Renal & Urology News - August 2015 Issue by Haymarket Media

AUGUST 2015

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VO L U M E 14, I S SU E N U M B E R 6

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PUL Outcomes in BPH Patients Durable Prostatic urethral lift provides symptom relief out to 3 years while preserving sexual function, study finds

TYPICAL ENDOSCOPIC appearance after a successful prostatic urethral lift procedure.

Sex May Clear Ureteral Stones SEXUAL INTERCOURSE may be an effective way to clear distal ureteral stones, researchers have concluded. Omer Gohhan Doluoglu, MD, and colleagues at the Clinic of Ankara Training and Research Hospital in Ankara, Turkey, randomly assigned 90 male patients with distal ureteral stones to 1 of 3 treatment arms: sexual

intercourse 3–4 times a week (group 1); tamsulosin 0.4 mg/day (group 2); and standard medical therapy (controls, group 3). The mean stone size was similar among the groups: 4.7, 5.0, and 4.9 mm in groups 1, 2, and 3, respectively. Of the 90 patients, 15 were excluded because of loss to follow-up. continued on page 9

PRACTICE MANAGEMENT

Medical groups may want to consider outsourcing certain business-related tasks. PAGE 18

BY JODY A. CHARNOW PROSTATIC urethral lift (PUL) for patients with bothersome lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH) is associated with rapid improvement in symptoms and quality of life durable out to 3 years, according to recently published findings from a randomized, sham-controlled, parallel-group, prospective study. “This study offers data from the largest population with the longest follow up of a randomized trial of the PUL procedure,” a research team led by Claus G. Roehrborn, MD, of the University of Texas Southwestern Medical Center in Dallas, wrote in The Canadian Journal of Urology (2015;22:7772-7782). “PUL also demonstrated a freedom from stress

Delayed mRCC Therapy Benefits Selected Patients DEFERRED SYSTEMIC therapy is a reasonable option for selected patients with metastatic renal cell carcinoma (mRCC), according to researchers. This approach may offer patients a better quality of life without negatively affecting survival, they say. Investigators at Duke University Medical Center in Durham, N.C., led by Daniel J. George, MD, reviewed data from 60 patients with mRCC who did not receive systemic therapy within the first year after diagnosis. Patients had a median age of 61.2 years, and their median duration from diagnosis of localized RCC to development of mRCC was 41.9 months. Of these patients, 36 (60%) were managed with surgical metastasectomy alone, 7 (12%) received multiple local treatment modalities, 8 (13%) underwent active surveillance, 4 (7%) were managed supportively, and 5 (8%) were categorized as “other.” The cohort had a median follow-up was 52.9 months. The 3-year survival was 83% continued on page 9

urinary incontinence, transfusion, and iatrogenic sexual dysfunction commonly associated with other BPH procedures.” The study included 206 patients from 19 centers in North America and Australia. PUL is a minimally invasive, mechanical approach to treating BPH that uses non-absorbable suture implants with a metallic anchor at each end to pull the lateral lobes of the prostate apart, the investigators explained. The implants are placed under transurethral, cystoscopic guidance. In previous studies, PUL has been shown to offer rapid and significant relief of lower urinary tract symptoms (LUTS) with minimal side effects, as well as preservation of continued on page 9

IN THIS ISSUE 8

Erectile dysfunction is linked to illicit amphetamine use

Prostatitis is associated with an increased prostate cancer risk

RCC risk is lower in individuals with a higher intake of vitamin E

AKI predicts subsequent elevation of blood pressure

Palliative pelvic radiotherapy may ease pelvic tumor symptoms

CKD is more likely to develop in female than male diabetics. PAGE 16

www.renalandurologynews.com AUGUST 2015

Renal & Urology News 3

FROM THE EDITORIAL ADVISORY BOARD EDITORIAL ADVISORY BOARD Medical Director, Urology

Medical Director, Nephrology

Robert G. Uzzo, MD, FACS G. Willing “Wing” Pepper Chair in Cancer Research Professor and Chairman Department of Surgery Fox Chase Cancer Center Temple University School of Medicine Philadelphia

Kamyar Kalantar-Zadeh, MD, MPH, PhD Medical Director, Nephrology Professor & Chief Division of Nephrology & Hypertension University of California, Irvine School of Medicine Orange, Calif.

Nephrologists

Urologists

Anthony J. Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C.

Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City

Suphamai Bunnapradist, MD Director of Research Department of Nephrology Kidney Transplant Research Center The David Geffen School of Medicine at UCLA

R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto Stanton Honig, MD Department of Urology Yale University School of Medicine New Haven, CT J. Stephen Jones, MD, FACS Vice President Regional Medical Operations Professor & Horvitz/Miller Distinguished Chair in Urological Oncology Cleveland Clinic Regional Hospitals Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California Irvine

Csaba P. Kovesdy, MD Chief of Nephrology Memphis VA Medical Center Fred Hatch Professor of Medicine University of Tennessee Health Science Center, Memphis Edgar V. Lerma, MD, FACP, FASN, FAHA Clinical Associate Professor of Medicine Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine, Chicago Allen Nissenson, MD Emeritus Professor of Medicine The David Geffen School of Medicine at UCLA, Chief Medical Officer, DaVita Inc.

James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City

Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto

Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto

Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J.

Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.

Renal & Urology News Staff Editor Jody A. Charnow Web editor

Natasha Persaud

Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Production manager Krassi Varbanov Production director Kathleen Millea Grinder Circulation manager Paul Silver National accounts manager William Canning Publisher Dominic Barone Editorial director Senior VP, medical journals & digital products Senior VP, clinical communications group CEO, Haymarket Media Inc.

Jeff Forster Jim Burke, RPh John Pal Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 14, Number 6. Published monthly, except for the combined January/February, June/July and November/ December issues, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2015.

Big Pharma and Academia: A Strained Relationship

aving been in academic medicine as a clinician and researcher for more than 2 decades, I have been able to witness first-hand the significant changes that have occurred in the relationship between academic medical centers and the pharmaceutical industry. It would seem that academia and the pharmaceutical industry are a good match. Academic medical centers identify clinical problems, and pharmaceutical companies try to solve them. Based on lessons learned from academic research, companies provide funding and develop new medications. These medicines are tested in clinical trials, often with academic medical centers participating. Unfortunately, this mutual relationship has suffered substantially over the last decade due to, of all things, free lunches and pens! The pharmaceutical industry has been portrayed as using unethical techniques to promote unneeded medications. The high price of drugs often is touted as evidence of pharmaceutical industry greed at a time when the mean annual tuition for private medical schools has increased to almost $50,000 per year. This conflict has created a void in education regarding new medications. Academic leaders who called for the virtual banishment of pharmaceutical representatives from academic hospitals did not develop a plan to educate house staff and faculty about new medications. Our previous system, whereby house staff arrived early at a symposium for a modest lunch provided gratis by pharmaceutical companies to hear about new medications for the first 5 minutes, in the presence of their faculty, has been replaced by house staff and faculty busily scurrying to get food, showing up 10–15 minutes late for the lecture, and coming away with little information about new medicines. Fortunately, in my view, the pendulum is starting to swing back. The decrease in National Institutes of Health funding and the overall decline in resources for academic medical centers will encourage more interactions with pharmaceutical companies. There is a new emphasis on translation of medical research to help patients. Pharmaceutical companies have long been doing this, and I hope that academia will learn from these companies about translation in the future. I still remember as a member of the house staff learning from pharmaceutical representatives about new medicines such as cimetidine, diltiazem, erythropoietin, and ranitidine. Then, as a young faculty member, I learned about omeprazole, amlodipine, siladenafil, atorvastatin, and sevelamer, among others. These medicines transformed healthcare and improved the health of our patients. I hope we can return to a more positive interaction with pharmaceutical companies that will enhance our knowledge about new medicines and lead to better ways to use them. Anthony Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C.

Contents

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AUGUST

2015

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ONLINE

this month at renalandurologynews.com 16

Clinical Quiz Take our latest quiz at renalandurologynews.com /clinical-quiz/. Answer correctly and you will be entered to win a $50 American Express gift card. Congratulations to our July winner: Pierre Ghosn, MD

HIPAA Our latest column discusses how practices should move forward with an action plan following a risk assessment.

Be sure to check our latest listings for professional openings across the United States.

News Coverage Visit our website for daily updates as well as on-site coverage of major medical meetings.

CALENDAR

Gout Increases Erectile Dysfunction Risk Researchers observed a 21% increased risk of ED in a study comparing 19,383 men with gout and 77,472 controls without gout. NLR Predicts GU Cancer Outcomes After Treatment An elevated pretreatment neutrophil to lymphocyte ratio is associated with an increased risk of adverse pathology following radical prostatectomy. Combination Rx Relieves Severe OAB Solifenacin plus mirabegron is more effective than either medication alone for severe overactive bladder in elderly patients. Targeted Prophylaxis Effective Basing antibiotic choice on rectal culture findings prior to prostate biopsy is as effective as empirical prophylaxis in preventing postbiopsy sepsis.

Nephrology 8

CKD Found to Increase Fracture Risk in Children Male and female patients have rates that are 2.4- to 3-fold higher, respectively, than genderspecific rates found in the general population.

AKI Is a Risk Factor for Elevated BP Acute kidney injury is associated with a significant 22% increased odds of subsequence development of a blood pressure higher than 140/90 mm Hg.

CKD Risk Higher in Female Diabetics Female sex was associated with a 35% increased risk of incident CKD compared with male sex in adjusted analyses that took into account death as a competing risk.

Hyponatremia Increases Death Risk in Heart Failure Patients Study of Asian patients found that the 12-month mortality rate was significantly higher in those with than without hyponatremia at hospital admission for heart failure.

Job Board

Renal & Urology News 7

VOLUME 14, ISSUE NUMBER 6

Urology 13

AUGUST 2015

Our novel study provides the first result in adults

of a connection between AKI and BP elevation, which could have important clinical and public health implications. See our story on page 13

International Continence Society Montreal October 6–9 American Society for Radiation Oncology (ASTRO) San Antonio, TX October 18–21 American Society of Nephrology Kidney Week San Diego November 3–8 Genitourinary Cancers Symposium San Francisco January 7–9, 2016 Annual Dialysis Conference Seattle February 27–March 1, 2016 National Kidney Foundation Spring Clinical Meetings Boston April 27–May 1, 2016 European Association of Urology 31st Annual Congress Munich, Germany March 11–15, 2016 American Urological Association Annual Meeting San Diego May 6–10, 2016

Departments 3

From the Editorial Advisory Board The strained relationship between Big Pharma and academia

News in Brief Prostatitis associated with higher prostate cancer risk

Practice Management Medical practices should explore the benefits of outsourcing

8 Renal & Urology News

AUGUST 2015 www.renalandurologynews.com

News in Brief

Please visit us at www.renalandurologynews.com for the latest news updates from the fields of urology and nephrology

Short Takes Illicit Amphetamine Use Increases ED Risk

online ahead of print in Nephrology Dialysis Transplantation.

Illicit use of amphetamine may increase

In a study of 18,316 dialysis and

a man’s risk of erectile dysfunction

67,256 CKD patients admitted with

(ED), researchers reported online in

TIA from 2005–2011, Fahad Saeed,

The Journal of Sexual Medicine.

MD, of Cleveland Clinic, and col-

Nan-Hua Chou, MD, of the National

leagues found that, compared with

Yang-Ming University, Taipei, Taiwan,

non-dialysis CKD patients, the HD pa-

and colleagues studied 1,159 illicit

tients had a significant 53% increased

users of amphetamine who had a

odds of moderate-to-severe disability

mean age of 31.2 years and 211

and 2.9 times increased odds of in-

age-matched controls. The mean dura-

hospital death after adjusting for age,

tion of amphetamine use was 30.7

sex, and potential confounders.

months. The prevalence of ED was than in controls (29.3% vs. 11.9%), a

FDA Clears Drug Combo To Treat Heart Failure

difference that translated into a 2.1

The FDA has approved Entresto (sa-

times increased odds of ED associ-

cubitril/valsartan) as a treatment for

ated with amphetamine use after

heart failure.

significantly higher in the drug users

adjusting for other risk factors.

In clinical trials that included more than 8,000 adults, the combination

TIA Outcomes Worse in Hemodialysis Patients

product reduced the rate of cardio-

Patients on maintenance hemodialysis

compared with enalapril. Most clinical

(HD) are significantly more likely to

trial participants were taking currently

suffer moderate-to-severe disability

approved medications for heart failure.

vascular death and hospitalization

and in-hospital mortality following a

Common side effects of Entresto

transient ischemic attack (TIA) than

include hypotension, hyperkalemia,

patients with other stages of chronic

and renal impairment, the FDA said.

kidney disease (CKD) who are not dialysis dependent, researchers reported

The drug is made by Novartis, based in East Hanover, NJ.

Renal Survival in Lupus Nephritis A recently published study examined the long-term renal outcomes in 1,814 Chinese patients with biopsy-proven lupus nephritis. Shown here are the renal survival rates out to 20 years. 100

93.1%

87.9%

81.0%

68.3%

5-year

10-year

15-year

20-year

Source: Yang J et al. Long-term renal outcomes in a cohort of 1814 Chinese patients with biopsy-proven lupus nephritis. Lupus 2015; published online ahead of print.

Long-Term Reoperation Rate Low After HoLEP for BPH H

olmium laser enucleation of the prostate (HoLEP) for managing symptomatic benign prostatic hyperplasia is associated with a low long-term reoperation rate, according to study findings presented at the Canadian Urological Association annual meeting in Ottawa. Mohamed A. Elkoushy, MD, an endourology fellow at McGill University Health Centre in Montreal, and colleagues analyzed data from 1,216 patients who underwent HoLEP. Patients had a mean prostate volume of 94.8 cc. After a mean follow-up of 7.3 years, 52 patients (4.3%) required a reoperation for recurrent lower urinary tract symptoms, including 13 patients (1.07%) with residual/recurrent adenoma, 14 (1.15%) with bladder neck contracture, and 25 (2.05%) with de novo urethral stricture. The rate of freedom from post-HoLEP reoperation was 96.9% at 5 years and 95.1% at 10 years, Dr. Elkoushy reported.

Study: Prostate Cancer Linked to a History of Prostatitis M

en with a history of prostatitis are at elevated risk of prostate cancer (PCa), according to a new study presented at the Canadian Urological Association annual meeting in Ottawa. In a study of 1,884 PCa patients and 1,965 controls, Katharina Boehm, MD, of Martini-Klinik am Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany, and colleagues demonstrated that a history of prostatitis was associated with a significant 83% increased risk of PCa being found at biopsy. Among individuals with prostatitis, those without a history of benign prostatic hyperplasia (BPH) had a nearly 3-fold increased risk of PCa, whereas those with a history of BPH had a significant 30% decreased risk. In their study abstract, the researchers concluded that their findings “should be used in clinical risk stratification of individuals in whom the risk of PCa is pertinent.”

CKD Found to Increase Fracture Risk in Children C

hildren with chronic kidney disease (CKD) are at significantly higher risk of fracture compared with the general population, according to a report published online ahead of print in the Journal of the American Society of Nephrology. Michelle R. Denberg, MD, of the Children’s Hospital of Pennsylvania in Philadelphia, and colleagues conducted a prospective cohort study of 537 children and adolescents with CKD. At enrollment, the patients had a median age of 11 years, and 16% of them reported a prior fracture. During a median of 3.9 years, 43 males and 24 females sustained incident fractures, or 395 and 323 fractures per 10,000 person-years, respectively. These rates are 2.4- to 3-fold higher, respectively, than gender-specific rates found in a large population-based study of fracture epidemiology in children and adolescents, Dr. Denberg’s group reported. In multivariable analysis, advanced pubertal age, difficulty walking and higher parathyroid hormone level were independently associated with greater fracture risk. Phosphate binder treatment was associated with a significant 63% decreased risk of fracture.

www.renalandurologynews.com AUGUST 2015

PUL outcomes durable continued from page 1

erectile and ejaculatory function. The therapeutic effect of PUL with respect to International Prostate Symptom Score (IPSS) was 88% greater than that associated with the sham procedure at 3 months, Dr. Roehrborn’s team noted. The average improvements from baseline through 3 years were significant for total IPSS (41.1%), quality of life (QoL, 48.8%), peak flow rate (Qmax, 53.1%), and individual IPSS components. Symptomatic improvement was independent of prostate size, they reported.

Delayed mRCC therapy continued from page 1

overall and 94% for patients who underwent surgical metastasectomy as the initial management strategy, Dr. George’s group reported in Clinical Genitourinary Cancer (2015;13:e159-e166). At 3 years, 49% of patients had no evidence of disease and 19% had died or been transitioned to hospice. The 5-year survival rate was 59%, and 24% still had no evidence of disease. “Although the new targeted therapies for mRCC are better tolerated than systemic chemotherapies, they still have serious side effects,” the authors wrote. “Therefore, a strategy of delaying therapy may result in significant quality of life gains for these patients.” In a discussion of study limitations, Dr. George’s group pointed out that their cohort included only patients treated at a large academic medical center, so their sample may not be representative of all mRCC patients or clinical environments because of sample bias and self-selection bias.

Mounting evidence The study by Dr. George and his colleagues adds to a growing body of evidence suggesting that deferred systemic therapy may be an attractive option for selected patients. For example, investi-

Sex and stones continued from page 1

After 2 weeks, 26 (83.9%) of 31 patients in the intercourse group passed their stones versus 10 (47.6%) patients in the tamulosin group and 8 (34.8%) in the control arm, according to a report in Urology (2015;86:19-24). The difference in stone passage rate was significantly greater in group 1 versus the other

Renal & Urology News 9

A total of 15 (10.7%) of the 140 men originally assigned to the PUL group required surgical reintervention for treatment failure within 3 yearsUL. The rate was similar to rates reported after transurethral resection of the prostate (TURP) and laser vaporization, according to the investigators. The men in the PUL group had no de novo sustained erectile or ejaculatory dysfunction. “All sexual function assessments showed average stability or improvement after PUL,” they wrote. “The PUL procedure offers a new solution for patients suffering from BPH,” Dr. Roehrborn’s team concluded. “It addresses a need for clini-

cally meaningful relief from LUTS that is superior to medications but without the morbidity and sexual side effects caused by TURP, laser or medical therapy while being a quick, safe, minimally invasive outpatient procedure.” The study population consisted of participants in the L.I.F.T. (Luminal Improvement Following Prostatic Tissue Approximation for the Treatment of LUTS secondary to BPH) study. Inclusion criteria included age older than 50 years, IPSS of 3 or greater, Qmax of 12 mL/sec or less, prostate volume of 30–80 cc, absence of obstructive median lobe, and absence of active urinary tract infection.

In a separate study of 102 men with symptomatic BPH who underwent PUL, Thomas A. McNicholas, MD, of the University of Hertfordshire, Stevenage, U.K., and colleagues concluded that the procedure had promise for BPH. The study, published in European Urology (2013:64;292-299), found that patients experienced symptom relief by 2 weeks that was sustained to 12 months, with mean IPSS, QoL, and Qmax improving significantly by 36%, 39%, 38%, respectively, by 2 weeks, and 52%, 53%, and 51% at 12 months. According to the researchers, adverse events were transient and mild. n

gators at the University of Ulsan College of Medicine in Seoul, South Korea, studied 58 patients with asymptomatic or minimally symptomatic mRCC placed on active surveillance. After a median follow-up of 31.4 months, the median time to progression—the primary endpoint of the study—was 12.4 months, and the median overall survival was not reached, the

mTOR inhibitors. “There are data to support that the efficacy of these agents is similar whether treatment is delayed or started immediately,” Dr. Cho said.

researchers reported in the Journal of Cancer Research and Clinical Oncology (2014;140:1421-1428). “Asymptomatic or minimally symptomatic mRCC patients can be observed for a prolonged period without active treatment,” the researchers concluded in their study abstract. Dr. George and his colleagues commented in their report, “In a time of quickly evolving treatment choices for patients with mRCC, it is critical that we understand treatment patterns and outcomes in routine clinical practice. The need to better understand the observed practice of delayed systemic therapy for patients with mRCC is such an example.”

‘Very reasonable approach’ Christopher G. Wood, MD, Professor and Deputy Chairman of the Department of Urology at the University of Texas MD Anderson Cancer Center in Houston, said he believes deferred systemic therapy is an appropriate way to address the adverse effects that targeted therapies have on patients. “There is no question that while targeted therapies have improved patient outcomes, they have chronic toxicity that can be a source of great angst for our patients,” Dr. Wood said. “So staving them [targeted therapies] off for a period of time avoids periods of toxicity but doesn’t alter their effectiveness when and if the disease kinetics change.” Dr. Wood called deferred systemic therapy for mRCC “a very reasonable approach in selected patients, where the kinetics of their disease growth are slow, their metastatic burden is low, and they are enjoying a good quality of life.” Daniel Cho, MD, Assistant Professor of Medicine, and Director of the Developmental Therapeutics Program at the Perlmutter Cancer Center at New York University Langone Medical Center, said he believes clinicians should consider deferral of systemic therapy more frequently when deciding whether to prescribe currently available molecularly targeted therapies such as VEGFR antagonists and

Patient selection critical Deferral of systemic therapy, he noted, has long been used as a management option by physicians caring for patients with mRCC. “The available data clearly suggest that there is a subset of patients who can experience prolonged periods of relative disease stability in the absence of systemic therapy,” he said. “The critical issue is identifying the patients for whom this strategy would be most appropriate.” With the acceptance that systemic therapy with currently available molecularly targeted therapies (such as VEGFR antagonists and mTOR inhibitors) does not have curative potential for the vast majority of patients, deferring such therapy in appropriately selected patients is certainly reasonable clinically. This decision, however, becomes more complicated for immunotherapies because these have the potential for inducing durable and complete responses. “As there is speculation that RCC becomes more immunosuppressive over time, the assumption that immunotherapy may be equally effective irrespective of timing of treatment may not be correct,” he said. n

groups. The mean stone expulsion time was significantly shorter in group 1 compared with the other groups: 10 days in group 1 versus 16.6 days in group 2, and 18 days in group 3. The researchers postulate that nitric oxide released during erection and sexual intercourse may affect the distal ureters, causing relaxation of ureteral muscle. “Today, MET [medical expulsive therapy] is recommended as the first-

line treatment in ureteral stones that do not necessitate surgery,” the authors concluded. “In our opinion, if the patient has a sexual partner, having sexual intercourse at least 3 times a week may be beneficial to increase the probability of spontaneous stone expulsion in patients with distal ureteral stones ≤6 mm in size.” In an accompanying editorial (page 24), Jeffrey J. Tosoian, MD, MPH, of

Johns Hopkins Medical Institutions in Baltimore, commented that the study by Dr. Doluoglu’s group “has great value in again bringing to light the potential role of the nitric oxide pathway in treatment of stone disease.” Dr. Tosoian cited previous studies that have identified nitrergic fibers in the distal ureter and demonstrated a relaxant effect of nitric oxide on ureteral smooth muscle. n

Quality of life can be improved without adversely affecting outcomes.

www.renalandurologynews.com AUGUST 2015

Renal & Urology News 13

AKI Is a Risk Factor for Elevated BP Hospitalized patients who experienced AKI had a 22% increased risk of elevated BP after 2 years of follow-up ACUTE KIDNEY INJURY (AKI) is an independent risk factor for the subsequent development of elevated blood pressure (BP), new findings suggest. Chi-yuan Hsu, MD, of the University of California San Francisco, and colleagues studied 43,611 adult members of Kaiser Permanente Northern California hospitalized from 2008 to 2011. Of these, 2,451 experienced AKI. After a follow-up period of 2 years postdischarge, elevated BP—defined as values greater than 140/90 mm Hg— developed in a significantly greater proportion of AKI versus non-AKI patients (46.1% vs. 41.2%), Dr. Hsu’s group reported online ahead of print in the Journal of the American Society of Nephrology. The difference between the groups was apparent within the first 180 days of follow-up (30.6% vs. 23.1%). In multivariate analysis, AKI was independently associated with a significant 22% increased odds of developing elevated BP during 2 years of follow-up. The investigators observed higher adjusted odds with more severe AKI. For example, patients with stage 3 AKI had a sig-

Vitamin E May Protect Against RCC HIGHER DIETARY INTAKE of vitamin E may decrease the risk of renal cell carcinoma (RCC), new findings suggest. In a meta-analysis of 7 casecontrol studies involving 5,789 cases and 14,866 controls, Yonggang Shang, MD, and colleagues at the Third Military Medical University in Chongquing, China, found that, overall, the highest dietary intake of vitamin E was associated with a significant 25%

nificant 82% increased odds in adjusted analyses, whereas patients with stage 1 AKI had only a 9% increased odds. The researchers defined AKI as a peak serum creatinine level during hospitalization that was 0.3 mg/dL or greater and/or 50% or greater than the baseline level. “Our novel study provides the first result in adults of a connection between AKI and BP elevation, which could have important clinical and public health implications,” the researchers concluded. The study population as a whole had a mean age of 56.1 years, with AKI patients being significantly older than the non-AKI patients (57.7 vs. 56 years). AKI was more likely to develop in men than women. Men made up 51.5% of the AKI group compared with 39.8% of the non-AKI group. Compared with the non-AKI group, a significantly higher proportion of the AKI group had diabetes mellitus (6.9% vs. 4.8%) and chronic heart failure (3.8% vs. 1%). Dr. Hsu and colleagues noted that study strengths include the plausibility of the physiologic connection between

AKI and Elevated BP A study found that acute kidney injury (AKI) is associated with increased odds of developing elevated blood pressure.* The odds increased with AKI severity, as indicated here. 2.0

1.82 1.45

1.5

1.09 1.0 0.5 0.0

AKI stage 1

AKI stage 2

AKI stage 3

* >140/90 mm Hg Source: Hsu CY et al. Elevated BP after AKI. J Am Soc Nephrol 2015; published online ahead of print July 1.

AKI and subsequent BP level and an analysis of a large, contemporary community-based population with a wide diversity in age, sex, and race/ethnicity. In addition, the researchers used actual BP readings during follow-up to define elevated BP instead of administrative diagnostic codes regarding hypertension. They said they also carefully controlled for a wide range of potential confounders.

Regarding study limitations, the authors said that because their investigation was observational, association does not prove causality. “It would be unethical to randomly assign patients to develop AKI or not and follow subsequent BP levels,” they noted. In addition, because the study was based on data collected as part of routine clinical care, they were unable to determine BP levels at specific time points. n

GPS Assay Predicts PCa Recurrence GENOMIC PROSTATE Score (GPS), a 17-gene molecular assay, strongly and independently predicts time to biochemical recurrence and adverse pathology in men with low- to intermediate-risk prostate cancer (PCa), a new study confirms. Investigators led by Jennifer Cullen, MPh, PhD, of the Department of Defense, Center for Prostate Disease Research, in Rockville, Md., tested the validity of GPS using biopsies from 431 men with very low to intermediaterisk PCa from 2 U.S. military medical centers. The researchers assessed GPS’ abilities to predict adverse pathology

at radical prostatectomy, biochemical recurrence, and metastasis. According to findings published in European Urology, 163 men had adverse pathology, 62 experienced biochemical recurrence, and 5 developed metastases during a median 5-year follow up period. GPS predicted time to biochemical recurrence and time to metastasis. GPS was also strongly linked with adverse pathology and predicted both high-grade (primary Gleason pattern 4 or any pattern 5) and non-organ-confined disease (pT3). Notably, GPS was predictive for both Caucasian and African American

patients (other racial groups were not adequately represented). The strong independent association of GPS with these near- and longer-term clinical endpoints “establishes this assay as a robust measure of PCa aggressiveness,” the researchers stated. The test predicted both early and late biochemical recurrence and metastasis. Together, GPS gives physicians a “more accurate risk assessment to guide treatment decisions for men with newly diagnosed disease.” The GPS assay includes genes representing “multiple, distinct biologic pathways involved in prostate tumorigenesis,” the researchers noted. n

decreased risk of RCC compared with the lowest intake. In European populations, the highest dietary intake of vitamin E was associated with a significant 42% decreased risk of RCC, the investigators reported in the Journal of Renal Nutrition (2015;25:339-344). The researchers found no link between dietary vitamin E intake and RCC risk in North American populations. n

Gout Increases Erectile Dysfunction Risk MEN WITH GOUT are at increased risk erectile dysfunction (ED), according to a new study. Researchers led by Wei-Sheng Chung, MD, of Taichung Hospital in Taichung City, Taiwan, compared 19,383 men with gout and 77,472 controls without

gout randomly selected from the general population. Gout sufferers had a 21% increased risk of ED in adjusted analyses, the researchers reported online ahead of print in The Journal of Rheumatology. Compared with patients who did not have gout or comorbidities,

those with both gout and any comorbidity had a 2-fold increased risk of developing ED. The incidence of ED increased with age in both cohorts, but it was greater among men in the gout cohort, according to the investigators. n

14 Renal & Urology News AUGUST 2015 www.renalandurologynews.com

■ AUA 2015

American Urological Association 2015 Annual Meeting, New Orleans

NLR Predicts GU Cancer Outcomes After Treatment New data suggest a prognosis role for the neutrophil to lymphocyte ratio NEW STUDIES demonstrate the potential usefulness of the neutrophil to lymphocyte ratio (NLR) in predicting outcomes after treatment for various genitourinary cancers. Researchers have found that an elevated NLR is associated with significantly higher rates of biochemical recurrence and positive surgical margins after radical prostatectomy (RP) for prostate cancer (PCa) and a significantly increased likelihood of tumor recurrence in patients who have undergone surgery for non-muscle invasive bladder cancer (NMIBC). Other researchers demonstrated that an elevated NLR predicts a greater likelihood of malignancy in patients undergoing surgery for renal tumors. An elevated NLR is a marker of systemic inflammation that previous research has linked to adverse outcomes in multiple malignancies. The NLR is calculated by dividing the number of neutrophils by the number of lymphocytes. Vidit Sharma, MD, of Mayo Clinic in Rochester, Minn., and colleagues studied 8,350 PCa patients who underwent RP patients and had a median follow-up of 9.7 years. Of these, 1,568 (18.7%) had a pre-RP NLR above 5. These patients were significantly more likely than those with an NLR below 5 to have pT3/4 disease at RP (22% vs. 17.1%) and positive surgical margins (33.2% vs. 25.8%) and significantly more likely to receive adjuvant hormonal therapy (13.8% vs. 8.2%) and radiation therapy (4.7% vs. 3.2%). Patients with an NLR above 5 also were significantly more likely to receive salvage hormonal therapy during followup (14% vs. 11.4%). After controlling for age, Gleason score, preoperative PSA level, pathologic state, and use of adjuvant hormonal or radiation therapy, an NLR above 5 remained a significant predictor of biochemical recurrence, according to investigators. Yoshihiro Nakagami, MD, and colleagues at Tokyo Medical University studied 1,010 patients with castrationresistant PCa treated with docetaxel.

The patients had an average of 11 treatment courses. The median overall survival time was 21 months. In multivariate analysis, an NLR of 2.6 or higher was associated with a 1.9 times increased risk of death. Also at AUA meeting, Vincenzo Favilla, MD, and collaborators at the University of Catania in Italy, presented

Potential usefulness demonstrated in prostate, bladder, and kidney cancer. findings of a prospective study of NLR in a cohort of 178 patients (mean age 69 years, 148 male and 30 female) newly diagnosed with NMIBC and who underwent transurethral resection of bladder tumor (TURBT). The median follow-up was 53 months. The median NLR was 2.55. During follow-up, 14 patients with an NLR less than 3 (23.3%) experienced recurrence compared with 44 patients with an NLR of 3 or higher (37.9%). In multivariate analysis, an NLR below 3 was associated with a 66% decreased risk of recurrence compared with an NLR of 3 or higher. The 5-year recurrence-free survival rate was 62% for those with an NLR less than 3 compared with 49% for patients with an NLR of 3 or higher. All of these between-group differences were statistically significant. The study found no significant association between NLR and progression risk. In a separate study, Emrah Yuruk, MD, of the Bagcilar Training and Research Hospital, Istanbul, Turkey, and colleagues reviewed the medical records of 428 consecutive bladder cancer patients who underwent TURBT. After excluding patients without a preoperative NLR or a minimum of 6 months of follow-up, as well as patients with muscle-invasive disease, the researchers had a study population that included 390 NMIBC

patients with a mean age of about 66 years (range 18–95 years). Of these, 68 (17.4%) experienced disease recurrence. These patients had a significantly higher mean NLR than those who did not have recurrence (2.62 vs. 2.20). Another Mayo Clinic team presented findings showing that an elevated NLR prior to nephrectomy for renal tumors is associated with an increased risk of RCC at the time of surgery as well as higher-grade tumors and more aggressive histologic subtypes. The study, by Boyd R. Viers, MD, and colleagues, included 2,039 patients who underwent nephrectomy for localized renal masses and had an NLR calculated 90 days prior to surgery. Results demonstrated that patients with malignant renal tumors had a significantly higher NLR than those who had benign tumors (median 3.12 vs. 2.92). The lowest NLR (median 2.48) occurred in patients with cystic clear-cell RCC; the highest NLR (median 5.99) was found in those with collecting-duct RCC. Across all RCC subtypes, the investigators observed a significant increase in NLR with larger tumor size and nuclear grade. n

Key Points An elevated pretreatment neutrophil to lymphocyte ratio is associated with: n An increased risk of adverse

pathology, such as positive surgical margins, after radical prostatectomy for prostate cancer (PCa). n An increased risk of death among

patients with castration-resistant PCa treated with docetaxel. n An increased risk of tumor

recurrence among patients who undergo surgery for non-muscle invasive bladder cancer. n An increased risk of renal cell car-

cinoma among patients undergoing nephrectomy for renal tumors.

Hematuria Workups Fall Short BY NATASHA PERSAUD NEW ORLEANS—In a survey, primary care doctors and emergency medicine physicians reported a wide variety of practices for the diagnosis of hematuria, researchers revealed at the 2015 American Urological Association (AUA) annual meeting. Almost all respondents believed clinical care pathways would improve adherence to evidence-based guidelines. For the study, investigators led by Lisa Parrillo, MD, of the Hospital of the University of Pennsylvania in Philadelphia, distributed a 22-question electronic survey to primary care providers in an academic health system. The survey gauged practice patterns in the evaluation and care coordination of gross and microscopic hematuria. Of the 135 providers who completed the survey, only 13% were aware of AUA guidelines on asymptomatic microscopic hematuria. Just 30% could define the symptom as 3 or more red blood cells per high-power field as viewed under a microscope based on a single urinalysis. An additional 51% defined it correctly based on the previous definition of 2 urinalyses with 3 red blood cells per high-power field. For the work-up, the majority (65%) would not send a voided urine cytology; that means that 35% would, however. Slightly more than half (53%) would only image patients with additional indications, and 21% would not image patients at all. When imaging was performed, a computed tomography urogram was used as often as a renal ultrasound. “Although upper tract tumors are relatively rare, especially in asymptomatic microscopic hematuria, an appropriate evaluation with contrast enhancement is necessary,” Dr. Parrillo explained. Less than half (46%) of providers would appropriately recommend urology consultation for any hematuria, 38% for gross hematuria only, 10% for microscopic hematuria only, and 7% never, according to the study. Almost all survey participants (93%) felt that a clinical care pathway for the evaluation and management of hematuria would prove valuable in their practice. n

16 Renal & Urology News

AUGUST 2015 www.renalandurologynews.com

CKD Risk Higher in Female Diabetics New study adjusted for mortality as a competing risk factor, depressive symptoms, diabetes self-care groups and appeared to be driven mainly by differences in the development of low eGFR rather than microalbuminuria. “To our knowledge, this is the first study to find that women with diabetes had a greater risk of developing CKD compared with men, after taking into account mortality as a competing risk factor,” Dr. Yu’s team wrote. The researchers defined incident CKD as the first measurement of an eGFR less than 60 mL/min/1.73 m2 by the Chronic Kidney Disease-Epidemiology (CKDEPI) equations or sex-specific microalbuminuria (urinary albumin/creatinine ratio) of 25 mg/g or higher for women and 17 mg/g or higher for men. The investigators assessed depressive symptoms using the Patient Health Questionnaire-9, which has been validated in patients with CKD. They assessed diabetes self-care using the modified Summary of Diabetes Self-Care Activities tool, which asks how many days per week a self-care activity was performed.

Surgery Ups Survival in Cancer Patients with Kidney Metastases PATIENTS WITH non-renal primary can-

diagnosis and metastatic diagnosis

cers that metastasize to the kidneys

was 4.81 and 2.24 years, respectively.

appear to have better survival if they

“Since renal metastases appear early

undergo surgical treatment, new find-

in the metastatic process and survival

ings suggest.

appears to be longer in patients treated

A team at the University of Texas MD

with surgery, surgical intervention in care-

Anderson Cancer Center in Houston

fully selected patients with oligometa-

led by Jose A. Karam, MD, conducted

static disease and good performance

a retrospective study of 151 patients

status should be considered,” the authors

diagnosed with a primary non-renal

concluded. “A multidisciplinary approach,

malignancy accompanied by renal

with input from urologists, oncologists,

metastases. Patients had a median age

radiologists and pathologists, is needed

of 56.7 years. The most common pre-

to achieve the optimum outcomes for

senting symptoms were flank pain (30%),

this specific patient population.”

hematuria (16%), and weight loss (12%). The most common primary tumor

The authors acknowledged that selection bias could explain the better

site was the lung (43.7% of cases). The

survival outcomes observed in the

median overall survival (OS) from pri-

surgery patients because “patients

mary tumor diagnosis was 3.08 years,

undergoing surgery with curative

and the median OS from the time of

intent are likely to be those with

metastatic diagnosis was 1.13 years,

minimal metastatic disease and good

Dr. Karam’s group reported online

performance status.” A difference in

ahead of print in BJU International. For

systemic therapies used in the surgery

surgically-treated patients, median

patients also could explain the better

overall survival from primary tumor

observed outcomes in this cohort. n

A study of diabetics found that women were at 35% higher risk of CKD than men.

The investigators pointed out that prospective cohort studies involving patients with diabetes generally have found that men are at higher risk of incident CKD than women, but these studies were not designed to examine

Combination Rx Relieves Severe OAB COMBINED TREATMENT with solifenacin and mirabegron is more effective than either medication alone in managing severe overactive bladder (OAB) in elderly patients, according to a new study. The risk of side effects with the combination treatment did not increase compared with monotherapy. Russian investigators led by Kirill Kosilov, MD, of Far Eastern Federal University in Vladivostok, compared OAB treatments over 6 weeks in 143 women and 95 men (ages 65 and older; average 71.2 years) with severe OAB symptoms, such as 3 or more incontinence episodes daily. The researchers randomly assigned patients to 4 treatment groups: mirabegron 50 mg/day for 6 weeks (63 patients); solifenacin 10 mg/ day for 6 weeks (52 patients); mirabegron plus solifenacin at the sames doses simultaneously for 6 weeks (65 patients); or placebo (59 patients). All patients completed bladder diaries and questionnaires on OAB symptoms and were examined via cystometry.

sex differences and have limitations. Mortality was not accounted for as a competing event, which is relevant because diabetic men have a shorter life expectancy than women, Dr. Yu and her colleagues explained. Most studies did not use sex-specific microalbuminuria thresholds, which account for sex differences in urine creatinine concentrations. CKD incidence was ascertained by incident albuminuria alone or older methods of estimating GFR—such as the change in the reciprocal serum creatinine, CockcroftGault equation, or the Modification of Diet in Renal Disease study equation—which are less accurate than the CKD-EPI equation in patients without CKD, women, and the elderly, according to Dr. Yu’s group. Additionally, no previous study assessed depressive symptoms or diabetes self-care activities, which differ by sex and are associated with increased CKD risk, the authors noted. n

During the study, the researchers determined that 64% of patients had detrusor overactivity incontinence, 23% had phasic detrusor overactivity, and 12% had terminal detrusor overactivity. Over 6 weeks, all active drug treatments showed some efficacy in reducing OAB symptoms, according to findings published online ahead of print in the Archives of Gerontology and Geriatrics. Combination therapy was associated with the largest benefit. The mean number of incontinence episodes decreased from 5.1 to 1.6; mean urination decreased from 9.1 to 5.3 instances per day; and mean post-void residual urine increased from 19.4 to 29.9 mL. Solifenacin, an antimuscarinic, and mirabegron, an agonist of β3-adreno receptors, probably work synergistically to suppress afferent noise and improve detrusor function, according to the researchers. Treatment with either drug alone may be insufficient to manage severe OAB symptoms in elderly patients, they noted. Reported side effects of the combination therapy included dry mouth, increased blood pressure, and elevated heart rate. For this study, standard doses of the OAB medications were used for the combination therapy; however, future research should look at optimal dosages and duration of treatment. n

CHRONIC KIDNEY disease (CKD) is more likely to develop in female diabetics than male diabetics, a recently published study suggests. Margaret K. Yu, MD, of the VA Puget Sound Health Care System in Seattle, and colleagues studied 1,464 adult patients with diabetes and normal renal function. Over 6,187 patient-years, 924 cases of incident CKD developed, for a total incidence rate of 149.3 cases per 1,000 patient-years. The incidence rate was significantly higher for women than men (154 vs. 144.3 per 1,000 patientyears). Female sex was associated with a 35% increased risk of incident CKD compared with male sex in adjusted analyses that took into account death as a competing risk, demographics, duration of diabetes, baseline estimated glomerular filtration rate (eGFR), CKD risk factors, depressive symptoms, and diabetes self-care, according to a report in Nephrology (2015;20:451-458). The sex differences were consistent across age

www.renalandurologynews.com AUGUST 2015

Renal & Urology News 17

PPRT Eases Pelvic Tumor Symptoms In a small study, palliative pelvic radiotherapy was most effective in relieving macroscopic hematuria PALLIATIVE PELVIC radiotherapy (PPRT) can alleviate symptoms in men with castration-resistant prostate cancer (CRPC) and symptomatic pelvic tumors, according to a Norwegian study. Marte Grønlie Cameron, MD, of Sørlandet Hospital in Kristiansand, and colleagues prospectively studied 47 CRPC patients with a symptomatic pelvic mass who were prescribed PPRT with 30–39 Gy. The most common target symptoms were lower urinary tract symptoms (LUTS, 45%), macroscopic hematuria (26%), and pain (19%). The study’s primary endpoint was patientreported improvement or complete resolution of target symptoms 12 weeks after PPRT. Of the 40 patients evaluable for target symptom severity 12 weeks after PPRT, 18 reported complete resolution, 10 reported improvement, 10 reported unchanged severity, and 2 reported worsening target symptoms, Dr. Cameron’s group reported online

Targeted Prophylaxis Effective TARGETED PROPHYLAXIS based on rectal cultures is as effective as empirical prophylaxis at preventing sepsis in patients undergoing prostate biopsy, but avoids the use of multiple antibiotics, according to a new study. Researchers led by Richard J. Szabo, MD, of the Southern Permanente Medical Group in Irvine, Calif., studied the outcomes of 5,355 prostate biopsy procedures performed from May 1, 2013 to April 30, 2014. Urologists used targeted prophylaxis (TP) in 1,802 procedures (34%) and empirical prophylaxis in 3,553 (66%). In the TP group, rectal cultures were obtained prior to biopsy. The antibiotic sensitivities of Escherichia coli were used to guide the selection of a single antibiotic for prophylaxis. Urologists using empirical prophylaxis continued the usual regimen of ciprofloxacin monotherapy, but sometimes added another prophylactic antibiotic. Sepsis developed in 8 cases (0.44%) in the TP group and 20 cases (0.56%) in the empirical group, a between-

Target Symptom Relief The proportion of evaluable patients reporting improvement or complete resolution of their target symptom—the main pelvic complaint they hoped pelvic radiotherapy would relieve—changed over time, as shown here. 80 70 60 50 40 30 20 10 0

62%

80%

70%

At end of radiotherapy

After 6 weeks

After 12 weeks

Source: Cameron MG, et al. Palliative pelvic radiotherapy of symptomatic incurable prostate cancer—A prospective multicenter study. Radiother Oncol. 2015; published online ahead of print.

ahead of print in Radiotherapy and Oncology. Improvement or complete resolution of the target symptom was achieved in 62% of evaluable patients at the end of radiotherapy, 80% after 6 weeks, and 70% after 12 weeks. Based on an intent-to-treat analysis, the overall response rate for the 47 patients

group difference that was not statistically significant, Dr. Szabo’s group reported in The Journal of Urology (2015;194:397-402). “Our study suggests that TP can reduce antibiotic use by exchanging ciprofloxacin rather than augmenting ciprofloxacin without subjecting the patient population to an increased risk of sepsis,” the researchers wrote. Results also showed that the prevalence of ciprofloxacin-resistant E. coli based on rectal cultures was 25%. In 9 of the 5,355 biopsy cases, sepsis developed from ciprofloxacin-sensitive bacteria despite the use of ciprofloxacin prophylaxis. Possible reasons for this prophylaxis failure include noncompliance with taking the antibiotic as directed and decreased bioavailability due to impairment of ciprofloxacin absorption by concomitant intake of dairy products or antacids. The incidence of post-biopsy sepsis has been increasing, according to the researchers. This has led to increased prophylactic use of multiple broadspectrum antibiotics, which may accelerate the development of resistant bacteria, the researchers pointed out. Limitations of the study included retrospective data collection and a control group in which various usual care practices were used, the researchers noted. n

enrolled in the study was 60% after 12 weeks. For the patients with LUTS, hematuria, and pain, the response rates were 38%, 92%, and 78%, respectively. “In patients with CRPC and a symptomatic pelvic mass, PPRT with doses in the range of 30–39 Gy contributes to effective palliation of macroscopic

hematuria, pain and other pelvic symptoms,” the researchers concluded. “The applied radiotherapy does not impart significant toxicity.” The investigators stated that, to their knowledge, their study is the first prospective investigation “exploring symptomatic effects of PPRT of CRPC, yielding information not only about the magnitude, but also the onset and duration of effects and toxicities.” For the study, the researchers scheduled 4 patient visits: baseline, at the completion of radiotherapy, and 6 and 12 weeks after completion of treatment. At baseline, patients were asked to identify a “target symptom,” the main pelvic complaint they hoped radiotherapy would relieve. At each of the 3 follow-up visits, patients were asked to describe the target symptom severity compared with baseline as either “worse,” “unchanged,” “better,” or “resolved.” The latter 2 descriptions were regarded as “response.” n

Hyponatremia Increases Death Risk in Heart Failure Patients HYPONATREMIA at hospital admission

to optimal medical therapy (OMT) was

for heart failure independently predicts

lower in hyponatremic patients than the

an increased risk of death in Asian

normonatremia group. The proportion

patients, according to a study pub-

of patients with OMT was only 25.5% at

lished in the Korean Journal of Internal

admission and 44.2% at discharge.

Medicine (2015;30:460-470). Byung-Su Yoo, MD, of Yonsei University

The researchers defined as OMT as the combined use of ACE inhibitor/angio-

Wonju College of Medicine in Wonju,

tensin receptor blocker and beta-blocker.

Korea and colleagues studied 1,470

The investigators noted that their study

hospitalized HF patients from 9 centers

was limited by the fact that it was not a

in 3 countries. Patients had a mean

prospective, randomized trial. “Although

sodium level of 138 mmol/L at admis-

we tried to adjust for significant clinical

sion. Of the 1,470 patients, 247 (16.8%)

variables and performed propensity

had hyponatremia, defined as a sodium

score matching for the analysis,” they

level below 135 mmol/L.

wrote, “unmeasured confounding factors

The 12-month mortality rate was

may have biased the study result.”

significantly higher in the patients with

In the first 12 months, 247 patients

than without hyponatremia (27.9% vs.

died. These patients were significantly

14.6%). Hyponatremia was independently

older (mean 71.9 vs. 65.2 years) and

associated with a 72% increased risk of

had significantly lower mean body mass

12-month mortality.

index (22.2 vs. 24.2 kg/m2) than those

Hyponatremia improved in 57% of the

who did not die. Significantly higher

patients with the condition during their

proportions of deceased patients had

hospital stay, but this was not associated

diabetes, hypertension, coronary artery

with improved outcomes. Adherence

disease, and chronic kidney disease. n

18 Renal & Urology News AUGUST 2015 www.renalandurologynews.com

Practice Management Outsourcing certain business components of a medical practice, such as billing, could enhance the bottom line BY TAMMY WORTH

Billing and collections According to the Medical Group Management Association, each claim an office has to rework after a denial costs an average of $25. Of those that are returned, up to 65% don’t ever get reworked. This could equal a huge revenue loss. Unless it is clearly less

expensive to outsource a task, keep it in the practice, Glassman said. Because of this, large offices can often afford to keep billing in house. For larger practices, it often only makes sense to bill through an outside group if collections are “horrible and you are too busy to manage it,” or if space is so tight it is wiser to use a room for clinical instead of billing functions. For smaller groups, however—those with 3 to 4 providers—it often makes sense to have an outside firm take over billing, she said.

Contract management Payer contract management can be crucial to the financial success of a business. Often, Glassman said, hiring a manager can net an extra 5% annually, and if an office is making $10 million a year, that’s no small change. Contracts can come in without a fee schedule (instead they pay their “customary fees”). They may have stipulations saying a physician isn’t paid for certain services. Physicians or office managers

The only way to know if outsourcing administrative tasks is right for an office is to perform a cost-benefit analysis.

ochelle Glassman, president and CEO of United Physician Services in Phoenix, has worked with plenty of doctors who don’t think of their practice as a business. “Some are profiting $20 [million] to $30 million a year and running it like the corner sweet shop,” she said. One way to bring more business into a practice is to explore outsourcing. While most physicians are comfortable using outside experts to come in and train on technical issues like ICD-10 conversion or HIPAA compliance, they are unaware there are external resources to make their lives easier or practice more lucrative.

For smaller groups, it often makes sense to have an outside firm take over billing.

may not think the contracts are negotiable (though most are).

Understanding costs The only way to know if outsourcing administrative tasks is right for an office is to perform a cost-benefit analysis. Tabulate the cost of the staff time, upgrades, training and office space required to perform a task. Compare that with a quote from an outside company. Glassman recommends getting quotes from 3 vendors for any task. Because of the rate at which technology and regulations are changing, it is

important to make sure you are working with a consultant that is up to date. Lastly, don’t sign contracts for longer than a year, and always think about exit strategies upfront, she said. If you terminate a billing arrangement or switch to a different provider of electronic health records, it should be spelled out in the contract how the data will be transferred to a new system. Timelines and cost for this function are often not even included in a contract. n Tammy Worth is a freelance medical journalist based in Blue Springs, MO.

In men with mCRPC who progressed on ADT

The story for ZYTIGA® has significantly evolved. Presenting…

mCRPC = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy.

INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Please see additional Important Safety Information on the next pages. Please see brief summary of full Prescribing Information on subsequent pages.

In men with mCRPC who progressed on ADT, consider ZYTIGA® (abiraterone acetate) first.

Final analysis of the pivotal phase 3 trial.*

Every day tells a story.

IMPORTANT SAFETY INFORMATION

Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. * Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were OS and radiographic progression-free survival (rPFS). Select exclusion criteria included AST and/or ALT ≥ 2.5X ULN, liver metastases, moderate or severe pain, opiate use for cancer pain, and visceral organ metastases. † At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® + prednisone compared with 71% (387/542) of patients treated with placebo + prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer. § rPFS was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 [PCWG2] criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally reviewed radiographic assessment of progression. IIAt the prespecified rPFS analysis, 150 (28%) of patients treated with ZYTIGA® + prednisone and 251 (46%) of patients treated with placebo + prednisone had radiographic progression.

Please see brief summary of full Prescribing Information on subsequent pages.

In the final analysis…

ZYTIGA® (abiraterone acetate) + prednisone achieved a median overall survival (OS) of almost 3 years (34.7 months).1† • 4.4 months improvement in median OS—34.7 months with ZYTIGA® + prednisone vs 30.3 months with placebo + prednisone (active compound)‡ Co-primary end point—median OS: hazard ratio (HR)=0.81; 95% CI: 0.70, 0.93; P=0.0033. Co-primary end point—rPFS: median not reached for ZYTIGA® + prednisone vs a median of 8.28 months for placebo + prednisone; HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.§II

With a median 49 months of follow-up, there were no notable changes in the safety profile of ZYTIGA® + prednisone since the previously reported interim analyses.1 In your patients with mCRPC…

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). Reference: 1. Ryan CJ, Smith MR, Fizazi K, et al; for the COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160.

Learn more today at

www.zytigahcp.com.

Every day tells a story.

034441-150514

CONSIDER ZYTIGA® FIRST.

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of Z YTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving Z YTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with Z YTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced Z YTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt Z YTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of Z YTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

ZYTIGA® (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralo corticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions]. Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 Z YTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to Z YTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

ZYTIGA® (abiraterone acetate) Tablets

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Table 3: A dverse Reactions in ≥5% of Patients on the Z YTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 4 Includes

Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: A dverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: L aboratory Abnormalities in >15% of Patients in the Z YTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking Z YTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis. Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis. DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. Z YTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving Z YTIGA in Phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of Z YTIGA increased by approximately 1.1‑fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, Z YTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of Z YTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: May 2015 034443-150514