NAC Underused for MIBC in Older Adults

Study Challenges ADT Use at PSA Relapse

Waiting until metastasis to start treatment has minimal impact on overall survival, investigators found

OVERALL SURVIVAL is not meaningfully prolonged for patients with biochemically recurrent (BCR) prostate cancer who receive continuous androgen deprivation therapy (ADT) at the time of PSA relapse rather than metastasis, according to investigators. “Metastasis-free survival and overall survival of men with BCR who delay hormone therapy is long. This underscores the need to reevaluate when to start primary ADT in this patient population,” Catherine Handy Marshall, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and her colleagues team concluded in a report published online in The Journal of Urology.

Dr Marshall’s team studied 806 highrisk patients (mean age 61 years; 16% Black) from Johns Hopkins Hospital and Walter Reed National Military Medical Center in Bethesda, Maryland, who experienced BCR after radical prostatectomy and delayed ADT initiation until metastasis. From the time of local treatment, median metastasis-free

survival (MFS) was 144 months and 192 months for men with a PSA doubling time of less than 6 months and less than 10 months, respectively, the investigators reported. Median overall survival (OS) from the time of local treatment was 168 and 204 months, respectively. Older age, higher pathologic T stage, higher Gleason sum, and faster PSA doubling time were all associated with higher likelihood of death.

Dr Marshall and her collaborators compared their results with MFS and OS times from pivotal trials of highrisk patients with nonmetastatic castration-resistant prostate cancer who were treated with surgery, radiation, or primary ADT alone. Estimated median MFS was 136 vs 110 months in the apalutamide and placebo arms, respectively, of the SPARTAN trial, and 127 vs 103 months in the darolutamide and placebo arms, respectively, of the ARAMIS trial. Estimated median OS was 169 vs 154 months in the apalutamide and placebo arms, respectively, of the SPARTAN trial and not reached in the ARAMIS trial. OS times from these trials are comparable to those from the current study.

In an accompanying editorial, David VanderWeele, MD, PhD, and Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center at the Northwestern University Feinberg School of Medicine, in Chicago, Illinois, agreed that the risks of early ADT in men with biochemically recurrent prostate cancer may not outweigh the benefits.

“These data provide context for patients with BCR and providers on whether to undergo ADT for years despite unproven benefit and quality of life impact,” they wrote. “New imaging may help or further add to the controversy, since BCR patients may have metastases on newer imaging. Until definitive data are available, men with BCR should be counselled regarding the lack of data to support ADT benefit in nonmetastatic BCR.” ■

Long survival time observed for men with biochemical recurrent PCa who delay ADT.

Study: Biomarkers May Predict COVID-19 Death Risk in KTRs

AMONG KIDNEY TRANSPLANT recipients (KTRs) infected with SARS CoV-2, those who have elevations in biomarkers of inflammation, cardiac injury, and coagulation appear more likely to die.

In a French nationwide registry of 494 KTRs with COVID-19 during the first wave of the pandemic, 101 (20%) died. Patients with levels of serum creatinine above 150 μmol/L, C-reactive protein above 50 mg/L, procalcitonin above 0.3 mg/L, hs-troponin I above 20 ng/L, lactate dehydrogenase above 280 UI/L, and D-dimer above 1500 UI/L were at increased risk for COVID-19related mortality.

On multivariate analysis, only procalcitonin and troponin I remained independently associated with a significant 3.7- and 2.9-fold increased risk for mortality, respectively, Sophie Caillard, MD, PhD, of the Strasbourg University Hospital in Strasbourg Cedex, France, and colleagues reported in Kidney International Reports. Subgroup analyses additionally identified D-dimer as a prognostic biomarker.

The 60-day survival rate was as high as 92% among patients without elevation in any of the 3 biomarkers, but the rate declined to 77% among those with elevation of at least 1 of the biomarkers. The 60-day survival rate declined to 58% and 40% among patients with elevations in 2 and 3 biomarkers, respectively.

Several studies in the adult general population have found an association between elevation of cardiac injury, coagulation, and inflammatory biomarkers and COVID-19-related mortality, the investigators noted.

“If independently validated, the use of biomarkers may help to guide therapeutic decision making in transplant patients,” Dr Caillard’s team concluded.

Of the 494 KTRs (approximately 5% dual organ transplants) with COVID-19, 83% were admitted to the hospital and 30.6% of these were sent to an intensive care unit. Mechanical ventilation was required by 26% of the cohort. Overall, acute kidney injury occurred in 57.8%, and renal replacement therapy was initiated in 15.6%. ■

Finerenone’s Benefits Span CKD Spectrum

FINERENONE REDUCES the risk for cardiovascular and renal outcomes in patients with type 2 diabetes who have mild to advanced chronic kidney disease (CKD) and those with diagnosed diabetic kidney disease, investigators announced at the 2021 congress of the European Society of Cardiology.

The nonsteroidal mineralocorticoid receptor antagonist (MRA) carries an increased risk for hyperkalemia.

“The FIDELITY analysis demonstrates that finerenone reduced the risk of cardiovascular and kidney outcomes compared with placebo across the spectrum of chronic kidney disease in patients with type 2 diabetes,” study author Gerasimos Filippatos, MD, of the National and Kapodistrian University of Athens Medical School in Greece stated in an ESC congress press release. “The cardiovascular benefits of the drug were consistent across eGFR and UACR categories, indicating that treatment should be initiated in the early stages of renal disease.”

In FIDELITY, a prespecific metaanalysis combining individual patient data from of data from 13,026 patients in the FIDELIO-DKD and FIGARODKD randomized trials. CKD severity was defined according to categories of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR).

The primary endpoint was time to first occurrence of a composite of cardiovascular (CV) death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The secondary endpoint was time to first occurrence of a composite of kidney failure, decrease in eGFR by 57% or more, or renal death.

Over a median of 3.0 years of follow-up, the composite CV endpoint occurred in a lower proportion of patients receiving finerenone compared with placebo: 12.7% vs 14.4%, according to investigators. Finerenone reduced the risk for the CV outcome by a significant 14%.

The composite renal endpoint also occurred in a smaller proportion of patients receiving finerenone vs placebo: 5.5% vs 7.1%. Finerenone reduced the risk for the renal outcome by a significant 23%.

Hyperkalemia was more common with finerenone than placebo: 14.0% vs 6.9%. Discontinuation of treatment due to hyperkalemia occurred in 1.7% of the finerenone and 0.6% of the placebo group. ■

Salt Substitute May Decrease Stroke Risk

Large trial reveals cardiovascular benefits of using a salt containing 25% potassium chloride

A STUDY of individuals at elevated risk for cardiovascular events found that use of a salt substitute with reduced sodium levels instead of regular salt decreased the risk for stroke without increasing the likelihood of serious adverse effects, according to investigators.

In the randomized Salt Substitute and Stroke Study (SSaSS), participants who used a salt substitute (75% sodium chloride and 25% potassium chloride) had a significant 14% lower risk for stroke — the trial’s primary outcome — compared with those who used regular salt (100% sodium chloride), Bruce Neal, MB, ChB, PhD, of the George Institute for Global Health at the University of New South Wales in Australia, and colleagues reported in the New England Journal of Medicine.

Users of the salt substitute also experienced a significant 13% decreased risk for major cardiovascular events and 12% decreased risk for death from any cause.

The rate of serious adverse events due to hyperkalemia was not significantly higher with salt substitute use.

The study included 20,995 persons who lived in 600 rural villages throughout China. Participants had a history of stroke or were aged 60 years or older and had poorly controlled blood pressure. Of the study population, 72.6% had a history of stroke, and 88.4% had a history of hypertension. Individuals had a mean age of 65.4 years. The mean duration of followup was 4.74 years. The study excluded individuals if they or others living in their household had a potential contraindication to the salt substitute used in the trial (such as use of a potassium supplement, use of a potassium-sparing diuretic, or known serious kidney disease).

The rates of stroke, major cardiovascular events, and death (in events per 1000 person-years), all higher in saltsubstitute group than the regular-salt group, were 29.14 vs 33.65, 49.09 vs 56.29, and 39.28 vs 44.61, respectively. The investigators defined major cardiovascular events as a composite of nonfatal stroke, nonfatal acute coronary syndrome, or death from vascular causes.

The rates of definite, probable, or possible hyperkalemic events were 3.35 and 3.30, respectively, a nonsignificant difference between the groups.

In an acknowledgment of study limitations, the authors noted that potassium “was not measured serially, and elevated potassium levels might have been missed in some participants.” Further, only a single preparation of a salt substitute was used in the trial, “so graded decreases in sodium intake, which might have induced graded responses, were not evaluated.”

“The results of the SSaSS appear impressive,” the journal’s deputy editor Julie R. Ingelfinger, MD, wrote in an accompanying editorial. “If the strategy is feasible over time, the salt-substitute approach might have a major public health consequence in China, and possibly, elsewhere.” ■

Fewer CV Events With Salt Substitute Use

In a randomized trial that included 20,995 rural Chinese residents, use of a salt substitute lowered the risk for stroke, major cardiovascular (CV) events, and death compared with the use of regular salt. Shown here are the event rates per 1000 person-years.

60

40

29.14% 33.65% 49.09% 56.29%

39.28%

■ Salt substitute ■ Regular salt

44.61%

20

0

Stroke Major CV events Deaths

Source: Neal B, Wu X, Feng R, et al. Effect of salt substitution on cardiovascular events and death. N Engl J Med. Published online ahead of print on August 29, 2021.

Dual Combo for Advanced RCC Cleared

THE FDA HAS approved pembrolizumab in combination with lenvatinib for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). The agency based its approval on data from the multicenter, open-label, randomized phase 3 CLEAR (Study 307)/KEYNOTE-581 trial, which evaluated the efficacy and safety of pembrolizumab plus lenvatinib compared with sunitinib.

“This is a significant milestone for newly diagnosed patients with advanced renal cell carcinoma and introduces a promising combination option in the first-line setting,” study investigator Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York, said in a press release issued by Merck and Eisai, the makers of pembrolizumab and lenvatinib, respectively. ■

Serious CV Events Tied to Low BMD

LOW BONE mineral density (BMD) may increase the risk for major adverse cardiovascular events and progression of coronary artery calcification among patients with predialysis chronic kidney disease (CKD), new study findings suggest.

In a prospective cohort study that included 1957 patients with predialysis CKD, the lowest tertile of total hip BMD was significantly associated with a nearly 2.2-fold increased risk for major adverse cardiovascular events (MACE) compared with the highest tertile after adjusting for age, sex, smoking, diabetes, systolic blood pressure, and other potential confounders, Hyoungnae Kim, MD, of Soonchunhyang University Seoul Hospital in Seoul, Korea, and colleagues reported in the Clinical Kidney Journal. The investigators also found the association of MACE with BMD at the femur neck, but not with BMD at the lumbar spine.

In a subgroup of 977 patients with repeat measurements of coronary artery calcification (CAC) at year 4 of the study, higher total hip BMD was significantly associated with 25% decreased odds for CAC progression.

Baseline CAC scores of 100 to 400 and higher than 400 were significantly associated with 3.0-fold and 5.9-fold increased risks for MACE compared with no CAC at baseline, according to the investigators.

Dr Kim and colleagues measured BMD using dual-energy X-ray absorptiometry and CAC using coronary computed tomography scans. MACE occurred in 115 patients during a median follow-up of 4.2 years. ■

Urate-Lowering Therapy May Cut Gout Flare Risk

CONTROLLING asymptomatic hyperuricemia with urate-lowering therapy (ULT) may decrease the likelihood of gout flares, according to an analysis of real-world data from Japan.

A retrospective study of 19,261 patients with serum uric acid levels of 8.0 mg/ dL or higher found that patients with either gout or asymptomatic hyperuricemia who achieved levels of 6.0 mg/dL or lower with ULT had fewer occurrences of gout flare compared with those whose serum uric acid level remained above 6.0 mg/dL, Ruriko Koto, MMSc, of Teijin Pharma Limited in Tokyo, and colleagues reported in the Annals of the Rheumatic Diseases. Patients with asymptomatic hyperuricemia and those with gout who were on ULT and had serum uric acid levels of 6.0 mg/dL or less but higher than 5 mg/dL had a significant 55% and 35% decreased risk for gout flare compared with untreated patients whose serum uric acid levels were 8.0 mg/dL or higher.

The researchers identified study patients using the JMDC Claims Database, which contains information from health insurance associations that include only limited data from individuals aged 65 years or older and no data from those aged 75 years or older, “so our findings cannot be generalized to the entire Japanese population.” ■

Wide BMI Fluctuations in CKD Linked to Worse Outcomes

High variability in body mass index found to increase risks for death, MI

BY JOHN SCHIESZER PATIENTS WITH chronic kidney disease (CKD) and wide body mass index (BMI) variability are at elevated risks for death, myocardial infarction, and stroke as well as an increased likelihood for requiring kidney replacement therapy, according to a recent study.

Previous studies have demonstrated that BMI variability or metabolic parameter variability is associated with a higher risk for heart disease in the general population. Investigators in South Korea examined whether BMI variability may affect the prognosis of patients with kidney dysfunction.

The retrospective observational study, published in the Journal of the American Society of Nephrology, included 84,636 patients with CKD who were listed in a national health screening database. Patients had a mean age of 68 years and median BMI of 24.6 kg/m2. At baseline, all the individuals had persistent predialysis CKD (defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m2 or dipstick albuminuria of 1 or higher), and had 3 or more health screenings before the baseline visit. The analysis included factors such as sex, waist circumference, current smoking history, alcohol intake, regular physical activity, diabetes mellitus, income status and other factors.

After a median followup of 4 years, 6% of patients died, 4% needed kidney replacement therapy, 2% had an MI, and 3% had a stroke. Compared with individuals who had the least BMI variability, those with the greatest variability had a 66% higher risk for death, 20% higher risk for kidney replacement therapy, and 19% higher risk for an MI or stroke.

Study investigator Sehoon Park, MD, of the Kidney Research Institute at Seoul National University, said a high BMI is traditionally considered a risk factor for adverse cardiovascular disease (CVD) and mortality in the general population. However, this did not appear to apply to patients with CKD, as baseline BMI was inversely associated with major adverse outcomes.

Assess BMI Trends “The major point which was surprising was that the significance remained both in those with an increasing trend of body mass index and in those with a decreasing trend,” Dr Parks said. “This highlights the importance of unstable metabolic status, which would be more important than obesity or increasing body mass index, even though a higher BMI is one of the most widely acknowledged bad metabolic health statuses in the general population.”

Variabilities in certain metabolic syndrome components were also significantly associated with the prognosis of patients with CKD not on dialysis. Those with a higher number of metabolic syndrome components with higher BMI variability had a worse prognosis.

Clinicians should ask, record, and assess the trends of BMI and metabolic health parameters at regular clinic visits, according to the researchers. “Focusing on a single time point may miss important clinical risk factors associated with the prognosis of CKD patients,” Dr Parks said. “A high variability state of body mass index or metabolic parameters should be carefully assessed. We believe the findings can be generalizable for Western countries, including North America, as unstable metabolic health status also appears to be associated with worse prognosis.”

Explore BMI Changes Holly Kramer, MD, MPH, a professor of public health sciences and medicine at Loyola University in Maywood, Illinois, said the study findings are not surprising because BMI fluctuations may indicate other serious comorbid conditions. “You have to look at depression and other issues,” Dr Kramer said. “Nutritional parameters are an excellent way to access a patient’s wellbeing.”

Dr Kramer, who is a past president of the National Kidney Foundation, said the study underscores the importance of asking patients about appetite and how they feel mentally. “If you are seeing large fluctuations in their body weight that may mean something is not stable in their life and it could be social problems and not medical problems. Looking at trajectories of body weight can give you information and lead to queries about issues,” Dr Kramer said. Some patients may be using food as an emotional crutch or in some cases they may not have access to food, she said.

She added, “If you don’t look at their weight, you might not find out that the wife died and did all the cooking.”

It is well established that bariatric surgery improves metabolic parameters, but Dr Kramer said it is necessary to investigate further the effects that big drops in weight among patients with CKD have on their risk for CVD, the leading cause of mortality in this patient population. ■

A recent study highlights the importance of unstable metabolic status, a researcher said.

Exercise May Postpone PCa Progression

EXERCISE MAY DELAY biochemical progression of localized prostate cancer while improving cardiorespiratory fitness, according to the results of the small randomized ERASE clinical trial.

“The findings of this study indicate that exercise may be an effective intervention for improving cardiorespiratory fitness and suppressing the progression of prostate cancer for patients undergoing active surveillance,” a team led by Kerry S. Courneya, PhD, of the University of Alberta in Edmonton, Alberta, Canada, reported in JAMA Oncology.

For the trial, investigators randomly assigned 52 men (mean age 63.4 years) on active surveillance for localized lowor intermediaterisk prostate cancer to a usual care group or a highintensity interval training (HIIT) group. Each group had 26 patients.

Men in the HIIT group were asked to complete 12 weeks of thriceweekly supervised aerobic sessions on a treadmill including eight 2minute intervals at 85% to 95% peak oxygen consumption. The usualcare group maintained their usual exercise levels.

Compared with the usualcare group, the HIIT group experienced significantly improved peak oxygen consumption (the study’s primary outcome) — which rose by 0.9 mL/kg/min in the HIIT group and decreased by 0.5 mL/ kg/min in the usual care group, the investigators reported.

From baseline to postintervention, the mean PSA level declined from 6.1 ng/mL at baseline to 5.7 ng/mL following intervention in the HIIT group, whereas it increased from 8.3 to 8.6 ng/mL in the usualcare group, resulting in a significant adjusted betweengroup mean difference of –1.1 favoring the HIIT group, according to Dr Courneya’s team. The mean PSA velocity decreased from 1.1 to 0.1 ng/ mL per year in the HIIT group and from 1.3 to 1.2 ng/mL per year in the usualcare group, resulting in a significant adjusted betweengroup mean difference of –1.3 ng/mL per year favoring the HIIT group. The investigators adjusted betweengroup differences for baseline values of the outcomes and resistance exercise behavior.

Dr Courneya’s team found no significant changes in PSA doubling time or testosterone level. ■