Renal & Urology News November 2012 Issue

NOVEMBER 2012

■ ■ ■

VOLUME 11, ISSUE NUMBER 11

■ ■ ■

www.renalandurologynews.com

PCa Recurrence Linked to Hypertension

© THINKSTOCK

Moderately and severely obese patients also have a twofold increased risk, new study finds

HYPERTENSION IN MEN after PCa surgery raises their PSA failure risk by 51%.

BY JODY A. CHARNOW HYPERTENSION MAY be a novel independent risk factor for the biochemical recurrence of prostate cancer (PCa) after radical prostatectomy, a new study suggests. The study also confirmed previous research showing that obesity increases the risk.

Of 1,428 men who underwent RP, 107 (8%) experienced biochemical recurrence after a median follow-up period of 3.6 years. Hypertension and obesity were associated with a significant 51% and 37% increased risk of biochemical recurrence, respectively, after adjusting for age, surgical margin status, tumor stage, Gleason score, and metabolic syndrome features, researchers reported online ahead of print in

Laser Prostatectomy Use On the Rise COPD Raises LASER PROSTATECTOMY use has in Ann Arbor identified 54,399 TURP Dialysis Patient increased substantially as a treatment and 29,457 laser prostatectomy procefor benign prostatic hyperplasia (BPH) dures that took place during the study at the expense of transurethral resection period (2001 to 2009). Although the Death Risk of the prostate (TURP), a study found.

Using the Florida State Inpatient Database and Ambulatory Surgery Database, Florian R. Schroeck, MD, and colleagues at the University of Michigan

CME FEATURE

overall rates of transurethral surgery for BPH remained stable during the study period at 248/100,000 men in 2001 and 233 per 100,000 men in 2009, laser proscontinued on page 10

Earn 1 CME credit in this issue

Nonmuscle Invasive Bladder Cancer: Guidelines for Treatment PAGE 38

BY JODY A. CHARNOW CHRONIC OBSTRUCTIVE pulmonary disease (COPD) in patients starting dialysis increases their mortality risk and decreases their likelihood of receiving a kidney transplant, especially in current smokers, according to researchers.

Austin G. Stack, MD, of the University of Limerick Graduate Entry Medical School in Ireland, and colleagues analyzed data on 769,984 U.S. dialysis patients who commenced dialysis between May 1995 and December 2004. Of these, 7.5% had COPD. After adjusting for potential confounders, patients with COPD had a 20% increased risk of death compared with those who did not have COPD, the researchers reported in the American Journal of Nephrology (2012;36:287-295).

The risk was increased by 28% for patients who had COPD and also smoked.

In addition, in adjusted analyses, nonsmokers with COPD had a 46% continued on page 10

Prostate Cancer and Prostatic Disease.

The presence of both conditions was associated with a significant twofold increased risk.

The investigators, led by Ramsey Asmar, MD, of the University of Michigan Medical School and Comprehensive Cancer Center in Ann Arbor, noted that their finding of a link between obesity and PCa biochemical recurrence is consistent with a previous study led by Stephen J. Freedland, MD, then at Johns Hopkins University School of Medicine in Baltimore, but now at Duke University Medical Center in Durham, N.C. The study by Dr. Freedland and his colleagues showed that moderately and severely obese PCa continued on page 10

IN THIS ISSUE 7

Mortality more likely in repeat renal transplant candidates

8

Contrast-enhanced ultrasound detects more high-grade PCa

12

Men’s Health Update: Walnuts improve sperm health

14

Adjuvanted influenza vaccine safe for kidney transplant patients

15

Radium-223 benefits confirmed for CRPC patients

20

Coronary artery calcification raises death risk in HD patients

28

Cherries found to decrease gout attack risk Nutrition and metabolic acidosis in renal transplant recipients PAGE 22

www.renalandurologynews.com

NOVEMBER 2012

Renal & Urology News 3

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Obesity and PCa Risk

N

early one in three Americans is obese and therefore at increased risk of heart disease, diabetes, hypertension, CKD, and other potentially preventable ailments.

Although data suggest that cancer rates are also higher in obese patients, the associations are largely based on observational/population studies.

Regarding prostate cancer (PCa), new data suggest three significant relationships between obesity and PCa: 1) obese men are less likely to be diagnosed with PCa; 2) when they are diagnosed, they are more likely to harbor aggressive disease; and 3) weight loss may mitigate the shortcomings of screening and slow down tumor growth.

In overweight men, the primary means of early PCa detection (PSA screening and digital rectal examination [DRE]) are less reliable. It has been hypothesized that lower PSA values in obese men may be due to dilution secondary to increased blood volumes. Moreover, DRE is difficult to perform in obese men and therefore may be performed less often and/or inadequately interpreted. Lower PSAs and inadequacy of DRE may impair early detection of PCa. Additionally, obese men often have larger prostates, resulting in a higher risk of sampling error on biopsy. The net result is that obese men are less likely to be diagnosed with PCa than their slimmer counterparts.1 Several investigators have noted an association between obesity and aggressive PCa. To further explore the relationship, Freedland et al. analyzed the results of the REDUCE PCa prevention trial comparing daily dutasteride to placebo in men with PSA levels of 2.5-10 ng/mL and a negative biopsy.

Importantly, all men underwent protocol-mandated biopsies at two and four years regardless of PSA/DRE results. The investigators evaluated the relationship between BMI and PCa risk/Gleason score and noted that obese men (body mass index greater than 30 kg/m2) had a significant 28% increased likelihood of being diagnosed with high-grade PCa.2 While the biological cause of the association is unclear, it is likely that growth factors, cholesterol, androgens/estrogens, insulin resistance and/or adiponectin play a role.3 Whether weight control diminishes the risk or alters PCa biology is uncertain. Nevertheless, it remains our role as physicians to alert obese men that their risks extend beyond cardiovascular concerns and to counsel that weight may be one of the few modifiable risk factors to prevent death from PCa. Awareness is always the first step.

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

REFERENCES 1. Freedland SJ, Platz EA, Presti JC Jr, et al. J Urol 2006;175:500-504 2. Freedland SJ, Gerber L, Bañez LL, et al. J Urol 2011;185 (Suppl). Abstract 157 3. Buschemeyer WC 3rd, Freedland SJ. Eur Urol 2007;52:331-343

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 Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto Stanton Honig, MD Associate Clinical Professor of Surgery/Urology University of Connecticut School of Medicine, Urology Center New Haven J. Stephen Jones, MD, FACS, MBA Chief of Surgical Operations Fairview Hospital, a Cleveland Clinic hospital Professor of Surgery (Urology) Cleveland Clinic Lerner College of Medicine at Case Western Reserve University Leonard Horvitz and Samuel Miller Distinguished Chair in Urological Oncology Research Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California, Irvine James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

Anthony J. Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C. Suphamai Bunnapradist, MD Director of Research Department of Nephrology Kidney Transplant Research Center The David Geffen School of Medicine at UCLA R. Michael Hofmann, MD Associate Professor and Medical Director, Living Kidney Donor Program University of Wisconsin School of Medicine and Public Health, Madison Csaba P. Kovesdy, MD Associate Professor of Clinical Medicine University of Virginia, Charlottesville Chief of Nephrology Salem VA Medical Center Salem, Va. 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. Rulan Parekh, MD, MS Associate Professor Johns Hopkins Children’s Center, Baltimore 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. Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.

Renal & Urology News Staff Editor Executive editor Senior editor Web editor Editorial coordinator Art director Group art director, Haymarket Medical VP, audience development and operations Production assistant Group production manager Product manager, digital products Circulation manager National accounts manager Editorial director Publisher VP medical magazines and digital products CEO, Haymarket Media Inc.

Jody A. Charnow Marina Galanakis Delicia Honen Yard Stephan Cho Candy Iemma Andrew Bass Jennifer Dvoretz John Crewe Brian Wask Kathleen Millea Chris Bubeck Paul Silver William Canning Jeff Forster Dominic Barone Jim Burke Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 11, Number 11. Published monthly 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. For reprints, contact Wright’s Reprints at 1.877.652.5295. 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 © 2012.

Contents

NOVEMBER 2012

■

VOLUME 11, ISSUE NUMBER 11

Urology 15

ONLINE

this month at renalandurologynews.com

16

Expert Q&A Madeleine V. Pahl, MD, Professor of Medicine at the University of California-Irvine, discusses pregnancy in kidney disease patients.

Radium-223 Benefits Confirmed for CRPC Patients This novel investigational medication improves overall survival and time to first skeletal-related event in patients with castration-resistant prostate cancer and bone metastases.

Higher Prevalence of Priapism Reported An analysis of data from 39,964 emergency department encounters nationwide from 2006-2009 showed that there were 8.05 priapism-related visits per 100,000 encounters, higher than previous estimates.

17

Testosterone Declines Not Inevitable Study implicates factors other than aging, including weight gain, smoking cessation, depression, and cardiovascular disease.

Take our latest quiz at renalandurologynews.com /clinical-quiz/. Answer correctly and you will be entered to win a $50 American Express gift card.

Congratulations to our September winner: Faris Azzouni, MD

31

Calcified Peyronie’s Plaques May Predict Surgery Men with severe calcified Peyronie’s disease plaques are more likely to progress to surgical treatment than men with noncalcified plaques, study shows.

The Medical Minute

Nephrology

Clinical Quiz

Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies.

Our latest include: • Robotic Partial Nephrectomy Advance Reported • Taking Aspirin After Prostate Cancer Treatment May Be Beneficial • Tax Breaks Do Little to Boost Living Kidney Donation

14

17

News Coverage Visit our website for reports from Kidney Week 2012 in San Diego.

Elevated FGF-23 Linked to Insulin Resistance Insulin resistance (IR) is associated with increased fibroblast growth factor-23 levels in patients with chronic kidney disease, suggesting a link between IR and renal phosphorus homeostasis.

Post-KT Early Readmission Factors Identified Older kidney transplant recipients and those of African-American race are at significantly higher risk of early hospital readmission after transplantation, a study found.

“

“

19

Adjuvanted Influenza Vaccine Safe Researchers find that it does not affect acute rejection or graft function in kidney transplant recipients.

While still not definitively proven,

why not eat a few cherries and potentially decrease the risk of gout?

See our story on page 28

38

CME Feature 38

Nonmuscle Invasive Bladder Cancer: Guidelines for Treatment Matthew J. Resnick, MD, and Michael S. Cookson, MD, of Vanderbilt University Medical Center, review guidelines developed by the American Urological Association and the European Association of Urology.

22

Departments 3

From the Medical Director Obesity and PCa risk

8

News in Brief Retinopathy may reflect renal disease

12

Men’s Health Update Walnuts may improve sperm health

18

On the Forefront Metabolic abnormalities after urinary diversion

22

Renal Nutrition Update Metabolic acidosis in kidney disease patients

27

Expert Q&A Post-RP UI surgery rates rise

NOW APPROVED for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previouslyy received docetaxel

AND...

• 37% reduction in risk of death vs placebo (P < 0.0001; HR = 0.63 [95% CI, 0.53, 0.75])1

• XTANDI can be taken with or without food1 • Patients were allowed, but not required, to take glucocorticoids1 —

In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1

• Oral, once-daily dosing1 • The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1

• Seven patients (0.9%) out of 800 treated AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel.

Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved.

Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial

with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1

were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs.

If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

Learn more at XtandiHCP.com

Reference: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. © 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012I-076-6330 9/12 XTANDI is a registered trademark of Astellas Pharma Inc. Astellas and the flying star logo are trademarks of Astellas Pharma US, Inc.

B19814_5b_NowApp_STDTab.indd 09.19.12 133 L/S HP

B19814x01A_RedTagLogo_4C_HR_simp.psd B19814x02A_fpgradient.tif B19814x04B _3u.tif

MEDPC9886 - Branded Journal Ad — TAB : Oncology Times Colors: 4CP Trim/live: DO NOT PRINT Bleed: 11.25"w × 14.25"h Trim: 10.5"w × 13.5"h Live: 9.875"w × 12.5"h Output @ 100% Giant Creative Strategy

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

6 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Hypertension Independently Increases Gout Risk HYPERTENSION predicts an increased risk of gout among middleaged African-American and white adults independent of gout risk factors and regardless of gender, race, or obesity.

Researchers speculate that serum urate levels may be a partial intermediate on

the pathway between hypertension and gout. In an analysis of data from 10,872 participants in the population-based Atherosclerosis Risk in Communities (ARIC) study, Mara A. McAdamsDeMarco, MS, PhD, and colleagues found that hypertension was associated

a twofold increased risk of gout after adjusting for potential confounders.

When the investigators further adjusted for serum urate level, hypertension was associated with a 36% increased risk.

The researchers observed no effect of gender, race, or obesity at baseline on

gout risk, the researchers reported in The Journal of Clinical Hypertension (2012;14:675-679).

Of the 10,872 subjects, 45% had hypertension during follow-up. Over nine years, gout developed in 274 subjects (2.5%). â&#x2013;

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information.

------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel.

--------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI 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 >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@.

-------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures.

The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

--------------------------------- ADVERSE REACTIONS ------------------------------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 WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo.

All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4.

7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders

9.0 44.4 9.3 Asthenic Conditionsa Peripheral Edema

1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4

24.3 4.0 Arthralgia

17.3 1.8 Musculoskeletal Pain

1.3

0.3 Muscular Weakness 9.8

6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1

0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9

0.0

Dizzinessb Spinal Cord 7.4 6.6

3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0

0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0

0.3 Upper Respiratory Tract Infectiond Lower Respiratory

2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0

Anxiety

0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8

1.0 Pollakiuria 4.8 0.0

0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin

0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH

Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo.

Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms.

Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

www.renalandurologynews.com

NOVEMBER 2012

Renal & Urology News 7

Repeat Renal Tx Candidates More Likely to Die

BY JILL STEIN PARISâ&#x20AC;&#x201D;Patients starting dialysis after primary renal transplant failure who are waitlisted for repeat transplantation have a higher risk of dying over the first three years after graft loss than dialysis patients waitlisted for their first transplant, investigators reported

at the 49th Congress of the European Renal Association-European Dialysis and Transplant Association.

Lynsey Webb, MD, a clinical research fellow at the U.K. Renal Registry at Southmead Hospital in Bristol, and coworkers determined survival after transplant failure only in patients deemed

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers.

Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ

DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @.

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @.

-------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI 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 XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, 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 XTANDI in pediatric patients have not been established.

Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment.

Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@.

Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

suitable for repeat transplantation.

The analysis included 1,498 patients starting hemodialysis (HD) or peritoneal dialysis (PD) after failure of a first renal transplant and who were waitlisted for repeat transplantation within two years of graft failure and 11,412 patients starting HD or PD as

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose.

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8&

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\

XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember.

If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 0HGLYDWLRQ ,QF 6DQ )UDQFLVFR &$ Issued: August 2012 $ (1= %56 Rx Only Š 2012 Astellas Pharma US, Inc. XTANDIŽ is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

their initial form of renal replacement therapy (RRT) who were waitlisted for transplantation within two years of starting RRT. Patient data were obtained from the U.K. Renal Registry database from 2000-2008.

Comorbidities a factor Patients with established renal failure (ERF) who undergo successful renal transplantation have improved survival and quality of life compared with patients who remain on dialysis, Dr. Webb said. Patients starting dialysis after graft failure have increased mortality compared with dialysis patients waitlisted for primary renal transplantation because patients with failed transplants have had ERF for a significantly longer period and are thus likely to have more comorbidities.

Dr. Webb emphasized that the U.K. Renal Registry does not collect annual co-morbidity data and thus cannot adjust for the effect of the accrued co-morbidity in failed transplant recipients. Thus, the analysis included only failed transplant recipients who were deemed â&#x20AC;&#x153;fit enoughâ&#x20AC;? to be listed for re-transplantation when comparing survival with waitlisted incident dialysis patients. Patients with failed grafts who are listed for a second transplant are likely to have fewer comorbidities than failed transplant recipients not fit for waitlisting (for example, due to cardiovascular disease, infection, or malignancy) and, therefore, are arguably a more appropriate comparator group, she said.

Results showed that in the first year following graft loss, re-listed patients were 1.6 times more likely to die than dialysis patients awaiting their first transplant. This increased risk persisted over the first three years.

Timely waitlisting advised â&#x20AC;&#x153;This study suggests that patients with failing transplants need to be reviewed regularly with timely planning for their return to dialysis,â&#x20AC;? Dr. Webb said. â&#x20AC;&#x153;Careful consideration should be given to timely waitlisting for repeat transplantation, the hope being prompt waitlisting prior to dialysis commencement would minimize any time on dialysis.â&#x20AC;?

Dr. Webb acknowledged that missing co-morbidity data may represent a possible study limitation. She also said that studies are needed to examine the causes of mortality and morbidity after graft failure. â&#x2013;

8 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

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

Short Takes Many Back Incentives to Boost Kidney Donation

of marijuana to develop the disease.

In Canada, more than 70% of

demonstrated a specific associa-

2,004 members of the public,

tion between marijuana use and

40% of 339 health professionals,

nonseminoma and mixed-histology

and 40% of 268 people with

tumors. The study by Victoria K.

or affected by renal disease

Cortessis, PhD, of the University

support offering financial incentives

of Southern California in Los Angeles,

to increase kidney donations.

and colleagues, which was

Stratification on tumor histology

However, only 45%, 14%,

published online in Cancer, also

and 27%, respectively, support

found that cocaine use was

monetary payments for living

associated with a 46% reduced risk

donors. Overall, reimbursement of

of TGCT compared with non-use.

funeral expenses for deceased donors were deemed the most ac-

Study: Retinopathy May Reflect Renal Disease

ceptable incentives. The

In an analysis of 1,936 participants

findings of the survey, by Lianne

of the Chronic Renal Insufficiency

Barnieh, PhD, of the University

Cohort study, greater severity of

of Calgary in Alberta, and

retinopathy was strongly associated

colleagues, were published online

with lower estimated glomerular

in the Clinical Journal of the

filtration rate (eGFR) after adjusting

American Society of Nephrology.

for traditional and nontraditional

donors and a tax break for living

risk factors, suggesting that retino-

Testicular Cancer, Pot Smoking Linked

vascular pathology reflects renal

Among 163 men diagnosed with

abnormalities usually associated

testicular germ cell tumor (TGCT)

with hypertension was also associ-

and 292 controls, those who

ated with lower eGFR, according to a

had ever smoked marijuana were

report in Archives of Ophthalmology

almost twice as likely as non-users

(2012;130:1136-1144).

disease. The presence of vascular

Should Buying Kidneys Be Allowed?

In a recent online poll, Renal & Urology News asked readers if they thought, in general, it would ever be a good idea to offer payments to people to donate a kidney. Here’s what the poll revealed based on 156 responses. (See article on this page under “Short Takes.”)

Yes 41.67%

No 56.41%

No opinion 1.92%

0

10

20

30

40

50

60

Antiandrogen Therapy May Thwart Bladder Cancer A

protein that confers a worse prognosis in bladder cancer when present in high levels may be regulated by androgens, suggesting a role for antiandrogen agents in the treatment of this disease. Overexpression of the protein CD24 is associated with poor outcomes in urothelial carcinoma and contributes to tumor growth and metastasis. Dan Theodorescu, MD, PhD, of the University of Colorado Cancer Center in Aurora, and colleagues reported in the Proceedings of the National Academy of Sciences that mice—particularly male mice—unable to produce CD24 had fewer primary bladder tumors and metastases than did mice with intact CD24 levels.

In human tumor samples, higher rates of relapse and shorter disease-free survival were associated with higher CD24 levels, again especially in males. Because such findings implied androgen involvement, the researchers knocked down androgen receptors in human bladder cancer cell lines and observed a corresponding drop in CD24 levels as well as reduced cell proliferation.

Carotid Atherosclerosis Seen in Pediatric CKD Patients C

arotid intima-media thickness (cIMT) is significantly elevated in children with mild to moderate chronic kidney disease (CKD), according to study findings published online in the Clinical Journal of the American Society of Nephrology.

The study, which included 101 children aged 2-18 years who had a median glomerular filtration rate (GFR) of 42.9 mL/min/1.73 m2, found that the median cIMT in these patients was 0.43 mm compared with 0.41 mm in healthy controls, pediatric nephrologist Tammy Brady, MD, MHS, of Johns Hopkins Children Center in Baltimore, and colleagues reported. The children with CKD also had a high prevalence of other cardiovascular risk factors, with dyslipidemia and hypertension significantly associated with increased cIMT (0.05 mm and 0.04 mm greater mean cIMT, respectively).

Detecting High-Grade PCa Improved with Ultrasound C

ontrast-enhanced ultrasound can detect almost three times as many higher-grade prostate cancers using half a many needle biopsies compared with systematic biopsy methods, a study found. In a randomized, double-blind, placebo-controlled trial, Ethan J. Halpern, MD, and collaborators at Thomas Jefferson University and Hospitals in Philadelphia graded contrast-enhanced ultrasound findings and used them to direct targeted biopsy (up to six cores per prostate). A blinded 12-core systematic biopsy was subsequently performed on each study participant (272 of the 311 men randomized completed the study). Of the 118 patients with positive biopsies, contrast-enhanced ultrasound with microbubbles detected significantly more highervolume/higher-grade prostate tumor than did conventional biopsies (55% vs. 17%), Dr. Halpern’s group reported online in the Journal of Urology. Although preliminary studies have suggested that pretreatment with a 5-alpha reductase inhibitor may improve the efficiency of contrast-enhanced ultrasound targeted biopsy, dutasteride pretreatment had no significant impact on cancer detection.

INHIBIT ANDROGEN PRODUCTION

BLOCK THE ANDROGEN RECEPTOR

Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered.

References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN ®, NCCN GUIDELINES ®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 K08Z12191CR1

Y11429ALT_Ad1_DSA_K08Z12191CR1_King_v1.indd 1

10/18/12 11:34 AM

10 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Laser prostatectomy

PCa/hypertension continued from page 1

patients had a twofold significantly increased risk of post-RP biochemical recurrence, after controlling for preoperative characteristics (J Clin Onc 2004;22:446-453). In addition, in the past decade, Dr. Asmar’s team pointed out, a consistent association has been observed between higher body mass index and prostate cancer aggressiveness, progression, and mortality.

Older and sicker patients are less likely to undergo the procedure.

“Our observation may be explained at least in part by the fact that surgery is more technically challenging in the obese or morbidly obese patient, or due to delayed detection of depressed PSA concentrations among obese men,” the authors wrote. “However, our increased recurrence rate was independent of surgical margin status, arguing in favor of a biological mechanism by which obesity confers risk.”

With regard to the finding of an independent association between hypertension and increased risk of biochemical recurrence, Dr. Asmar

Laser prostatectomy may shorten hospital stays and catheterization time.

“Given the potential advantages of laser prostatectomy, our results raise concern about possible underuse of this new technology among elderly and infirm patients,” the authors concluded.

Studies suggest that laser prostatectomy may be associated with shorter hospital stays and catheterization time, and a decreased risk of clot retention compared with TURP. In a discussion of study limitations, the researchers

noted that they were unable to elicit which type of laser or TURP equipment was used in a specific procedure.

“Therefore, we cannot describe differential trends in the use of these laser procedures but it appears unlikely that the lack of these procedural details biased our results.”

The investigators also acknowledged that they did not have access to clinical information such as symp-

and his collaborators said their fi ndings are consistent with those of a study by Jennifer M. Post, MD, of Wayne State University in Detroit (Prostate Cancer 2011;2011:245642), which found that hypertension was associated with a significant twofold increased risk of biochemical recurrence following RP. In a discussion of study limitations, Dr. Asmar’s group acknowledged that patient comorbidities may not have been accurately reported. They noted, for example, that they were unable to account for patients who failed to report a history of hypertension or diabetes to their medical providers.

“This study nicely corroborates multiple prior studies which found obesity correlated with poor outcome after surgery,” said Dr. Freedland, Associate Professor of Surgery at Duke and editor of Prostate Cancer and Prostatic Disease.

The finding of a significant association between hypertension and poor outcome is novel, Dr. Freedland told Renal & Urology News. The effect of hypertension on biochemical recurrence of PCa previously has not been well studied and requires validation, he said. “However, as hypertension is part of the metabolic syndrome—along with obesity—these data add to the growing body of literature that metabolic disturbances appear to be associated with more aggressive prostate cancer.” ■

COPD/dialysis patient continued from page 1

decreased likelihood of receiving a kidney transplant compared with subjects who did not have COPD. Smokers with COPD had a 53% decreased likelihood of transplantation.

The detrimental impact of COPD was similar for men and women and varied inversely with age, the study showed.

Emerging evidence suggests that chronic kidney disease is an important comorbidity in patients with COPD, said Dr. Stack, senior author of the study, but few studies have addressed the impact of COPD on clinical outcomes among patients with advanced kidney failure. To their knowledge,

tom severity or the amount of irritative symptoms. “Elderly patients may have had more irritative symptoms than younger patients,” Dr. Schroeck and his colleagues stated. “This could have dissuaded some physicians from offering laser prostatectomy, which has more irritative side effects than TURP postoperatively.”

The researchers explained that they chose Florida for their study because it is one of the larger and more ethnically diverse states participating in the Healthcare Cost and Utilization Project (HCUP), and the state captures discharges from various practice locations, including freestanding ambulatory surgery centers.

HCUP is sponsored by the federal Agency for Healthcare Research and Quality (AHRQ). Its databases bring together data collection efforts of state data organizations, the federal government, hospital associations, and private data organizations to create a national information resource of patientlevel healthcare data, according to the AHRQ website. ■

he said, this is the fi rst large-scale study to examine specifically the conjoint impact of COPD and continued smoking in a cohort with end-stage kidney disease.

“Our findings illustrate not only the detrimental effect of COPD on survival and kidney transplantation, which are major clinical outcomes, but also the deleterious effect of continued smoking in this high-risk and vulnerable population,” Dr. Stack told Renal & Urology News. “It also suggests the need for greater recognition of COPD in patients commencing dialysis and the need for cooperation between primary care physicians, pulmonologists, and nephrologists in the care of these highrisk patients.” ■

© JOHN THYS / SCIENCE SOURCE / PHOTO RESEARCHERS, INC.

tatectomy use increased 400% from 25 to 114 procedures per 100,000 men during that same period, replacing about half of all TURPs, the researchers reported online in The Journal of Urology.

Older and sicker patients are less likely to undergo laser prostatectomy.

Compared with patients aged 40-64, those aged 65-89 and 80 or older were 16% and 26% less likely to undergo laser prostatectomy after adjusting for year of treatment, race, socioeconomic status, surgeon volume, and type of primary payer. Compared with patients without comorbidities, those who had one and two or more comorbidities were, respectively, 21% and 52% less likely to undergo laser prostatectomy.

In addition, Dr. Schroeck’s team found that most of the variation in laser prostatectomy use was determined by the urologist seen by the patient, “implying that who the patient sees is a major determinant of which type of surgery is performed.”

© KEITH BROFSKY / STOCKBYTE / THINKSTOCK

continued from page 1

Chronic obstructive pulmonary disease increases mortality risk in dialysis patients.

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies.

Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed.

Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

Janssen Biotech, Inc. Š Janssen Biotech, Inc. 2012 8/12 08Z12235C

10474Alt_DSA_08Z12235C_K_v1.indd 1

9/13/12 6:26 PM

12 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Men’s Health Update Please visit us at www.renalandurologynews.com for the latest news updates from the fields of urology and nephrology

A Clue to Moderate Drinking’s Protective Effect Moderate drinkers of alcohol have lower risk of cardiovascular disease than nondrinkers or heavy drinkers, and a be a contributing factor.

Shinji Makita, MD, of Iwate Medical University in Morioka, Japan, and colleagues measured total adiponectin in 527

© THINKSTOCK

recent study of men suggests that adiponectin levels may

men aged 40-60 years participating in health check-up programs. They placed subjects into one of three groups based on alcohol consumption: none or occasional (A1), less than 50 g per day for at least three per week (A2), and 50 g or more per day for at least three days per week (A3).

Among men without metabolic syndrome (MetS), the researchers observed no significant difference in adiponectin levels among the three groups. Among men with MetS, however, adiponectin levels were significantly higher in group A2 (moderate consumption) than in both groups A1 and A3, according to a report published online ahead of print in Metabolism. In addition, MetS subjects in group

Walnut Consumption Found to Improve Sperm Health H

ealthy young men who add walnuts to a Western-style diet may improve the health of their sperm, according to a recent study.

The 12-week dietary intervention study, led by Wendie A. Robbins, PhD, of the University of California-Los Angeles, included 117 healthy men aged 21-35 years who routinely ate a Western-style diet. The researchers randomly assigned 59 men to add 75 grams of wholeshelled walnuts daily to their diet 58 men (controls) to consume their usual diet but refraining from eating tree nuts. Compared with controls, the walnut group experienced improvements in sperm vitality, motility, and morphology, Dr. Robbins’ team reported online in Biology of Reproduction. In addition, the investigators found that serum fatty acid profiles improved in the walnut group, with increases in omega-6 and omega-3, but not in the control arm. © THINKSTOCK

Short Takes

A2 had higher high-density lipoprotein cholesterol levels than those in group A1, but levels in group A3 did not differ significantly from those in group A2.

Survey: Men Less Aware of Their Hypertension More men than women in the United States have hypertension, but men are less likely than women to be aware of their condition and to be currently taking antihypertensive medication, according to 2009-2010 data from the National Health and Nutrition Examination Survey.

The survey of adults aged 18 years and older showed that the age-adjusted prevalence of hypertension in the United States is 29.4% among men and 27.5% among women. Data showed that 79.6% of men were aware of their condition compared with 84.9% of women. In addition, 73.1% of men were currently taking medication for hypertension compared with 80.6% of women.

The findings appear in a report by the National Center for Health Statistics.

Metabolic Syndrome More Common in ED Sufferers Men with erectile dysfunction (ED) have a higher prevalence of metabolic syndrome than those without ED, a Spanish Miguel Angel Arrabal-Polo, MD, of San Cecilio University Hospital in Granada and colleagues found that metabolic syndrome was present in 64.9% of 37 ED patients

© THINKSTOCK

study found.

Prostate Cancer Risk Higher Among Night Workers M

en who work at night may be at increased risk for prostate cancer (PCa) and other malignancies, according to a Canadian study. Marie-Élise Parent, PhD, of the University of Quebec in Laval, and colleagues analyzed data from a population-based case-control study conducted in Montreal between 1979 and 1985 that elicited information about job histories, including work hours, from 3,137 men with incident cancer at one of 11 anatomic sites and from 512 controls. Compared with men who never worked at night, those who had ever worked at night had a 2.7 times increased PCa risk after adjusting for potential confounders, Dr. Parent and her colleagues reported online ahead of print in the American Journal of Epidemiology. They had a twofold increased risk for colon, rectal, and pancreatic cancers and non-Hodgkin’s lymphoma, as well as a 76% and 74% increased risk of lung and bladder cancer, respectively.

Night work might influence cancer risk possibly via suppression of melatonin release as a result of exposure to light at night. Such suppression, Dr. Parent’s group pointed out, has been associated with disruption of circadian rhythms as well as a reduction in non-specific anti-cancer effects of the pineal gland (which produces melatonin), and an increase in reproductive hormone levels.

compared with only 9.5% of 28 healthy controls, according to a report in The

likelihood of having metabolic syndrome. The study found no link between ED and levels of total, free, or bioavailable testosterone. In addition, higher systolic blood pressure and levels of C-reactive protein, a marker for systemic inflammation, predicted a high percentage of changes in the International Index of Erectile Function scores.

“Chronic inflammation found in patients with ED might explain the association between ED and metabolic syndrome,” the authors concluded.

11.9

The percentage of men aged 18 years and older in the United States in fair or poor health.

PERCENT

Source: National Health Interview Survey, 2010, National Center for Health Statistics.

© THINKSTOCK

After adjusting for confounding factors, ED patients had a 20 times increased

MEDISTAT

Scientific World Journal (2012; published online ahead of print).

Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer.

References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 K08Z12236BR1

Y11429ALT_Ad3_DSA_K08Z12236BR1_King_v1.indd 1

10/18/12 11:31 AM

14 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Adjuvanted Influenza Vaccine Safe It does not affect acute rejection or graft function in kidney transplant recipients, study finds

BY JOHN SCHIESZER SAN FRANCISCO—The use of adjuvanted pandemic (H1N1) 2009 influenza vaccine appears to be safe in terms of risk for acute rejection and long-term graft outcome in kidney transplant recipients, researchers reported at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy.

“Some transplant groups have recently raised concerns about the safety of adjuvanted influenza vaccination in terms of graft survival,” said lead investigator Mario Fernández-Ruiz, MD, an attending physician at the Unit of Infectious Diseases of the University Hospital “12 de Octubre,” in Madrid, Spain. “Our results are in the line of previous studies in confirming the short- and long-term safety of such strategy, since we have not found a higher incidence of acute rejection in those patients receiving adjuvated pandemic H1N1 influenza vaccination, or a worse graft function at the end of the follow-up period, as compared to those receiving seasonal non-adjuvanted vaccine or no vaccination.”

Currently, annual influenza immunization is strongly recommended in solid organ transplant (SOT) recipients due to increased risk of morbidity and

mortality related to influenza infection.

Safety concerns recently have been raised about the use of adjuvanted vaccines in SOT recipients. It has been theorized that the upregulation of the immune system might increase humoral and cellular alloreactivity.

The use of adjuvants (potent immunopotentiators without intrinsic antigenicity) was encouraged during the 2009 influenza A (H1N1) virus pandemic with the goal of minimizing antigen requirements, while also increasing and maintaining efficacy. However, recent research has suggested that multiple doses of adjuvanted influenza vaccine may lead to the development of antiHLA antibodies in a significant number of kidney transplant recipients Dr. Fernández-Ruiz and his colleagues conducted a single-center, observational, prospective cohort study that included 140 consecutive adult patients (age 16-83 years) who underwent kidney transplantation between November 2008 and December 2009. The investigators analyzed three groups that included recipients who received the adjuvanted pandemic H1N1 influenza vaccine alone or following seasonal vaccine (41 patients), those who only received the seasonal vaccine (31 patients) and those

Mario Fernández-Ruiz, MD

who did not received any vaccination (68 patients). The researchers assessed graft function, histologically proven rejection rate, graft loss (return to dialysis or retransplantation), and all-cause mortality up to April 2012 (unless death or graft loss occurred earlier).

The study demonstrated no significant differences in terms of acute rejection or graft function among the three groups.

In addition, the researchers found no differences in all-cause mortality rates among the different groups.

Dr. Fernández-Ruiz, who presented

the study findings at the meeting, said the median follow-up was 932.5 days.

Following vaccination, the researchers observed three episodes of rejection in the seasonal vaccine group (mean interval: 260 days) and four episodes of rejection in the pandemic vaccine group (mean interval: 300.2 days). Dr. Fernández-Ruiz said the study showed no differences in the rate of subsequent rejection during the follow-up after the vaccine was administered or offered among the three groups (0.12 for the seasonal vaccine group vs. 0.13 for the pandemic vaccine group and 0.15 episodes for the no vaccine group per 1,000 transplant-days).

Graft function, as estimated by the Modification of Diet in Renal Disease (MDRD) study formula, at the end of follow-up was better in the pandemic vaccine group (60.8 mL/min/1.73 m2) than in the seasonal vaccine group (47.2 mL/min/1.73 m2) or no vaccine groups (49.9 mL/min/1.73 m2).

“In view of our findings, we conclude that both seasonal and pandemic adjuvanted influenza vaccines are safe in terms of graft survival, so we would encourage nephrologists to offer vaccination to their patients in a proactive manner,” Dr. Fernández-Ruiz said. ■

Urinary Pathogens Changing in Renal Tx Patients

BY JOHN SCHIESZER SAN FRANCISCO—Over the past decade, gram-negative organisms have become more prevalent when organisms are isolated from the urine of renal transplant recipients, and resistance to levofloxacin and ceftriaxone has increased among Escherichia coli, the most frequently isolated urinary pathogen in these patients, a new study suggests.

“Increases in multidrug-resistance, especially among gram-negative organisms, are complicating treatment of straight forward infections, like urinary tract infections,” said lead investigator Christine J. Kubin, PharmD, Clinical Pharmacy Manager at New York-Presbyterian Hospital, Columbia University Medical Center in New York.

“At our institution and nationwide, we have noticed increases in resistance among cephalosporins and quinolones among urinary isolates. Renal transplant recipients are at increased risk post-

transplant and increases in multidrugresistance may increase the need for readmissions to receive intravenous antimicrobials.”

Dr. Kubin presented study findings at the 52nd Annual Meeting of Interscience Conference on Antimicrobial Agents and Chemotherapy.

She and her colleagues conducted a retrospective review of unique urine isolates (ISO) identified in 2002-2011 from renal transplant recipients up to 12 months post-transplant. In this study, unique ISO were separated by14 days or more. The researchers defined multidrug resistance as resistance to three or more classes of antibiotics and recurrence as a patient with two or more ISO within six months or three or more within 12 months.

The study included 1,595 renal transplant patients. Among these patients, 1,250 ISO were identified in 571 patients (36%). Gram-negative organisms were

more common than gram-positive organisms or Candida species (67% vs. 32% and 0.5%, respectively).

The most common organisms were Escherichia coli (31% of ISO), Enterococcus faecalis (19%), Klebsiella pneumoniae (16%), and Enterococcus faecium (12%).

The median time to first ISO was 29 days.

The initial ISO was gram negative in 383 patients (67%). Of these patients, 23% had multidrug-resistant ISO. The investigators compared two time periods (2002-2006 and 2007-2011) and found that the proportion of gramnegative organisms increased from 62% in the first period to 72% in the second period. The biggest increase occurred among E. coli (from 25% to 36%).

“Bacteriuria most often occurs one to six months post-transplant, and increases in gram-negative organisms as a cause of bacteriuria have occurred over the last 10 years,” Dr. Kubin told Renal & Urology News. “Increases in

cephalosporin and quinolone resistance, especially among E. coli, have occurred during this time period. Therefore, the early post-transplant period (the first month) may be a time of opportunity to limit unnecessary antibiotic use.”

Among all gram-negative organisms, resistance was similar between the two periods, but E. coli resistance to levofloxacin increased from 39% to 57% of ISO and E. coli resistance to ceftriaxone increased 10% to 21% of ISO. Among K. pneumoniae, carbapenem resistance did not change significantly (18% vs. 20%) and vancomycin resistance did not increase in E. faecium (78% vs. 75%).

Overall, the investigators found more multidrug resistance among gram-negative organisms in the second period (27% versus 33%). Bacteriuria did not significantly impact graft survival at one year compared to those without bacteriuria (94% vs. 96%). ■

www.renalandurologynews.com

NOVEMBER 2012

Renal & Urology News 15

Radium-223 Benefits Confirmed for CRPC Patients greater well-being in terms of physical, emotional, and functional parameters, prostate cancer score, and total score, and significantly better QOL (EQ-5D) scores compared with placebo at week 16. The drug improved QOL response rate compared with placebo (27% vs. 18%). Moreover, radium-223

was better at preserving QOL compared with placebo as shown by FACT-P total scores. The updated analysis demonstrated that radium-223 significantly prolonged OS by 3.6 months compared with placebo, which translated into a significant 30.5% reduction in risk of death.

Any moment is an accident waiting to happen.

TOVIAZ provides powerful efficacy.1,2 Mean UUI episodes per 24 hours at baseline

0

Novel medication improves overall survival and quality of life, data showed. improved overall survival (OS), with a 30.5% reduction in risk of death.

Chris Parker, MD, a consultant clinical oncologist with The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom, and colleagues reported updated survival, QOL, and safety data from ALASYMPCA. Eligible patients in this trial had previously received or refused docetaxel or were docetaxel ineligible. Investigators randomized patients to receive radium-223 chloride (50 kBq/kg IV) or placebo every four weeks for six weeks.

The updated analysis included all enrolled patients prior to crossover who had been assessed for effects of radium-223 on the primary endpoint of OS and secondary endpoints that included skeletal-related events (SREs), QOL, and safety. The investigators assessed QOL with the Functional Assessment of Cancer Therapy—Prostate (FACT-P) and EuroQoL (EQ-5D) instruments.

The updated analysis looked at 921 patients (614 treated with radium-223 chloride and 307 who received placebo). The mean age of the patients was 70 years and 94% were Caucasian.

The time to first SRE was six months longer with radium-223 compared with placebo. Patients treated with radium-223 reported significantly

The agent was very well tolerated, with a low incidence of myelosuppression (2.2% grade 3/4 neutropenia; 6.3% grade 3/4 thrombocytopenia). “We found that radium-223 not only improves overall survival of men with metastatic CRPC, but that it also improves quality of life,” Dr. Parker said. ■

For your OAB patients with urge urinary incontinence

Median % reduction from baseline in UUI episodes at Week 12

BY JOHN SCHIESZER VIENNA—Radium-223, a novel investigational medication, improves overall survival and time to first skeletal-related event, with a highly favorable safety profile, in castration-resistant prostate cancer (CRPC) patients with bone metastases, according to findings presented at the European Society for Medical Oncology 2012 Congress.

Moreover, radium-223 preserves quality of life (QOL), with better functioning and well-being, compared with placebo.

Radium-223 is a first-in-class alphaemitter. It targets bone metastases with high-energy, very short range alpha particles. An interim analysis of ALSYMPCA study compared radium-223 chloride and placebo in CRPC patients with bone metastases receiving best standard of care. The drug

Placebo

TOVIAZ 4 mg

TOVIAZ 8 mg

(n=211)

(n=199)

(n=223)

3.7

3.8

3.7

-20 -40

-50% -80%*

-60 -80

-88%*

-100 Mean UUI episodes per 24 hours at Week 12 *P≤0.001 vs placebo.1

2.5

1.8*

1.4*

Results of a 12-week, fixed-dose, randomized, double-blind, placebo- and active-controlled international ex-US study to assess the efficacy, tolerability, and safety of TOVIAZ in adults with overactive bladder. The coprimary efficacy end points were change in micturitions per day and change in UUI episodes per day. Subjects (N=1132) were treated once daily with placebo, TOVIAZ 4 mg or 8 mg, or an active-control agent (an oral antimuscarinic). The median percent change in micturitions at Week 12 was 19% for TOVIAZ 8 mg, 17% for TOVIAZ 4 mg, and 11% for placebo (P<0.001). The least squares (LS) mean change in micturitions at Week 12 was -1.9 episodes for TOVIAZ 8 mg, -1.8 episodes for TOVIAZ 4 mg, and -1.0 episodes for placebo (P<0.001). The median percent reduction in UUI episodes at Week 12 was 88% for TOVIAZ 8 mg, 80% for TOVIAZ 4 mg, and 50% for placebo (P≤0.001).

The LS mean change in UUI episodes at Week 12 was -2.2 episodes for TOVIAZ 8 mg, -2.0 episodes for TOVIAZ 4 mg, and -1.1 episodes for placebo (P≤0.001).1

TOVIAZ is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

Important Safety Information TOVIAZ is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma, and in patients with known hypersensitivity to the drug or its ingredients or to DETROL® (tolterodine tartrate) tablets or DETROL® LA (tolterodine tartrate extended release capsules).

Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine, in some cases after the first dose. Patients should be advised to promptly discontinue fesoterodine therapy and seek immediate medical attention if they experience edema of the tongue, laryngopharynx, or difficult breathing.

TOVIAZ tablets should be used with caution in patients with clinically significant bladder outlet obstruction, decreased gastrointestinal motility, controlled narrow-angle glaucoma, or myasthenia gravis.

TOVIAZ is associated with anticholinergic central nervous system (CNS) effects including headache, dizziness and somnolence. Advise patients not to drive or operate heavy machinery until they know how TOVIAZ affects them. Consider dose reduction or drug discontinuation if a patient experiences anticholinergic CNS effects.

The recommended starting dose of TOVIAZ is 4 mg once daily swallowed whole. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily. Doses greater than 4 mg are not recommended in patients with severe renal insufficiency (CL CR <30 mL/min), or in patients taking a potent CYP3A4 inhibitor. TOVIAZ is not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

The most frequently reported adverse events (≥4%) for TOVIAZ were: dry mouth (placebo, 7%; TOVIAZ 4 mg, 19%; TOVIAZ 8 mg, 35%) and constipation (placebo, 2%; TOVIAZ 4 mg, 4%; TOVIAZ 8 mg, 6%).

OAB=overactive bladder.

References: 1. Chapple C, Van Kerrebroeck P, Tubaro A, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol.

2007;52(4):1204-1212. 2. Data on file. Protocol SP583 table scs763 13.2.1.1.1. Pfizer Inc, New York, NY.

For more information, visit www.ToviazHCP.com.

Please see brief summary of prescribing information on next page.

FSD502910

© 2012 Pfizer Inc.

All rights reserved.

October 2012

16 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Researchers Report Higher Prevalence of Priapism CHICAGO—Priapism is more common in the U.S. population than previously recognized, researchers reported at the World Meeting of Sexual Medicine.

Analyzing data from 39,964 emergency department (ED) encounters nationwide from 2006-2009, lead researchers Daniel

M. Stein, MD and Andrew S. Flum, MD, and colleagues at Northwestern University Feinberg School of Medicine in Chicago, found that there were 8.05 priapism visits per 100,000 ED encounters. By comparison, earlier studies revealed a priapism incidence of 0.84 cases per 100,000 male patients in Western Australia, 0.34-0.52

TOVIAZ® (fesoterodine fumarate) extended release tablets Rx only BRIEF SUMMARY OF PRESCRIBING INFORMATION. The following is a brief summary only; see full Prescribing Information for complete product information.

INDICATIONS AND USAGE Toviaz is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

CONTRAINDICATIONS Toviaz is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Toviaz is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules.

WARNINGS AND PRECAUTIONS Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be lifethreatening. If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided.

Bladder Outlet Obstruction: Toviaz should be administered with caution to patients with clinically significant bladder outlet obstruction because of the risk of urinary retention.

Decreased Gastrointestinal Motility: Toviaz, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility, such as those with severe constipation.

Controlled Narrow-Angle Glaucoma: Toviaz should be used with caution in patients being treated for narrow-angle glaucoma, and only where the potential benefits outweigh the risks.

Central Nervous System Effects: Toviaz is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, dizziness, and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Toviaz affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

Hepatic Impairment: Toviaz has not been studied in patients with severe hepatic impairment and therefore is not recommended for use in this patient population.

Renal Impairment: Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment.

Concomitant Administration with CYP3A4 Inhibitors: Doses of Toviaz greater than 4 mg are not recommended in patients taking a potent CYP3A4 inhibitor (eg, ketoconazole, itraconazole, clarithromycin). No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (eg, erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). While the effect of weak CYP3A4 inhibitors (eg, cimetidine) was not examined by clinical study, some pharmacokinetic interaction is expected, albeit less than that observed with moderate CYP3A4 inhibitors.

Myasthenia Gravis: Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.

ADVERSE REACTIONS Clinical Trials Experience: The safety of Toviaz was evaluated in Phase 2 and 3 controlled trials in a total of 2859 patients with overactive bladder, of which 2288 were treated with fesoterodine. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase 2 or 3 studies with treatment periods of 8 or 12 weeks.

Approximately 80% of these patients had >10 weeks exposure to Toviaz in these trials.

A total of 1964 patients participated in two 12-week, Phase 3 efficacy and safety studies and subsequent open-label extension studies. In these two studies combined, 554 patients received Toviaz 4 mg/day and 566 patients received Toviaz 8 mg/day. In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving Toviaz who reported one serious adverse event each: angina, chest pain, gastroenteritis, and QT prolongation on ECG. The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth was higher in those taking 8 mg/day (35%) and in those taking 4 mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.

The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking 4 mg/day, and 6% in those taking 8 mg/day.

Table 1 lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Toviaz 4 or 8 mg once daily for up to 12 weeks.

Table 1. Adverse events with an incidence exceeding the placebo rate and reported by ≥1% of patients from double-blind, placebo-controlled Phase 3 trials of 12 weeks treatment duration Placebo N=554 %

Toviaz 4 mg/day N=554 %

Toviaz 8 mg/day N=566 %

Dry mouth

7.0

18.8

34.6

Constipation

2.0

4.2

6.0

System organ class

Gastrointestinal disorders

Infections

Preferred term

Dyspepsia

0.5

1.6

2.3

Nausea

1.3

0.7

1.9

Abdominal pain upper

0.5

1.1

0.5

Urinary tract infection

3.1

3.2

4.2

Upper respiratory tract infection

2.2

2.5

1.8

Eye disorders

Dry eyes

0

1.4

3.7

Renal and urinary disorders

Dysuria

0.7

1.3

1.6

Urinary retention

0.2

1.1

1.4

Respiratory disorders

Cough

0.5

1.6

0.9

Dry throat

0.4

0.9

2.3

General disorders

Edema peripheral

0.7

0.7

1.2

Musculoskeletal disorders

Back pain

0.4

2.0

0.9

Psychiatric disorders

Insomnia

0.5

1.3

0.4

Investigations

ALT increased

0.9

0.5

1.2

GGT increased

0.4

0.4

1.2

Rash

0.5

0.7

1.1

Skin disorders

ALT = alanine aminotransferase; GGT = gamma glutamyltransferase Patients also received Toviaz for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received Toviaz for at least 6 months, 1 year, 2 years, and 3 years, respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth,

cases per 100,000 male patients in Finland, and 1.5 cases per 100,000 person-years in The Netherlands.

The new study showed that 21.1% of patients with priapism had a concurrent diagnosis of sickle cell disease (SCD) and 72.1% of all patients were discharged home from the ED, whereas

constipation, dry eyes, dyspepsia, and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator and reported more than once during the open-label treatment period of up to 3 years, included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases).

Post-marketing Experience: The following events have been reported in association with fesoterodine use in worldwide post-marketing experience: Eye disorders: Blurred vision; Cardiac disorders: Palpitations; General disorders and administrative site conditions: hypersensitivity reactions, including angioedema with airway obstruction, face edema; Central nervous system disorders: Dizziness, headache, somnolence; Skin and subcutaneous tissue disorders: Urticaria, pruritus. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of fesoterodine in their causation cannot be reliably determined.

DRUG INTERACTIONS Antimuscarinic Drugs: Coadministration of Toviaz with other antimuscarinic agents that produce dry mouth, constipation, urinary retention, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.

CYP3A4 Inhibitors: Doses of Toviaz greater than 4 mg are not recommended in patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin. Coadministration of the potent CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately a doubling of the maximum concentration (Cmax ) and area under the concentration versus time curve (AUC) of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. Compared with CYP2D6 extensive metabolizers not taking ketoconazole, further increases in the exposure to 5-HMT were observed in subjects who were CYP2D6 poor metabolizers taking ketoconazole.

There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, the average (90% confidence interval) increase in Cmax and AUC of the active metabolite of fesoterodine was approximately 19% (11%-28%) and 27% (18%-36%) respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (eg, erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice).

The effect of weak CYP3A4 inhibitors (eg, cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors.

CYP3A4 Inducers: No dosing adjustments are recommended in the presence of CYP3A4 inducers, such as rifampin and carbamazepine. Following induction of CYP3A4 by coadministration of rifampin 600 mg once a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal half-life of the active metabolite was not changed.

CYP2D6 Inhibitors: The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively. No dosing adjustments are recommended in the presence of CYP2D6 inhibitors.

Drugs Metabolized by Cytochrome P450: In vitro data indicate that at therapeutic concentrations, the active metabolite of fesoterodine does not have the potential to inhibit or induce Cytochrome P450 enzyme systems.

Oral Contraceptives: In the presence of fesoterodine, there are no clinically significant changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel.

Warfarin: A clinical study has shown that fesoterodine 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity (PT/INR) of warfarin 25 mg. Standard therapeutic monitoring for warfarin should be continued.

Drug-Laboratory Test Interactions: Interactions between Toviaz and laboratory tests have not been studied.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies using Toviaz in pregnant women.

No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. In mice at 6 to 27 times the expected exposure at the maximum recommended human dose (MRHD) of 8 mg based on AUC (75 mg/kg/ day, oral), increased resorptions and decreased live fetuses were observed. One fetus with cleft palate was observed at each dose (15, 45, and 75 mg/kg/day), at an incidence within the background historical range. In rabbits treated at 3 to 11 times the MRHD (27 mg/kg/day, oral), incompletely ossified sternebrae (retardation of bone development) were observed in fetuses. In rabbits at 9 to 11 times the MRHD (4.5 mg/kg/day, subcutaneous), maternal toxicity and incompletely ossified sternebrae were observed in fetuses (at an incidence within the background historical range). In rabbits at 3 times the MRHD (1.5 mg/kg/day, subcutaneous), decreased maternal food consumption in the absence of any fetal effects was observed. Oral administration of 30 mg/kg/day fesoterodine to mice in a pre- and post-natal development study resulted in decreased body weight of the dams and delayed ear opening of the pups. No effects were noted on mating and reproduction of the F1 dams or on the F2 offspring.

Toviaz should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Nursing Mothers: It is not known whether fesoterodine is excreted in human milk. Toviaz should not be administered during nursing unless the potential benefit outweighs the potential risk to the neonate.

Pediatric Use: The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.The safety and effectiveness of Toviaz in pediatric patients have not been established.

Geriatric Use: No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.

Of 1567 patients who received Toviaz 4 mg/day or 8 mg/day in the Phase 2 and 3, placebo-controlled, efficacy and safety studies, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies; however, the incidence of antimuscarinic adverse events, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8 mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients.

Renal Impairment: In patients with severe renal impairment (CLCR <30 mL/min), Cmax and AUC are increased 2.0and 2.3-fold, respectively. Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment. In patients with mild or moderate renal impairment (CLCR ranging from 30-80 mL/min), Cmax and AUC of the active metabolite are increased up to 1.5- and 1.8-fold respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate renal impairment.

Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh C) have not been studied; therefore Toviaz is not recommended for use in these patients. In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are increased 1.4- and 2.1-fold, respectively, as compared to healthy subjects.

No dose adjustment is recommended in patients with mild or moderate hepatic impairment.

Gender: No dose adjustment is recommended based on gender. The pharmacokinetics of fesoterodine are not significantly influenced by gender.

Race: Available data indicate that there are no differences in the pharmacokinetics of fesoterodine between Caucasian and Black healthy subjects following administration of Toviaz.

OVERDOSAGE Overdosage with Toviaz can result in severe anticholinergic effects. Treatment should be symptomatic and supportive.

In the event of overdosage, ECG monitoring is recommended.

Manufactured by: Aesica Pharmaceuticals GmbH, Galileistraße 6, 08056 Zwickau, Germany Distributed by: Pfizer Labs, Division of Pfizer Inc, NY, NY 10017 This brief summary is based on TOVIAZ Prescribing Information LAB-0381-13.0, revised August 2012.

FSD503219

© 2012 Pfizer Inc.

All rights reserved.

October 2012

only 49.6% of patients with SCD were discharged home. Concurrent SCD was associated with a nearly fourfold increased likelihood of being admitted to the hospital.

The mean hospital charge was $1,778 per encounter if the patient was discharged home and $41,909 per encounter if the patient was admitted. The researchers calculated that hospital charges associated with priapism totaled more than $110 million annually, and more than 90% of these charges were associated with inpatient admission.

“If we can find ways to manage the condition more effectively in the emergency room, we can actually cut [some] of the charges associated with the condition,” Dr. Flum told Renal & Urology News. ■

RCC Drug Shows Better Tolerability VIENNA—Tivozanib, an investigational drug for treating metastatic renal cell carcinoma (mRCC), is well tolerated and associated with fewer drug-related adverse events (AEs) than sorafenib, according to phase 3 study findings presented at the European Society for Medical Oncology 2012 Congress.

The randomized study included 516 treatment-naïve mRCC patients.

Of the 259 tivozanib recipients, 175 (67.6%) experienced drug-related AEs compared with 214 (83.3%) of 257 patients treated with sorafenib.

Hypertension was the most frequent tivozanib-related AE, investigators reported. Fewer patients in the tivozanib arm than the sorafenib arm had grade 3 or higher drug-related AEs (36.3% vs. 51%). Fewer tivozanib than sorafenib recipients required overall dose reductions (13.9% vs.

44.4%). Tivoazanib recipients also stayed on treatment longer.

Earlier this year, researchers presented data showing that tivozanib treatment was associated with significantly longer progression-free survival (PFS) compared with sorafenib (median PFS of 12.7 vs. 9.1 months). ■

www.renalandurologynews.com

NOVEMBER 2012

Renal & Urology News 17

Testosterone Declines Not Inevitable Study implicates factors other than aging, including weight gain, smoking cessation, depression

BY JOHN SCHIESZER HOUSTON—Declines in testosterone levels may not be inevitable with aging, but instead could be due to changes in smoking habits, body size, mental health status and chronic cardiovascular disease, according to new findings presented at The Endocrine Society’s 94th Annual Meeting.

Many older men have low levels of testosterone, but the cause is not known, said study investigator Gary Wittert, MD, Professor of Medicine at the University of Adelaide in Adelaide, Australia. Few population-based studies have tracked changes in testosterone levels among the same men over time.

Dr. Wittert and his colleagues analyzed testosterone levels in the longitudinal Male Adelaide Inflammation Lifestyle Environment Study, which enrolled 1,869 community-based men.

“Men who had declines in testosterone were more likely to be those who became obese, had stopped smoking, were depressed at either clinic visit, or who had persistent or new onset cardiovascular disease,” Dr. Wittert said.

After the researchers excluded from the analysis any men who had established disorders of the testes, or who were taking medications or had medical

conditions known to affect hormones, they included 1,382 men in the data analysis. The men ranged in age from 35 to 80 years, with a mean age of 54 at baseline. The researchers accumulated complete data at baseline and at five years.

On average testosterone levels did not decline significantly over the study period, with an average decrease of less than 1% each year. At baseline, 21% of the men were unmarried and 19% were current smokers. In addition, 30% of the men had a body mass index (BMI) of 30 kg/m2 or higher (obese), 48% had a waist circumference of 100 cm or more (central obesity), and 8% were depressed at baseline. The mean baseline testosterone level was 16.2 nmol/L (3% below 8 nmol/L, 36% 8-15 nmol/L, and 61% greater than 15 nmol/L). At follow-up, the mean testosterone level was 15.6 nmol/L. The study showed that this represented a non-significant 0.13 nmol/L decline per year or 0.80% per year.

When the investigators analyzed the data by subgroups, they found that certain factors were linked to lower testosterone levels at five years than at the beginning of the study. Compared with married men, unmarried men had

Gary Wittert, MD

“Testosterone deficiency can be a marker of underlying disease.” a significantly greater yearly decline in testosterone levels. Men who quit smoking during the study had a significantly greater annual decline than nonsmokers. The researchers also

observed significantly greater annual declines among men who developed central obesity (versus those who did not have central obesity) and among those who became obese during the study (versus those with a BMI below 25), had persistent depression at both time points, or persistent or new onset cardiovascular disease.

Although a transition from normal weight to obesity resulted in decreases in testosterone, the researchers found no increases in luteinizing hormone.

They theorize that a failure at the hypothalamic/pituitary level may help explain the lower testosterone levels.

They believe their findings are clinically relevant because they suggest that preventing obesity could be an important strategy for preventing testosterone declines.

“Testosterone deficiency can be a marker of underlying disease,” Dr. Wittert said. “Urologists should care about these findings for two reasons.

To dismiss declining testosterone levels as a consequence of aging instead of correcting the underlying problem is one reason. The second reason is that people see [supplemental] testosterone as a panacea and we don’t have any longterm data to support that.” ■

Elevated FGF-23 Linked to Insulin Resistance

BY LOUISE GAGNON QUEBEC CITY—Insulin resistance (IR) is associated with increased fibroblast growth factor-23 levels in chronic kidney disease (CKD) patients, suggesting a link between IR and renal phosphorus homeostasis, according to a cross-sectional study.

Presented at a poster session at the 3rd International Congress on Abdominal Obesity, the analysis of 72 patients with stage 3-5 CKD also showed that IR is associated with a greater severity of coronary artery calcification (CAC).

Patients with type 2 diabetes who were treated with insulin were excluded from the study. Investigators looked at fibroblast growth factor-23 (FGF-23) as a biomarker to assess disrupted renal phosphorus homeostasis. IR was assessed by the homeostasis model assessment of IR (HOMA-IR). The mean age of patients in the study was 64, the mean estimated glomerular filtration rate was 25.9 mL/

min/1,73m2, the median HOMA-IR was 2.19, and the median CAC was 112 Agatston units.

“Our research question was if phosphorus homeostasis would be affected

by IR in CKD patients,” explained nephrologist and principal investiga-

Insulin resistance may have an impact on phosphorus homeostasis. tor Jocelyn S. Garland, MD, FRCPC, an assistant professor in the department of medicine at Queen’s University, Kingston, Ontario, Canada. As a secondary outcome, they looked at whether there was a difference in CAC. She noted that elevated phosphorus is considered to be a cardiovascular risk

factor. Studies have found that even in individuals who have phosphorus levels in the normal range, but in the higher tertile of normal, are at increased risk of cardiovascular morbidity and mortality, according to Dr. Garland.

“It is not commonly known that insulin affects a receptor in the kidney that deals with phosphorus re-absorption,” Dr. Garland said.

Dr. Garland and co-investigators divided patients into two groups, placing those with HOMA-IR values below the median in one group and those with values above the median in another group. Patients with greater HOMA-IR had significantly increased FGF-23 levels (179 vs. 109 RU/ mL) and 40% higher log CAC scores (2.1 vs. 1.6). FGF-23 was also significantly and positively associated with other IR markers like abdominal waist circumference and body mass index.

“We found patients with higher levels of insulin resistance had greater FGF-

23 levels, and to our knowledge that has not been described before,” Dr. Garland said.

A multi-regression statistical model showed that IR was a risk factor for elevated FGF-23, even after adjusting for factors such as parathyroid hormone, kidney function, and 1,25 dihydroxyvitamin D, all known for influencing FGF-23, according to researchers.

“Insulin resistance had an independent effect on FGF-23 levels,” she said.

“As insulin resistance increased, so too did the FGF-23 levels, implying that patients with higher levels of insulin resistance might be re-absorbing more phosphorus, and the effect may be higher FGF-23 levels to try and encourage the elimination [of phosphorus].”

Since IR commonly predates CKD development, an unexpected impact of IR may be excessive phosphorus retention, Dr. Garland said. “It is a very negative effect in our population,” she said. ■

18 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

On the Forefront

Urologists and nephrologists working together: an emerging model of patient care

Metabolic Abnormalities Found Following Urinary Diversion

BY JEFFREY J. TOMASZEWSKI, MD, AND ROBERT G. UZZO, MD, FACS Background Radical cystectomy with urinary diversion including neobladder remains the standard of care for muscle-invasive bladder cancer. There has been a slow shift over the past 15 years toward a more inclusive use of bowel based neobladder reconstruction to the native urethra.

Modern forms of urinary diversion are being widely employed, necessitating an awareness by both the urologist and nephrologist of possible long term complications and appropriate follow-up to monitor oncologic, functional, and metabolic outcomes. In a large contemporary series of urinary diversion, 12.8% of patients experienced metabolic complications at a median of 1.9 years (range 0.1 to 25.9) following urinary diversion.1 A case study A 65-year-old male with coronary artery disease, hypercholesterolemia, hypertension, morbid obesity (BMI 49 kg/m2), and CKD stage 2 (eGFR 70 mL/min/1.73m2) underwent radical cystoprostatectomy and

creation of an ileal neobladder (Studer) for pT3aN0 (0/48)M0 7cm high grade urothelial carcinoma of the bladder. The patient remains cancer-free after eight years of follow-up, but developed progressive CKD 3 (eGFR 32 mL/min/1.73m2) with chronic metabolic acidosis (serum HCO3- 15 mmol/L) requiring alkalinization with sodium bicarbonate. The patient maintains close follow-up with nephrology with normalization of HCO3 (2225 mmol/L ), and receives prophylactic vitamin B12 supplementation.

Discussion Malabsorption of calcium and fat soluble vitamins A, D, E, and K following ileal resection and incorporation of bowel segments into the urinary tract can result in hyperchloremic metabolic acidosis (Table 1). When defined as a serum bicarbonate level less than 20 mg/dL or requiring treatment with an alkalinizing agent, metabolic acidosis was present in 10.2% of patients following diversion.1 The incidence of hyperchloremic acidosis is higher in continent diversions and is most frequently encountered in diversions constructed from the sigmoid

Table 1. Metabolic Consequences of Urinary Diversion Bowel Segment

Stomach

Serum Electrolyte Abnormalities

~ Cl~ K+

Acid-Base Metabolic Disorder Effects

Metabolic alkalosis

Treatment Options

B12 malabsorption (secretes intrinsic factor which is required for B12 absorption)

Hydration

Peptic ulcers

Antacids

B12 supplementation

Hematuria-dysuria syndrome ~ Na+ Jejunum

~ Cl}K

Metabolic acidosis

+

Dehydration

Hydration

Stimulation of aldosterone secretion

NaCl

Hydration

~ K+ Ileum & Colon

} Cl~ Ca2+

NaHCO3

Metabolic acidosis

~ Mg+

On The Web

Dehydration

NaHCO3

B12 malabsorption

Nicotinic acid (CI transport inhibitor) B12 supplementation

Jeffrey J. Tomaszewski, MD

Robert G. Uzzo, MD, FACS

colon. Compensatory hyperventilation may effectively counter acidosis and prevent serum electrolyte abnormalities acutely, but chronic metabolic acidosis has been shown to stimulate osteoclastic bone resorption, inhibit osteoblastic collagen synthesis, and result in hypophosphatemia due to renal phosphate wasting,2 the combined effects of which can induce metabolic bone disease with features of both osteoporosis and osteomalacia.3 Patients with pre-existing CKD or those who subsequently develop it, as in this case, are particularly prone to acidosis-induced bone demineralization due to loss of phosphate buffer from bone and impaired activated vitamin D production secondary to tubular cell damage.4 Irrespective of its cause, even mild degrees of acidosis could be sufficient to cause appreciable bone loss over time.3 Prophylactic administration of alkalinizing agents such as potassium or sodium citrate should be readily performed. With early correction of base excess following urinary diversion, a majority of patients demonstrate normal bone mineral density at long interval follow-up (30 years).5 Malabsorption of bile acid strongly correlates with the length of ileum resected, and urologists should strive to use the shortest feasible segment of ileum.

Vitamin B12 is exclusively absorbed in the distal ileum, and serum levels may not deplete for five years. In patients with

normal vitamin B12 levels at the time of cystectomy, 3.0% of patients develop deficient B12 levels at a median of 9.1 years (range 0.4 to 25.8) following ileal conduit diversion.1 Vitamin B12 levels should be checked annually and routinely supplemented following urinary diversion.3 The late occurrence of vitamin B12 deficiency underscores the need for vigorous long-term physiologic monitoring following urinary diversion.

Long term management of bladder cancer patients with urinary diversions requires attention not only to the oncologic implications of their care, but also to the potential metabolic consequences. â&#x2013; Jeffrey J. Tomaszewski, MD, is a urologic oncology fellow and Robert G. Uzzo, MD, FACS, is Chief of Surgery at Fox Chase Cancer Center in Philadelphia.

Dr. Uzzo also is Medical Director for Urology at Renal & Urology News.

REFERENCES 1. Shimko MS, Tollefson MK, Embreit EC, et al.

Long-term complications of conduit urinary diversion. J Urol 2011;185:562-567.

2. Roosen A, Gerharz EW, Roth S, et al. Bladder, bowel and bonesâ&#x20AC;&#x201D;skeletal changes after intestinal urinary diversion. World J Urol 2004;22:200-209.

3. Cody JD, Nabi G, Dublin N, et al. Urinary diversion and bladder reconstruction/replacement using intestinal segments for intractable incontinence or following cystectomy. Cochrane Database Syst Rev 2012;2:CD003306.

4. Fichtner J. Follow-up after urinary diversion. Urol Int 1999;63:40-45.

5. Stein R, Fisch M, Andreas J, et al. Whole-body potassium and bone mineral density up to 30 years after urinary diversion. Br J Urol 1998; 82:798-803.

See more of what your colleagues are doing to create cutting-edge models of patient care at www.renalandurologynews.com/forefront.

www.renalandurologynews.com

NOVEMBER 2012

Renal & Urology News 19

Post-KT Early Readmission Factors Identified OLDER KIDNEY transplant (KT) recipients and those of AfricanAmerican race are at significantly higher risk of early hospital readmission (EHR) after transplantation, a study found.

In addition, EHR, defined as at least one hospital readmission to an acute care hospital within 30 days after discharge from initial KT, was significantly more likely among recipients of expanded criteria donor (ECD) kidneys, obese patients, those with diabetes or other comorbidities, and those who had a longer initial hospital length of stay, according to an online report in the American Journal of Transplantation.

The new findings may have important implications for clinical practice by helping to identify which KT recipients are at increased risk for readmission,

Transplant patients are at higher risk if they are older or African American. researchers led by Dorry L. Segev, MD, PhD, of the Johns Hopkins University School of Medicine in Baltimore, concluded. “Recipients at risk could be targeted for better transitions of care and coordination of care at discharge from KT.” Dr. Segev’s team examined data from 32,961 Medicare patients who underwent primary kidney transplantation from 2000 to 2005. Of these, 31% had EHR. “We were surprised by the very high rate of early readmission,” Dr. Segev told Renal & Urology News. “Nearly one-third of transplant patients are readmitted. It is highly likely that some, if not many, of these readmissions are preventable through targeted intervention, surveillance, and novel postdischarge mechanisms.”

Each 10-year increment in age at transplantation was associated with a significant 6% increased risk of EHR for patients younger than 40 years, a 2% increased risk for those aged 40-70, and a 40% increased risk for recipients older than 70, Dr. Segev’s group reported. A 60-year-old had a 17% increased risk of EHR compared with a 20-year-old after controlling for all other factors.

African-American recipients had a significant 11% increased risk compared with non-African-American patients.

Compared with patients who received a kidney from a live donor, those who received an ECD kidney had a 12% increased risk of EHR. In addition, the study found that women with diabetes had a 29% increased risk of EHR compared with women who did not. Men with diabetes

had a 12% increased risk compared with men who did not.

The study also demonstrated an association between hospital length of stay after transplantation. Patients whose stay was less than five days had a significant 17% decreased risk of EHR per day, whereas recipients whose stay

was five days or more had a significant 7% increased risk per day. “A short length of stay was likely associated with a low risk of readmission because short length of stay, in many cases, reflects a low-risk recipient with an organ from a low-risk donor,” Dr. Segev and his colleagues explained. ■

It’s time to turn OAB on its head.

OAB remains a problem for many patients As the number of patients diagnosed with overactive bladder (OAB) continues to grow, so does the need for improved prevention, diagnosis, and management.1 For many Americans now living with OAB, the disease can have a significant negative impact on their quality of life. 2,3 Current OAB treatments may work well for some, but they are not for everyone.4

Why are many patients suffering despite current therapeutic options?

One potential reason is lack of persistence with OAB therapy.5 While discontinuation of therapy is a significant issue among patients with chronic conditions, OAB therapy has demonstrated a higher rate of discontinuation compared with other drug classes.5 In a 2008 study investigating discontinuation rates of OAB therapy in the UK,* the median time to discontinuation was 4.76 months, with 77% of patients discontinuing their OAB treatment by 1 year.6

*A national health record database of women under the care of general practitioners in the UK (National Health Service).6 References: 1. Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int. 2011;108:1132-1138. 2. Coyne KS, Sexton CC, Irwin DE, Kopp ZS, Kelleher CJ, Milsom I. The impact of overactive bladder, incontinence and other lower urinary tract symptoms on quality of life, work productivity, sexuality and emotional well-being in men and women: results from the EPIC study. BJU Int. 2008;101:1388-1395. 3. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20:327-336. 4. Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int. 2009;105:1276-1282. 5. Yeaw J, Benner JS, Walt JG, Sian S, Smith DB. Comparing adherence and persistence across 6 chronic medication classes. J Manag Care Pharm. 2009;15:728-740.

6. Gopal M, Haynes K, Bellamy SL, Arya LA. Discontinuation rates of anticholinergic medications used for the treatment of lower urinary tract symptoms. Obstet Gynecol. 2008;112:1311-1318. © 2012 Astellas Pharma US, Inc.

All rights reserved.

Printed in USA

012F-500-5743

July 2012

20 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Post-Op Acute Dialysis Rate Rising The trend is mainly among patients undergoing cardiac and vascular surgery, Canadian study shows

BY ROSEMARY FREI, MSc THE RATE of acute dialysis after elective major surgery tripled in Ontario between 1995 and 2009, new findings suggest. The increase was primarily among patients undergoing cardiac and vascular surgery.

The investigators, led by Amit Garg, MD, PhD, of the London Health Sciences Centre in London, Ontario, said they believe the cause may be an increase in proportion of individuals with preoperative chronic kidney disease who undergo major surgery. They are now testing interventions aimed at reducing the postoperative rates of acute kidney injury (AKI), particularly among patients with compromised kidney function before the surgery.

“One of our trials, which are all funded by the CIHR [Canadian Institutes of Health Research], is looking at the spice turmeric for the prevention of AKI in the elective abdominal aortic

aneurysm repair setting, where there are high rates of AKI,” Dr. Garg told Renal & Urology News.

Dr. Garg and his colleagues used data on hospital admissions from the Canadian Institute for Health Information’s discharge-abstract database, information on inpatient and outpatient services from the Ontario Health Insurance Plan, and vital statistics on all permanent Ontario residents from the Registered Persons Database.

Secondary CA Risk Is Not Higher with RT

treated at their center—including 897 treated with external beam radiotherapy (EBRT), 413 treated with brachytherapy (BT), and 1,348 treated with RP—the researchers found that the 10-year likelihoods for secondary bladder or colorectal cancer development in the EBRT, BT, and RP groups were 4%, 2%, and 3%, respectively, a non-significant difference between groups.

Among 243 patients who developed an SM, the five-year likelihood of SM-related mortality in the EBRT and BT groups was 43.7% and 15.6%, respectively, compared with 26.3% in the RP cohort. The differences among the groups were not significant, the researchers stated.

The 10-year secondary malignancy (SM)-free survival for the EBRT, BT, and RP cohorts were 83%, 89%, and 87%, respectively. Compared with RP, EBRT was associated with significantly worse SM-free survival and BT was not.

Older age and a history of smoking were significant predictors for SM development.

The researchers observed that the l ower incidence of secondary bladder and colorectal cancers found in their study could possibly be related to the highly targeted nature of the radiotherapy delivery (e.g., intensity-modulated radiotherapy) used at their institution. ■

RADIOTHERAPY (RT) for prostate cancer is no more likely than radical prostatectomy (RP) to result in secondary cancers, a new study suggests.

In addition, the secondary cancers that develop after radiotherapy are not more lethal than those that develop after RP, according to an online report in BJU International.

Older age and smoking were significant predictors for secondary cancer.

The findings dispel a number of misconceptions regarding the frequency and presumed behavior of secondary malignancies (SMs) in patients treated with radiotherapy, Michael J. Zelefsky, MD, and colleagues at Memorial SloanKettering Cancer Center in New York stated. In a retrospective study of 2,658 patients with localized prostate cancer

Aging population The study showed that 50.6% of patients were 65 years and older in 2006-2009, compared with 39.5% in 1995-1997, according to a report published in the Canadian Medical Association Journal (2012;184:12371245). In addition, the researchers found an increase in the proportions of diseases associated with postoperative acute dialysis, such as diabetes and chronic kidney disease.

The incidence of post-operative acute dialysis increased steadily from 0.2% in 1995 to 0.6% in 2009. The increase occurred in all age groups, but primarily among those who underwent cardiac and vascular surgery. Dr. Garg’s team noted that “in recent years, as

The rate of acute dialysis tripled in Ontario between 1995 and 2009. many as one in 80 patients had their cardiac surgery complicated by acute dialysis, compared to one in 390 in 1995.”

In addition, the time to the start of acute dialysis post-operatively grew shorter: In 1995, the first dialysis treatment was done a median of five days after surgery, and in 2009 it was two days.

The type of dialysis used also changed over time. After 1998, the researchers observed a shift almost completely away from peritoneal dialysis and toward continuous renal replacement therapy.

Among the 2,231 patients who receive post-operative acute dialysis, 937 deaths occurred within 90 days of surgery. The study did not show a significant change over time in 90-day post-operative mortality among those who received acute dialysis.

For the study, Dr. Garg’s group analyzed data from 552,672 adults admitted to hospital for an overnight stay for elective major surgery between January 1, 1995 and December 31, 2009.

“We wanted to restrict our analysis to people who had major surgery,” Dr. Garg said. “Day surgery procedures are much less invasive, and the complication rate there, particularly for acute kidney injury—whether it requires dialysis or not—has not been an important medical concern.” ■

Radiographic CAC Raises Death Risk in HD Patients CORONARY ARTERY and aortic arch

97% were men. A radiologist deter-

calcification are highly prevalent on

mined the presence of CAC and AAC.

chest radiographs of hemodialysis (HD)

Of the 93 patients, 23 (24.7%) had

patients and each is independently and

visible CAC on chest radiographs and

strongly associated with increased mor-

54 (58%) had AAC. During 20 months

tality risk, according to a study.

of follow-up, 26 patients (28%) died.

“Because these images are nearly

CAC was associated with a significant

ubiquitous, inexpensive, and often ob-

two- to threefold increase risk of all-

tained for other indications, they should

cause mortality that was not attenuated

be considered for risk assessment in

after adjusting for standard cardiovas-

hemodialysis patients,” the research-

cular or dialysis-related risk factors or

ers concluded in a paper published

the presence of AAC, the researchers

online ahead of print in the American

reported. AAC was associated with

Journal of Kidney Diseases. Coronary

a sevenfold increased risk in a fully

artery calcification (CAC) and aortic

adjusted model and a sixfold increased

arch calcification (AAC) “should be

risk after adjustment for CAC.

mentioned specifically by radiologists

“To our knowledge, this is the first

in their chest radiographic reports,”

study to show that CAC observed on

they stated.

conventional chest radiography is

The study, led by Joseph A. Abdel-

associated independently with mortality

malek, MD, and Dena E. Rifkin, MD,

in hemodialysis patients,” the investiga-

MS, of the University of California-San

tors wrote.

Diego, included 93 patients receiving

The researchers acknowledge

maintenance HD at the San Diego Vet-

some study limitations, including the

erans Affairs Medical Center. Patients

relatively small patient sample size that

had an average age of 64 years and

consisted mostly of men. ■

www.renalandurologynews.com

NOVEMBER 2012

Renal & Urology News 21

Axitinib, Sorafenib Offer Similar Survival, Data Show

BY JOHN SCHIESZER VIENNA—Axitinib therapy is associated with overall survival (OS) similar to that of sorafenib therapy as second-line treatment of metastatic renal cell carcinoma (mRCC), according to updated findings presented at the European Society for Medical Oncology 2012 Congress. Study investigator Brian Rini, MD, reported updated findings from the phase 3 AXIS trial, which showed that axitinib prolonged progression-free survival compared with sorafenib as second-line therapy for mRCC (median 6.7 vs.

4.7 months).

He presented data on 723 patients with clear cell mRCC who experienced progressive disease after an initial course of systemic therapy. Patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 were stratified by ECOG PS and prior therapy and then enrolled in the study. All patients were randomized to receive axitinib 5 mg twice daily or sorafenib 400 mg twice daily.

Prognostic factors associated with longer OS with second-line therapy included type of prior therapy and ECOG PS = 0, Dr. Rini and colleagues found. Other factors associated with longer OS were elevated hemoglobin levels, the absence of bone metastases, and low corrected calcium levels.

OS in both arms of the study was significantly longer in patients with a DBP of 90 mm Hg or greater compared with a lower DBP (20.7 vs. 12.9 months in the axitinib arm and 20.2 vs.

14.8 months in the sorafenib arm) at the 12-week evaluation, according to the investigators.

“They [the drugs] both have different targets and we need to get a handle on which one may work better in different patient subgroups,” he said.

“We don’t have any biomarkers as yet to predict yet which patients will do better with each agent,” Dr. Rini concluded. ■

She had normal kidney function.

She became critically ill.

She was diagnosed with AKI.

Study compared the two drugs as second-line mRCC treatment.

Dr. Rini and his colleagues analyzed OS as a secondary endpoint based on 425 events. The investigators grouped subjects according to diastolic blood pressure (DBP) on therapy (one or more DBP measurements of 90 mm Hg or higher compared with DBP less than 90 mm Hg).

Results not surprising The median OS was 20.1 months for the axitinib arm and 19.2 months for the sorafenib arm. “It was not surprising that the overall survival was not significantly better, but numerically different,” said Dr. Rini, Professor of Medicine at Cleveland Clinic’s Lerner College of Medicine of Case Western Reserve University.

The investigators studied prior therapy subsets and found that the median OS with axitinib compared to sorafenib with prior cytokine use favored axitinib over sorafenib (29.4 vs. 27.8 months). Among patients previously treated with sunitinib, however, sorafenib was associated with better OS than axitinib (15.2 vs.

16.5 months).

She was treated differently.

AKI and ESRD patients are not the same.

For the first time ever, KDIGO has published a Clinical Practice Guideline that focuses on acute kidney injury (AKI). The Guideline is based on systematic reviews of relevant clinical studies and aims to assist practitioners caring for patients at risk for or with AKI. If you want to optimize outcomes for AKI patients—treat them differently.

Find out how by visiting crrtcounts.com/guideline or go to gambro.com/prismaflex to learn why the Prismaflex® System is the most widely used CRRT device in the world.

Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury.

Kidney International Supplements 2012; Volume 2, Issue 1: 1–126.

22 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Renal Nutrition Update M

etabolic acidosis is a typical concern in renal populations, including renal transplant recipients (RTRs). The role of nutrition on metabolic acidosis has often been studied in different populations with renal insufficiency, but data specifically addressing nutrition and metabolic acidosis in RTR populations have been lacking.

Thus, a group of researchers from the Netherlands recently published an observational study on this topic (Clin J Am Soc Nephrol 2012; published online ahead of print). A cohort of 707 RTRs was recruited for the study. Researchers collected dietary intake data from 625 of these patients. They used a food frequency questionnaire to assess intake, and results related to 177 different food choices were recorded as the number of times a particular defined serving was consumed per day, week, or month. The results were validated by comparing the estimated protein intake with 24-hour urinary urea excretion. The validity was further assessed by analyzing the threeday food records of a subgroup of 60

urinary excretion of ammonia, phosphorus, sulfate, and titratable acid; use of mycophenolate; and serum chloride.

NAE was negatively associated with serum and urine pH and bicarbonate, time since transplantation, and use of azathioprine. After adjustment, NAE, PRAL, and NEAP were all inversely associated with both serum bicarbonate and serum pH. The associations between NAE and serum pH and bicarbonate were significant regardless of whether the patients exhibited metabolic acidosis. NAE was also negatively associated with cholesterol and serum phosphate. NAE was positively associated with cheese intake and negatively associated with fruit intake. Regarding specific nutrients, NAE was positively associated with total protein, animal protein, phosphorus, and calcium.

Dietary choices and acid-base balance Although these results are observational, there appears to be a strong correlation between the dietary choices that RTRs make and overall acid-base balance. This association has been found in the general

For kidney transplant patients, protein intake for stable patients should follow general guidelines of approximately 0.8 g/kg body weight. patients. Dietary acid load was assessed using two formulas, the potential renal acid load (PRAL) and the estimated net endogenous acid production (NEAP).

Net acid excretion In all, 31% of the patients exhibited metabolic acidosis, and nearly half had a pH less than 7.35. The mean net acid excretion (NAE) was 40.7 mEq/ day (range 22.2 – 60.0 mEq/d) and was positively associated with eGFR;

On The Web

population as well as CKD populations, and prior studies have indicated that reducing dietary load can provide positive benefits for long-term kidney health.

The authors of the paper noted that, based on their models, consuming 100 g (3.5 oz) of vegetables and 100 g (3.5 oz) of fruit while eliminating 50 g of meat (1.8 oz) and 20 g of cheese (0.7 oz) could reduce NAE by 15 mEq/day, resulting in a serum bicarbonate increase of 0.5 mmol/L. This change could theo-

© THINKSTCOK

New findings suggest a link between dietary choices by renal transplant recipients and overall acid-base balance BY GRISSIM CLARK CONNERY, MS, RD, LD

Higher intake of fruits and vegetables may help reduce metabolic acidosis risk.

retically lead to a 5% reduction in the metabolic acidosis prevalence. For RTRs, protein intake for stable patients should follow general guidelines of approximately 0.8 g/kg body weight.

The first and third tertile ranges for estimated glomerular filtration rate (eGFR) in this study were 48 and 56 mL/min/1.73 m2, respectively. Thus, many of these patients would benefit from avoiding excessive animal protein intake, especially from cheese sources, to ensure prolonged kidney function.

(Note: If graft rejection occurs, a protein intake of 1.4 g/kg body weight/day is recommended, similar to that within four weeks post-transplant). Of note, dairy products typically have high phosphorus content, which, in addition to contributing an acidotic effect, may be a risk for cardiovascular health should serum phosphorus be elevated.

Increased intake of fruits and vegetables can be of benefit in helping reduce metabolic acidosis. This effect is typically achieved through the intake of alkaline salts such as citrate. These salts are often

bound with electrolytes such as potassium, calcium, and magnesium. Meanwhile, the contributions of phosphate salts and sulfur-containing amino acids often contribute to an acidotic effect in the body.

Elevated potassium levels For some CKD patients, potassium levels may be elevated and thus a restriction on high potassium items like fruit and vegetables may be necessary. This restriction may also reduce the potential intake of alkalinizing anions like citrate and potentially increase the risks for acidosis. As noted, the eGFR’s for the RTRs in this cohort ranged from 48-56.

Patients with this level of renal function will not often have trouble with high potassium levels. Consequently, this population most likely will be able to safely consume higher intakes of fruits and vegetables to help reduce the risks of metabolic acidosis. ■ Mr. Connery is Research Coordinator at Case Western Reserve University in Cleveland.

We’ve got more on our website highlighting effective diets for delaying CKD progression and for helping patients manage sodium and phosphorus intake. See us at www.renalandurologynews.com/nutrition.

A N E W I N D I C AT IO N

COMING SOON Please see adjacent pages for current indication, Important Safety Information, and brief summary of full Prescribing Information.

Janssen Biotech, Inc. Š Janssen Biotech, Inc. 2012 8/12 08Z12244A

10851ALT_653737_ZYT_King_v1 1

9/12/12 11:02 AM

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) 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 hypertension, hypokalemia, and 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 because these patients were excluded from the randomized clinical trial. 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 has been reported in clinical trials 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—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. 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.

Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.

08Z11121R3

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

www.zytiga.com Please see brief summary of full Prescribing Information on the following pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 8/12 08Z12244A

10851ALT_653737_ZYT_King_v1 4

9/12/12 11:02 AM

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castrationresistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. 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, the patient should be apprised of the potential hazard to the fetus.

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. 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. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. 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: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA 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 ZYTIGA. 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: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. 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 ZYTIGA 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 ZYTIGA 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 ZYTIGA 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.

Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions].

Adrenocortical insufficiency [see Warnings and Precautions].

Hepatotoxicity [see Warnings and Precautions].

Food effect [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.

In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months.

The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA).

Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions].

Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities).

Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Prednisone (N=791) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % Musculoskeletal and connective tissue disorders 29.5 4.2 Joint swelling/discomfort2 26.2 3.0 Muscle discomfort3 General disorders 4 26.7 1.9 Edema Vascular disorders Hot flush 19.0 0.3 Hypertension 8.5 1.3 Gastrointestinal disorders Diarrhea 17.6 0.6 Dyspepsia 6.1 0 Infections and infestations Urinary tract infection 11.5 2.1 Upper respiratory tract infection 5.4 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 Nocturia 6.2 0 Injury, poisoning and procedural complications 5.9 1.4 Fractures5 Cardiac disorders Arrhythmia6 7.2 1.1 Chest pain or chest discomfort 7 3.8 0.5 8 Cardiac failure 2.3 1.9 1 2 3

Placebo with Prednisone (N=394) All Grades Grade 3-4 % % 23.4 23.1

4.1 2.3

18.3

0.8

16.8 6.9

0.3 0.3

13.5 3.3

1.3 0

7.1 2.5

0.5 0

7.6

0

5.1 4.1

0.3 0

2.3

0

4.6 2.8 1.0

1.0 0 0.3

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

10851ALT_653737_ZYT_King_v1 2

ZYTIGA® (abiraterone acetate) Tablets 4 5 6

Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture 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 Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms.

Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations.

In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated.

Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%).

Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebocontrolled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 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 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. 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 vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8.

Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo.

Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA 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, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. 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: ZYTIGA is not indicated in children.

Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients.

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 ZYTIGA 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.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily.

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].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. 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: There have been no reports of overdose of ZYTIGA during clinical studies. 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 to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA 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].

Manufactured by: Patheon Inc. Mississauga, Canada

Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044

© Janssen Biotech, Inc. 2012

Revised: July 2012

08Z12237B

9/12/12 11:02 AM

26 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Metabolic Syndrome Raises CKD Risk Longitudinal study shows that it increases the likelihood of chronic kidney disease by 42%.

METABOLIC SYNDROME increases a person’s risk for chronic kidney disease (CKD), according to a longitudinal study of Chinese individuals.

In a nationally representative sample of 4,248 Chinese adults in Taiwan, 637 individuals (15%) had metabolic syndrome at baseline. During a median follow-up of 5.4 years, CKD developed in 208 subjects (4.9%). After adjusting for multiple variables, participants with metabolic syndrome had a 42% increased risk for CKD compared with subjects who did not have the syndrome, the investigators reported in Nephrology (2012;17:532-538).

Furthermore, the researchers, led by Chien-An Sun, MD, of Fu-Jen Catholic University in New Taipei, found that as the number of metabolic syndrome components increased, so did CKD risk. The presence of elevated blood pressure or elevated fasting plasma glucose, both components of metabolic syndrome, were associated with a 48%

and 33% increased CKD risk, respectively, compared with the absence of these components.

Big Kidneys Increase RCC Death Risk

are uncommon, the authors used a case-cohort design to compare 144 pT1 RCC patients who were alive or died from other causes (mean followup 12.2 years) to 47 similar patients who died from RCC (mean follow-up of 6.3 years).

Based on data from prostate cancer research showing that a larger prostate volume is associated with a lower risk of biochemical recurrence, the researchers had hypothesized that a larger kidney size might offer better survival for patients with pT1 RCC. Their results showed the opposite, however. “One explanation could be that those patients with larger kidneys also have larger tumors, and it is well accepted that a larger tumor size is a strong predictor of a poor outcome,” they wrote. The authors underscored, however, that the fact that the association remains after adjustment for tumor size casts some doubt on this potential explanation.

Regarding study limitations, Dr. Parker’s group pointed out their study population consisted only of patients with pT1 organ-confined clearcell RCC. Consequently, they did not have information on whether kidney size has a similar association with an increased risk of RCC death among patients with larger tumors or other RCC subtypes. ■

AMONG PATIENTS with early stage (pT1) renal cell carcinoma (RCC), a larger kidney size is associated with an increased the risk of dying from the malignancy, new data show.

In a study of 191 patients with pT1 RCC who underwent radical nephrectomy, investigators at Mayo Clinic reported that each 1-cm increment in kidney size (i.e., largest measured dimension) was associated with an 18% increased risk of RCC-related death, even after adjusting for well-known prognostic variables such as tumor size, nuclear grade, and the presence of necrosis, according to a report in Urology (2012;80:147-150).

In addition, after multivariable adjustment, pT1 RCC patients with a kidney size of 12 cm or greater had a significant 95% increased risk of death from RCC compared with those patients with a kidney size less than 12 cm, the researchers, led by Alexander S. Parker, PhD, of Mayo Clinic Florida in Jacksonville, found. Given that deaths among patients with pT1 RCC

BMI an important factor Additionally, the association between metabolic syndrome and CKD risk was stronger in subjects with a body mass index (BMI) greater than 27.5 kg/m2 than in those with a lower BMI. Among individuals with a BMI greater than 27.5, the presence of metabolic syndrome was associated with a 2.2 times increased risk of CKD compared with the absence of the syndrome, in adjusted analyses. By comparison, among participants with a BMI below 22.6 and from 22.6-27.5, the presence of metabolic syndrome was associated with a 14% and 3% increased risk of CKD, respectively, compared with the absence of the syndrome.

Prior findings corroborated The new findings are consistent with those of previous epidemiologic stud-

The CKD-Metabolic Syndrome Link Compared with their absence, the presence of metabolic syndrome and two of its components—elevated blood pressure and elevated fasting plasma glucose—are significantly associated with an increased risk of chronic kidney disease (CKD) in adjusted analyses, a study found. The magnitude of increased CKD risk is shown here.

50 40 30 20 10 0

42% Metabolic syndrome

48% Elevated BP

33% Elevated fasting plasma glucose

Source: Yang T, Chu CH, HSU CH, et al. Impact of metabolic syndrome on the incidence of chronic kidney disease: A Chinese cohort study. Nephrology 2012;17:532-538.

ies. For example, in a study of 6,217 participants in the Third National Health and Nutrition Examination Survey, researchers at Tulane University in New Orleans found that subjects with metabolic syndrome had a 2.6 times increased risk of CKD compared with those who did not have the syn-

drome, according to a report in Annals of Internal Medicine (2004;140:167174). In addition, compared with individuals with no or one component of metabolic syndrome, those with two, three, four, and five components had a 2.2, 3.4, 4.2, and 5.8 times increased risk of CKD, respectively. ■

CVD Tied to Reduced Kidney Function in Transplant Patients LOWER KIDNEY function is independent-

Reduced eGFR is independently asso-

ly associated with an increased risk of

ciated with CVD events and mortality in

cardiovascular disease (CVD) and death

the general population, the researchers

in stable kidney transplant recipients,

noted. “Finding a similar relationship in

according to investigators.

kidney transplant recipients as in the

At an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 2

general population suggests a possible direct effect of reduced GFR, since the

m2, each 5 mL/min/1.73 m incre-

transplanted kidney is likely to not have

ment in eGFR is associated with a

had a long exposure to traditional and

15% decreased risk of both CVD and

nontraditional CVD risk factors,” the

death, researchers reported online in

authors stated.

the American Journal of Transplanta-

Dr. Weiner and his colleagues con-

tion. The investigators, led by Daniel

ducted a post-hoc analysis of data from

E. Weiner, MD, of Tufts Medical Center

4,016 participants in the Folic Acid

in Boston, observed no association

for Vascular Outcome Reduction in

between eGFR and outcomes at eGFR

Transplantation (FAVORIT) trial—which

levels above 45.

included patients who received a kidney

“The presence of an association be-

transplant at least six months before

tween low eGFR and cardiovascular dis-

enrollment. Over a median of 3.8 years,

ease in transplant recipients suggests

527 CVD events occurred in the 3,676

that comorbid conditions associated

subjects who had complete data.

with low GFR itself rather than concur-

The authors noted that the study has

rent comorbidities that result in both low

some weaknesses, including a lack of

eGFR as well as systemic cardiovascular

data on albuminuria and it had only a

disease may be impacting cardiovascu-

single assessment of serum creatinine

lar risk,” the investigators wrote.

for eGFR determination. ■

www.renalandurologynews.com

NOVEMBER 2012

Renal & Urology News 27

UI Surgery Rates Rise Years after RP & QA

Long-term quality of life for men who have undergone radical prostatectomy (RP) is inextricably tied to urinary

incontinence (UI) issues. Robert K. Nam, MD, MSc, and colleagues helped shed light on the impact of this side effect by studying rates of UI-corrective surgery occurring up to 15 years following RP.

it could be 50. The bottom line is, it’s a high-volume surgeon. In our study, the average number of radical prostatectomy surgeries performed per surgeon was 30 per year, and the median was 21.

How can urologic surgeons get to that high-volume mark?

Dr. Nam: Subspecialty training, which is one way of moving toward being a high-volume surgeon.

Dr. Nam, head of genitourinary cancer care and an

Have your findings affected your opinion of RP?

associate scientist at Sunnybrook Health Sciences

Dr. Nam: The results haven’t significantly altered how I counsel my patients. I think the outcome of our study allows me to give patients more information, but it hasn’t changed my outlook on the success and long-term benefits of surgery.

Centre in Toronto, told Renal & Urology News about the biggest eye-openers for him among his team’s results (Urology 2012;188:502-506).

Dr. Nam: Yes and no. Yes, in that we were surprised the rate of UI surgery almost doubled from 2.6% at five years to 4.8% at 15 years. I thought the rate would be constant over the years.

But the observation that the rate went up actually is not surprising, if you think about it further. It just goes to the issue of cancer survivorship and that as patients live longer from their cancer treatment, they will be subjected to the normal diseases of aging. As they age and develop overactive bladder, their ability to handle these conditions is reduced because they’ve had prostate surgery.

Did you evaluate varying age groups?

Dr. Nam: Age was definitely a factor.

The older you were, the more likely you were going to get a urinary-sphincter procedure. And that was shown in our study as well.

What do you think might or should change in how men are counseled about this side effect?

Dr. Nam: Our findings provide additional information so that men can make a more informed decision as to whether

On The Web

prostate surgery is right for them. They also demonstrate that it’s the younger patients who will benefit from surgery the most in terms of the side-effect profile, so this indicates that maybe older patients shouldn’t opt for surgery as much as younger patients should.

Where does robotic prostatectomy fit into this picture?

Dr. Nam: We excluded those patients because robotic surgery wasn’t adopted as quickly in Ontario as it was in the U.S., so we had insufficient numbers to make any conclusions.

What do you think will lower the long-term rate of UI surgery for men treated for prostate cancer?

Dr. Nam: There are host factors that you can’t change, such as patient age and level of comorbidity. And you can’t really control whether a patient will need radiation therapy; that is disease-dependent.

What you can control, though, is surgeon volume. Surgeons who performed the highest volume of radical prostatectomy per year—that was 49 or more in our study—had the lowest rates of patients requiring sphincter surgery. The rates of urinary sphincter surgery were half of those surgeons who had the lowest volume of radical prostatectomy surgeries.

How was the “49” calculated?

Dr. Nam: It’s a number derived from a quintile breakdown of the distribution of our surgical volume. It’s the top fifth percentile of volume. So 49 is not a magic number—it just emphasizes the point that the surgeon has to have done a high number of operations. It could be 45;

Dr. Nam: No, and that’s another thing: this study is only a starting point. It’s quantifying the impact of survivorship among patients who get treated for prostate cancer. This area is largely unknown. For example, we don’t know how many patients can’t work because of the severity of their incontinence.

Can the incontinence be that bad?

Dr. Nam: It can be that bad. Just think of it: The patients our study describes are so bad that they’re willing to subject themselves to a secondary operation to have their incontinence fixed. So, that’s just the tip of the iceberg. There are less severe and there are more severe cases, and we need to quantify this so at least we can go to the government and say, “Look, we need this area funded.

Patients need help to manage how they survive after being treated for prostate cancer.” It just opens up a huge avenue of how we can really go about quantifying this. We really need to be able to better describe it.

How do patients usually fare after the follow-up UI procedure?

Dr. Nam: There’s an improvement in quality of life, but there are risks as well.

MEDIASOURCE / DOUG NICHOLSON

Were you surprised by your team’s research findings that 5% of RP patients are expected to undergo surgery for UI within 15 years of prostatectomy?

Regarding artificial urinary sphincter insertion and urethral sling placement, did you find one procedure to be superior?

Younger patients will benefit the most from surgery [for UI].

—Robert K. Nam, MD, MSc

Can anything be done during the prostatectomy, such as a urethral procedure, to reduce the secondary UI procedure rate?

Dr. Nam: That, unfortunately, we couldn’t conclude from the study. There are lots of opinions about what could be done, but I don’t think any of these ideas would be evidence-based.

Will you be continuing your research in this area?

Dr. Nam: Well, the next question concerns patients who get radiation treatment rather than prostatectomy. We’ll look at what their problems have been in terms of urinary control and other factors? So, our next study will compare the complication rates of men who get treated with any form of radiation compared with this exact same group. ■

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

28 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Cherries May Decrease the Risk of Gout Attacks

BY JODY A. CHARNOW GOUT PATIENTS who eat cherries may lower their risk of gout attacks, new findings suggest.

In a study of 633 gout patients, researchers led by Yuqing Zhang, DSc, of Boston University, found that any consumption of cherries in the previous two days lowered the risk of a gout attack by 35% compared with not eating cherries, after adjusting for potential confounding factors, according to a report in Arthritis & Rheumatism.

The researchers adjusted for purine intake and use of alcohol, diuretics, allopurinol, colchicines, and nonsteroidal anti-inflammatory drugs.

The investigators also observed that the greater cherry consumption generally was associated with increased risk reduction. Compared with nonconsumption, eating one, two, three, or four or more servings of cherries in the previous two days was associ-

Dr. Zhang and his colleagues said that to the best of their knowledge, no previous study has assessed whether cherry consumption decreases the risk of gout attacks.

“The results of this study are in general good news,” said gout specialist Anthony J. Bleyer, MD, Professor

Any consumption in the previous two days lowered the risk by 35%. ated with a 2%, 48%, 61%, and 38% decreased risk, respectively. The researchers defined a serving of cherries as one half cup of the fruit (about 10-12 cherries).

Dr. Zhang’s team looked separately at consumption of cherry extract.

Compared with non-consumption, consumption of any amount of extract in the previous two days was associated with a 45% decreased risk of gout attacks.

Furthermore, the study showed that cherry intake combined with allopurinol use decreased the risk of gout attacks by 75% compared with not eating cherries and taking allopurinol.

The researchers concluded that that if their findings are confirmed by randomized clinical trials, “cherry products could provide a novel nonpharmacological preventive option against gout attacks.”

Small experimental studies in healthy human subjects and animals have shown that cherry consumption reduces serum uric acid levels, the authors noted. Other studies have demonstrated that cherry products contain high levels of anthocyanins that possess anti-inflammatory and antioxidant properties.

3744_takpeg_fa2_run_2pg.indd 1

of Internal Medicine-Nephrology at Wake Forest School of Medicine in Winston-Salem, N.C. “Many patients desire natural remedies for their ailments, and physicians are trying to shift their patients’ dietary intake to healthy foods such as fruits. While still not proven, why not eat a few cherries

and potentially decrease the risk of gout? If cherry pie decreases the risk of gout, this will be even better news.”

A previous study by Robert A. Jacob, MD, and colleagues (J Nutr 2003;133:18261829) found that healthy women who consumed cherries experienced a decrease in plasma urate concentrations, which

www.renalandurologynews.com

Dr. Bleyer said suggests an effect of cherries on the renal tubular transport of urate. “While increased urate excretion may have contributed to a decreased risk of gout in the current study, another possibility is that cherries or cherry juice extract have an anti-inflammatory effect that decreases gout attacks,” Dr. Bleyer

told Renal & Urology News. The new study will likely lead to additional studies that will more definitively prove the value of cherries in preventing gout, Dr. Bleyer said.

“But what should we do now with these findings? Fortunately, cherries are in general considered to be a healthy

NOVEMBER 2012

food choice,” he observed. “For our patients with kidney disease, we are frequently concerned with potassium intake.

Cherries are reported to have a moderate amount of potassium, with about 10 cherries containing between 150 and 250 mg. They are also seasonal and expensive when consumed out of season,

Reducing the burden of

ESA administration Consider the first once-monthly, non-EPO ESA offering less-frequent dose administration.

INDICATION AND LIMITATIONS OF USE OMONTYS® (peginesatide) Injection is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis.

OMONTYS is not indicated and is not recommended for use in patients with CKD D not on dialysis, in patients receiving treatment for cancer and whose anemia is not due to CKD, or as a substitute for red blood cell (RBC) transfusions in patients who require immediate correc ction of anemia. OMONTYS has not been shown to improve sympto oms, physical functioning, or health-related quality of life.

• In controlled clinical trials of ESAs in patients with cancer,

IMPORTANT SAFETY INFORMATION

Increased mortality and/or increased risk of tumor progression or recurrence in patients with cancer: The safety and efficacy of OMONTYS have not been established for use in patients with anemia due to cancer chemotherapy. OMONTYS is not indicated in patients with cancer receiving chemotherapy.

Hypertension: OMONTYS is contraindicated in patients with uncontrolled hypertension. Appropriately control hypertension prior to initiation of and during treatment with OMONTYS. Reduce or withhold OMONTYS if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.

Lack or loss of response to OMONTYS: For lack or loss of hemoglobin response to OMONTYS, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for antibodies to peginesatide.

Dialysis management: Patients receiving OMONTYS may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

Laboratory monitoring: Evaluate transferrin saturation and serum ferritin prior to and during OMONTYS treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%.

WARNING: ESA As INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMB BOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR T PROGRESSION OR RECURRENCE. Chronic Kidneyy Disease: • In controlledd trials, patients experienced greater risks for death, se erious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAss) to target a hemoglobin level of greater than 11 g/dL. • No trial has iddentified a hemoglobin target level, ESA dose, or dosing stra ategy that does not increase these risks.

• Use the loweest OMONTYS dose sufficient to reduce the need for red blood cell (RBC) transfusions.

Contraindications OMONTYS is contraindicated in patients with uncontrolled hype ertension.

Warnings and Precautions Increased mortalitty, myocardial infarction, stroke, and thromboemboolism: • Using ESAs to target t a hemoglobin level of greater than 11 g/dL increases the riisk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patie ents with coexistent cardiovascular disease and stroke. Patientss with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients.

A rate of hemog globin rise of >1 g/dL over 2 weeks may contribute to th hese risks

•

•

increased risk for death and serious adverse cardiovascular reactions was observed. These adverse reactions included myocardial infarction and stroke In controlled clinical trials of ESAs, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and deep venous thrombosis (DVT) in patients undergoing orthopedic procedures In 2 trials of OMONTYS, patients with CKD not on dialysis experienced increased specific cardiovascular events

Adverse reactions The most common adverse reactions in clinical studies in patients with CKD on dialysis treated with OMONTYS were dyspnea, diarrhea, nausea, cough, and arteriovenous fistula site complication.

Please see accompanying Brief Summary.

Reference: Schiller B, Doss S, De Cock E, Del Aguila MA, Nissenson AR. Costs of managing anemia with erythropoiesis-stimulating agents during hemodialysis: a time and motion study. Hemodial Int.t 2008;12(4):441-449.

03-12-00191-A.; DSG-00261. © 2012 Affymax, Inc. and Takeda Pharmaceuticals America, Inc. All rights reserved. Affymax, the Affymax logo, OMONTYS, and the OMONTYS logo are trademarks of Affymax, Inc. and/or its subsidiaries. Takeda and the Takeda logo are trademarks of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.

9/24/12 3:23 PM

Renal & Urology News 29

making their use likely sporadic. Cherry extract is more of a problem, as these products are largely unregulated, and whether all extracts provide benefit has not been determined. In addition, patients with chronic kidney disease will have to pay attention to the potassium content of these extracts.” ■

30 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Data Support Intermittent ADT for Metastatic PCa INTERMITTENT androgen deprivation therapy (ADT) may be as safe as continuous ADT in the treatment of metastatic prostate cancer (PCa).

In a study of 383 men with metastatic PCa, Nicolas Mottet, MD, of the Clinique Mutualiste de la Loire, Saint-Etienne,

France, and colleagues observed no statistical difference in either overall or progression-free survival between the two treatment strategies, according to an online report in BJU International. They concluded that intermittent ADT “could be an option in highly responding and

well-informed metastatic patients even if no clear benefit in health-related quality of life was shown.” Dr. Mottet’s team added that intermittent ADT may be of interest to patients with metastatic PCa who experience significant treatment-induced side effects. Of the 383 patients, 173 had a

PSA level below 4 ng/mL after six months of induction of ADT. Subjects were randomized to receive either continuous or intermittent ADT. Median overall survival was 52 and 42 months, respectively, and median progression-free survival was 15.1 and 20.7 months, respectively. ■

Table 2 Adverse Cardiovascular Outcomes in Randomized Controlled Trials Comparing Higher and Lower Hemoglobin Targets in Patients with CKD ®

Brief Summary of Prescribing Information for: OMONTYS (peginesatide) Injection for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE. See full prescribing information for complete boxed warning.

Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks [see Warnings and Precautions]. s • Use the lowest OMONTYS dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions]. s INDICATIONS AND USAGE Anemia Due to Chronic Kidney Disease OMONTYS is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis.

Limitations of Use OMONTYS is not indicated and is not recommended for use: • In patients with CKD not on dialysis because of safety concerns in this population [see Warnings and Precautions].

• In patients receiving treatment for cancer and whose anemia is not due to CKD, because ESAs have shown harm in some settings and the benefit-risk factors for OMONTYS in this setting have not been evaluated [see Warnings and Precautions].

• As a substitute for RBC transfusions in patients who require immediate correction of anemia.

• OMONTYS has not been shown to improve symptoms, physical functioning or health-related quality of life.

CONTRAINDICATIONS OMONTYS is contraindicated in patients with: • Uncontrolled hypertension [see Warnings and Precautions].

WARNINGS AND PRECAUTIONS Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism • In controlled clinical trials of other ESAs in patients with CKD comparing higher hemoglobin targets (13 – 14 g/dL) to lower targets (9 - 11.3 g/dL) (see Table 2), increased risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events was observed in the higher target groups.

• Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.

• In controlled clinical trials of ESAs in patients with cancer, increased risk for death and serious adverse cardiovascular reactions was observed. These adverse reactions included myocardial infarction and stroke.

• In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and deep venous thrombosis (DVT) was observed in patients undergoing orthopedic procedures.

The design and overall results of 3 large trials comparing higher and lower hemoglobin targets are shown in Table 2 (Normal Hematocrit Study (NHS), Correction of Hemoglobin Outcomes in Renal Insufficiency (CHOIR) and Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT)).

3744_takpeg_fa1_run_2pg.indd 3

NHS (N = 1265) 1993 to 1996

CHOIR (N = 1432) Time Period of Trial 2003 to 2006 Patients with CKD Patients with CKD not on dialysis with on hemodialysis hemoglobin with coexisting CHF < 11 g/dL Population or CAD, hematocrit not previously 30 ± 3% on administered epoetin alfa epoetin alfa Hemoglobin Target; 14.0 vs. 10.0 13.5 vs. 11.3 Higher vs. Lower (g/dL) 12.6 (11.6, 13.3) 13.0 (12.2, 13.4) Median (Q1, Q3) vs. vs.

Achieved Hemoglobin 10.3 (10.0, 10.7) 11.4 (11.1, 11.6) level (g/dL) Primary Endpoint

TREAT (N = 4038) 2004 to 2009 Patients with CKD not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL 13.0 vs. ≥ 9.0

12.5 (12.0, 12.8) vs.

10.6 (9.9, 11.3) All-cause mortality, All-cause mortality, MI, myocardial All-cause mortality MI, hospitalization or non-fatal MI ischemia, heart for CHF, or stroke failure, and stroke

Hazard Ratio or 1.28 (1.06 – 1.56) 1.34 (1.03 – 1.74) 1.05 (0.94 – 1.17) Relative Risk (95% CI) Adverse Outcome for All-cause mortality All-cause mortality Stroke Higher Target Group Hazard Ratio or 1.27 (1.04 – 1.54) 1.48 (0.97 – 2.27) 1.92 (1.38 – 2.68) Relative Risk (95% CI) Patients with Chronic Kidneyy Disease Not on Dialysis y OMONTYS is not indicated and is not recommended for the treatment of anemia in patients with CKD who are not on dialysis.

A higher percentage of patients (22%) who received OMONTYS experienced a composite cardiovascular safety endpoint event compared to 17% who received darbepoetin alfa in two randomized, active-controlled, open-label, multi-center trials of 983 patients with anemia due to CKD who were not on dialysis. The trials had a pre-specified, prospective analysis of a composite safety endpoint consisting of death, myocardial infarction, stroke, or serious adverse events of congestive heart failure, unstable angina or arrhythmia (hazard ratio 1.32, 95% CI: 0.97, 1.81).

Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer receiving ESAs OMONTYS is not indicated and is not recommended for reduction of RBC transfusions in patients receiving treatment for cancer and whose anemia is not due to CKD because ESAs have shown harm in some settings and the benefit-risk factors for OMONTYS in this setting have not been evaluated.

The safety and efficacy of OMONTYS have not been established for use in patients with anemia due to cancer chemotherapy. Results from clinical trials of ESAs in patients with anemia due to cancer therapy showed decreased locoregional control, progression-free survival and/or decreased overall survival. The findings were observed in clinical trials of other ESAs administered to patients with: breast cancer receiving chemotherapy, advanced head and neck cancer receiving radiation therapy, lymphoid malignancy, cervical cancer, non-small cell lung cancer, and with various malignancies who were not receiving chemotherapy or radiotherapy.

Hypertension OMONTYS is contraindicated in patients with uncontrolled hypertension.

Appropriately control hypertension prior to initiation of and during treatment with OMONTYS. Reduce or withhold OMONTYS if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.

Lack or Loss of Response to OMONTYS For lack or loss of hemoglobin response to OMONTYS, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate the patient for the presence of antibodies to peginesatide. In the absence of antibodies to peginesatide, follow dosing recommendations for management of patients with an insufficient hemoglobin response to OMONTYS therapy.

Contact Affymax, Inc. (1-855-466-6689) to perform assays for binding and neutralizing antibodies.

Dialysis Management Patients may require adjustments in their dialysis prescriptions after initiation of OMONTYS. Patients receiving OMONTYS may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

Laboratory Monitoring Evaluate transferrin saturation and serum ferritin prior to and during OMONTYS treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course

9/14/12 2:49 PM

www.renalandurologynews.com

NOVEMBER 2012

Renal & Urology News 31

Calcified Peyronie’s Plaques May Predict Surgery CHICAGO—Men with severe calcified Peyronie’s disease (PD) plaques are more likely to progress to surgical treatment than men with non-calcified plaques, researchers reported at the World Meeting on Sexual Medicine.

Laurence Levine, MD, and James Rybak, MD, and colleagues at Rush

University Medical Center in Chicago reviewed data from 792 men presenting with PD from 1993 to 2009 and identified 98 who had have PD plaque calcification detected by ultrasound.

A urologist evaluated the degree of calcification, grading the calcification as follows: grade 1 (less than 0.3 cm

of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin every 2 weeks until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin should be monitored at least monthly provided hemoglobin levels remain stable.

ADVERSE REACTIONS The following serious adverse reactions observed during clinical trials with OMONTYS are discussed in greater detail in other sections of the labeling: • Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions] • Hypertension [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of OMONTYS cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

Patients with Chronic Kidneyy Disease Adverse reactions were determined based on pooled data from two active controlled studies of 1066 dialysis patients treated with OMONTYS and 542 treated with epoetin, including 938 exposed for at least 6 months and 825 exposed for greater than one year to OMONTYS. The population for OMONTYS was 20 to 93 years of age, 58.5% male, and the percentages of Caucasian, Black (including African Americans), and Asian patients were 57.9%, 37.4%, and 3.1%, respectively. The median weight adjusted dose of OMONTYS was 0.07mg/kg and 113 U/week/kg of epoetin.

Table 3 summarizes the most frequent adverse reactions (≥ 10%) in dialysis patients treated with OMONTYS. Table 3 Adverse Reactions Occurring in ≥10% of Dialysis Patients treated with OMONTYS Adverse Reactions

Dialysis Patients Treated with OMONTYS (N = 1066)

Gastrointestinal Disorders Diarrhea 18.4% Nausea 17.4% Vomiting 15.3% Respiratory, Thoracic and Mediastinal Disorders Dyspnea 18.4% Cough 15.9% Injury, Poisoning and Procedural Complications Arteriovenous Fistula 16.1% Site Complication Procedural Hypotension 10.9% Nervous System Disorders Headache 15.4% Musculoskeletal and Connective Tissue Disorders Muscle Spasms 15.3% Pain in Extremity 10.9% Back Pain 10.9% Arthralgia 10.7% Vascular Disorders Hypotension 14.2% Hypertension 13.2% General Disorders and Administration Site Conditions Pyrexia 12.2% Metabolism and Nutrition Disorders Hyperkalemia 11.4% Infections and Infestations Upper Respiratory Tract Infection 11.0%

Dialysis Patients Treated with Epoetin (N = 542) 15.9% 19.6% 13.3% 19.4% 16.6% 16.6% 12.5% 15.9% 17.2% 12.7% 11.3% 9.8% 14.6% 11.4%

binding antibodies in patients dosed subcutaneously (1.9%) as compared to those dosed intravenously (0.7%). Peginesatide neutralizing antibodies were detected in vitroo using a cell-based functional assay in 21 of these patients (0.9%). In approximately half of all antibody-positive patients, the presence of antibodies was associated with declining hemoglobin levels, the requirement for increased doses of OMONTYS to maintain hemoglobin levels, and/or transfusion for anemia of CKD. No cases of pure red cell aplasia (PRCA) developed in patients receiving OMONTYS during clinical trials.

DRUG INTERACTIONS No formal drug/drug interaction studies have been performed. Peginesatide does not bind to serum albumin or lipoproteins as demonstrated in in vitroo protein binding studies in rat, monkey and human sera. In vitro o studies conducted with human hepatocytes or microsomes have shown no potential for peginesatide to induce or inhibit CYP450 enzymes.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women.

Peginesatide was teratogenic and caused embryofetal lethality when administered to pregnant animals at doses and/or exposures that resulted in polycythemia. OMONTYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Administration of peginesatide by intravenous injection to rats and rabbits during organogenesis was associated with embryofetal toxicity and malformations.

Dosing was every third day in rats for a total of 5 doses and every fifth day in rabbits for a total of 3 doses (0.01 to 50 mg/kg/dose). In rats and rabbits, adverse embryofetal effects included reduced fetal weight, increased resorption, embryofetal lethality, cleft palate (rats only), sternum anomalies, unossification of sternebrae and metatarsals, and reduced ossification of some bones.

Embryofetal toxicity was evident in rats at peginesatide doses of ≥ 1 mg/kg and the malformations (cleft palate and sternoschisis, and variations in blood vessels) were mostly evident at doses of ≥ 10 mg/kg. The dose of 1 mg/kg results in exposures (AUC) comparable to those in humans after intravenous administration at a dose of 0.35 mg/kg in patients on dialysis. In a separate embryofetal developmental study in rats, reduced fetal weight and reduced ossification were seen at a lower dose of 0.25 mg/kg. Reduced fetal weight and delayed ossification in rabbits were observed at ≥ 0.5 mg/kg/dose of peginesatide. In a separate embryofetal developmental study in rabbits, adverse findings were observed at lower doses and included increased incidence of fused sternebrae at 0.25 mg/kg. The effects in rabbits were observed at doses lower (5% - 50%) than the dose of 0.35 mg/kg in patients.

Nursing Mothers It is not known whether peginesatide is excreted in human milk. Because many drugs are excreted into human milk, caution should be exercised when OMONTYS is administered to a nursing woman.

Pediatric Use The safety and efficacy of OMONTYS in pediatric patients have not been established.

Geriatric Use Of the total number of dialysis patients in Phase 3 clinical studies of OMONTYS, 32.5% were age 65 and over, while 13% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

OVERDOSAGE OMONTYS overdosage can elevate hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of OMONTYS dosage and/or with phlebotomy, as clinically indicated. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

14.0%

Marketed by: Affymax, Inc. Palo Alto, CA 94304

11.8%

Distributed and Marketed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015

12.4%

Seizures have occurred in patients participating in OMONTYS clinical studies. During the first several months following initiation of OMONTYS, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely.

Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency.

Allergic reactions have been reported in patients treated with OMONTYS. Discontinue OMONTYS and administer appropriate therapy if a serious allergic, anaphylactic or infusion-related reaction occurs.

Immunogenicity Of the 2357 patients tested, 29 (1.2%) had detectable levels of peginesatidespecific binding antibodies. There was a higher incidence of peginesatide-specific

3744_takpeg_fa1_run_2pg.indd 4

thick), grade 2 (greater than 0.3 cm but less than 1.5 cm thick), and grade 3 (greater than 1.5 cm wide or the presence of two or plaques more than 1.0 cm thick). These men were compared with a control group of 236 PD patients with non-calcified plaques; controls were matched for age, disease duration,

For more detailed information, see the full prescribing information for OMONTYS at www.omontys.com or contact Takeda Pharmaceuticals America, Inc. OMONTYS is a trademark of Affymax, Inc. registered in the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. All other trademarks are the property of their respective owners. ©2012 Takeda Pharmaceuticals America, Inc. March 2012 PEG096 R1 L-DSG-0312-4

9/14/12 2:49 PM

date of presentation, and mean curvature.

In the calcified plaque group, 23% of patients with grade 1, 32% of those with grade 2, and 55% of men with grade 3 calcification progressed to surgery. In the matched control group, 34% progressed to surgery. Men with grade 3 calcification had greater than twofold increased likelihood of electing surgical intervention for PD compared with controls. Calcification by itself was not a significant predictor of progression to surgery. ■

Statement of Ownership, Management and Circulation 1. Publication Title: Renal & Urology News 2. Publication Number: 022-226 3. Filing Date: Sept. 30, 2012 4. Issue Frequency: Monthly 5. Number of Issues Published Annually: 12 6. Annual Subscription Price: U.S.: United Stated $75.00 7. Complete Mailing Address of Known Office of Publication: 114 West 26th Street, 4th Floor New York, NY 10001 8. Complete Mailing Address of Headquarters or General Business Office of Publisher: 114 West 26th Street, 4th Floor New York, NY 10001 9. Full Names and Complete Mailing Addresses of Publisher, Editor, and Managing Editor: Publisher: Dominic Barone, 114 West 26th Street, 4th Floor, New York, NY 10001; Editor: Jody Charnow, 114 West 26th Street, 4th Floor, New York, NY 10001; Managing Editor: Marina Galanakis, 114 West 26th Street, 4th Floor, New York, NY 10001 10. Owner: Haymarket Media Group, LTD. 174 Hammersmith Road, London, UK W6J7P 11. Known Bondholders, Mortgages, and Other Security Holders Owning or Holding 1 percent or More of Total Amount of Bonds, Mortgages, or Other Securities: None 12. Tax Status: The purpose, function, and nonprofit status of this organization and the exempt status for federal income tax purposes: Has Not Changed During Preceding 12 Months. PS Form 3526-R. August 2012 13. Publication Title: Renal & Urology News 14. Issue Date for Circulation Data Below: Sept. 2011 15. Extent and Nature of Circulation [i] Average No. Copies Each Issue During Preceding 12 Months [ii] No. Copies of Single Issue Published Nearest to Filing Date a. Total Number of Copies (Net press run) [i] 16,731 [ii] 17,084 b. Paid and/or Requested Circulation (1) Paid/Requested Outside—County Mail Subscriptions Stated on Form 3541 [i] 8,607 [ii] 8,913 (2) Paid In-County Subscriptions Stated on Form 3541 [i] 0 [ii] 0 (3) Sales Through Dealers and Carriers, Street Vendors, Counter Sales, and Other Non-USPS Paid Distribution [i] 0 [ii] 0 (4) Other Classes Mailed Through the USPS [i] 0 [ii] 0 c. Total Paid and/ or Requested Circulation [i] 8,607 [ii] 8,913 d. Free Distribution by Mail (1) Outside-County as Stated of Form 3541 [i] 7,524 [ii] 7,902 (2) In-County as Stated on Form 3541 [i] 0 [ii] 0 (3) Nonrequested Copies Distributed Through the USPS by Other Classes of Mail [i] 0 [ii] 0 (4) Nonrequested Copies Distribution Outside the Mail [i] 296 [ii] 0 e. Total Nonrequested Distribution [i] 7,820 [ii] 7,902 f. Total Distribution [i] 16,427 [ii] 16,815 g. Copies not Distributed [i] 305 [ii] 269 h. Total [i] 16,731 [ii] 17,084 i. Percent Paid and/or Requested Circulation [i] 52.40% [ii] 53.01% 16. Total Circulation includes electronic copies: No. 17. Publication of Statement of Ownership for a Requestor Publication is required and will be printed in the November 2012 issue of this publication 18. Manager, or Owner: John Crewe, VP Audience Development & Operations 09/30/2012 I certify that all information furnished on this form is true and complete.

I understand that anyone who furnishes false or misleading information on this form or who omits material or information requested on the form may be subject to criminal sanctions (including fines and imprisonment) and/or civil sanctions (including civil penalties).

32 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Legal Issues in Medicine D

r. B, 60, was a general practitioner with her own solo practice.

One thing Dr. B had learned in her more than 30 years of practice was that patients differ greatly in what they expect from a physician. One of Dr. B’s more unusual patients was Mr. S, 67.

Dr. B had been treating Mr. S for about five years. At his very first appointment, Mr. S immediately told the physician that he wasn’t looking for a primary care physician and that he only wanted her to check his blood pressure (BP).

“I am aware that my BP is borderline high, and I want to have it monitored by you. I’ll come in twice a year. I will pay out of pocket—no insurance. But I’m not looking for anything more than to have my blood pressure checked,” Mr. S said.

At first, Dr. B tried to reason with the patient. “Well, if you don’t have a primary care physician, you should,” she said.

“And don’t you want to have a complete physical?”

“No,” Mr. S said. “I don’t want a physical or anything else. Just take my blood pressure, please.”

A perplexing mindset Dr. B was somewhat bewildered at the patient’s attitude, but nonetheless she started a patient file for Mr. S, in which noted his BP readings every six months for the past five years.

One day, Mr. S failed to show up for his regular appointment, and Dr. B heard that he’d gone to the emergency room after several days of acute stomach pain and no bowel movements.

An abdominal pelvic ultrasound and a pelvic computed tomography scan showed free intraperitoneal air, indicating a perforated bowel. Mr. S was taken for emergency surgery. During the surgery, it was discovered that Mr. S had colon cancer. The pathology report revealed invasive adenocarcinoma which had spread to the lymph nodes. Mr. S was then told that he had stage 3 colon cancer.

On The Web

Within the next few months, the cancer meatatacized to his lungs and his condition deteriorated. Mr. S died less than six months after his diagnosis.

After Mr. S died, his widow sought a plaintiff’s attorney.

“My husband was going to a doctor every six months for five years before he was diagnosed with cancer,” she told the attorney. “I don’t think that doctor ever once suggested that my husband get a colonoscopy. Maybe if she had, he would still be alive!”

The attorney hired an expert to look at the medical records.

“These are some of the strangest medical records I’ve seen,” the expert said. “It appears that the physician did nothing other than check Mr. S’s blood pressure for five years.”

“What should the doctor have been doing?” the attorney asked.

“A general physical, blood work, and certainly some sort of colorectal cancer screening—either a digital rectal exam, a fecal occult blood card test, or a sigmoidoscopy, or colonoscopy. For a patient of that age, these things are standard.”

The attorney filed a malpractice lawsuit against Dr. B. Dr. B realized right away, upon finding out about the lawsuit, that the medical records would look odd—with just BP readings. Plus, she had never made notes anywhere about the special arrangement that she had with Mr. R. She met with the defense attorney provided by her malpractice insurance and explained the situation. The attorney looked grave, and suggested that they begin the discovery and deposition process but that they consider settling the case if it looked like it would go to trial.

Dr. B’s attorney warned her that during the depositions she would be questioned by the plaintiff’s attorney and that it was essential that she be honest and consistent since anything she said in the deposition could be used at trial. As expected,

© THINKSTOCK

A physician finds herself culpable after agreeing to an unorthodox arrangement with a patient BY ANN W. LATNER, JD

Dr. B should have documented that the patient was offered—and had declined—to take advantage of standard primary care services.

when the plaintiff’s counsel questioned Dr. B, she was forced to admit that the standard of care for a primary care physician does require such screenings. But, she immediately qualified here, stating that she wasn’t actually Mr. R’s primary care physician—that he’d only hired her to do BP screenings.

The attorney looked skeptical, and asked whether that was written in the patient file, or anywhere in the notes from the past five years. Dr. B was forced to respond that it was not.

On the advice of her attorney, Dr. B settled the case, prior to trial, for a sum of $1.5 million.

Legal background In the course of a lawsuit, depositions provide both parties with the opportunity to question witnesses in preparation for trial. They are conducted as part of the discovery process in civil cases, and testimony of witnesses is transcribed during depositions and can be used at trial to contradict what the witness says at that time. A judge is not present at depositions, and the process is carried out by the attorneys in the case.

Protecting yourself All clinicians will, at some point, be confronted with a patient who doesn’t want to follow advice, or declines full exams.

While you cannot force a patient to have a blood test or pap smear or colon cancer screening, the standard of practice requires informing patients about the benefits and risks, and offering these services. If a patient declines, write it in the patient records so that there is evidence of it being offered and declined.

Dr. B had an unusual relationship with her patient, who simply wanted hypertension screenings. Dr. B’s error was in not noting this arrangement anywhere in Mr. R’s records. Once Mr. R died, Dr. B appeared to be negligent. A few sentences in the patient’s chart could have changed the outcome of this case. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y. Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended.

What do you think? Did the jury make the right decision in this case? We want to know your thoughts.

Leave us a comment at the end of this article—or any article—at www.renalandurologynews.com/legal.

www.renalandurologynews.com

NOVEMBER 2012

Renal & Urology News 33

Factors Affecting Long-Term Renal Graft Survival RENAL TRANSPLANT patients who are female, younger, or receive a kidney from a living-related donor are significantly more likely to have a functioning renal allograft at 20 years, a study found. Absence of acute rejection also is associated with such long-term allograft survival.

Among 1,174 renal transplant recipients, Irish investigators led by Carol Traynor, MD, of Beaumont Hospital in Dublin, identified 255 (21.7%) who had a functioning graft for 20 years or more.

They compared these patients with 747 recipients who died, returned to dialysis or had a second renal transplant in less than 20 years.

After adjusting for multiple potential confounders, men had a significant 23% increased risk of long-term graft loss compared with women, Dr. Traynor’s group reported online in the American Journal of Transplantation.

Female gender, younger age lower the odds of graft failure at 20 years.

with a functioning graft (45.1% of graft failures) and interstitial fibrosis/tubular atrophy (39.4%). In the patients who graft failed prior to 20 years, the most common causes were death with a functioning graft (38.6%) and interstitial fibrosis/tubular atrophy (35.2%).

“As increasing numbers of patients are transplanted, and graft survival improves,” the authors wrote, “physicians will encounter greater numbers of patients with long-term exposure to immunosuppression.

Use of a living donor, implementation of appropriate prevention mea-

sures and early diagnosis and treatment of long-term complications may further improve long-term transplant survival.”

Dr. Traynor’s group noted that their investigation was a single-center study and has the limitations inherent in any such study. ■

WE’RE

CHANGING THE WAY

PROSTATE CANCER PATIENTS ARE TREATED EVEN WHEN THEY’RE NOT BEING TREATED When it comes to treating prostate cancer, we do not believe

“To our knowledge, we are the first to demonstrate superior 20-year graft survival in female recipients,” the authors stated.

Additionally, each one-year increment in recipient age was associated with a significant 1.3% increased risk of graft failure. Recipients of living-related donor kidneys had a 49% decreased risk. Acute rejection was associated with a 25% increased risk.

The researchers observed that 49% of the 20-year group had a history of early acute rejection, so “even in the setting of acute rejection, ultra longterm graft function is possible.”

The study is the first large investigation to characterize the outcome of renal transplantation 20 years later, the researchers noted.

Dr. Traynor and her colleagues also found that five-year graft survival in 20-year survivors (after the 20-year time point) was 74.7%, which is comparable to the proportion found in the general kidney transplant population.

The most common causes of death after 20 years were cardiovascular events (31.6% of deaths) and malignancy (28.9%).

The main causes of graft failure in the 20-year group were death

in a one-size-fits-all approach. That’s why doctors at UPMC are experts in both traditional methods of urologic surgery and in cutting-edge robotic surgery. But our doctors also recognize when the best management is not an operation, but careful observation. We believe it is important to be well versed in all options to ensure patients receive the right treatment at the right time. Because our job is not only to save lives, but to preserve the quality of life of every patient we treat. Learn more at UPMCPhysicianResources.com/ProstateCancer.

UPMC is affiliated with the University of Pittsburgh School of Medicine.

NOVEMBER 2012

www.renalandurologynews.com

Kidney Slated for Transplant Is Accidentally Discarded A medical center in Toledo, Ohio, has temporarily suspended its living donor kidney transplant program on a voluntary basis after a nurse accidently threw out a kidney taken from a live donor which was supposed to go to the donor’s sister. The incident, which happened in early August at the University of Toledo Medical Center (UTMC), occurred after a brother volunteered to donate a kidney to his older sister. The siblings were a perfect match. However, following nephrectomy, a nurse inadvertently disposed of the man’s kidney, which was later found among medical waste. Physicians attempted for over two hours to resuscitate the kidney, but were unsuccessful.

According to Jeffrey Gold, MD, chancellor and vice president for biosciences and health affairs at UTMC, “efforts were made to restore the kidney to a usable state, however, the physician in consultation with the family decided to not take the risk knowing there was a good chance for another highly compatible donor.”

A spokesperson for the United Network for Organ Sharing (UNOS) said the patient will not get any special consideration because of the unfortunate situation, but will be placed on the national kidney waiting list like any other patient. Places on the waiting list

On The Web

are determined by a complex algorithm, and patients are not given preferential treatment for botched procedures.

It was unclear how the error happened, but two operating room nurses have been suspended from their jobs pending the investigation. UTMC started its own internal investigation at the same time as the program was suspended, but it is likely that other agencies will become involved as well.

Two Physicians Sue Patient for Malicious Prosecution Can physicians sue a patient who originally took them to court for malpractice but then dismissed the case? This was the issue recently decided by the Tennessee Supreme Court. The case involved a female patient who went to Vanderbilt University Medical Center (VUMC) for placement of a port-a-cath. After the procedure, the patient was notified by her physician that he noticed a guide wire had been left in a vein leading to her heart. The physician believed that the guide wire had been left during a previous procedure at Williamson Medical Center the year before. The patient filed a lawsuit alleging negligence against the two physicians who had performed the procedure at Williamson. Both physicians denied liability. A year later, the

BY ANN W. LATNER, JD

patient was informed by a VUMC physician that it was actually VUMC that was responsible for the presence of the guide wire. The patient withdrew her complaint against the original two physicians, and the case was dismissed by the trial court judge. The patient then sued VUMC, and the parties to that case eventually reached a settlement.

The original two physicians, however, were not happy about having been sued and filed a complaint against the patient alleging that her prior lawsuit against them constituted malicious prosecution and abuse of process. The patient moved for summary judgment, claiming that the physicians could not prove essential elements of their malicious prosecution or abuse of process claims.

Summary judgment is a procedural device used during civil litigation to promptly dispose of litigation without a trial. It is used when there is no dispute as to the material facts of the case and the party is clearly entitled to judgment when the law is applied to those facts.

The trial court denied the patient’s motion, as did the Court of Appeals.

However, the Tennessee Supreme Court disagreed. The Supreme Court held that for physicians to prevail in a trial for malicious prosecution, they would have to prove that the patient instituted the original lawsuit without probable cause, with malice, and that the prior suit was ended in favor of the physicians. The Supreme Court held that the patient’s voluntary withdrawal of the case could not be considered a “favorable termination” for the purposes of the malicious prosecution claim, and dismissed the case against the patient.

ICU Misdiagnoses May Cost Up To 40,500 Lives Per Year

The Tennesse Supreme Count hears a unique case when two doctors take a patient to court.

© THINKSTOCK

A kidney that was slated for directed donation was thrown away in the medical waste unit.

© PHOTO RESEARCHERS, INC. / CLIFF MOORE

Malpractice News

A study by researchers at the Johns Hopkins University of School of Medicine in Baltimore has revealed that 28% of patients had at least one missed diagnosis at the time of death in the intensive care unit (ICU). The

A new study reports on diagnostic—and sometimes fatal—errors in the intensive care unit.

© PHOTO RESEARCHERS, INC. / B. SLAVEN

34 Renal & Urology News

results of the study, titled “Diagnostic errors in the intensive care unit: a systemic review of autopsy studies,” was published online ahead of print in BMJ Quality & Safety. The investigators, led

by Bradford Winters, MD, PhD, examined studies that used autopsy to detect diagnostic errors in adult ICU patients.

In 8% of patients, the diagnostic error was serious enough that it may have caused or directly contributed to the patient’s death, and had doctors been aware of the proper diagnosis, the treatment likely would have been different.

Three quarters of these fatal flaws were caused by infections and vascular issues such as heart attack or stroke. About a third of all illnesses that doctors failed to detect were attributable to one of four conditions: heart attack, pulmonary embolism, pneumonia, and aspergillosis. The authors concluded: “Our data suggest that as many as 40,500 adult patients in an ICU in United States may die with an ICU misdiagnoses annually.

Despite this, diagnostic errors receive relatively little attention and research funding. Future studies should seek to prospectively measure the prevalence and impact of diagnostic errors and potential strategies to reduce them.” ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

Looking for more malpractice news? Visit us at renalandurologynews.com/malpractice to see noteworthy jury verdicts, recent trends in legislation, and surprising settlements!

36 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Lifestyle Changes May Reverse Low T

BY JOHN SCHIESZER HOUSTON—Lifestyle modifications that lead to weight loss may help reduce the prevalence of low testosterone levels by almost 50% in overweight, prediabetic middle-aged men, according to a new study presented at The Endocrine Society’s 94th Annual Meeting.

“Doctors should first encourage overweight men with low testosterone levels to try to lose weight through diet and exercise before resorting to testosterone therapy to raise their hormone levels,” said study co-author Frances Hayes, MD, Professor of Medicine at St. Vincent’s University Hospital, Dublin, Ireland.

The study involved 891 men with impaired glucose tolerance (IGT) from the Diabetes Prevention Program (DPP). The men were not on medications that interfere with testosterone levels. Of the 891 subjects, 293 were randomized to lifestyle modification, 305 were randomized to receive metformin, and 293 were randomized to placebo. Because overweight men are more likely to have low testosterone levels, Dr. Hayes and her colleagues studied the impact of changes in body weight and insulin sensitivity on serum testosterone levels in men. In a previ-

ous study, the researchers had shown that increasing insulin resistance was associated with a decrease in Leydig cell testosterone secretion.

The researchers analyzed anthropometric variables (body mass index [BMI], waist circumference), physical activity (metabolic equivalent hours/ week), insulin sensitivity (homeostatic model assessment (HOMA-IR) and reproductive hormone levels (testosterone and luteinizing hormone [LH]) at baseline and at 12 months. Men were excluded from the study if they had a known diagnosis of hypogonadism or were taking medications that could interfere with testosterone levels.

Lifestyle modifications consisted of exercising for 150 minutes a week and eating less fat and fewer calories.

The mean age of the men at baseline was 53.9 years and the mean BMI was 31.9 kg/m2. The researchers observed that the mean testosterone levels (407 ng/dL) were not significantly different among treatment groups at baseline and, in the group as a whole, did not change (417 ng/dL at 12 months).

However, the men randomized to lifestyle modification had a 15% increase in testosterone levels (417 vs. 460 ng/dL).

The researchers observed no change

© THINKSTOCK

Measures that led to weight loss found to raise levels significantly in overweight, prediabetic men

Men experienced a 15% increase in testosterone levels, a study finds. in LH (3.1 vs. 3.1 IU/L). Testosterone levels were unchanged in the other two treatment groups.

The overall prevalence of hypogonadal testosterone levels (below 300 ng/dL) at baseline was 23.7%.

Through lifestyle modification, the prevalence of hypogonadal testosterone levels decreased from 20.4% to 11.1%, a 46% decline. The prevalence was not significantly changed in the metformin group (24.8% vs. 23.8%) and the placebo group (25.6% vs.

24.6%). Reduction in body weight was greater with lifestyle modification than metformin (-7.8 vs. -2.8 kg), as was the decrease in HOMA-IR (7.0 to 5.2 with lifestyle modification vs. 7.2 to 6.0 with metformin).

Changes in testosterone levels correlated with changes in body weight, waist circumference, and HOMA-IR. They observed no relationship between change in testosterone and physical activity levels. “We didn’t see any benefit with exercise. That surprised us. I thought that it would lead to some improvement in testosterone, but we were not able to see any relationship there,” Dr. Hayes told Renal & Urology News.

Men in the lifestyle modification group lost an average of about 17 pounds (7.8 kg) over the one-year study.

“Losing weight not only reduces the risk of prediabetic men progressing to diabetes but also appears to increase their body’s production of testosterone,” Dr. Hayes said. ■

U.S. Long-Term Renal Transplant Survival Lags

BY ROSEMARY FREI, MSc BERLIN—Long-term failure rates of transplanted kidneys are more than 30% higher in the U.S. than in Australia, New Zealand, and the U.K., a new study shows.

“We have some hypotheses regarding the findings, and believe that they may related to fundamental differences in the health-care delivery system in the U.S. compared to the other three countries represented in the study,” said lead investigator Robert Merion, MD, President of Arbor Research Collaborative for Health and Professor of Surgery at the University of Michigan, both in Ann Arbor. “Although we did account for a wide variety of factors that are known to affect graft outcome in our analyses, it is possible that there are unmeasured differences in patient comorbidities.”

Dr. Merion, who presented the results at the 24th International Congress of

The Transplantation Society, said he was surprised at the magnitude of the differences.

He and his co-investigators previously had performed preliminary registryspecific analyses of unadjusted graft outcomes. To extend these findings,

New Zealand, Australia, and the U.K. have lower failure rates. they conducted risk-adjusted analyses of data from the Scientific Registry of Transplant Recipients in the United States, the organ-donor registry of the U.K.’s National Health Service Blood and Transplant organization and the Australia and New Zealand Dialysis and Transplant Registry.

They examined data from 259,531 kidney transplants in the United States, 34,776 in the United Kingdom, 10,655 in Australia, and 2,036 in New Zealand, all of which took place between 1988 and 2010. Median patient follow-up was 6.7 years.

Dr. Merion and his colleagues found significantly higher proportions of living-donor transplants in the United States, Australia, and New Zealand (37%, 34%, and 36%, respectively) compared with the U.K. (20%).

Furthermore, 23% of recipients in the United States received transplants for diabetic nephropathy compared with only 9% in the U.K. and 6% in Australia and New Zealand.

The study also revealed a higher proportion of zero human leukocyte antigen (HLA)-mismatched transplants in the U.S. (10% vs. 9% in the U.K. and 6% in Australia and New Zealand).

The proportion of adjusted graft failure was 30% higher at one year in the U.K. and New Zealand than in the United States. Long-term graft failure, however, was 30% higher in the United States than in the each of the other three countries studied. The overall risk of graft failure was lower in more recent years, the researchers noted. However, the magnitude of this improvement was significantly greater in the U.K., Australia, and New Zealand.

The effects of recipient sex, donor age (40 years and older) and type, and cause of death on the risk of graft loss were not significantly different between the three registries. However, the effects of recipient age, race, diagnosis, donor age (among donors under 40) and sex, number of HLA mismatches, and year of transplant were significantly different in the United States compared with the other three countries. ■

www.renalandurologynews.com

NOVEMBER 2012

Renal & Urology News 37

Your Money Make sure your assets are rolling in dividend reinvestment, as this can be a stable source of long-term returns BY STAN LUXENBERG

A sound strategy Focusing on companies that pay dividends can be a sound strategy. Many dividend companies are mature businesses with a rich cash flow. Such shares can be resilient in downturns and produce solid long-term returns. But investors should be careful not to simply buy stocks with the highest dividends. In the arithmetic of the markets, dividend yields rise when stocks fall. If a stock costs $20 and sends out $1 in dividend checks annually, the yield is 5%. Now if the company runs into trouble and the shares fall to $10, the yield will jump to 10%. While the big yield may be tempting, investors should be wary because shaky companies can cut dividends or stop them altogether.

For better results, look for stocks that pay dividends of 2% to 5% and increase them every year. A solid choice is ketchup maker H. J. Heinz, which yields 3.7%.

Heinz has a long record of raising its dividend. While the company paid $1.68

On The Web

per share in 2010, it increased the payout to $1.80 in 2011 and $1.92 in 2012.

Keep in mind that stocks like Heinz are very different from bonds. Bonds make fixed payouts that never increase. Bonds may be safer, but by buying stocks that increase their payouts like clockwork, you can achieve a steady flow of income that will grow for years.

S&P Dividend Aristocrats To find potential investments, consider the S&P Dividend Aristocrats, a group of stocks that is listed at S&P.com. To be included on the list, a stock must have increased its dividend every year for the past 25 years. Only 52 companies qualify.

The group includes such reliable blue chips as drug chain Walgreen, oil giant Exxon Mobil, and bleach maker Clorox.

Companies on the list tend to be extremely committed to raising their dividends.

Managements will move heaven and earth before they cut payouts to shareholders.

Make no mistake: The companies on the list do not come with ironclad guarantees.

During the financial crisis, a number of them cut their dividends and were eliminated from the list. One of the biggest disappointments came when General Electric cut its dividend for the first time since the Great Depression. Still, the list provides a good starting point for investors seeking reliable performers.

Utility-based stocks The list has several utilities, including Consolidated Edison, a New York power company that yields 4%. Utility payouts are typically safe because state governments regulate such businesses, and the demand for power remains steady. But investors should be careful about weighting their portfolio with utility stocks.

Seeking security, investors have poured into utilities, pushing up prices well above

© THINKSTOCK

I

nvestors have been pouring into stocks that produce dividend payments.

Reliable performers reward shareholders with quarterly dividend checks year after year. Popular stocks include phone giant AT&T, which pays a dividend yield of 4.6%, and Duke Energy, a power company that yields 4.8%. For many investors, the rush into dividend payers represents a change from past patterns. For decades, income-oriented investors focused on bonds. That made sense because as recently as 2000, 10-year Treasury bonds yielded 6.0%, while the stocks of the S&P 500 yielded less than 2%. But since the financial crisis in 2008, the Federal Reserve has been holding down interest rates. Now Treasuries yield only 1.65%, much less than what many stocks pay. As a result, investors have been looking to dividend stocks.

Many dividend companies are resilient and poised for growth due to their ample cash flow.

normal levels. The high prices may not be justified because many utilities only increase earnings slowly.

To hold dividend stocks, consider buying a mutual fund. A top choice is T. Rowe Price Dividend Growth. During the past five years, the fund returned 2.2% annually, outdoing the S&P 500 by about one percentage point. Portfolio manager Tom Huber is wary of utilities. Instead of high-yielding stocks, he is focusing on companies with smaller dividends that are growing steadily. “You can find some attractive situations where the stocks are yielding 2%, and the dividends are growing at 9% annual rates,” he says.

Huber likes United Technologies, the maker of Pratt and Whitney aircraft engines and Otis elevators. The stock yields 2.7%, and the dividend has been increasing steadily. The company has been boosting sales by expanding into emerging markets. Huber also likes Kohl’s, the department store chain. The stock yields 2.4%. He says that the management is committed to raising the dividend, and the company has plenty of cash.

Another solid fund is Rochdale Dividend & Income, which returned 4.2% annually during the past five years. To find growing dividends, portfolio manager David Abella has been buying healthcare REITs (real estate investment trusts). Those own facilities that house hospitals, medical offices, or nursing homes. The Rochdale fund holds Ventas, a REIT that yields 4.0%. Ventas owns properties that house nursing homes and assisted living facilities.

Demand for such properties is growing relentlessly as the population ages, Abella says. But there has been relatively little construction lately because the financial crisis discouraged lenders from taking risks. That has helped to keep properties filled. Healthcare REITs should do well even if the economy remains sluggish.

He has been wary about pharmaceutical stocks because patents are expiring on many drugs. That should hurt sales and earnings. But Abela favors Bristol-Myers Squibb, which yields 4.0%. The company is developing some promising drugs that should provide enough cash to cover the dividend. ■

Where’s the best investment? Check out what our financial columnist has to say about how to invest your money. We’ve got lots more online at www.renalandurologynews.com/money.

38 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

CME FEATURE

Nonmuscle Invasive Bladder Cancer: Guidelines for Treatment The routine incorporation of NMIBC clinical practice guidelines will reduce variation in care by closing the gap on inappropriate delivery, whether over- or underuse.

Release Date: November 2012 Expiration Date: November 2013 Estimated time to complete the educational activity: 1 hour

BY MATTHEW J. RESNICK, MD AND MICHAEL S. COOKSON, MD

This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education.

STATEMENT OF NEED: Urologists who care for patients with NMIBC must incorporate established clinical practice guidelines for treatment, and, in doing so, reduce the current substantive and inappropriate variation in practice patterns surrounding NMIBC. Improving guideline adherence will close the gap on inappropriate care delivery.

TARGET AUDIENCE: This activity has been designed to meet the educational needs of urologists and allied healthcare professionals who treat patients with bladder cancer.

EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Review the content and development process of clinical practice guidelines for NMIBC. • Review data surrounding poor adherence to guidelines, which will serve as a cue to action for urologists to improve guideline adherence.

ACCREDITATION STATEMENT: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Medical Education. MER is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION: Medical Education Resources designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

DISCLOSURE OF CONFLICTS OF INTEREST: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all its educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest.

The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty • Matthew J. Resnick, MD • Michael S. Cookson, MD

Reported Financial Relationship Consultant: Bayer Healthcare, Dendreon Consultant: Photocore, Endo Pharmaceuticals

T

he Institute of Medicine (IOM) has defined clinical practice guidelines as “systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances.”1 The overarching goals of guideline-based practice are to improve the quality, efficiency, and value of care delivery. Interest in guideline-based practice largely lies in well-known challenges to the U.S. healthcare system.

Healthcare spending in the United States continues to grow, with the U.S. spending nearly 2.5 times more per capita on healthcare than any other developed country. Despite this investment, care in the U.S. fails to produce superior outcomes with regard to life expectancy and disease-specific mortality when compared to other nations.2 There are numerous explanations for the observed disparities in healthcare costs between industrialized countries; however, many believe that the most important contributor to disproportionate spending is overutilization.3

Indeed, there is ample evidence to suggest that increased spending is inversely associated with various quality measures in numerous disease states.4,5 While overutilization is commonplace in the U.S. healthcare environment, in many disease states, including bladder cancer, underutilization is equally (if not more) common. Proponents of guidelinebased practices believe that the routine incorporation of clinical practice guidelines will reduce variation in care by closing the gap on inappropriate delivery, whether over- or underuse.

Toward improving patient care While clinical practice guidelines have been touted as a means to reduce cost and improve overall healthcare efficiency, one must not discount the level of patient benefits with guideline implementation. It is well known that the implementation of clinical practice guidelines improves both the process of care as well as observed outcomes in numerous disease states. Grimshaw and Russell reviewed 59 studies evaluating the effect of clinical practice guidelines and found that 55 of the 59 studies documented improvements in the process of care after guideline

The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Medical Education, and Julie Johnson, PharmD, of Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest.

METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period November 2012 through November 2013, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/renalanurologynews, and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.

Matthew J. Resnick, MD, (left), and Michael S. Cookson, MD, (right) are in the Department of Urologic Surgery at Vanderbilt University Medical Center in Nashville. Dr. Resnick is an Instructor and Dr. Cookson is the Rodes and Patricia Hart Professor and Vice Chair of the Department.

www.renalandurologynews.com

implementation. Furthermore, nine of 11 studies evaluating outcome, documented improvements after guideline implementation.6 Addtionally, there is clear evidence in the surgical literature that guideline implementation improves outcomes. Stulberg et al. recently reported that adherence to the Surgical Care Improvement Project (SCIP) process-of-care improvement measures reduced the rate of surgical site infections (SSI) from 14.2 to 6.8 per 1,000 discharges.7 Berenguer et al. also reported significant reductions in SSI rates after colorectal surgery following the implementation of SCIP measures.8 Taken together, these data indicate that the implementation of clinical practice guidelines has the potential to directly improve both the processes and outcomes of patient care.

Ancillary benefits In addition, there are ancillary benefits to guideline-based practice that frequently go unrecognized. Many clinical guidelines offer lay versions that inform patients of treatment options as well as the expected risks and benefits associated with different therapies.

Practice guidelines also allow patients to make informed choices and to consider personal utility when evaluating diagnostic and therapeutic treatment paradigms.9 Finally, clinical practice guidelines may improve patient care by influencing healthcare policy, as they frequently improve public awareness of under-recognized diseases, preventative interventions, and other at-risk or high-risk groups.9

Shortcomings in development Clinical practice guidelines have the ability to improve the quality of care at both the population and patient levels; however, there a number of shortcomings in the development and implementation of guidelines that deserve mention. Wolf et al. recently reviewed the development of clinical practice guidelines and discuss, in detail, the process of guideline development.10 Various organizations have published their specific process of guideline development, and each of these processes consists of some combination of evidence assessment and expert opinion.11-13 Unfortunately, there remains little high-quality evi-

dence upon which to base guidelines.

Harpole et al. evaluated the published guidelines for the management of lung cancer and found that only 53% of the lung cancer guidelines were evidencebased, and furthermore, only 29% of the recommendations furnished in these guidelines were evidence-based.14 More recently, Poonacha and Go studied the levels of evidence and consensus upon which National Comprehensive Cancer Network (NCCN) Guidelines are based and found a varied degree of highquality evidence driving recommendations in the 10 most common cancers.15 One must consider the biases of those responsible for guideline development, which may affect the recommendations furnished by panels. These biases can range from one scientist’s “stake” in a particular issue to a direct financial conflict of interest.16,17 To address many of these issues, the IOM recently released a report identifying standards for developing trustworthy clinical practice guidelines.18 Incorporating these standards into guideline development will hopefully result in improved transparency and, ultimately, improved implementation.

NOVEMBER 2012

in the outcomes’ tables and expert opinion, the panel developed treatment guidelines.”19 As in prior AUA clinical practice guidelines, each recommendation was graded with respect to the degree of flexibility that could be applied in its implementation. Findings were characterized as follows: “option,” “recommendation,” and “standard,” meaning one has decreasing levels of flexibility (Table 1).

The guidelines review five index patients as a means to communicate the findings and recommendations. The AUA guideline panel considered the immediate use of single-dose intravesical chemotherapy an “option” second-

Renal & Urology News 39

ary to cost, absence of pathologic data, side effects, and patient preference.

For the patient with multifocal and/ or large histologically confirmed lowgrade Ta lesions, or a patient with recurrent low-grade Ta lesions, the panel assigned a “recommendation” to the administration of an induction course of intravesical mitomycin-c (MMC) or Bacillus Calmette-Guérin (BCG).

Furthermore, the administration of maintenance MMC or BCG was considered an “option.” The panel considered re-resection of a histologically confirmed high-grade T1 lesion in the absence of muscularis propria “standard,” secondary to high rates of understaging.

Table 1. Grading the recommendations

AUA

Standard: A guideline statement is a standard if: (1) the health outcomes of the alternative interventions are sufficently well known to permit meaningful decisions and (2) there is virtual unanimity about which intervention is preferred Recommendation: A guideline statement is a recommendation if: (1) the health outcomes of the alternative intervention are sufficently well known to permit meaningful decisions, and (2) and appreciable but not unanimous majority agrees on which intervention is preferred Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate

NCCN

Category 2a: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate

AUA guidelines: the 2007 update

Category 2b: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate

The American Urological Association (AUA) most recently published guidelines on the management of NMIBC in 2007.19 These 2007 AUA guidelines set out to address questions only when there was sufficient evidence upon which to base conclusions. The guideline panel accepted 158 articles from 1998 to 2005 for consideration when drafting the guidelines. The panel performed hierarchical meta-analyses on the available data surrounding the clinical questions to be answered. Unlike prior AUA guidelines, the 2007 NMIBC guideline panel performed meta-analysis on both randomized and nonrandomized observational data. For the purpose of the guidelines, outcomes assessed included probability of recurrence and risk of overall progression, defined as either stage progression (stage Ta, T1, and carcinoma in situ [CIS]) or radical cystectomy (RC). Attempts were made to evaluate the risk of complications with particular treatments. However, the authors note significant heterogeneity with regard to complication reporting in the studies evaluated for the guidelines. “From the evidence

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate Grade A: Based on clinical studies of good quality and consistency that addressed the specific recommendations, including at least one randomized trial EAU

Grade B: Based on well-conducted clinical studies, but without randomized clinical trials Grade C: Made despite the absence of directly applicable clinical studies of good quality

Adapted with permission from Philipp Dahm, MD, MHSc

Table 2. Grading the quality of evidence AUA NCCN

No information provided High level: Randomized controlled trials (RCT) Lower level: Broadly defined, including observational studies or phase II trials Modified classification system based upon Oxford Centre for Evidence-based Medicine Level 1a: Evidence obtained from meta-analysis of RCTs Level 1b: Evidence obtained from at least one RCT

EAU

Level 2a: Evidence obtained from one well-designed controlled study without randomisation Level 2b: Evidence obtained from at least one other type of well-designed quasi-experimental study Level 3: Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case report Level 4: Evidence obtained from expert committee reports or opinions or clinical experienced of respected authorities

Adapted with permission from Philipp Dahm, MD, MHSc

40 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

Furthermore, the panel considered the administration of an induction course of BCG followed by maintenance therapy a “recommendation” in the patient with high-grade noninvasive disease. Finally, for the patient with recurrent high-grade noninvasive disease after intravesical therapy, the panel assigned a “recommendation” rating to consideration of RC and an “option” rating to the consideration of salvage intravesical therapy.

While the panel did apply a “standard” rating to the need for periodic surveillance cystoscopy following the histologic diagnosis of bladder cancer, neither interval nor duration was defined in the most recent AUA guidelines.19

EAU guidelines: the 2011 update The European Association of Urology (EAU) most recently updated guidelines for the diagnosis and management of NMIBC in 2011.20 Unlike the most recent AUA update, the 2011 EAU guidelines include more specific recommendations for diagnosis and follow-up. Similar to the methodology used to develop the AUA guidelines, EAU panel members performed a thorough literature search for studies on Ta and T1 disease from 2008 to 2010 and CIS from 2004 to 2010.

Panel members rated studies according to the Oxford Centre for Evidence-based Medicine Levels of Evidence (Table 2).21 Using available data, the panel members assigned a grade to each guideline recommendation. Grade A recommendations are based upon data that include at least one randomized clinical trial. Grade B recommendations are based upon well-performed studies in the absence of randomized data. Lastly, grade C recommendations are furnished despite the absence of directly applicable clinical studies of good quality.

The 2011 EAU guidelines comprehensively review the tools available for the diagnosis of bladder cancer.

The EAU guidelines assign a grade A recommendation to the routine use of cystoscopy in patients with symptoms suggestive of bladder cancer and clearly state that there is no urine marker that can replace cystoscopy in the diagnostic algorithm for hematuria. Despite these recommendations, the EAU guidelines systematically review the data regarding the use of various bladder cancer biomarkers. Unlike the AUA guidelines, the EAU guidelines give a grade B recommendation to the use of

A

B

C

D

Figure legend. The above four figures show the cystoscopic appearance of several nonmuscle invasive bladder tumors. Figure A shows a papillary Ta tumor in the bladder diverticulum; Figure B illustrates a solitary low-grade Ta tumor; Figure C shows a multifocal low-grade Ta tumor; and Figure D depicts a papillary tumor located anteriorly.

fluorescence cystoscopy when CIS is suspected, and like the AUA guidelines, recommend re-resection of high-grade and/or T1 tumors.

The EAU guidelines strongly advocate for the incorporation of published prognostic models into therapeutic decision-making. The guidelines specifically endorse the European Organization for Research and Treatment of Cancer (EORTC) scoring system and risk tables,22 which incorporate variables such as the number of tumors, tumor size, prior recurrence rate, T-stage, presence of concomitant CIS, and tumor grade to predict the risk of both recurrence and progression.

Additionally, the guidelines recommend the routine application of the Spanish Club Urológico Español de Tratamiento Oncológico (CUETO) group’s predictive model for BCGtreated patients.23 Like the AUA guidelines, the most recent EAU update pays considerable attention to adjuvant treatment paradigms for NMIBC. In patients with Ta or T1 tumors at low risk of recurrence, the EAU guidelines assign a grade A recommendation to the administration of a single instillation of perioperative chemotherapy. For patients at intermediate- to high-risk of recurrence and intermediate risk of progression, the EAU guidelines endorse, with a grade A recommendation, the administration of a minimum of one year of BCG or intravesical chemotherapy. The guidelines do not advocate for any particular dosing schedule given the lack of

good quality data upon which to base such recommendations. Similarly, for patients with Ta or T1 disease at high risk of progression or for patients with CIS, the guidelines endorse, again with a grade A recommendation, the administration of intravesical BCG for at least one year. In addition to treatment recommendations, the EAU guidelines use the aforementioned EORTC risk stratification model to dictate surveillance following resection of the index tumor. Considering the poor quality data upon which surveillance protocols are based, the EAU guidelines assign grade C recommendations to this riskstratified surveillance schema.

The 2012 NCCN Bladder Cancer Guidelines The NCCN is a nonprofit collaboration of 21 participating National Cancer Institute (NCI)-designated cancer centers. The NCCN publishes clinical practice guidelines on the management of 35 cancers, which are commonly accepted as standards by the Center for Medicare Services (CMS) and private insurers.15,24 Like the AUA and EAU guidelines, the NCCN guidelines incorporate both scientific evidence and consensus opinion into their recommendations. Unlike the AUA and EAU guidelines, the method and extent of literature review for each NCCN guideline update are not well described. The NCCN grades recommendations based upon the relevant levels of evidence and consensus. Evidence is graded as

high-level (referring to large randomized clinical trials or meta-analyses) or lower level (which is broad in scope and ranges from well-performed observational studies to case series). The NCCN grades recommendations from category 1 to category 3, with category 1 representing high-level evidence and uniform opinion, categories 2A and 2B representing variable levels of evidence and consensus, and category 3 representing major disagreement amongst panel members.25 Within the 2010 NCCN Bladder Cancer Guidelines, 86% of recommendations were graded category 2A and 14% 2B, with no category 1 or category 3 recommendations.15 Interestingly, the most recent update to the NCCN Bladder Cancer Guidelines does contain category 1 recommendations that will be discussed below.

Similar to the EAU guidelines, the NCCN provides recommendations for diagnosis, treatment, and followup. The NCCN guidelines advocate for cystoscopy, urinary cytology, and the routine application of upper tract imaging upon suspicion of NMIBC. Similar to both the AUA and EAU guidelines, the NCCN recommends as an option the administration of a single dose of perioperative, intravesical chemotherapy. Additionally, the guidelines offer as an option the administration of induction immunotherapy or chemotherapy. For patients with highgrade noninvasive disease, the NCCN guidelines recommend re-resection in the context of incomplete index resection or the absence of muscle in the initial specimen. For patients with high-grade T1 disease, the guidelines strongly advise re-resection and offer, as an alternative, consideration of radical cystectomy. The 2012 NCCN guidelines assign a category 1 recommendation to the administration of intravesical BCG to patients with T1 disease, either low- or high-grade, and recommend the administration of BCG to patients with CIS. While the most recent guidelines do state that there are data to support the use of maintenance BCG, there is no specific recommendation regarding the application of maintenance BCG in the absence of cytologic or cystoscopic disease recurrence. The guidelines provide a comprehensive framework for the treatment of bladder cancer patients with recurrent disease and offer as an option the administration

IMAGES PROVIDED COURTESY OF MATTHEW J. RESNICK, MD, AND MICHAEL S. COOKSON, MD.

CME FEATURE

www.renalandurologynews.com

of intravesical valrubicin for BCGrefractory CIS. Like the EAU guidelines, the NCCN uses a risk-adapted follow-up paradigm.

For patients with low-grade noninvasive disease the guidelines recommend cystoscopy at three months, then increasing intervals as appropriate. For patients with invasive disease, high-grade disease, or CIS, the guidelines recommend cystoscopy every three to six months for two years then at increasing intervals as appropriate. Furthermore, surveillance upper tract imaging is recommended every one to two years for patients with high-grade disease.

Variations in adherence Despite the potential population-level and patient-level benefits to the dissemination and widespread application of clinical practice guidelines, there remains a considerable variation in practice patterns among urologists who treat NMIBC. Hollingsworth and colleagues evaluated variation in treatment intensity among a Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort of patients with NMIBC and found substantial variation in patterns of care.26 Indeed, these investigators documented a greater than twofold difference in bladder cancer expenditures among patients treated by high-intensity providers when compared to low-intensity providers.26,27 Furthermore, provider factors accounted for more of the observed variation in care intensity than any measureable patient characteristics.

While patients treated by high-intensity providers were more likely to undergo radical therapy for bladder cancer, treatment by a high-intensity provider did not confer any cancer-specific survival benefit.26 The same investigators also then specifically evaluated variation in the use of cystoscopy, urine cytology, and intravesical therapy and, again, found considerable variation in the use of these services among treatment providers. Neither increasing utilization of cystoscopic surveillance nor increasing utilization of intravesical therapy was associated with a patient-level survival benefit. Interestingly, maximal use of urine cytology was associated with a reduction in bladder cancer death when compared to the lowest level of utilization.27 These data underscore the considerable degree of provider-level

variation in treatment patterns among urologists caring for patients with NMIBC. Furthermore, these data may ultimately be used in future guidelines to identify optimal population-based care intensity paradigms.

Studies addressing adherence rates There are few well-performed studies that specifically address adherence to recent bladder cancer guidelines.

Schrag et al. evaluated adherence to cystoscopic surveillance following the diagnosis of NMIBC and found that only 40% underwent appropriate cystoscopic surveillance.28 More recently, Chamie et al. evaluated adherence to published guidelines using SEERMedicare data, specifically studying the use of surveillance cystoscopy, upper tract imaging, intravesical BCG, and perioperative mitomycin-C within the first 2-years of diagnosis. Of the 4,545 patients in the study cohort, only one patient (0.02%) received appropriate guideline-based therapy, including eight cystoscopic examinations, eight urine cytologies, an induction course of BCG, two upper tract studies, and a single dose of perioperative mitomycin-C.29

NOVEMBER 2012

parameter that demonstrated improvement in adherence after the publication of clinical practice guidelines was the administration of an induction course of BCG. Unexplained provider-level variation largely contributed to the low compliance rates for cystoscopy, cytology, perioperative chemotherapy, and postoperative BCG.29 In addition to the aforementioned population-based studies, Bolenz et al. recently reported data surrounding adherence to EAU guidelines among a cohort of 206 elderly bladder cancer patients treated at a single tertiary care institution. This study revealed appropriate initial surgical management including re-resection and the administration of a single dose of intravesical chemotherapy in 71.4% of patients. Of the 43 conservativelytreated patients with an indication for BCG, 28 patients (65.1%) received an induction course of BCG and 11 patients (25.6%) received maintenance BCG.30 These data closely resemble those published by Gontero et al., who evaluated adherence to EAU guidelines in 306 patients treated at eight Italian referral centers. Of the 124 patients with high-risk disease, 61 patients

The clinical management of NMIBC continues to evolve, and the incorporation of clinical guidelines provides a framework to assist practitioners in providing care.

Relaxing their definition to exclude perioperative mitomycin and upper tract imaging resulted in 19 patients (0.4%) having received care adherent to published guidelines. Indeed, nearly two-thirds of patients in the study cohort did not receive one or more cystoscopy, one or more cytology, and one or more BCG instillation. The investigators also evaluated provider-level guideline adherence and documented equally sobering results, finding that 99% of treating physicians failed to provide eight or more cystoscopies, eight or more cytologies, and six or more BCG instillations within two years following diagnosis to a single patient captured by the study within their practice. Furthermore, 42% of providers failed to provide one or more cystoscopy, one or more cytology, and one or more BCG instillation to a single patient. Interestingly, the only

(49.2%) underwent re-resection, and 96 patients (77.4%) received either induction BCG or induction intravesical chemotherapy. Clearly, there are profound differences in rates of guideline adherence between published studies. Many of these differences may be attributed to the definition of adherence, the parameter studied, the site of care delivery, and the specific dataset evaluated. Furthermore, one must take into account the considerable degree of publication bias that is likely associated with reporting adherence to published clinical practice guidelines.

Variations in practice: the initial evaluation of hematuria While there are ample data demonstrating considerable variation in practice patterns following the diagnosis of blad-

Renal & Urology News 41

der cancer, there is also a great deal of variation in care with regard to the initial evaluation of hematuria. Elias et al. recently studied patterns of care in a nested cohort of high-risk patients with microscopic hematuria. This study found that 42.1% of men with one episode of microscopic hematuria never received any further evaluation. Within this cohort, 36% underwent repeat urinalysis, 15.2% had a urine culture, 10.4% underwent urine cytology, 22.6% received some form of imaging, and 12.8% underwent cystoscopy. A multivariate analysis revealed that tobacco use was the only predictive factor for referral and urologic evaluation.

Toward improving guideline adherence While selected series reveal acceptable rates of guideline adherence, it is clear from population-based data that adherence to published guidelines remains poor. Therefore, two questions must be answered here: a) what are the barriers to guideline implementation; and b) How can we overcome these barriers?

As part of a recent study evaluating regional collaboration to improve guideline adherence, Miller et al. further defined the barriers to implementation as follows: a) clinicians have little empirical data regarding their own practice patterns; and b) there is significant uncertainty amongst clinicians regarding the means to implement quality improvement initiatives.32 Members of the collaborative, which included both academic and private urology practices, implemented a system of data collection, education, and feedback that resulted in significant improvements in guideline-adherent practices.31

In summary The clinical management of NMIBC continues to evolve, and the incorporation of clinical guidelines provides a framework to assist practitioners in providing the highest quality care for their patients. There are a variety of resources available to assist the clinician in the diagnosis, treatment, and follow-up of patients with NMIBC. Like any guideline, each of these documents has at its core the goal of improving the quality of healthcare deliveryâ&#x20AC;&#x201D;and each has inherent strengths and weaknesses.

Future improvements in guideline devel-

42 Renal & Urology News

NOVEMBER 2012

www.renalandurologynews.com

CME FEATURE opment include the continuous surveillance of published data and the timely incorporation of significant results to ensure that we are utilizing the most contemporary information. Finally, incentivizing healthcare providers with programs and tools that encompass education, feedback, and implementation will improve adherence to guidelines and ultimately improve the quality of care that we deliver to our patients. ■ REFERENCES 1. Field MJ, Lohr KN, eds. Clinical practice guidelines: Directions for a New Program. National Academy Press. Washington DC;1990.

2. Public Policy Committee of the American College of Physicians, Ginsburg JA, Doherty RB, et al.

Achieving a high-performance health care system with universal access: what the United States can learn from other countries. Ann Intern Med 2008 Jan.;148:55-75.

3. Emanuel EJ, Fuchs VR. The perfect storm of overutilization. JAMA 2008;299:2789-2791.

4. Fisher ES, Wennberg DE, Stukel TA, et al. The implications of regional variations in Medicare spending.

Part 1: the content, quality, and accessibility of care.

Ann Intern Med 2003;138:273-287.

5. Fisher ES, Wennberg DE, Stukel TA, et al. The implications of regional variations in Medicare spending.

Part 2: health outcomes and satisfaction with care.

Ann Intern Med 2003;138:288-298.

6. Grimshaw JM, Russell IT. Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations. Lancet 1993;342:1317-1322.

7. Stulberg JJ, Delaney CP, Neuhauser DV, et al. Adherence to surgical care improvement project measures and the association with postoperative infections.

JAMA 2010;303:2479-2485.

8. Berenguer CM, Ochsner MG, Lord SA, Senkowski CK. Improving surgical site infections: using National Surgical Quality Improvement Program data to institute Surgical Care Improvement Project protocols in improving surgical outcomes. J Am Coll Surg 2010;210:737-743.

9. Woolf SH, Grol R, Hutchinson A, et al. Clinical guidelines: potential benefits, limitations, and harms of clinical guidelines. BMJ 1999;318:527-530.

10. Wolf JS Jr, Hubbard H, Faraday MM, Forrest JB. Clinical practice guidelines to inform evidence-based clinical practice. World J Urol 2011;29:303-309.

11. Woolf SH. Practice guidelines, a new reality in medicine. II. Methods of developing guidelines. Arch Intern Med 1992;152:946-952.

12. Buie WD. Clinical practice guidelines: appraising the evidence. Dis Colon Rectum 2010;53:1107-1109.

13. Qaseem A, Snow V, Owens DK, et al. The development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann Intern Med 2010;153:194-199.

14. Harpole LH, Kelley MJ, Schreiber G, et al. Assessment of the scope and quality of clinical practice guidelines in lung cancer. Chest 2003;123:7S–20S. 15. Poonacha TK, Go RS. Level of scientific evidence underlying recommendations arising from the National Comprehensive Cancer Network clinical practice guidelines. J Clin Oncol 2011;29:186-191.

16. Shaneyfelt TM, Centor RM. Reassessment of clinical practice guidelines: go gently into that good night.

JAMA 2009;301:868-869.

17. Detsky AS. Sources of bias for authors of clinical practice guidelines. CMAJ 2006;1751033,1035.

18. Report: Clinical Practice Guidelines We Can Trust page. Institute of Medicine of the National Academies webpage. Available at www.iom.edu/Reports/2011/ Clinical-Practice-Guidelines-We-Can-Trust.aspx. Accessed on October 11, 2012.

19. Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol 2007;178:2314-2330.

20. Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol 2011;59:997-1008.

21. Oxford Centre for Evidence-Based Medicine—Levels of Evidence (March 2009) page. Center for Evidence Based Medicine website. Available at http://www. cebm.net/index.aspx?o=1025. Accessed on October 11, 2012.

22. Sylvester RJ, van der Meijden APM, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2,596 patients from seven EORTC trials. Eur Urol 2006;49:466-477.

23. Fernandez-Gomez J, Madero R, Solsona E, et al.

Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model.

J Urol 2009;182:2195-2203.

24. McGivney WT. NCCN Guidelines and Their Impact on Coverage Policy. J Natl Compr Canc Netw 2010;8:625.

25. NCCN Guidelines page. National Comprehensive Cancer Network website. Available at www.nccn. org/professionals/physician_gls/f_guidelines.asp.

Accessed on October 11, 2012.

26. Hollingsworth JM, Zhang Y, Krein SL, et al. Understanding the variation in treatment intensity among patients with early stage bladder cancer. Cancer 2010;116:3587-3594.

27. Hollingsworth JM, Zhang YS, Miller DC, et al. Identifying Better Practices for Early-stage Bladder Cancer.

Med Care 2011;49:1112-1117.

28. Schrag D, Hsieh LJ, Rabbani F, et al. Adherence to surveillance among patients with superficial bladder cancer. J Natl Cancer Inst 2003;95:588-597.

29. Chamie K, Saigal CS, Lai J, et al. Compliance with guidelines for patients with bladder cancer: Variation in the Delivery of Care. Cancer 2011;117:5392-5401.

30. Bolenz C, Ho R, Nuss GR, et al. Management of elderly patients with urothelial carcinoma of the bladder: guideline concordance and predictors of overall survival. BJU Int 2010;106:1324-1329.

31. Miller DC, Murtagh DS, Suh RS, et al. Regional collaboration to improve radiographic staging practices among men with early stage prostate cancer. J Urol 2011;186:844-849.

DISCLAIMER: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Medical Education Resources or Haymarket Medical Education. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of Medical Education Resources or Haymarket Medical Education. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

On The Web Looking for additional credit?

We’ve got many more CME activities online on topics relevant to your practice. Come take a look at www.renalandurologynews.com/CME.

CME Post-test Expiration Date: November 2013 Medical Education Resources designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Participants should claim only the credit commensurate with the extent of their participation in the activity. Physician post-tests must be completed and submitted online. Physicians may register at no charge at www.myCME.com /renalandurologynews. You must receive a score of 70% or better to receive credit.

1. Theoretical benefits to the widespread implementation of guidelinebased care include all of the following, EXCEPT: a. Reduction in the overuse of clinical services b. Reduction in the underuse of clinical services c. Increasing public awareness of to underrepresented diseases d. Developing new documents for patient education e. Increasing healthcare spending 2. All of the following are true regarding guideline development, EXCEPT: a. They are routinely developed by a panel of experts in a particular field b. They are based upon a combination of evidence and expert opinion c. All guideline panels use the same approach to development d. The IOM has set standards for the development of trustworthy guidelines e. They are frequently limited by a paucity of high-quality evidence 3. The 2007 AUA Guidelines for the management of NMIBC grade recommendations as: a. Grade A, Grade B, Grade C b. Standard, Recommendation, Option c. Category 1, Category 2, Category 3 d. Level 1, Level 2, Level 3 e. None of the above 4. The AUA, EAU, and NCCN clinical practice guidelines on the management of NMIBC share in common recommendations regarding the: a. Intervals of surveillance cystoscopy during follow-up b. Intervals of a upper tract imaging during follow-up c. Utility of flourescence cystoscopy d. Administation of a single dose of perioperative intravesical chemotherapy after transurethral resection of bladder tumor for low-grade tumors e. SWOG maintenance BCG protocol for patients with CIS 5. According to the 2011 EAU guidelines, a patient found to have high-grade noninvasive bladder cancer should be treated with intravesical BCG: a. Once weekly for 6 weeks b. Once weekly for 12 weeks c. Once weekly for 6 weeks, followed by monthly for 6 months d. Once weekly for 6 weeks, followed by maintenance for 12 months e. Once weekly for 6 weeks, followed by maintenance for 36 months 6. A patient is diagnosed with a solitary high-grade urothelial carcinoma invading the lamina propria (clinical T1) without the presence muscularis propria in the specimen. Which of the following is considered “standard” by the 2007 AUA guidelines? a. Administration of a single dose of perioperative mitomycin-C b. Administration of an induction (6-week) course of BCG c. Administration of maintenance BCG d. Radical cystectomy e. Re-resection if the index specimen does not contain muscularis propria

CODE: FER-12-5 Delivery Support: 212.237.7000

PRODUCTION: R. Panariello

LIVE: 10” x 13.5”

DESCRIPTION: Nocturia

PUB/POST: Renal & Urology News - cover

WORKORDER #: 004688

TRIM: 10.5” x 14”

FILE: 05A-004688-05A-FER-12-5 TAB.indd

SAP #: TEMP.01584

BLEED: 10.75” x 14.25”

If it’s not BPH or OAB that’s keeping your patients up at night, something else quite common may be causing their 1

Excessive production of urine at night is one of the leading causes of nocturia, with a diagnosis confirmed in the majority of patients.1-4 Learn more about the causes of nocturia, and access useful tools and resources.

Visit NocturiaResources.com.

References: 1. Weiss JP, van Kerrebroeck PEV, Klein BM, et al. Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia. J Urol. 2011;186:1358-1363. 2. Nørgaard JP, Hashim H, Malmberg L, et al. Antidiuresis therapy: mechanism of action and clinical implications. Neurourol Urodyn. 2007;26:1008-1013. 3. van Kerrebroeck P, Hashim H, Holm‑Larsen T, et al. Thinking beyond the bladder: antidiuretic treatment of nocturia. Int J Clin Pract. 2010;64:807-816. 4. Nørgaard JP, Holm-Larsen T. Impact of nocturia on the patient and consequences for the payer. Impact dossier (publications summary). 2012:1-73.

UY/374/2012/US ©2012 Ferring B.V. 11/12

Art: LtBlueBkgd_CMYK_RW_v1.psd (CMYK; 264 ppi, 279 ppi; Up to Date), Ferring_Logo_KO_RW_v1.ai (Up to Date), knowNocturiaLogo_RW_v1.ai (Up to Date)