.

These data indicated that in the setting of NAFLD, T2DM associated with increased risk for poorer hepatic outcomes. Study authors concluded, “[W]e demonstrate that T2DM is associated with a significantly higher risk of hepatic decompensation and HCC. These data have important implications for clinical practice and clinical trial design.”

A virus may be the original pathogen leading to the development of interstitial cystitis, and studies have found associations with BK polyomavirus and JC virus, De-yi Luo, MD, PhD, of West China Hospital, Sichuan University in China, and colleagues noted. Interferon may promote an antiviral response to these infections.

In a double-blind randomized clinical trial of 52 Chinese women aged 18-70 years with interstitial cystitis (ClinicalTrials.gov Identifier: NCT05912946), pain intensity assessed by the visual analog scale decreased by a significant 1.3 points more at 6 months in patients receiving intravesical interferon, the investigators reported in JAMA Network Open. From baseline to 6 months, pain score had decreased 4.5 points in the intravesical interferon group compared with 3.6 points in the intravesical hyaluronic acid group. A greater proportion of patients receiving intravesical interferon experienced a 30% of more reduction in the visual analog scale score before and at 6 months (77% vs 46%). At baseline, similar proportions had Hunner ulcers (38% vs 35%).

Scores on the interstitial cystitis problem index and interstitial cystitis symptom index also decreased by a significant 3.0 and 2.5 points more, respectively, over 6 months in the interferon vs hyaluronic acid group. Along with patient-reported outcomes, an objective measure, moderate or greater improvement on the global response assessment, was reported by significantly more patients treated with interferon rather than hyaluronic acid (85% vs 54%). There were no significant differences between groups in 24-hour urinary frequency and functional bladder capacity.

The interferon group received installation of 1 mL of 300 international units recombinant human interferon alpha-2b injection with 40 mL sterile saline. The hyaluronic acid group received instillation of 40 mg of hyaluronic acid solution per 50 mL sterile saline. Patients received 4 weekly instillations, followed by monthly instillations for the subsequent 4 months.

The most common adverse events in both groups were bladder irritation and urinary infection that resolved or were successfully treated. One patient discontinued hyaluronic acid for poor effectiveness.

Previous pilot studies have investigated intravesical cidofovir, certolizumab pegol, and oral valacyclovir for these patients.

“This research underscores the potential benefits of antiviral approaches in [interstitial cystitis] management, which may improve patient care and quality of life,” according to Dr Luo’s team. “Further prospective multicenter evaluation is necessary to validate these findings.”

Kidney function remains stable over 12 months in most patients with uncontrolled gout treated with a combination of pegloticase and methotrexate, investigators reported at the National Kidney Foundation’s 2023 Spring Clinical Meetings in Austin, Texas.

Methotrexate is used cautiously in patients with mild to moderate chronic kidney disease (CKD) because it is primarily excreted by the kidneys and can contribute to acute kidney injury. The disease-modifying antirheumatic drug is contraindicated in advanced CKD.

Investigators hypothesized that methotrexate would reduce immunogenicity from treatment with pegloticase, a pegylated mammalian recombinant uricase. Results from the original MIRROR randomized controlled trial (Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Krystexxa) showed a higher urate-lowering response rate (71% vs 39%) and lower infusion reaction risk (4% vs 31%) at 6 months among patients randomly assigned to methotrexate (15 mg/week) or placebo, in combination with pegloticase (8mg biweekly infusion). At baseline, patients had a serum uric acid level of 7mg/dL or higher, failure or intolerance to urate-lowering therapy, and 1 or more gout symptoms. Patients with an estimated glomerular filtration rate (eGFR; in mL/min/1.73 m²) less than 40 using the Modification of Diet in Renal Disease equation were excluded.

At 12 months, urate lowering with pegloticase was sustained in 50.0% and 75.8% of the combination treatment group compared with 25.0% and 43.8% of the placebo recipients who had a baseline eGFR of more than 60 and 40-59, respectively, Abdul Abdellatif, MD, of Baylor College of Medicine in Houston, Texas, and colleagues reported.

Over 12 months, mean eGFR increased by 4.6 in the combination treatment group from a baseline value of 69.8 and increased by 1.7 in the placebo group from a baseline level of 69.7. Among patients in the combination group with a baseline eGFR of more than 60 and 40 to 59, CKD stage improved in 14.0% and 44.4%, remained stable in 72.1% and 48.1%, and worsened in 14.0% and 7.4%, respectively, over 12 months.

Dr Abdellatif’s team concluded that “eGFR remained stable in the majority of uncontrolled gout patients treated with pegloticase both in the presence and absence of [methotrexate] co-therapy.” The investigators noted that they observed this effect in patients with stage 3 CKD and an eGFR higher than 40 at baseline. These study findings extend 6 month results presented at an earlier conference.  

Disclosure: This research was supported by Horizon Therapeutics plc. Please see the original reference for a full list of disclosures.

Reference

Abdellatif A, Botson J, Obermeyer K, Padnick-Silver L, Marder B. eGFR changes during pegloticase treatment with and without methotrexate co-therapy: 12-month findings of MIRROR RCT. Presented at: NKF 2023, Austin, Texas, April 11-15. Poster 232.