Renal & Urology News - October 2015 Issue

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V O L U M E 14, I S S U E N U M B E R 8

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Adjuvant Chemo Ups Post-RC Survival

© PHANIE / ALAMY STOCK PHOTO

In a study, high-risk bladder cancer patients experienced a 29% decreased risk of death from the malignancy

ADJUVANT CHEMOTHERAPY after radical cystectomy improves outcomes, study finds.

Obesity Not a TOT Failure Risk

BY NATASHA PERSAUD OBESITY AND SEVERE obesity do not appear to increase the risk of surgical failure of the transobturator tape (TOT) procedure over 3 years, a new study finds.

Tarik Yonguc, MD, and colleagues of Izmir Bozyaka Training and Research Hospital in Izmir, Turkey, reviewed

outcomes for 470 women (average age 53) with stress or mixed urinary incontinence who underwent a TOT procedure. Women with urge-predominant mixed incontinence were excluded.

The investigators divided patients into 3 groups by body mass index (BMI) for analysis: the normal-weight group (BMI continued on page 7

EXPERT Q & A

David F. Penson, MD, offers his perspective on major advances in prostate cancer.

PAGE 11

ADJUVANT chemotherapy after radical cystectomy (RC) for high-risk bladder cancer may decrease overall and cancer-specific mortality, according to investigators.

Michael Fröhner, MD, of Technischen Universität Dresden, and colleagues studied 798 patients who underwent RC for high-risk superficial or muscleinvasive urothelial or undifferentiated bladder cancer from 1993 to 2011. Of these, 23% received adjuvant cisplatinbased chemotherapy and 5% received neoadjuvant chemotherapy. Of the patients who received adjuvant chemotherapy, 75% received cisplatin plus gemcitabine, 22% received cisplatin plus methotrexate with or without epirubicine and vinblastine, and 3%

Bladder Cancer Mortality Tied to Blood Type A

BY JODY A. CHARNOW PATIENTS WHO undergo radical cystectomy (RC) for bladder cancer are at increased risk of dying from the malignancy if they have blood type A rather than O, a study found.

In a retrospective study of 2,086 patients with urothelial carcinoma (UC) of the bladder treated with RC, a team at Mayo Clinic in Rochester, Minn., led

by Boris Gershman, MD, found that non-O blood type was associated with significantly worse 5-year recurrencefree survival and cancer-specific survival compared with O blood type (65% vs.

69% and 64% vs. 70%, respectively). On multivariate analysis, blood type A was independently associated with a significant 22% increased risk of death from bladder cancer compared with blood type O, the researchers reported online ahead of print in Urologic Oncology.

Blood types B and AB were not associated with bladder cancer-specific mortality compared with blood type O. The continued on page 7

received other combinations with cisplatin. Patients had a median age of 69 years; the median follow-up for censored patients was 7.1 years.

The use of adjuvant chemotherapy was associated with a significant 50% decreased risk of overall mortality and 29% decreased risk of bladdercancer specific mortality. Patients who received adjuvant chemotherapy were significantly younger than those who did not (66 vs. 68 years). They also were healthier, with 31% of recipients having a Charlson score of 2 or higher compared with 40% of patients who did not receive adjuvant chemotherapy.

“Although patients who received adjuvant chemotherapy were somewhat continued on page 7

IN THIS ISSUE 5

Finasteride may lower bladder cancer risk in men

6

Erectile dysfunction not less likely in NSAID users

8

Smoking not a risk factor for all RCC subtypes

15

Propofol safer than midazolam for ICU patient sedation

15

Perineural invasion predicts PCa bone metastasis

21

Improved survival after radical cystectomy documented

21

High uric acid at hospital admission raises AKI risk Critically ill patients with high phosphorus levels are at increased risk of death.

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www.renalandurologynews.com OCTOBER 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.

Kathleen Walsh Tulley Jim Burke, RPh John Pal Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 14, Number 8. 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.

NIH Blood Pressure Trial Is a Game Changer

W

ow! This is the first word I think of to describe the recent announcement of the early termination of the Systolic Blood Pressure Intervention Trial (SPRINT) sponsored by the National Institutes of Health (NIH). The study began in the fall of 2009 and included more than 9,300 participants aged 50 years and older from about 100 medical centers in the United States and Puerto Rico. The study specifically excluded individuals with diabetes mellitus, prior stroke, and polycystic kidney disease. Patient inclusion criteria included a systolic blood pressure (BP) greater than 130 mm Hg and one of the following: a history of cardiovascular disease or subclinical cardiovascular disease, an estimated glomerular filtration rate of 20–59 mL/min/1.73 m2 or age 75 years or older, or a 10-year Framingham cardiovascular disease risk score greater than 15%. The trial looked at a target systolic BP of 120 mm Hg versus 140 mm Hg. The results were impressive: The risk of death was decreased by almost 25%, and the risk of cardiovascular events was decreased by almost one-third. This is clearly a landmark trial that will have a clinical impact similar to that of earlier studies of ACE inhibitors in diabetic nephropathy.

A press release issued by the NIH gives us reason for enthusiasm, but we must learn more about the results before we apply them to our clinical practice. It will be especially important for nephrologists to see treatment effects specifically in the large subgroup with chronic kidney disease as compared to the elderly subgroup. Application of what we learn from this trial will improve the health of our patients but also make our jobs quite a bit harder. Achieving a systolic BP less than 120 mm Hg requires more medication, better balancing of side effects, and more careful evaluation of patients to avoid hypotension.

I think it will be difficult to attain this goal without having patients measure their BP frequently at home and being more involved in their care. SPRINT included individuals who were motivated to be in a clinical trial; many of our patients will not have the same enthusiasm, and we will have to inspire them as well.

Congratulations! This is the second word I think of when I think of SPRINT. Congratulations to the many patients and investigators (including my colleagues here at Wake Forest and many readers of Renal & Urology News) who worked over the past 5 years on this important trial. The results will have a tremendous impact on the health of millions of patients.

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

Renal & Urology News invites readers to submit editorials. Contact Jody A. Charnow, editor, at jody.charnow@haymarketmedia.com.

4 Renal & Urology News

OCTOBER 2015

www.renalandurologynews.com

Contents

OCTOBER 2015 ■ VOLUME 14, ISSUE NUMBER 8

Urology

ONLINE

this month at renalandurologynews.com

8

Smoking Not a Risk Factor for All RCC Subtypes Investigators find no association between tobacco smoking and the chromophobe variant.

15

PNI Predicts PCa Bone Metastasis Perineural invasive increases the risk of bone metastasis by 11-fold in patients for whom a bone scan is indicated, study found.

17

Clinical Quiz Take our latest quiz at renalandurologynews.com /clinical-quiz/.

17

Answer correctly and you will be entered to win a $50 American Express gift card.

Congratulations to our September winner: Leslie Deane, MD

HIPAA

High Uric Acid Increases Mortality in the Elderly Highest versus lowest quartile of serum uric acid associated with a 17% increased risk of all-cause mortality.

Subcutaneous Erythropoietin Safer for HD Patients Researchers observe a reduced risk of death and hospitalization for cardiovascular complications compared with intravenous administration.

15

Renal Risks Lower with Propofol For sedating critically ill patients on mechanical ventilation, the drug is associated with a lower risk of acute kidney injury compared with midazolam.

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

Bladder Wall Thickness May Predict BOO Severity, Study Finds As thickness increases, so does the number of bladder outlet obstruction parameters in men with lower urinary tract symptoms.

10

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

Prostate Cancer AS Safety Confirmed Cancer-related deaths among men with favorable-risk disease are rare 10–15 years after diagnosis, data show.

Nephrology 6

How practices can ensure they are releasing only the minimum amount of protected health information.

CALENDAR

21

Resistant Hypertension Ups ESRD Risk Patients with resistant hypertension (RH) have a 32% increased risk of end-stage renal disease compared with non-RH patients.

Using the admission [serum uric acid] level in clinical practice may help identify patients with a high risk of AKI during hospitalization in order to promptly prevent AKI events.

See our story on page 21

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

18

Departments 5

From the Editorial Advisory Board Results of a landmark blood pressure trial are a game changer

8

News in Brief Bladder cancer risk is lower in men who use finasteride

18

Practice Management What to do after the HIPAA risk assessment

www.renalandurologynews.com OCTOBER 2015

Renal & Urology News 5

News in Brief

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

Short Takes Waist-to-Height Ratio Best Predictor of MetS

in Stockholm, Sweden. The research-

Waist-to-height ratio may be a useful

clinically localized PCa. Those with the

anthropometric predictor of meta-

highest levels of perceived stress had

bolic syndrome (MetS) in patients on

a 66% increased risk of PCa-specific

maintenance hemodialysis (HD), a new

mortality compared with men who

study suggests.

had low stress levels, the investiga-

ers surveyed 4,105 men treated for

Jacqueline Costa Teixeira Caramori,

tors reported online ahead of print in

MD, PhD, and colleagues at the Univer-

the Scandinavian Journal of Urology.

sidade Estadual Paulista in São Paulo,

They also had a high frequency of

Brazil, conducted a cross-sectional

grieving and sleep loss, as well as

study of 98 maintenance HD patients

fewer people with whom to share their

(mean age 57.8 years, 54% male).

emotional problems.

MetS was present in 74.5% of the coaccumulation of abdominal fat and

Odds of ED Decrease with Increasing Exercise

general obesity. Waist-to-height ratio

Men who exercise more have a

was the best independent predictor of

lower risk of erectile dysfunction (ED),

MetS, followed by waist circumference

according to a recent report in the

and body mass index, the researchers

Journal of Sexual Medicine.

hort. Patients with MetS had increased

reported in Nutrition in Clinical Practice (published online ahead of print).

In a study of data from 692 men aged 50–85 years who participated in the 2003–2004 National Health

Prostate Cancer Death Risk Linked to Stress

and Nutrition Examination Survey,

High stress levels are associated with

Edwards, BS, of the University of

an increased rate of prostate cancer

Mississippi in Oxford, found that

(PCa)-specific mortality among men

every 30-minute per day increase in

treated for clinically localized PCa, ac-

moderate-to-vigorous physical activity

cording to Michael Jan, MD, and col-

was associated with a significant 43%

laborators at the Karolinska Institutet

reduced odds of having ED.

Paul D. Loprinzi, PhD, and Meghan

Diabetes On the Rise A recently published analysis of National Health and Nutrition Examination Survey data showed that the prevalence of diabetes is increasing in the United States. Shown here are the age-standardized prevalence figures.

15

12.4%

12

9.8%

10.8%

9

6

3

0

1988-1994

2001-2002

2011-2012

Source: Menke A et al. Prevalence of and trends in diabetes among adults in the United States, 1988–2012.

JAMA. 2015;314:1021-1029.

Finasteride Use May Lower Bladder Cancer Risk in Men M

en who use finasteride may be at lower risk of bladder cancer than those who do not, according to a new study.

The study included 72,370 men who participated in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial. Bladder cancer was diagnosed in 65 (1.07%) of the 6,069 men who reported using finasteride compared with 966 (1.46%) of the 66,301 men who reported no finasteride use, investigators led by Michael A. Liss, MD, of the University of Texas Health Science Center at San Antonio, reported online ahead of print in European Urology. After controlling for age and smoking, finasteride use was associated with a significant 36% decreased risk of a bladder cancer diagnosis.

Regarding study limitations, the authors noted that their study was observational and not randomized. In addition, many confounding variables for bladder cancer, such as alcohol use, were not available for analysis.

In-Hospital Hyponatremia Risk Factors Identified A

history of fatigue and the presence of ascites increase the likelihood that hyponatremia will develop during a patient’s hospital stay for congestive heart failure (CHF).

In a study of 464 CHF patients, researchers at Charles Darwin University, Northern Territory, Australia, found that hyponatremia—defined as a serum sodium level less than 135 mEq/L—developed in 22% of patients during hospitalization. Of these, 44% had normal sodium levels at admission, researchers reported online in BMC Cardiovascular Disorders (2015;15:88). The study also found that 56% of patients who had hyponatremia on admission continued to be hyponatremic during hospitalization.

A history of fatigue and the presence of ascites were associated with a significant 3.2-fold and 4.1-fold increased odds of developing hyponatremia during hospitalization, respectively. Results also showed that administration of heparin and antibiotics were associated with a significant 3.8-fold and 3.0-fold increased odds, respectively.

Early Chemotherapy Offers No Survival Edge in mCRPC E

arly use of chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC) is not associated with significantly improved survival, new findings suggest.

In a retrospective study of 58 mCRPC patients, researchers found no significant difference in progression-free and overall survival between patients who received docetaxel chemotherapy followed by abiraterone hormonal therapy and patients who received the reverse sequence in propensity score-weighted multivariate analyses.

“Treatment sequencing should be determined by patient and disease characteristics, comorbidities and end-organ function, ability to tolerate side effects, and patient preferences,” Benjamin L. Maughan, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, and colleagues concluded in The Prostate (published online ahead of print). Patients in the abiraterone-todocetaxel group had greater metastatic burden in bone and higher median PSA levels compared with the docetaxel-to-abiraterone group, the investigators noted.

6 Renal & Urology News

OCTOBER 2015 www.renalandurologynews.com

ED Risk Not Diminished

by NSAIDs USE OF ASPIRIN and other nonsteroidal anti-inflammatory drugs (NSAIDs) does not reduce the risk of erectile dysfunction (ED), new study findings suggest.

Researchers led by Darshan P. Patel, MD, of University of Utah Health Care in Salt Lake City, analyzed data from 4,726 men in the placebo arm of the prospective Prostate Cancer Prevention Trial (PCPT) who had no evidence of ED at baseline. Aspirin use was associated with a significant 16% increased risk of severe ED and non-aspirin NSAID use was associated with a significant 16% increased risk of mild or moderate ED, Dr. Patel’s group reported online ahead of print in BJU International. These increased risks became non-significant in a model that adjusted for medical conditions associated with NSAID use, including arthritis, chronic musculoskeletal pain, general musculoskeletal pain, headaches, sciatica, and atherosclerotic disease. In

Study included 4,726 men in the placebo arm of the Prostate Cancer Prevention Trial. the study, these conditions were associated with a significant 56%, 36%, 44%, 50%, and 60% increased risk of mild or moderate ED, respectively. General musculoskeletal pain, headaches, and atherosclerotic disease were associated with a significant 22%, 47%, and 60% increased risk of severe ED. For the PCPT, mild or moderate ED was defined as a “decrease in normal function or able with difficulty to achieve vaginal penetration” and severe ED was defined as the “absence of function/no erections,” based on self-report.

In a discussion of study limitations, the researchers noted that they only captured initiation of NSAID use and assumed subsequent continued usage. “This would be a reasonable assumption for chronic NSAID use, but may not be accurate for acute use.”

Additionally, they did not capture data on NSAID dosing, so they could not evaluate potential dose-dependent associations of NSAID use with ED risk. n

High Uric Acid Levels Up Death Risk in the Elderly Highest vs. lowest quartile associated with a 17% increased risk HIGH SERUM uric acid levels are associated with an increased risk of allcause and cardiovascular (CV) mortality, but not cancer mortality, among elderly individuals, according to a recent study.

The study, led by Chung-Pin Li, MD, PhD, of Taipei Veterans General Hospital in Taiwan, included 77,541 participants aged 65 years and older identified using the Taipei Geriatric Health Examination Database. The group included 39,365 men and 38,176 women. During an average of 3.3 years of follow-up, 3,842 subjects (5%) died.

Compared with the lowest quartile of serum uric acid level (less than 5.4 mg/ dL), the highest quartile (greater than 7.3 mg/dL) was associated with a significant 17% increased risk of all-cause mortality among both men and women, Dr. Li’s group reported online ahead of print in the Journal of the American Geriatrics Society. The second and third quartiles (5.4–6.3 and 6.4–73 mg/dL, respectively) were associated with a significant 20% and 11% decreased risk of all-cause mortality, respectively, in men, and the third quartile was associated with a significant 36% increased risk in women.

The highest quartile of serum uric acid level was associated with a significant 39% increased risk of cardiovascular mortality in men and a 35% increased risk in women. The second quartile, however, was associated with a significant 26% decreased risk of cardiovascular mortality in men.

The researchers also looked at the effect of high versus normal uric acid levels on the risk of all-cause and cardiovascular mortality. The cutoff was 7 mg/ dL for men and 6 mg/dL for women.

Compared with normal uric acid levels, high levels were associated with a significant 17% and 39% increased risk of all-cause and cardiovascular mortality, respectively, in men, and 17% and 35% increased risk in women.

According to the researchers, the association between uric acid and CV mortality is independent of other CV risk factors, such as diabetes mellitus, hyperlipidemia, and hypertension.

The investigators found no significant association between serum uric acid level and cancer mortality risk in either men or women.

Uric Acid Levels and Mortality In a study, compared with normal uric acid levels (less than 7 mg/dL for men and 6 mg/ dL for women), higher levels are associated with the following increased risks of all-cause and cardiovascular mortality:

n All-cause mortality n Cardiovascular mortality 40 35 30 25 20 15 10 5 0

17%

39% Men

17%

35% Women

Source: Wu CY et al. High Serum uric acid levels are associated with all-cause and cardiovascular, but not cancer, mortality in elderly adults. J Am Geriatr Soc. 2015; published online ahead of print.

Dr. Li and colleagues noted that many in-depth studies have investigated the association between hyperuricemia and mortality, but these studies mainly included middle-aged individuals.

“Elderly adults have a higher prevalence of hyperuricemia and a higher risk of developing cardiovascular events or mortality,” the authors wrote.

“Because the elderly population is growing, a better understanding of the role of serum uric acid as a risk factor for mortality is merited.”

Strengths of the study include its large sample size, detailed assessment and adjustment for risk factors, and reliable assessment of the cause of death, the investigators noted. They also acknowledged limitations. For example, uric acid levels were measured only once, “so the effect of changes in serum uric acid levels during follow-up on mortality risk could not be investigated.” In addition, they researchers did not have information available on the severity of pre-existing diseases or the use of medications by participants, so they could not examine the possible confounding effects of diuretics on the association between uric acid level and mortality.

In a previous study published in the American Journal of Kidney Diseases (2014;64:550-557), researchers who analyzed data from 10,956 participants in the National Health and Nutrition Examination Survey (1988–1994 and 1999–2002) found that high uric acid levels were associated with an increased

risk of CV and all-cause mortality, but the relationship was no longer statistically significant after adjusting for kidney function.

Although the current study did not find a significant association between high uric acid levels and cancer mortality risk, previous studies have. For example, researchers in The Netherlands found that elevated serum uric acid levels were associated with a decreased risk of cancer mortality, according to findings published in Cancer Causes & Control (2014;25:1075-1080).

The study included 1,823 men in a general population-based cohort who had serum uric acid data available. Of these, 254 (13.9%) died from any cancer.

Serum uric acid levels in the highest tertile (above 5.8 mg/dL) were associated with a 32% decreased risk of any cancer compared with levels in the lowest tertile (less than 5.0 mg/dL).

Findings from another study, however, suggest that high serum uric acid levels increase cancer mortality risk. The study examined prospective data from a cohort of 83,683 apparently healthy Austrian adults who had a median follow-up of 13.6 years. Compared with men in the lowest quintile of serum uric acid level, those in the highest quintile had a 41% increased risk of death from any cancer in adjusted analyses, the investigators reported in Cancer Causes & Control (2007;18:1021-1029).

Participants younger than 65 years had a 53% increased risk. n

Blood type A continued from page 1

study, which the researchers believe is the first to demonstrate an association of blood type with mortality following RC, found no significant association between blood type and disease recurrence and all-cause mortality.

“ABO blood type represents an appealing prognostic marker given its universal availability and simplicity,” Dr. Gershman told Renal & Urology News. “While it has previously been associated with oncologic outcomes for a number of malignancies, its potential prognostic utility for patients undergoing radical cystectomy has been understudied. We found that non-O blood type, particularly blood type A, was independently associated with an increased risk of cancer-specific mortality among patients undergoing radical cystectomy for urothelial carcinoma of the bladder, even after adjusting for a variety of clinicopathologic features.”

The study’s findings have several implications. “From a clinical standpoint, ABO blood may hold value in

Obesity and TOT failure continued from page 1

less than 25 kg/m2), obese group (BMI 30–34 kg/m2), and severely obese group (BMI 35–39 kg/m2). Morbidly obese women with a BMI above 40 were not studied. The investigators also chose to omit overweight women (BMI 25–29 kg/m2) to clarify differences associated with obesity.

Average operative time was significantly longer in the obese groups, according to results published in Urology (2015;86:244-249). Passing the needle through the obturator foramen in obese women is more difficult than in slimmer patients, the researchers noted.

The rates of objective cure, subjective success, and patient satisfaction were similar between groups, however. Objective cure meant there was no need for

Chemo after RC continued from page 1

younger and/or healthier, the consistent identification of adjuvant chemotherapy as an independent predictor of reduced mortality in various models may most likely be explained, at least in part, by a true treatment effect,” the researchers wrote in a paper published online ahead of print in European Urology. “These observations support

risk-stratification to identify patients who may benefit from more aggressive treatment and/or altered surveillance regimens,” Dr. Gershman said.

In addition, he said the findings are provocative with respect to the biologic mechanisms underlying the association of ABO blood type with oncologic outcomes, particularly in light of prior studies suggesting a potential role for ABO blood type in tumor immunology.

The researchers acknowledged that the study was limited by its retrospective design and selection bias, as all subjects underwent RC. “Therefore, although our findings may be used for prognostication among patients undergoing RC, these data cannot be extrapolated to predict the association between blood type and cancer biopsy for all patients with UC of the bladder.”

Previous studies have identified ABO blood type as a prognostic oncologic marker and found associations between blood type and outcomes for various urologic and non-urologic malignancies, the authors observed.

Additionally, studies have shown that ABO blood group antigens are located

Renal & Urology News 7

on chromosome 9q34, an area frequently deleted in bladder cancer.

The study by Dr. Gershman and his colleagues included 913 (44%), 881 (42%), 216 10%), and 76 (4%) patients with blood type O, A, B, and AB, respectively. The median post-RC follow-up among survivors was 11 years.

In a previous retrospective study of 931patients with non-muscle invasive bladder UC treated with transurethral

bladder resection, Tobias Klatte, MD, of the Medical University of Vienna in Austria, and colleagues found that patients with blood type O had significantly increased risks of disease recurrence and progression compared with other blood types, according to a paper published in The Journal of Urology (2014;191:1238-1243).

Furthermore, in a separate retrospective study of 7,906 patients undergoing RC for UC of the bladder, Dr. Klatte and colleagues found no independent association between ABO blood type and mortality, according to findings published in Urologic Oncology (2014;32:625-630).

“The somewhat contrasting results to the findings of our present series may reflect underlying differences between the study populations,” Dr. Gershman’s group stated. “Indeed, we noted that the association of blood type with outcome was particularly evident among patients with organ-confined disease.”

In the study by Dr. Klatte’s group, nearly 25% of patients had pN+ disease and about 42% had pT3/T4 disease, Dr. Gershman and colleagues pointed out. n

assessed by the visual analog scale (score of 80 or above). More women in the severely obese group showed improvement instead of cure.

“The high satisfaction rate of both obese and severely obese women from

surgery is respectable and encouraging for the surgeons who will perform antiincontinence surgery in women in both these groups in the future,” according to the investigators.

They observed no meaningful differences in intra-operative and post-­ operative complications. Overall complication rates were similar at 10.4%, 11.1%, and 9.3% for the n ­ ormal-weight, obese, and severely obese groups, respectively. New onset of urge urinary incontinence occurred in 1.9%, 2.7%, and 3.1%, respectively, with more severely obese women experiencing it.

Urinary retention requiring catheterization was seen only in 1 normal-weight patient. No bladder or intestinal perforation occurred.

Groin and leg pain was the most common post-operative complication, occurring in 4.2% of patients. These

symptoms resolved with the use of non-steroidal anti-inflammatory drugs.

“The authors should be complimented on making a timely contribution to the urologic literature,” Steven P. Petrou, MD, of Mayo Clinic in Jacksonville, Fla., wrote in an accompanying editorial.

Dr. Petrou cited a study showing that in 2009–2010, approximately 41 million obese women were in the United States, and many of them will suffer from incontinence. He said it is reassuring to know that based on the paper

by Dr. Yonguc’s group and other articles, a TOT procedure “may be offered to the incontinent obese woman with the expectation of a good result.”

The next hurdle, he noted, will be management of the extremely obese (BMI greater than 40 kg/m2), who now constitute 8% of the U.S. female population. n

the concept of offering adjuvant chemotherapy to high-risk patients after RC, particularly since they were made in a largely unselected sample with a meaningful proportion of patients who were unfit or unwilling to undergo chemotherapy.”

The study builds on other investigations that have demonstrated survival benefits associated with post-RC adjuvant chemotherapy. In a study 2,044 patients who underwent RC for mus-

cle-invasive bladder cancer, Canadian researchers led by Christopher M. Booth, MD, of Queen’s University in Kingston, Ontario, found that adjuvant chemotherapy was associated with a 29% decreased risk of all-cause mortality and 27% decreased risk of death from bladder cancer, according to a report in Cancer (2014;120:16301638). In separate study of 746 patients who underwent RC for bladder cancer, Taekmin Kwon, MD, and colleagues at

Asan Medical Center in Seoul, Korea, showed that patients who received adjuvant chemotherapy had a significant 44% decreased risk of dying from bladder cancer than those who did not, according to findings published in the Journal of Cancer Research and Clinical Oncology (2015;141:169-176). Patients who received adjuvant chemotherapy were significantly younger 60 vs. 63 years) and more likely to have adverse pathologic features. n

r­ e-operation, negative cough test results, and no need for pads. Subjective success was determined by lack of additional treatment, slight or moderate symptom scores on the International Consultation on Incontinence Questionnaire-Short Form, and s­atisfaction with surgery, as

Obese and non-obese patients had similar rates of objective cure, study showed.

Blood typing may have diagnostic utility for patients undergoing radical cystectomy.

© TTHINKSTOCK / KEITH BROFSKY

www.renalandurologynews.com OCTOBER 2015

8 Renal & Urology News OCTOBER 2015 www.renalandurologynews.com

Smoking Not a Risk Factor for All RCC Subtypes TOBACCO smoking is a well recognized modifiable risk factor for renal cell carcinoma (RCC), but not for all RCC histologic subtypes, according to researchers.

In a study of 816 patients undergoing nephrectomy, a team led by Eric C. Kauffman, MD, of the Roswell Park Cancer Institute in Buffalo, discovered that smoking is a risk factor for clear cell and papillary RCC (ccRCC and pRCC, respectively), but not chromophobe RCC (chRCC).

Using propensity analyses adjusting for multiple variables, active smoking was independently associated with a significant 2.2 and 2.4-fold increased odds of ccRCC and pRCC, respectively, Dr. Kauffman’s group reported in The Journal of Urology (2015;194:640-646).

Researchers find no association between smoking and the chromophobe variant.

According the investigators, their study provides the first demonstration that smoking, the most important modifiable risk factor for RCC, increases the risk of certain common RCC subtypes but not others. “These findings underscore the distinct carcinogenic mechanisms underlying RCC subtypes, including a differential effect of tobacco carcinogens,” they concluded. “Important in this regard may be tobacco induced oxidative stress injury to the renal proximal tubule, the presumed origin of ccRCC and pRCC but not chRCC.” Dr. Kauffman and his colleagues said the new findings may be clinically useful in predicting renal tumor histologic subtype. Given the lower metastatic potential of chRCC compared with pRCC and ccRCC, knowledge of the histologic subtype “can aid in clinical risk stratification, including among older or sicker patients with early stage renal tumors who are debating surgical resection vs active surveillance.”

The authors noted that the mechanisms by which tobacco might promote development of RCC are unclear.

“Oxidative stress injury with smoking mediated by increases in local hypoxia and reactive oxygen species could explain the risk of ccRCC and pRCC and not chRCC,” they wrote.

They pointed out that the association of smoking with angiogenesis might also contribute to ccRCC tumorigenesis.

“Nicotine is known to increase endothelial cell number, capillary network formation, and angiogenic response in neoplasia, mediated in part by the vascular endothelial growth factor protein commonly up-regulated in ccRCC.” Dr. Kauffman’s team acknowledged study limitations, including the retro-

spective study design and restriction to a single institution and geographic region.

Additionally, they noted, smoking may be associated with confounding variables that affect RCC risk but were not measured, including a history of hypertension.

Of the 816 patients in the study, 705 had nonfamilial RCC and 111 had

benign pathology and 51% reported smoking (21% active smokers and 30% former smokers).

The new study adds to a growing number of recent investigations characterizing the different RCC histologic subtypes and their associated risk factors. For example, researchers at

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Vanderbilt University Medical Center in Nashville, Tenn., studied RCC tumors from 1,532 patients who underwent nephrectomy and found a substantially higher proportion of patients with pRCC among black patients than white patients, according to a paper published online ahead of print in BJU

International. Additionally, patients with chRCC were significantly more likely to be female. In a separate study of 487 RCC patients, also published in BJU International (2014;114:496502), researchers demonstrated that increased visceral fat was associated with ccRCC, and visceral fat area

outweighed the effects of body mass index (BMI) and type 2 diabetes for predicting RCC pathology in multivariate analyses. Additionally, a South Korean study of 2,769 patients with non-metastatic RCC demonstrated that higher BMI was associated with greater recurrence-free survival (RFS)

Renal & Urology News 9

and cancer-specific survival (CSS) rates among patients with ccRCC and lower RFS and CSS rates among those with chRCC, according to a findings published in Clinical Genitourinary Cancer (2015;13:461-468). The study found no association between BMI and RFS or CSS in patients with pRCC. n

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10 Renal & Urology News OCTOBER 2015 www.renalandurologynews.com

Subcutaneous Erythropoietin Safer for HD Patients HEMODIALYSIS (HD) patients who receive erythropoietin subcutaneously rather than intravenously are at lower risk of death, hospitalization for cardiovascular complications, or both, according to a new study.

The study, led by Daniel G. Wright, MD, of the National Institute of

Diabetes and Digestive and Kidney Diseases in Bethesda, Md., included 62,710 adult HD patients treated with either intravenous (IV) or subcutaneous (SC) epoetin alfa and followed up for 24 months.B:7.25” Subjects were enrolled in the Centers T:7” for Medicare S:7” and Medicare Services (CMS) ESRD

Clinical Performance Measures (CPM) Project from 1997 to 2005. The study population had a mean age of 61.4 years, and 52.4% were men.

Patients managed with IV epoetin had an 11% increased risk of a composite outcome of death or hospitalization for acute myocardial infarction,

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­congestive heart failure, and stroke within 1 year compared with those managed with SC epoetin after adjusting for potential confounders, the investigators reported online ahead of print in the Clinical Journal of the American Society of Nephrology.

As expected, epoetin doses used to achieve equivalent hemoglobin responses, on average, were 25% higher with IV versus SC administration, according to the investigators.

The authors concluded that their study provides evidence that routine use of SC rather than IV epoetin to treat anemia in HD patients “could enhance survival and reduce hospitalizations for cardiovascular complications by minimizing epoetin dosing.”

Assuming that their study findings accurately represent all ESRD patients in the United States from 1997 to 2005, they estimated that nearly 30,000 early deaths and/or hospitalizations for cardiovascular complications might have been avoided had all patients been managed with SC epoetin.

Dr. Wright and his colleagues noted that concerns about the development of drug-associated pure red cell aplasia (PRCA) have led to recommendations that HD patients be treated with IV rather than SC epoetin. Therefore, they examined records from the Centers for Medicare and Medicaid Services for occurrences of PRCA among the study subjects within 5 years after their entry into the ESRD CPM Project. Prior to 2008, no specific ICD-9 code was defined for PRCA, but this diagnosis was included among other forms of acquired aplastic anemia (248.8), the authors pointed out. They screened records for this ICD-9 code and then used other diagnosis, procedure, and treatment codes to look for possible cases of PRCA using criteria described

by Alan J. Collins, MD, and colleagues in the American Journal of Kidney Diseases (2004;43:464-470). These criteria included records of bone marrow examination, persistent anemia, and repeated red cell transfusions but not other causes of marrow failure.

Of 57,602 patients treated with IV epoetin, 92 (0.16%) had a 284.8 code recorded at some time within 5 years of entry to the CPM Project compared with 3 (0.06%) of 5,108 patients managed with SC epoetin. Of the entire cohort, however, only 1 case of possible PRCA fulfilled the criteria of Collins et al during 201,655 patient-years of follow-up. n

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OCTOBER 2015

Renal & Urology News 11

Interview with David F. Penson, MD David F. Penson, MD, MPH, is Professor and Chair of the Department of Urologic Surgery at Vanderbilt University Medical Center in Nashville, Tenn., where he is director of the Center for Surgical Quality and Outcomes Research. His primary research interests include assessing patientreported outcomes in conditions treated with surgical procedures, specifically prostate cancer. Renal & Urology News asked Dr. Penson for his views about key recent developments in prostate cancer management.

If you had to pick the most important advance in prostate cancer management in the past 10 years, what would it be?

Dr. Penson: I think the most important advance we have seen in the past decade in prostate cancer management has been the discovery and approval of numerous agents that have been shown to prolong survival in castrateresistant disease. While none of these individual agents is “curative” on its own, all represent important steps in that direction. I can only imagine what will happen when we start combining therapies and adding other newly discovered agents.

A number of studies have demonstrated that multiparametric MRI can improve the accuracy of prostate cancer detection. Should clinicians use it routinely in the diagnostic work-up if it is available?

Dr. Penson: I completely agree that MRI has become an important adjunct to prostate biopsy that is improving our ability to detect prostate cancer.

This is particularly true when the MRI is used in conjunction with ultrasound to perform a so-called fusion biopsy.

I don’t know if we should be using it routinely in all men at risk for prostate cancer, however. This may not be the most cost-effective way to approach prostate cancer detection. In my practice, I try to reserve MRI-fusion TRUS [transrectal ultrasound] biopsy for

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men who have a rising PSA and a prior negative TRUS biopsy or men who I am following on active surveillance.

I am particularly excited about MRI as it is applied to active surveillance, as it may ultimately allow us to avoid some repeat biopsies. That being said, we still need more research in this space.

rule out the inferiority of intermittent ADT when compared with continuous ADT. In other words, it is possible that intermittent ADT may not work as well. Conversely, in the Canadian trial of men with biochemical failure M0 disease only (Crook et al, N Engl J Med. 2012;367:895-903), the results documented that intermittent therapy was statistically non-inferior to continuous treatment. To translate the results out of statistical-ese and into somewhat plain English, it is probably still best to treat men with documented metastatic disease with continuous ADT. In the case of M0 disease (biochemical failures), however, intermittent therapy is certainly a reasonable choice and may even be superior in terms of cardiovascularevent rates and quality of life outcomes.

Would you consider using active surveillance for selected men with intermediate-risk prostate cancer, and if so, what would be the selection criteria?

Dr. Penson: I remain reluctant to endorse active surveillance in intermediate-risk disease. Simply put, many

It remains unclear whether roboticassisted radical prostatectomy (RARP) results in better oncologic control, but evidence suggests this approach offers advantages over traditional surgery in terms of recovery of potency and urinary continence. Do these advantages by themselves justify the preferential use of RARP?

Dr. Penson: I really feel as though the jury is still out on this one. The results of the SWOG study of men with metastatic disease (Hussain et al, N Engl J Med. 2013;368:1314-1325) couldn’t

In your view, what is the most critical study in prostate cancer management that has yet to be conducted?

Dr. Penson: There are so many studies that need to be done. A big part of the problem is that they take so long to complete that researchers are not willing to undertake them. Rather than focus on a particular study, I will state that the greatest need for research is in the patient who has biochemical recurrence after primary therapy. We have no idea when to treat these patients, nor do we know how best to treat these patients. This is a big segment of the prostate cancer population, and it’s clear that many biochemical recurrences are clinically indolent, so any information to guide treatment here would be highly impactful.

Is there a place for surgery as a salvage therapy for prostate cancer patients who experience biochemical recurrence after primary radiotherapy?

Dr. Penson: Yes, there is but it’s the great minority of patients in my opinion. In my practice, I reserve salvage prostatectomy for younger patients with biopsy-proven higher-grade localized disease recurrence.

Dr. Penson: At this point, the question is effectively moot. Roughly 85%–90% of prostatectomies performed in the U.S. use the robotic-assisted laparoscopic (RALP) approach, so from a purely quality of care perspective, RALP is preferred because it is the usual approach of most urologists in 2015.

Does the current evidence support the use of intermittent over continuous androgen deprivation therapy (ADT) in men with advanced prostate cancer who require ADT?

and perhaps the majority of these cancers are clinically significant, and patients might realize a benefit from aggressive intervention as early as possible. The advent of genomic testing may change this over the next few years. But right now, I don’t recommend active surveillance to my patients with intermediate-risk disease.

What do you predict will be the most important game changer in prostate cancer management in the next 10 years?

I am particularly excited about MRI as it is applied to active surveillance.

—David F. Penson, MD, MPH

Dr. Penson: Additional novel medical therapies to treat prostate cancer and earlier use of the existing medical therapies. I think we have gone as far as we are going to go in the treatment of localized disease with surgery or radiation, but we are just scratching the surface with regard to medical treatment of this common malignancy. There is surely more to come in the next decade which will really help our patients. ■

Continue the conversation online! We have many experts who weigh in on controversial topics important to you. Catch our discussions at www.renalandurologynews/expertqa.

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Renal & Urology News 15

Renal Risks Lower with Propofol In a study, AKI was less likely to develop in ICU patients treated with propofol rather than midazolam Clinical Journal of the American Society of Nephrology. Oliguria (less than 400 mL/day) occurred significantly less frequently in the propofol than midazolam group (12.4% vs. 19.6%). In addition, propofol-treated patients had diuretics prescribed less frequently than the midazolam-treated patients (8.5% vs. 14.3%).

The need for RRT in the first 7 days of ICU stay occurred significantly less often in the propofol than midazolam group (3.4% vs. 5.9%). The ICU mortality rate was significantly lower in the propofol recipients (14.6% vs. 29.7%).

Critically ill patients often are managed using a continuous-infusion sedative for comfort and to reduce anxiety, the researchers explained. The ICU sedation strategy can include either benzodiazepine or non-benzodiazepine medications. Propofol has anti-inflammatory and immunomodulatory properties in addition to its intrinsic anesthetic properties. It has been shown to provide protection against renal ischemia/reperfusion injury experimentally,

PNI Predicts PCa Bone Metastasis

Results revealed no significant association between PNI and bone metastasis in group 1, but a strong association between PNI and bone metastasis in group 2. PNI had a sensitivity and specificity for bone metastasis of 72.4% and 81.7%, respectively, and a positive predictive value of 77.7%, Seyfettin Ciftci, MD, of Sivas Numune State Hospital in Sivas, Turkey, and colleagues reported.

“We recommend that PNI should be kept in mind as an adverse parameter for the appropriate evaluation of bone metastasis,” Dr. Ciftci’s group concluded.

The researchers said that to the best of their knowledge, their study is first to examine the correlation between PNI and bone metastases.

The investigators acknowledged that their study had limitations, including its retrospective nature. Another limitation was the low number of patients with metastatic disease in group 1.

Consequently, they could not come to any conclusions about the predictive value of PNI for bone metastasis in this group. Additionally, PNI cannot be precisely evaluated in prostate needle biopsies because these only sample a very limited portion of the prostate, the authors noted. Thus, PNI may be present in areas not sampled. n

PERINEURAL INVASION (PNI) in prostate biopsy specimens is a strong predictor of prostate cancer (PCa) bone metastasis, new findings suggest.

In a retrospective study of 633 PCa patients, investigators found that PNI was associated with an 11-fold increased risk of bone metastasis among patients for whom a bone scan is indicated on the basis of National Comprehensive Cancer Network (NCCN) criteria, according to a paper published online ahead of print in The Prostate.

The researchers divided patients into group 1 and group 2. Group 1 included 262 patients (mean age 65.5 years) who had none of the following: symptomatic disease, Gleason sum of 8 or higher, clinical stage T3 or T4, clinical stage T1 with a total PSA level greater than 20 ng/mL, or clinical stage T2 with total PSA greater than 10 ng/mL. Group 2 included 371 patients (mean age 69 years) who had any of the preceding clinical features.

Propofol may be a safer option than midazolam for ICU patient sedation.

but clinical evidence is limited to patients undergoing cardiac surgery, they pointed out. The investigators cited a recent randomly controlled study showing that propofol anesthesia was associated with a decrease in AKI incidence compared with sevoflurane anesthesia in patients undergoing

valvular heart surgery (Yoo YC et al.

Kidney Int. 2014;86:414-422).

Dr. Libório and his colleagues obtained data for their study from the Multiparameter Intelligent Monitoring in Intensive Care II database, which is maintained by the Massachusetts Institute of Technology Laboratory for Computational Physiology in Boston.

The database contains data from patients hospitalized in an ICU at Beth Israel Deaconess Medical Center in Boston from 2001 to 2008.

The use of this large and detailed database was among the study strengths, the authors noted “The detailed information provided by this database is of utmost importance, because it enables it to expand the baseline characteristics beyond the possibilities of an administrative database,” the researchers wrote.

They also acknowledged study limitations, including the retrospective nature of the study, the use of data from a single center, and a relatively low number of patients receiving midazolam.n

Hyperphosphatemia Increases Mortality in Critically Ill Patients HYPERPHOSPHATEMIA predicts an

In multivariate analysis, only hyper-

increased risk of death among hospi-

phosphatemia—and not sex, age, esti-

talized critically ill patients, according

mated glomerular filtration rate (eGFR),

to researchers.

ethnicity, and diuretic therapy—was an

Their cross-sectional study of

independent risk factor for mortality.

2,390 emergency room (ER) patients

Hypophosphatemia was not associated

found that hyperphosphatemia was

with mortality. Only eGFR was inde-

associated with a significant 3.3-fold

pendently associated with mortality in

increased odds of in-hospital death

patients with hypophosphatemia.

within 28 days, Dominik G. Haider, MD,

Of the 2,390 patients, 1,695 had

of University Hospital Bern in Bern,

normal phosphorus levels, 215 had

Switzerland, and colleagues reported

hyperphosphatemia, and 480 had hypo-

online in PLoS One.

phosphatemia. Of these, 37 (2.2%), 23

Noting that hyperphosphatemia

(10.7%), and 17 (3.5%) died, respectively.

has been linked repeatedly to chronic

The patients with hyperphosphatemia

kidney disease (CKD), the investigators

had a significantly lower mean eGFR that

wrote that while “hyperphosphatemia

those with normal phosphate levels and

may be a tangible indicator of deterio-

hypophosphatemia (22.4 vs. 92.8 and

rating kidney function, it appears that

90.7 mL/min/1.73 m2, respectively).

lack of phosphate homeostasis may

Previous studies have shown that the

also be associated with the increased

association between high phosphate

risk of cardiovascular events and

concentrations and increased mortality

mortality that has become a hallmark

is not restricted to patients with renal dis-

of CKD.”

ease, Dr. Haider’s group pointed out. n

© ISTOCK / TRISH233

PROPOFOL is safer than midazolam for sedating critically ill patients on mechanical ventilation, according to researchers.

In a large study, a team led by Alexandre Braga Libório, of the Federal University of Ceará in Ceará, Brazil, demonstrated that propofol use was associated with a significantly lower risk of adverse renal outcomes, including acute kidney injury (AKI), fluid-related complications, and need for renal replacement therapy (RRT) compared with midazolam use.

The study included 698 propofoltreated patients closely matched to the same number of midazolam-treated patients. All were adults experiencing their first intensive care unit (ICU) admission and all required mechanical ventilation.

The incidence of AKI in the first 7-day ICU time period was lower in the propofol than midazolam group using both urine output criteria (45% vs. 55.7%) and serum creatinine criteria (28.8% vs. 37.2%), Dr. Libório’s group reported online ahead of print in the

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Renal & Urology News 17

Prostate Cancer AS Safety Confirmed Cancer-related deaths among men with favorable-risk disease are rare 10–15 years after diagnosis RECENTLY PUBLISHED studies provide additional evidence of the safety of active surveillance (AS) as a management option for men with favorable-risk prostate cancer (PCa).

A study conducted by H. Ballantine Carter, MD, and colleagues at Johns Hopkins Hospital in Baltimore demonstrated that Caucasian men with favorable-risk PCa placed on AS have a low risk of progressing to lethal cancer for 10–15 years after diagnosis and have rates of cancer spread and death from PCa that are similar to those who undergo immediate radical treatment.

“Men with favorable-risk prostate cancer should be informed of the low likelihood of harm from their diagnosis and should be encouraged to consider surveillance rather than curative intervention,” Dr. Ballantine’s team concluded.

In another study, Peter R. Carroll, MD, and colleagues at the University of California San Francisco found that patients who delayed radical prostatectomy (RP) were not at higher risk for worse outcomes compared with those who had immediate RP and the same clinical features.

“When compared to men with similar pretreatment biopsy features, those who underwent delayed RP were not at higher risk of adverse pathology, indicating a window for cure was probably not missed,” Dr. Carroll’s team concluded.

Dr. Carter’s team studied 1,298 patients at their institution carefully selected for AS. The men had a median age of 66 years and 88% were Caucasian. Of the entire cohort, 926 had very-low-risk PCa (clinical stage T1c, PSA density [PSAD] less than 0.15 ng/mL, biopsy Gleason score 6 or lower, 2 or fewer positive biopsy cores, and no more than 50% cancer in any 1 core) and 372 had lowrisk disease (T2a or lower, PSA less than 10 ng/mL, and Gleason score 6 or lower).

No one had Gleason score 7 tumors.

The AS program, started in 1995, included an annual 12- to 14-core biopsy along with semi-annual PSA testing and digital rectal examinations.

Survival and disease recurrence Overall, cancer-specific and metastasisfree survival rates were relatively high: 93%, 99.9%, and 99.4% at 10 years and 69%, 99.9%, and 99.4%, respectively, at 15 years, the researchers reported online ahead of print in the Journal of Clinical Oncology. Survival rates may change with longer follow-up, the researchers stated. Only 2 deaths and 3 cases of PCa metastases occurred. One patient died after 16 years on AS with a clonally-distinct cancer, and the other died within 15 months of diagnosis after not entering the Johns Hopkins surveillance program. An additional 47 men died from cardiovascular disease or other causes.

The cumulative risk of dying of any cause as compared to developing PCA metastasis or dying of PCA was 24 to 1.

The investigators also assessed biochemical recurrence in a subset of patients and found the rates were similar for men who underwent surgery or radiation after AS. The median treatment-free survival for all patients was 8.5 years.

Reclassification to a higher grade of cancer occurred in 26% of patients at 10 years and 31% at 15 years. Older age, PSAD, and a greater number of positive biopsy cores were linked with a greater likelihood of cancer upgrading. PSAD and having more positive cores, indicators of cancer volume, increased the likelihood of intervention.

Paradigm shift needed For men with favorable-risk PCa, “the paradigm of immediate intervention must be replaced by one of immediate contemplation—a thoughtful assessment of prognostic risk, life expectancy, and the relative risks and benefits of

Active Surveillance and Survival A recent study showed that selected men with favorable-risk prostate cancer placed on active surveillance rarely die from the cancer 10–15 years after diagnosis.

n 10 years 100 80

99.9%

93%

n 15 years 99.9%

99.4%

99.4%

69%

60 40 20 0

Overall survival

Cancer-specific survival

Metastasis-free survival

Source: Tosoian JJ et al. Intermediate and longer-term outcomes from a prospective active-surveillance program for favorablerisk prostate cancer. J Clin Oncol. 2015; published online ahead of print.

available management options considered in the context of personal preferences,” the investigators concluded.

The study by Dr. Carroll and his colleagues compared outcomes among 521 patients who underwent RP within 6 months of diagnosis (immediate RP) and 157 patients who had delayed RP after a median of 20 months on AS. PCa was upgraded to Gleason Score (GS) 3 + 4 in 54 men on AS during follow-up biopsy, according to findings published online ahead of print in European Urology. Men who had immediate RP were 66% less likely to have adverse pathology (e.g., Gleason upgrade, extraprostatic extension, seminal vesicle invasion, positive lymph nodes, or positive surgical margins) than men who had delayed RP. To minimize the influence of selection bias, the investigators separately examined a subset of 216 men with GS 3 + 4 from both groups matched by pre-treatment biopsy features, including clinical stage, PSA, age, and year of diagnosis.

The rate of adverse pathology did not differ: 46% of the delayed RP group had at least 1 adverse feature compared with 44% of the immediate RP group.

“The presence of adverse pathologic features after surgery did not differ between men initially diagnosed with GS 3 + 4 disease and treated and men reclassified to GS 3 + 4 on follow-up biopsy after a period of AS and then treated,” the investigators explained.

Over 3 years after RP, the delayed and immediate RP groups showed no significant difference in the rates of biochemical recurrence (100% vs. 88%, respectively).

Last year at the European Association of Urology 29th congress, researchers reported on another study showing the safety of AS. The study, led by Laurence Klotz, MD, of Sunnybrook Health Sciences Centre, University of Toronto, included 993 men with favorable- or intermediate-risk who underwent AS for a median 8.1 years. The 10- and 15-year actuarial cancer-specific survival rates were 98.1% and 94.3%, respectively. Patients were 9.2 times more likely to die from other causes than from PCa. In a poster presentation, the authors concluded that AS for favorable-risk PCa is feasible and appears safe in the 15–20 year time frame. n

Bladder Wall Thickness May Predict BOO Severity, Study Shows BLADDER WALL thickness (BWT) may offer a quick and easy way to predict severity of bladder outlet obstruction (BOO) in men, researchers say.

In a study of 236 men with lower urinary tract symptoms secondary to benign prostatic hyperplasia, Özer Güzel, MD, and colleagues at

the Ankara Numune Research and Training Hospital in Turkey examined the relationship between BWT and poor indictors for BOO: International Prostate Symptom Score (IPSS) above 19, peak flow rate (Qmax) less than 15 mL/min, and post-void residual (PVR) greater than 100 mL. The investigators

used suprapubic ultrasonography to measure BWT. Patients had a mean age of 62.5 years and mean BWT of 3.8 mm. The mean IPSS, Qmax, PVR, and duration of LUTS were 17.7, 13.7 mL/min, 89.9 mL, and 46.5 months, respectively, the investigators reported in Urology

(2015;86:439-444). Results showed that BWT increased when the number of BOO parameters increased. BWT was 2.9 mm in patients without BOO, whereas BWT was 3.5, 4.1, and 4.5 mm in patients with any 1, any 2, and all parameters of BOO, respectively, according to the researchers. n

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Renal & Urology News 21

Resistant Hypertension Ups ESRD Risk The risk is higher in patients with uncontrolled vs. controlled resistant hypertension, study finds INDIVIDUALS WITH resistant hypertension (RH) are at higher risk for endstage renal disease (ESRD), cardiovascular events, and death compared with those whose hypertension is non-resistant, new data suggest.

Among patients with RH, individuals whose hypertension is uncontrolled on 3 or more medications (uRH) are at increased risk of ESRD and cerebrovascular accident (CVA) compared with those whose hypertension is controlled with 4 or more drugs (cRH).

In a 5-year retrospective cohort studyw, John J. Sim, MD, of Kaiser Permanente Los Angeles Medical Center, and collaborators examined the risk of ESRD, CVA, ischemic heart event (IHE), congestive heart failure (CHF), and all-cause mortality among 470,386 individuals with RH and non-RH. The researchers subcategorized the 60,327 individuals with RH into 2 groups: 23,104 patients with cRH and 37,223 with uRH. The study population consisted of members of the

Resistant vs. Non-Resistant Hypertension A study of 470,386 hypertensive patients showed that individuals with resistant hypertension (RH) are at elevated risk for ESRD and other adverse outcomes compared with those who have non-resistant hypertension (non-RH). Shown here are the increased risks associated with RH versus non-RH.

46%

50 40

32%

30

24%

20

14% 6%

10 0

ESRD

IHE

Kaiser Permanente Southern California (KPSC) health system.

Compared with non-RH patients, the cRH and uRH patients had a 32%, 24%, 46%, 14%, and 6% increased risk for ESRD, IHE, CHF, CVA, and allcause mortality, respectively, in adjusted

High Uric Acid At Hospital Admission Raises AKI Risk HIGH URIC ACID levels at hospital admis-

hospitalization in order to promptly

sion are associated with an increased

prevent AKI events,” the authors wrote.

risk of in-hospital acute kidney injury

“For example, hyperuricemia-related

(AKI), new study data suggest.

AKI has been reported in patients with

The retrospective study, led by Wisit

non-steroidal anti-inflammatory drug

Cheungpasitporn, MD, of Mayo Clinic in

use. Thus discontinuation or avoidance

Rochester, Minn., enrolled 1,435 hospi-

of such nephrotoxic agents in patients

talized adults who had admission serum

with elevated admission SUA should be

uric acid (SUA) data available. Of these,

considered.”

AKI developed in 263 (18%). An SUA

Dr. Cheungpasitporn’s group dis-

level above 9.4 mg/dL was associated

cussed some plausible explanations for

with 79% increased odds of AKI develop-

the increased AKI risk in patients with

ing during the hospital stay compared

elevated SUA levels. They noted, for

with a level of 5.8–7.6 mg/dL (reference)

example, that uric acid has been pro-

after adjusting for multiple potential

posed to play a role in AKI via crystal-

confounders, the researchers reported

independent mechanisms as well as

online in the Clinical Kidney Journal.

crystal-dependent pathways. “Elevated

Conversely, admission SUA levels below

SUA can induce renal vasoconstric-

3.4 and 3.4–4.5 mg/dL were associ-

tion and impair autoregulation, which

ated with 62% and 50% decreased odds

results in reduced renal blood flow and

of developing AKI, respectively.

glomerular filtration rate,” they stated.

“Using the admission SUA level in

CHF

CVA

All-cause mortality

ESRD: end-stage renal disease; IHE: ischemic heart event; CHF: congestive heart failure; CVA: cerebrovascular accident Source: Sim JJ et al. Comparative risk of renal, cardiovascular, and mortality outcomes in controlled, uncontrolled, and nonresistant hypertension. Kidney Int. 2015;88:622-632.

Limitations of the study include its

clinical practice may help identify

retrospective design and predominantly

patients with a high risk of AKI during

Caucasian study population. n

analyses, Dr. Sim’s team reported in Kidney International (2015;88:622-632).

Compared with cRH patients, uRH patients had a 25% and 23% increased risk of ESRD and CVA, respectively.

This finding supports the link between blood pressure and both outcomes, the

Post-RC Survival Has Improved SURVIVAL OUTCOMES after radical cystectomy (RC) for muscle-invasive bladder cancer have improved in the general population, with 5-year disease-specific and overall survival rates approaching those of academic centers of excellence, according to Australian researchers.

In a study of 804 patients who underwent RC from 2001 to 2009 in New South Wales (NSW), the 5-year disease-specific survival (DSS) and overall survival (OS) rates for the entire cohort were 59.6% and 53.2%, respectively, lead investigator Manish I. Patel, MD, of Westmead Hospital, University of Sydney, and colleagues reported online ahead of print in BJU International. The 5-year DSS for patients with localized, regional, and distant disease was 72%, 51%, and 10%, respectively.

Additionally, compared with patients undergoing RC at low-volume hospitals (0–3 RCs annually), those undergoing RC at high-volume hospitals (7 or more RCs annually) had a 44%

investigators stated. Additionally, results showed that men and Hispanics had an increased risk for ESRD in all 3 cohorts.

“Our findings underscore the hypothesis that resistant hypertension has a more adverse physiology and deserves better understanding in order to better manage this population,” the authors concluded.

The researchers noted that the observations from their study were derived from a single integrated health system in which all hypertensive patients received care in a comparable treatment environment, including medications.

KPSC has a relatively homogeneous hypertension management program.

“Nevertheless, the comparative outcomes reported represent findings from a real-world clinical practice environment in which decisions are made based on provider perceptions,” the authors wrote. “We also feel that the mixture, size, diversity, and length of follow-up in our cohort is a strength of our study.” n

increased likelihood of DSS, according to the investigators.

Dr. Patel and his colleagues stated that patients undergoing RC in NSW fared well compared with other contemporary reported outcomes from whole populations. A study of 1994–2008 data from the Ontario Cancer Registry demonstrated a 5-year DSS rate after RC of 33% (BJU Int. 2015;116:373-381). Researchers who analyzed 1992–2005 data from the Surveillance, Epidemiology and End Results (SEER) database found a 64% 5-year DSS rate after RC (Eur J Cancer 2012;48:1503-1511).

“Compared with older historical population outcomes, the NSW survival outcomes are substantially better,” the authors wrote.

For example, they cited a population-based study of 1990–1995 data in Victoria, Queensland, Australia that found 5-year DSS and OS rates after RC of only 28% and 13%, respectively (ANZ J Surg. 2005;75:270-274).

As the populations, hospital systems, and urologist training between NSW and Queensland were similar, Dr. Patel’s team wrote that “it is plausible that there has been a substantial improvement in RC outcomes over time in Australia.” n

22 Renal & Urology News

OCTOBER 2015 www.renalandurologynews.com

Practice Management After performing HIPAA risk assessments, practices must take actions to correct problems where information breaches could occur BY TAMMY WORTH

R

isk assessments are not only required by HIPAA, but they are supposed to be performed annually by anyone receiving meaningful use funds. It is important to know, however, that a risk assessment is not the end of your office’s duties. After the assessment is over, it is time to move forward to mitigate issues and fill gaps where breaches could occur.

“Part of the reality of security management is you are never done and it’s never perfect,” said Gary Pritts, president of Eagle Consulting Partners in Cleveland. “It’s like maintaining an old house … you are always living with some degree of imperfection.”

Password management is among the security measures than can protect health information.

frequent access to private health information. Protective measures could include encrypting laptops or getting a redundant internet connection, particularly if using a cloud-based system.

To make compliance more manageable, Cindy Winn, deputy director of consulting with the Fox Group LLC, based in Upland, Calif., said she often has clients focus on a single item at a time and start small to build confidence. Something like password management is a good first move. An administrator can analyze password management and put systems in place that do not allow people to use the

Regularly checking data backup to ensure it is working properly is among the easy procedures to implement. ways to do this. One is to determine the areas that present the greatest potential problems. The second is to pick the low-hanging fruit that will be easier to mitigate.

High priority areas might be those that focus on personnel who have

same password twice or ensure that passwords are changed every 90 days.

Another easy procedure to implement is regularly checking data backup to ensure it is working properly.

The next step is to create a work plan. Hodes said this could be as

easy as using an Excel spreadsheet with a list identifying all of the risks.

He recommends dividing up tasks among the staff and noting on the spreadsheet who is assigned to what.

Descriptions of each task should note what is currently being done in each area, recommendations to mitigate the problem, a timeline for completing the task, the status, and a date of completion. It may also be good to note what kind of access someone might need to

Follow-up meeting Within 4–8 weeks, there should be a follow-up meeting to gauge everyone’s progress, Hodes said. This meeting could include the HIPAA security and privacy official (which every office should have and may be the same person), someone from human resources (if the office has one), in-house or external IT staff, the doctor in charge of compliance oversight, and possibly legal counsel.

Documentation of the process and follow up on remediation practices are critical, Hodes said. Some of the mitigation may take time. It is important to have someone accountable for systematically following up on the process. “They should show they are doing something about the risk analysis and recommendations, but it doesn’t necessarily have to be everything,” Pritts said. n Tammy Worth is a freelance medical journalist based in Blue Springs, MO.

Areas to Focus on After a Risk Assessment Here’s a list of areas that small providers often need to focus on after a risk assessment, according to Gary Pritts, president of Eagle Consulting Partners in Cleveland.

• Do you have insurance for business interruption or a data breach?

• Do you have a redundant internet connection, particularly for cloud-based organizations?

• With server-based systems, software security flaws are the most common cause of breaches. This can be mitigated through using software security patches from providers including Microsoft, Adobe, Java, and any browsers used.

• Encryption of all mobile devices that have public health information.

• Implementation of a robust backup regimen including copies in multiple places and daily monitoring of the backup.

© THINKSTOCK / MILINDRI

Prioritize Jay Hodes, president of Colington Consulting in Washington, D.C., said when he completes a risk assessment for a client, there are pages of actionable items that have to be sifted through afterward. Any risk assessment should reveal a host of things that need to be changed. This can be daunting, but breaking it down and setting priorities can make it more manageable.

“There is always a real hesitancy leading up to a risk assessment but it’s not a gotcha exercise,” Hodes said. “An assessment is done to identify problems before they become breaches. It becomes a real eye-opening experience.”

The first step to take after receiving or completing an assessment is to prioritize the risks. There are a couple of

complete the task or vendors who need to be included in the process.

“They may just need to make sure proper policies and procedures are in place,” Hodes said. “In the smaller provider community, it’s usually not the case … it’s not that they don’t want to be compliant, it’s just that they don’t understand how to.”

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Death Risk Lower with HHD vs. PD

© THINKSTOCK / ERIKAMITCHELL

© JIM DOWDALLS / PHOTO RESEARCHERS, INC.

Daily home hemodialysis also decreases the likelihood of hospitalization and technique failure

PATIENT OUTCOMES MAY BE BETTER with home hemodialysis than peritoneal dialysis (above).

BY JODY A. CHARNOW DAILY HOME hemodialysis (HHD) is associated with lower risks of mortality, hospitalization, and technique failure than peritoneal dialysis (PD), according to researchers. Among patients who started home dialysis shortly after onset of end-stage renal disease (ESRD), however, mortality and hospitalization risks were similar for HHD and PD. The investigators concluded that “daily HHD may be a viable first modality for patients who choose to dialyze at home and may keep patients at home longer than PD does.”

For the study, Eric D. Weinhandl, PhD, and colleagues with the Chronic Disease Research Group, Minneapolis

Long Interdialytic Gap Ups Risks Rapid Kidney

BY JODY A. CHARNOW “Planning an intervention to reduce Function Loss, THE 2-DAY GAP BETWEEN hemo- mortality over the long break should dialysis (HD) sessions among patients clearly be focused on re-evaluating the Obesity Linked on a thrice-weekly HD schedule is standard dialysis pattern,” investigators associated with increased hospitalization and mortality rates compared with the 1-day interval, regardless of HD session pattern, researchers concluded.

wrote in a paper published in Kidney International (online ahead of print).

In a study of a cohort of 5,864 HD patients, James Fotheringham, MD, continued on page 7

EXPERT Q & A

David F. Penson, MD, offers his perspective on major advances in prostate cancer.

PAGE 11

OBESITY increases the risk of rapid loss of kidney function, particularly among older patients, according to a new study.

“Our results lend support to earlier findings of associations between obesity and increased prevalence of metabolic syndrome and chronic kidney disease,” researchers reported online ahead of print in The Lancet Diabetes & Endocrinology.

A team led by Csaba P. Kovesdy, MD, of the Veterans Affairs Medical Center in Memphis, studied a national cohort of 3,376,187 veterans (mean age 60 years) with an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m 2. Of these, 274,764 (8.1%) experienced a rapid decline in kidney function, defined as a decrease in eGFR greater than 5 mL/min/1.73 m2 per year.

The investigators observed a generally consistent U-shaped association between body mass index (BMI) and continued on page 7

Medical Research Foundation, matched 4,201 new HHD patients in 2007–2010 to 4,201 new PD patients identified using the U.S. Renal Data System database. The HHD and PD patients had a mean age of 53.8 and 54.6 years, respectively. The mean time from onset of end-stage renal disease (ESRD) to home dialysis therapy initiation was 44.6 months for HHD patients and 44.3 months for PD patients.

In an intention-to-treat analysis, daily HHD was associated with a significant 20% lower risk for all-cause mortality, 8% decreased risk for all-cause hospitalization, and 37% decreased risk for technique failure compared with PD, Dr. Weinhandl’s team reported continued on page 7

IN THIS ISSUE 5

Researchers identify in-hospital risk factors for hyponatremia

8

Smoking not a risk factor for all RCC subtypes

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Adverse outcomes less likely with subcutaneous erythropoietin

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Propofol safer than midazolam for ICU patient sedation

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Hyperphosphatemia increases mortality in critically ill patients

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High uric acid levels at hospital admission raises AKI risk

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ESRD is more likely in patients with resistant hypertension Critically ill patients with high phosphorus levels are at increased risk of death.

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HHD vs. PD continued from page 1

online ahead of print in the American Journal of Kidney Diseases. In a subset of 1,368 patients who started home dialysis within 6 months of ESRD onset, daily HHD and PD were associated with similar risks for all-cause mortality and all-cause hospitalization, but daily HHD was associated with a significant 30% decreased risk for technique failure.

The researchers defined technique failure as conversion to in-center hemodialysis for at least 2 months.

In intention-to-treat analyses involving all patients, daily HHD patients

Kidney function loss continued from page 1

rapid loss of kidney function in patients older than 40 years that was more pronounced with increasing age. BMI did not appear to predict renal function impairment in patients younger than 40. Patients with a BMI of at least 25 but less than 30 kg/m2 had the lowest risk of rapid decline in kidney function.

Over a median follow-up of 6.8 years, 672,341 patients died. BMIs of less than 25 kg/m2 and greater 35 kg/ m2 were associated with higher mortality rates than the other BMIs, the researchers reported.

“Considering the effects of obesity on both kidney function and mortality, we propose that weight reduction in very

Interdialytic gap continued from page 1

of the Sheffield Kidney Institute, Northern General Hospital in Sheffield, U.K., and colleagues found that the hospital admission rate was 2.4 per year after a 2-day gap compared with 1.4 per year after 1-day intervals, regardless of whether thrice-weekly HD commenced on a Monday or Tuesday (rate ratio 1.7). Dr. Fotheringham’s group observed the greatest differences in admission rates among patients admitted with fluid overload or with conditions associated with a high risk of fluid overload.

The overall mortality rate on HD was 17.3 deaths per 100 patient-years.

It was 20.5 per 100 patient-years after the 2-day gap compared with 16.7 per 100 patient-years for the rest of the week (rate ratio 1.22), with the increased rate driven by out-of-hospital deaths (rate ratio 1.59 vs. 1.06 for in-hospital death).

had a significant 19%, 38%, and 29% decreased risk of death from cardiovascular disease (CVD), cachexia or dialysis withdrawal, and infection, respectively, according to the investigators.

With respect to hospitalization, risk comparisons favored daily HHD for cardiovascular disease (CVD) and dialysis access infection and PD for bloodstream infection. For example, in intention-to-treat analysis involving all patients, daily HHD patients had a significant 15% decreased risk of CVD-related hospitalization compared with PD patients. Daily HHD patients had a significant 18%

increased risk of hospitalization for bacteremia and sepsis and 3-fold increased risk of hospitalization for cardiac infection compared with PD patients, the researchers reported.

Technique failure was 30% less likely with daily HHD than PD, study finds.

Dr. Weinhandl and his colleagues acknowledged some study limitations, including the observational design.

Renal & Urology News 7

“Matching is unlikely to reduce confounding attributable to unmeasured factors,” the researchers noted.

“Residual differences in biochemistry, residual kidney function, and peripheral vascular health may underlie observed relative risks.”

Additionally, the investigators said they lacked data regarding dialysis frequency, duration, and dose in daily HHD patients and frequency and solution in PD patients.

A third limitation was the use of diagnosis codes to classify hospital admissions. “Principal codes on inpatient claims may not accurately reflect morbidity,” they pointed out. n

obese individuals should be started at an early age, and maintained long term (potentially for several decades) to reap the most benefits,” they stated.

Strong evidence suggests that obesity exerts negative effects via various mechanisms, either directly (e.g., increased renal sinus fat) or indirectly (e.g., obesity-related hypertension or diabetes), Dr. Kovesdy’s group noted.

The glomerular hyperfiltration characteristic of higher BMI typically starts at a young age, and in stages of prehypertension or prediabetes, the authors explained. Substantial physiologic and structural changes, however, might only occur after long exposure, followed by irreversible pathologic changes after even longer time. “It is thus possible that progressive loss of

kidney function becomes most obvious in individuals who were exposed to the effects of obesity for the longest time, which could explain the accentuation of this association with older age in our study,” they wrote.

Another potential explanation for the observed findings is an accentuation of the deleterious renal effects of obesity by the structural changes occurring in aging kidneys.

For the study, researchers calculated eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. They said they used this equation because it is more accurate than other estimating equations in patients with normal and mildly decreased GFR. The study cohort had a mean eGFR of 83.8 mL/min/1.73 m2.

Regarding study limitations, the authors noted that most subjects were male U.S. veterans and had a high prevalence of comorbidities, which reduces the generalizability of the findings to women, the general population,

Of the 5,864 patients, 606 died outside of the hospital. Of these, 79% died on dialysis days without a corresponding HD session being coded, suggesting that the majority of deaths occurred before HD was due, according to the researchers. They called the

Thursday, Saturday, 47.3%; and Tuesday, Thursday, Sunday, 2.5%.

both excess fluid and uremic toxin accumulation during the long interval and rapid removal with the first dialysis treatment of the week may contribute to the heightened morbidity and mortality of the day after the long interdialytic gap.

Study implicates fluid overload as a risk factor for hospital admission. increase in out-of-hospital mortality “thought provoking.” The findings “suggest that excessive fluid removal necessitated by the 2-day break is unlikely to be a major factor accounting for the observed excess mortality.”

The study cohort had a median follow-up of 1.3 years. HD session patterns were as follows: Monday, Wednesday, Friday, 50.2%; Tuesday,

New insights “This study adds new insights to the underlying mechanisms and at-risk sub-populations of the long interdialytic gap,” Connie M. Rhee, MD, MSc, and Kamyar Kalantar-Zadeh, MD, MPH, PhD, of the Division of Nephrology and Hypertension at the University of California Irvine, wrote in an accompanying editorial.

Higher hospitalization rates observed on Monday, Tuesday, and Sunday for patients on the Monday-WednesdayFriday, Tuesday-Thursday-Saturday, and Tuesday-Thursday-Sunday HD schedules, respectively, “do not support the weekend lag effect as an explanatory factor for higher admission rates on the day after the long interdialytic gap,” they noted.

Based on collective data from the new study and others, Drs. Rhee and Kalantar-Zadeh said they believe that

The association is more pronounced with increasing age, data suggest. or individuals from other parts of the world. In addition, despite adjusting for multiple potential confounders, they could not rule out the effect of unmeasured confounders. n

Strategies to ease adverse effects They offered some potential strategies to ameliorate the adverse effects of the long interdialytic gap, such as incremental fluid/solute removal by aiming for higher dry weight at the beginning of the week, a lower fluid removal goal, and a lower dialysis dose the day after the long interdialytic gap compared with midweek targets.

Other possible approaches include eliminating the long interdialytic gap with more frequent HD sessions in patients with negligible residual kidney function and longer and more gentle HD sessions immediately following the long interdialytic gap, according to the editorial writers. n

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.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2015 6/15 028723-150602

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

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

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