Renal & Urology News June 2013 Issue by Haymarket Media

Volume 12, issue Number 6

RP May Prevent LUTS Progression Following surgery, symptom severity declined significantly and remained stable over 10 years BY JODY A. CHARNOW SAN DIEGO—Although radical prostatectomy (RP) frequently has negative effects on quality of life because of urinary incontinence and erectile dysfunction, removal of the prostate can prevent progression of lower urinary tract symptoms (LUTS), according to study findings presented at the American Urological Association annual meeting. A prospective study of 1,788 men who underwent RP found that men who had clinically significant LUTS preoperatively experienced a decline

in this issue 4 TRT not associated with increased risk of PCa 6 Silodosin aids in the management 1 of acute urinary retention

17 AUA updates PCa screening guidelines

22 Heparin-free hemodialysis is not safer, a study finds

28 Lithotripsy is effective for lower pole stones

Hemodialysis patients should eat more foods high in zinc like oysters. PAGE 23

in LUTS severity and remained stable over a 10-year interval, researchers reported. Prior studies have shown a progressive increase in LUTS for aging men with an intact prostate. “This is an unrecognized benefit of prostatectomy,” said investigator Vinay Prabhu, a fourth-year medical student at New York University School of Medicine. The study findings provide evidence that the prostate is the most important contributor to LUTS in men, Prabhu said.

Drinking Lots of Water May Cut CKD Risk BY ROSEMARY FREI, MSc MONTREAL—Individuals who drink lots of water may lower their risk of chronic kidney disease (CKD), according to investigators. At the Canadian Society of Nephrology’s 2013 annual meeting, researchers reported on an analysis of data from the 2005-2006 National Health and Nutrition Examination Survey (NHANES) data showing that CKD was 2.5 times less likely to develop in people in the highest tertile of water consumption (more than 4 L/day) compared with those in the lowest tertile (less than 2 L/day). continued on page 16

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Radical Prostatectomy’s LUTS Benefit In a study, prostate cancer patients with clinically significant lower urinary tract symptoms (LUTS) experienced significant improvements in American Urological Association Symptom Index (AUASI) score after radical prostatectomy that remained stable for 10 years. Baseline 10 years after surgery

Source: Prabhu V, et al. Radical prostatectomy (RP) prevents age-dependent progression of lower urinary tract symptoms (LUTS). Data presented at the 2013 American Urological Association annual meeting, San Diego. Abstract 80.

He and his colleagues ascertained subjects’ AUA Symptom Index (AUASI) score prior to surgery and three, six, 12, 24, 48, 60, 84, 96, and 120 months after surgery. The study is the longest reported longitudinal assess-

june 2013

ment of LUTS after RP, the researchers noted. The prevalence of clinically significant LUTS declined from 35.5% to 26.9% between baseline and 10 years, Prabhu reported. “This is the opposite continued on page 16

BPH Drug Use Increasing BY JODY A. CHARNOW SAN DIEGO—Physicians in the U.S. increasingly have been prescribing pharmacotherapy to treat lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH), according to data from two studies presented at the American Urological Association annual meeting. In an analysis of National Ambulatory Medical Care Survey 1993-2010 data, Christopher P. Filson, MD, and colleagues at the University of Michigan in Ann Arbor found more than 102 million outpatient visits for men with BPH/LUTS. Alpha blockers were the most commonly prescribed

cme feature

drug class. The proportion of visits in which physicians prescribed alpha blockers alone rose from 8.3% in 1993 to nearly 20% in 2010, Dr. Filson and his colleagues reported. The use of 5-alpha-reductase inhibitors (5-ARIs) alone increased from 3.2% of visits in 1993 to 7.5% of visits in 2009-2010. The use of anticholinergics alone increased from 1.2% of visits in 19992000 to 5.3% of visits in 2009-2010. In the modern era, the researchers noted, tamsulosin was the most common alpha blocker prescribed, accounting for the majority of alpha blocker prescriptions from 2008-2010. continued on page 16

Earn 1 CME credit in this issue

Managing Bone Loss Associated with ADT Page 31

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Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

45 (7.5) 39 (6.5) 38 (6.3) 38 (6.3)

3 (0.5) 1 (0.2) 4 (0.7) 0 (0.0)

14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)

0 (0.0) 3 (1.0) 3 (1.0) 0 (0.0)

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

35 (5.8) 34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2) 30 (5.0) 30 (5.0)

0 (0.0) 3 (0.5) 2 (0.3) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0)

17 (5.6) 14 (4.6) 24 (7.9) 18 (5.9) 10 (3.3) 3 (1.0) 9 (3.0)

0 (0.0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0.0) 0 (0.0) 0 (0.0)

Prostate Cancer Risk Not Higher with TRT Hypogonadal patients received testosterone replacement therapy for up to five years BY ROSEMARY FREI, MSc SAN ANTONIO—A study of hypogonadal men on testosterone replacement therapy (TRT) found no evidence of an increased risk of prostate cancer (PCa), researchers reported at the American Society of Andrology’s 2013 annual meeting. These men did, however, experience weight loss, according to a separate analysis of the same cohort.

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group. (See Adverse Reactions [6] of full Prescribing Information.) To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011. 2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

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Long-term TRT safe “Our evidence suggests that long-term testosterone replacement therapy in hypogonadal men is safe, provided that proper monitoring according to the guidelines is performed,” said Farid Saad, PhD, DVM, the first author of both studies. “And the majority of the men we studied were overweight or obese, so losing weight wasn’t deleterious for them. And 5% gained weight, but they had inflammatory bowel disease and were normal weight or slightly overweight at baseline, so it was beneficial for them to gain weight.” Dr. Saad is Director of Global Medical Affairs Andrology, Bayer Pharma, Berlin, which funded the study and makes the form of testosterone the patients were on. Clinical studies The investigations were open-label, prospective registry studies of 850 testosterone-deficient men. The men received 1,000 mg parenteral testosterone undecanoate six weeks after baseline and then every 12 weeks. They were treated for up to five years. There were three separate cohorts, one from a university-based andrology center and two from urology centers. The andrology center cohort included 334 patients with a mean age of 42 years. One urology-center cohort consisted of 261 men with a mean age of 58 years, and the other included 255 patients with a mean age of 60.6 years. The mean PSA in the first cohort increased from 1.8 to 1.9 ng/mL during the study period. For the other

two groups, the respective increases were from 0.86 to 1.38 ng/mL and from 1.7 to 1.82 ng/mL. Their respective increases in average prostate volume were from 16.1 to 19.7 mL, 28.51 to 30.23 mL and 27.9 to 36.98 mL.

Prostate cancer incidence The PCa incidence rates/10,000 patient-years in the three groups were 0%, 2.3% and 1.18%, respectively. These are significantly lower than the 116 and 96.6/10,000 patientyear rates reported, respectively, in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening

Men on testosterone replacement therapy experienced weight loss, however. Trial (N Engl J Med 2009;360:13101319) and the European Randomized Study of Screening for Prostate Cancer (N Engl J Med 2012;366: 981-990). In the first and second cohorts, the International Prostate Symptom Score decreased from 10.35 to 6.58 and from 6.73 to 2.83, respectively (data unavailable for the third cohort), while post-void residual volume fell from 23.82 to 17.59 mL and from 46.61 to 19.74 mL, respectively.

Unintended weight loss In the youngest cohort, the subjects’ mean body weight dropped from 106.22 to 90.07 kg. The middle cohort’s average body weight decreased from 100.15 to 92.46 kg, and the oldest group’s average weight fell from 103.0 to 79.1 kg. The respective decreases in waist circumference were from 107.24 to 98.46 cm, 107.68 to 97.36 cm, and 114.0 to 94.1 cm. The body mass indices fell from 33.93 to 29.17 kg/m 2, 31.75 to 29.32 kg/m2, and from 31.8 to 24.4 kg/m2, respectively, the researchers noted. n

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www.renalandurologynews.com june 2013

Renal & Urology News 5

News in Brief

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

Short Takes Sodium Bicarbonate May Harm Kidneys

Sildenafil had a browning effect on white fat in mice.

In a multicenter, double-blinded ranundergoing open heart surgery, uri-

Renal Risks Linked to Abdominal Fat

nary alkanization using sodium bicar-

In a recent study of 315 healthy

bonate infusion was associated with a

individuals with a mean body mass

higher incidence of acute kidney injury

index (BMI) of 24.9 kg/m2 and a mean

and a possible increase in mortality,

glomerular filtration rate (GFR) of 109

according to an online report in PLOS

mL/min/1.73m2, higher waist-to-hip

Medicine. Anja Haase-Fielitz, PharmD,

ratio—indicating more central-body

of the Otto-von-Guericke-University in

fat, or “apple-shaped” abdominal

in Magdeburg, Germany, and fellow

adiposity—was associated with lower

investigators recommended that so-

GFR, lower effective renal plasma

dium bicarbonate therapy not be used

flow, and higher filtration fraction. In

to reduce AKI risk in this setting.

an online report in the Journal of the

domized controlled trial of 350 adults

American Society of Nephrology, Arjan

Sildenafil May Have Anti-Obesity Effects

J. Kwakernaak, MD, of the University

The erectile-dysfunction (ED) drug

lands, and coauthors concluded that

sildenafil may also have a role in

central-body-fat distribution may be

the treatment of obesity, according

associated with an unfavorable pat-

to a report in The FASEB Journal

tern of renal hemodynamic measures

(2013;27:1621-1630). The phospho-

independent of BMI.

Medical Center Groningen, the Nether-

“We found that apple-shaped

diesterase type 5 inhibitor was found to stop the breakdown of cyclic GMP,

persons—even if totally healthy and

a messenger molecule that influences

with a normal blood pressure—have

whether the body stores unhealthy

an elevated blood pressure in their

“white fat” or the more desirable

kidneys,” Dr. Kwakernaak said. “When

“brown fat,” which has potential anti-

they are also overweight or obese,

obesity and insulin-sensitizing effects.

this is even worse.”

Acting as a Good Samaritan In a recent online poll, Renal & Urology News asked readers if they would render medical assistance as a “Good Samaritan” to a stranger if they happened to be on hand. Here are the poll findings based on 134 responses.

No, I would not want to risk getting sued 7.46%

Maybe, depending on the circumstances 29.1%

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en who are obese when they undergo a biopsy or transurethral resection of the prostate that yielded benign findings are significantly more likely than non-obese men to have precancerous abnormalities detected at that time, according to study findings published online ahead of print in Cancer Epidemiology, Biomarkers & Prevention. Epidemiologist Andrew Rundle, DrPH, of Columbia University’s Joseph L. Mailman School of Public Health in New York, and colleagues found that in 494 prostate cancer (PCa) cases and 494 matched controls, obesity was associated with the presence of prostatic intraepithelial neoplasia in the initial benign specimen. After adjusting for family history, PSA levels during the initial procedure, the number of PSA tests, and digital rectal examinations during follow-up (median duration of follow-up among cases was 1,538 days), and other variables, obesity at the time of the initial procedure associated with a 57% increased incidence of PCa during follow-up. PCa risk associated with obesity, however, was confined to cases with follow-up less than the 1,538-day median duration of follow-up among cases.

Growth Hormone Boosts Height in Kids on Dialysis G

rowth hormone therapy results in greater increases in height in pediatric dialysis patients regardless of underlying bone histologic features, Katherine Wesseling-Perry, MD, of the David Geffen School of Medicine at the University of California–Los Angeles, and colleagues reported online ahead of print in the Clinical Journal of the American Society of Nephrology. Among 33 patients (median age 11.7 years; median dialysis duration 0.4 year) randomized to therapy with or without growth hormone, the bone formation rate per bone surface increased from 15.0 to 154.6 µm2/ µm3 per year in those with low bone turnover treated with growth hormone and fell from 103.3 to 60.3 µm2/ µm3 per year in those with high bone turnover receiving standard therapy. Parathyroid hormone values did not differ between groups.

Kidney Cancer Mortality Decreased with Surgery E

Yes, as a physician I feel morally obliged to help 63.43%

Precancerous Lesions in the Prostate Linked to Obesity M

lderly patients with localized kidney tumors have a lower risk of cancer-specific mortality (CSM) if they undergo nephrectomy rather than nonsurgical management (NSM), according to researchers. In a study of 10,595 Medicare patients, Maxine Sun, PhD, of the University of Montreal Medical Center, and colleagues found that partial nephrectomy and radical nephrectomy were associated with a significant 55% and 42% decreased risk of CSM than NSM patients, the investigators reported online ahead of print in European Urology. Data did not demonstrate a similar benefit for patients aged 75 years and older. “The harms of surgery need to be weighed against the marginal survival benefit for some patients,” the authors wrote.

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From the Editorial Advisory Board Editorial Advisory Board

Let’s End the Small Renal Mass Dilemma

oming from a urologist who spends half his clinical time treating small renal masses (SRMs), the vow never to treat SRMs may seem hard to believe and selfdefeating. However, times change, and I have reached the point where every time I hear about the treatment of the “small renal mass,” I bristle. About five years ago in The Journal of Urology (2008;179:1227-1233), Robert G. Uzzo, MD, and colleagues published a review of treatment strategies for clinically localized renal masses in which they coined the phrase “the small renal mass dilemma.” The dilemma involved the seeming epidemic of SRMs being treated by urologists. The increased application of imaging technologies was identifying a large number of SRMs. So, what is wrong with treating small incidentally discovered renal tumors? Clearly, early identification and treatment would save lives, right? Sadly, the well-documented rising incidence and stable-torising mortality from renal tumors documents robust overtreatment. Contemporary series report treatment of benign tumors in 25% or more of cases. Another 10%-15% of patients typically have indolent renal cell carcinoma (RCC) subtypes which may not require intervention in older patients with significant co-morbidities. The SRM dilemma really comes down to the identification of the incidental small renal tumors that require treatment. Aggressive histopathologic subtypes of RCC do require intervention, and can be identified with renal biopsy. However, unlike the vast majority of other tumors treated, there is great resistance to renal tumor biopsy. Three major concerns are typically cited: 1) complications associated with the procedure; 2) the risk of tumor seeding; and 3) lack of sensitivity and specificity of results. It is also likely that we urologists are guilty of historical inertia: Tumors discovered in the past were typically large and did not require biopsy as they had a high probability of being aggressive malignancies. Historical concerns regarding SRM biopsy remain largely unfounded. In recent series, the major complication rate is typically less than 1%, and only a handful of reports of tumor seeding exist in the literature. Recent series using needle core biopsies have also demonstrated high sensitivity and specificity. At the University of California Irvine, our team routinely performs renal tumor biopsy in the office setting under local anesthesia with success. Routine biopsy of SRMs is safe and effective. Its application will avoid unnecessary surgery and its complications, and will save the healthcare system valuable resources. The time has come to end the SRM dilemma and vow to never treat SRMs again. Jaime Landman, MD Professor of Urology and Radiology Chair, Department of Urology University of California Irvine School of Medicine Orange, Calif.

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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 The Fred Hatch Professor of Medicine University of Tennessee Health Science Center Memphis Chief of Nephrology Memphis VAMC 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 of Pediatrics and Medicine University of Toronto Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J. Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.

Renal & Urology News Staff Editor Jody A. Charnow Executive editor Marina Galanakis Senior editor Delicia Honen Yard Web editor Stephan Cho Editorial coordinator Candy Iemma Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz VP, audience development and operations John Crewe Production manager Brian Wask Production director Kathleen Millea Circulation manager Paul Silver National accounts manager William Canning Editorial director Jeff Forster Publisher Dominic Barone VP medical magazines and digital products Jim Burke CEO, Haymarket Media Inc. Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 12, Number 6. 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 © 2013.

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Contents

j une

2 0 1 3

V olume

1 2 ,

issue

N um b er

Urology 4

ONLINE

this month at renalandurologynews.com Expert Q&A

Daniel C. Cattran, MD, FRCP(C), of the Toronto General Hospital, University Health Network, provides an update on membranous nephropathy

Clinical Quiz

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

RLS May Increase Risk of Erectile Dysfunction Men who have restless legs syndrome may be at higher risk for erectile dysfunction, new findings suggest.

Lithotripsy Suitable for Lower Pole Stones Extracorporeal shockwave lithotripsy has favorable efficacy in the treatment of lower pole renal stones, according to researchers.

CME Feature 31

Nephrology 22

Postpartum Diabetes Risk Factors ID’d Postpostum diabetes is twice as likely to develop in women with preeclampsia or gestational hypertension compared with those who do not have either condition.

Allopurinol AEs Linked to Colchicine, Statins Patients taking allopurinol are at increased risk for adverse effects from the drug if they also use either colchicine or statins, according to Korean researchers.

News Coverage

Visit our website for coverage of the European Renal Association-European Dialysis and Transplant Association annual congress in Istanbul (May 18-21).

More Physical Activity May Cut Stone Risk Physical activity and greater intake of dietary fiber, fruits, and vegetables may lower the risk of kidney stones in postmenopausal women.

The Medical Minute

Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • Selenium May Protect Against Advanced Prostate Cancer • Some Anemic Kids on Dialysis Are at Higher Death risk • Treating Lung Congestion in Dialysis Patients May Improve CV Health

Prostate Cancer Risk Not Higher with TRT A study of hypogonadal men on testosterone replacement therapy found no evidence of an increased risk of prostate cancer.

Elderly Have More Drug-Induced AIN Proton pump inhibitors found to a major cause of acute interstitial nephritis in this population. Restarting Warfarin Not More Risky in CKD/ESRD Patients The likelihood of recurrent hemorrhage is not significantly different from that of patients with normal kidney function.

Even mild to moderate amounts of exercise

Departments 5

News in Brief Precancerous prostate lesions linked to obesity

From the Editorial Advisory Board Ending the small renal mass dilemma

Renal Nutrition Update Zinc supplementation may benefit dialysis patients

Practice Management Group visits pay off for patients and doctors

Malpractice News Boston hospital divulges medical errors via newsletter

appear to protect against kidney stone formation.

See our story on page 17

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Managing Bone Loss Associated with Androgen Deprivation Therapy J. Bryant Byrd, MD, and William J. Aronson, MD, of the University of California Los Angeles, offer guidance for preventing fractures, treating osteoporosis, and delaying skeletal-related events in men on androgen deprivation therapy for metastatic prostate cancer.

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I0047B_KINGsizeLaunchAd_FR.indd 1

4/8/13 7:00 PM

ENVISION NEW

W B NO LA AI AV

In adults with type 2 diabetes,

POSSIBILITIES Introducing INVOKANA™—the first and only treatment option approved in the United States that reduces the reabsorption of glucose in the kidneys via sodium glucose co-transporter-2 (SGLT2) inhibition1 A1C Reductions as Monotherapy INVOKANA™ monotherapy provided statistically signiﬁcant A1C reductions vs placebo at 26 weeks1

Change in A1C (%) from baseline (adjusted mean)

A1C Change From Baseline With INVOKANA™ Monotherapy1

INVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. INVOKANA™ is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS >>History of a serious hypersensitivity reaction to INVOKANA™. >>Severe renal impairment (eGFR <30 mL/min/1.73 m2), end stage renal disease, or patients on dialysis. WARNINGS and PRECAUTIONS >>Hypotension: INVOKANA™ causes intravascular volume contraction. Symptomatic hypotension can occur after

I0047B_KINGsizeLaunchAd_FR.indd 2

initiating INVOKANA™, particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m2), elderly patients, and patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (eg, angiotensinconverting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA™ in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Please see additional Important Safety Information and Brief Summary of full Prescribing Information on the following pages.

+0.14

0.2 0

DIFFERENCE FROM PLACEBO

–0.4

(95% CI: –1.09, –0.73); P<0.001

(95% CI: –1.34, –0.99); P<0.001

–0.6

–0.77

–0.2

– 0.91

– 1.16

–0.8

–1.03 –1.0 –1.2

Placebo (n=192; mean baseline A1C: 7.97%)

INVOKANATM 100 mg (n=195; mean baseline A1C: 8.06%)

INVOKANATM 300 mg (n=197; mean baseline A1C: 8.01%)

A1C Reductions vs Sitagliptin INVOKANA™ 300 mg demonstrated greater A1C reductions vs sitagliptin 100 mg, in combination with metformin + a sulfonylurea, at 52 weeks (P<0.05)1 >> Difference from sitagliptin†: –0.37% Incidence of Hypoglycemia Monotherapy over 26 weeks: 100 mg: 3.6%; 300 mg: 3.0%; placebo: 2.6%1 With metformin and a sulfonylurea over 52 weeks: INVOKANATM 300 mg: 43.2%; sitagliptin 100 mg: 40.7%1 >> Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue Convenient Once-Daily Dosing1 >> Recommended starting dose: INVOKANA™ 100 mg >> Dose can be increased to 300 mg in patients tolerating 100 mg, who have an eGFR of ≥60 mL/min/1.73 m2, and require additional glycemic control

Eﬀect on Weight* Statistically signiﬁcant weight reductions vs placebo at 26 weeks (P<0.001)1

The most common (≥5%) adverse reactions were female genital mycotic infection, urinary tract infection, and increased urination.

>> Difference from placebo†: 100 mg: –2.2%; 300 mg: –3.3%

References: 1. Invokana [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013. 2. Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-382.

Impact on Systolic Blood Pressure (SBP)* Statistically signiﬁcant SBP lowering vs placebo at 26 weeks (P<0.001)2

Learn more at INVOKANAhcp.com/journal

>> Difference from placebo†: 100 mg: –3.7 mm Hg; 300 mg: –5.4 mm Hg INVOKANA™ is not indicated for weight loss or as antihypertensive treatment. *Prespeciﬁed secondary endpoint. †Adjusted mean.

4/8/13 7:01 PM

ENVISION NEW

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In adults with type 2 diabetes,

Change in A1C (%) from baseline (adjusted mean)

A1C Change From Baseline With INVOKANA™ Monotherapy1

I0047B_KINGsizeLaunchAd_FR.indd 2

+0.14

0.2 0

DIFFERENCE FROM PLACEBO

–0.4

(95% CI: –1.09, –0.73); P<0.001

(95% CI: –1.34, –0.99); P<0.001

–0.6

–0.77

–0.2

– 0.91

– 1.16

–0.8

–1.03 –1.0 –1.2

Placebo (n=192; mean baseline A1C: 7.97%)

INVOKANATM 100 mg (n=195; mean baseline A1C: 8.06%)

INVOKANATM 300 mg (n=197; mean baseline A1C: 8.01%)

Eﬀect on Weight* Statistically signiﬁcant weight reductions vs placebo at 26 weeks (P<0.001)1

The most common (≥5%) adverse reactions were female genital mycotic infection, urinary tract infection, and increased urination.

>> Difference from placebo†: 100 mg: –2.2%; 300 mg: –3.3%

Impact on Systolic Blood Pressure (SBP)* Statistically signiﬁcant SBP lowering vs placebo at 26 weeks (P<0.001)2

Learn more at INVOKANAhcp.com/journal

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IMPORTANT SAFETY INFORMATION (continued from first page)

DRUG INTERACTIONS >> UGT Enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (eg, rifampin, phenytoin, phenobarbitol, ritonavir) must be co-administered with INVOKANA™ (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA™ 100 mg once daily, have an eGFR greater than 60mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and requiring additional glycemic control. >> Digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA™ 300 mg. Patients taking INVOKANA™ with concomitant digoxin should be monitored appropriately. USE IN SPECIFIC POPULATIONS >> Pregnancy Category C: There are no adequate and wellcontrolled studies of INVOKANA™ in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at ≥0.5 times clinical exposure from a 300-mg dose. These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. >> Nursing Mothers: It is not known if INVOKANA™ is excreted in human milk. INVOKANA™ is secreted in the milk of lactating rats, reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA™ showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human

kidney. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from INVOKANA™, a decision should be made whether to discontinue nursing or to discontinue INVOKANA™, taking into account the importance of the drug to the mother. >> Pediatric Use: Safety and effectiveness of INVOKANA™ in pediatric patients under 18 years of age have not been established. >> Geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA™ in nine clinical studies of INVOKANA™. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA™ (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were ≥75 years of age. Smaller reductions in HbA1C with INVOKANA™ relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA™ 100 mg and -0.74% with INVOKANA™ 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA™ 100 mg and -0.87% with INVOKANA™ 300 mg relative to placebo). >> Renal Impairment: The efficacy and safety of INVOKANA™ were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/ 1.73 m2). These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR ≥60 mL/min/1.73 m2); patients treated with INVOKANA™ 300 mg were more likely to experience increases in potassium. The efficacy and safety of INVOKANA™ have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease (ESRD), or receiving dialysis. INVOKANA™ is not expected to be effective in these patient populations.

>> Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA™ has not been studied in patients with severe hepatic impairment and it is therefore not recommended. OVERDOSAGE >> There were no reports of overdose during the clinical development program of INVOKANA™ (canagliflozin). In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. ADVERSE REACTIONS >> The most common (≥5%) adverse reactions were female genital mycotic infections, urinary tract infections, and increased urination. Adverse reactions in ≥2% of patients were male genital mycotic infections, vulvovaginal pruritis, thirst, nausea, and constipation.

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WARNINGS and PRECAUTIONS (cont’d) >> Impairment in Renal Function: INVOKANA™ (canagliflozin) increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA™. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. >> Hyperkalemia: INVOKANA™ can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating INVOKANA™ in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. >> Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA™. >> Genital Mycotic Infections: INVOKANA™ increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections. Monitor and treat appropriately. >> Hypersensitivity Reactions: Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with INVOKANA™ treatment; these reactions generally occurred within hours to days after initiating INVOKANA™. If hypersensitivity reactions occur, discontinue use of INVOKANA™; treat per standard of care and monitor until signs and symptoms resolve. >> Increases in Low-Density Lipoprotein (LDL-C): Doserelated increases in LDL-C occur with INVOKANA™. Monitor LDL-C and treat per standard of care after initiating INVOKANA™. >> Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA™ or any other antidiabetic drug.

Please see Brief Summary of full Prescribing Information on the following pages.

Janssen Pharmaceuticals, Inc. Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. © Janssen Pharmaceuticals, Inc. 2013

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IMPORTANT SAFETY INFORMATION (continued from first page)

K02CAN13149

Please see Brief Summary of full Prescribing Information on the following pages.

Janssen Pharmaceuticals, Inc. Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. © Janssen Pharmaceuticals, Inc. 2013

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April 2013

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INVOKANA™

(canagliflozin) tablets, for oral use Brief Summary of Prescribing Information. IndIcatIons and Usage INVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14) in full Prescribing Information]. Limitation of Use: INVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. contraIndIcatIons • History of a serious hypersensitivity reaction to INVOKANA [see Warnings and Precautions]. • Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease or patients on dialysis [see Warnings and Precautions and Use in Specific Populations]. WarnIngs and PrecaUtIons Hypotension: INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Impairment in renal Function: INVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA [see Adverse Reactions]. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. Hyperkalemia: INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia [see Adverse Reactions]. Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. Hypoglycemia with concomitant Use with Insulin and Insulin secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA. genital Mycotic Infections: INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions]. Monitor and treat appropriately. Hypersensitivity reactions: Hypersensitivity reactions (e.g., generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat per standard of care and monitor until signs and symptoms resolve [see Contraindications and Adverse Reactions]. Increases in Low-density Lipoprotein (LdL-c): Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions]. Monitor LDL-C and treat per standard of care after initiating INVOKANA. Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA or any other antidiabetic drug. adverse reactIons The following important adverse reactions are described below and elsewhere in the labeling: • Hypotension [see Warnings and Precautions] • Impairment in Renal Function [see Warnings and Precautions] • Hyperkalemia [see Warnings and Precautions] • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions] • Genital Mycotic Infections [see Warnings and Precautions] • Hypersensitivity Reactions [see Warnings and Precautions] • Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions] clinical studies 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 the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pool of Placebo-Controlled Trials: The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on therapy [see Clinical Studies (14) in full Prescribing Information]. These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg. table 1: adverse reactions From Pool of Four 26−Week Placebo-controlled studies reported in ≥ 2% of InvoKana-treated Patients* InvoKana InvoKana 300 mg 100 mg Placebo n=834 n=833 Adverse Reaction n=646 Female genital mycotic infections† 3.2% 10.4% 11.4% Urinary tract infections‡ 4.0% 5.9% 4.3% Increased urination§ 0.8% 5.3% 4.6% Male genital mycotic infections¶ 0.6% 4.2% 3.7% Vulvovaginal pruritus 0.0% 1.6% 3.0% Thirst# 0.2% 2.8% 2.3% Constipation 0.9% 1.8% 2.3% Nausea 1.5% 2.2% 2.3% * The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone. † Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=312), INVOKANA 100 mg (N=425), and INVOKANA 300 mg (N=430). ‡ Urinary tract infections includes the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. § Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. ¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=334), INVOKANA 100 mg (N=408), and INVOKANA 300 mg (N=404). # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Pool of Placebo- and Active-Controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients participating in placebo- and active-controlled trials. The data combined eight clinical trials [see Clinical Studies (14) in full Prescribing Information] and reflect exposure of 6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the

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INVOKANA™ (canagliflozin) tablets population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m2). The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg and 1.1% with INVOKANA 300 mg). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In the pool of eight clinical trials with a longer mean duration of exposure to INVOKANA (68 weeks), the incidence rate of bone fracture was 14.2, 18.7, and 17.6 per 1000 patient years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Upper extremity fractures occurred more commonly on INVOKANA than comparator. In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated. Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Other adverse reactions occurring more frequently on INVOKANA than on comparator were: Volume Depletion-Related Adverse Reactions: INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletionrelated adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2) and age 75 years and older (Table 2) [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Use in Specific Populations]. table 2: Proportion of Patients With at Least one volume depletion-related adverse reactions (Pooled results from 8 clinical trials) InvoKana InvoKana comparator 300 mg 100 mg group* % % % Baseline characteristic Overall population 1.5% 2.3% 3.4% 75 years of age and older† 2.6% 4.9% 8.7% eGFR less than 60 mL/min/1.73 m2† 2.5% 4.7% 8.1% Use of loop diuretic† 4.7% 3.2% 8.8% * Includes placebo and active-comparator groups † Patients could have more than 1of the listed risk factors Impairment in Renal Function: INVOKANA is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes. table 3: changes in serum creatinine and egFr associated with InvoKana in the Pool of Four Placebocontrolled trials and Moderate renal Impairment trial InvoKana InvoKana 300 mg 100 mg Placebo n=834 n=833 n=646 Creatinine (mg/dL) 0.84 0.82 0.82 Baseline eGFR (mL/min/1.73 m2) 87.0 88.3 88.8 Pool of Four Creatinine (mg/dL) 0.01 0.03 0.05 PlaceboWeek 6 Change Controlled eGFR (mL/min/1.73 m2) -1.6 -3.8 -5.0 Trials End of Treatment Creatinine (mg/dL) 0.01 0.02 0.03 Change* -1.6 -2.3 -3.4 eGFR (mL/min/1.73 m2) InvoKana InvoKana 300 mg 100 mg Placebo n=89 n=90 n=90 Creatinine (mg/dL) 1.61 1.62 1.63 Baseline eGFR (mL/min/1.73 m2) 40.1 39.7 38.5 Moderate Creatinine (mg/dL) 0.03 0.18 0.28 Renal Week 3 Change Impairment eGFR (mL/min/1.73 m2) -0.7 -4.6 -6.2 Trial End of Treatment Creatinine (mg/dL) 0.07 0.16 0.18 Change* -1.5 -3.6 -4.0 eGFR (mL/min/1.73 m2) * Week 26 in mITT LOCF population In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline. In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information], the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with INVOKANA 100 mg, and 22.5% with INVOKANA 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with INVOKANA 100 mg, and 3.4% with INVOKANA 300 mg had a significant renal function decline. In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m2 (mean baseline eGFR 48 mL/min/1.73 m2), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed. Use of INVOKANA was associated with an increased incidence of renal-related adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment. In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with INVOKANA 100 mg, and 9.3% with INVOKANA 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with INVOKANA 100 mg, and 1.6% with INVOKANA 300 mg [see Warnings and Precautions]. Genital Mycotic Infections: In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and antimicrobial agents [see Warnings and Precautions]. In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA

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INVOKANA™ (canagliflozin) tablets

versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions]. Hypoglycemia: In all clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies (14) in full Prescribing Information], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 4) [see Warnings and Precautions]. table 4: Incidence of Hypoglycemia* in controlled clinical studies

dilatation were evident at greater than or equal to 0.5 times clinical exposure from a 300 mg dose [see Nonclinical Toxicology (13.2) in full Prescribing Information]. These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. nursing Mothers: It is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.2) in full Prescribing Information]. Pediatric Use: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established. geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA [see Clinical Studies (14.3) in full Prescribing Information]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) in full Prescribing Information and Adverse Reactions]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo). renal Impairment: The efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information]. These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2); patients treated with INVOKANA 300 mg were more likely to experience increases in potassium [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Adverse Reactions]. The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications and Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3) in full Prescribing Information]. overdosage There were no reports of overdose during the clinical development program of INVOKANA (canagliflozin). In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. PatIent coUnseLIng InForMatIon See FDA-approved patient labeling (Medication Guide). Instructions: Instruct patients to read the Medication Guide before starting INVOKANA (canagliflozin) therapy and to reread it each time the prescription is renewed. Inform patients of the potential risks and benefits of INVOKANA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change. Instruct patients to take INVOKANA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time. Inform patients that the most common adverse reactions associated with INVOKANA are genital mycotic infection, urinary tract infection, and increased urination. Inform female patients of child bearing age that the use of INVOKANA during pregnancy has not been studied in humans, and that INVOKANA should only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Instruct patients to report pregnancies to their physicians as soon as possible. Inform nursing mothers to discontinue INVOKANA or nursing, taking into account the importance of drug to the mother. Laboratory Tests: Due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine. Hypotension: Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake. Genital Mycotic Infections in Females (e.g., Vulvovaginitis): Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions]. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis): Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions]. Hypersensitivity Reactions: Inform patients that serious hypersensitivity reactions such as urticaria and rash have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction or angioedema, and to take no more drug until they have consulted prescribing physicians. Urinary Tract Infections: Inform patients of the potential for urinary tract infections. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur.

Monotherapy (26 weeks) Overall [N (%)] In combination with Metformin (26 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin (52 weeks) Overall [N (%)] Severe [N (%)]† In combination with sulfonylurea (18 weeks) Overall [N (%)] In combination with Metformin + sulfonylurea (26 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin + sulfonylurea (52 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin + Pioglitazone (26 weeks) Overall [N (%)] In combination with Insulin (18 weeks) Overall [N (%)] Severe [N (%)]†

Placebo (n=192) 5 (2.6) Placebo + Metformin (n=183)

InvoKana 100 mg (n=195) 7 (3.6) InvoKana 100 mg + Metformin (n=368)

InvoKana 300 mg (n=197) 6 (3.0) InvoKana 300 mg + Metformin (n=367)

3 (1.6) 0 (0) glimepiride + Metformin (n=482) 165 (34.2) 15 (3.1) Placebo + sulfonylurea (n=69) 4 (5.8) Placebo + Metformin + sulfonylurea (n=156) 24 (15.4) 1 (0.6) sitagliptin + Metformin + sulfonylurea (n=378) 154 (40.7) 13 (3.4) Placebo + Metformin + Pioglitazone (n=115) 3 (2.6) Placebo (n=565) 208 (36.8) 14 (2.5)

16 (4.3) 1 (0.3) InvoKana 100 mg + Metformin (n=483) 27 (5.6) 2 (0.4) InvoKana 100 mg + sulfonylurea (n=74) 3 (4.1) InvoKana 100 mg + Metformin + sulfonylurea (n=157) 43 (27.4) 1 (0.6)

17 (4.6) 1 (0.3) InvoKana 300 mg + Metformin (n=485) 24 (4.9) 3 (0.6) InvoKana 300 mg + sulfonylurea (n=72) 9 (12.5) InvoKana 300 mg + Metformin + sulfonylurea (n=156) 47 (30.1) 0 InvoKana 300 mg + Metformin + sulfonylurea (n=377) 163 (43.2) 15 (4.0) InvoKana 300 mg + Metformin + Pioglitazone (n=114) 6 (5.3) InvoKana 300 mg (n=587) 285 (48.6) 16 (2.7)

InvoKana 100 mg + Metformin + Pioglitazone (n=113) 3 (2.7) InvoKana 100 mg (n=566) 279 (49.3) 10 (1.8)

* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population † Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) Laboratory Tests: Increases in Serum Potassium: Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information]. In this trial, increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. More severe elevations (i.e., equal or greater than 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions]. Increases in Serum Magnesium: Dose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean change in serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Serum Phosphate: Dose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C): In the pool of four placebo-controlled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions]. Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups. Increases in Hemoglobin: In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal. drUg InteractIons Ugt enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3) in full Prescribing Information]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately. Use In sPecIFIc PoPULatIons Pregnancy: Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular

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Water and CKD risk continued from page 1

The mechanism is likely to be decreased production of arginine vasopressin, a hormone that has negative effects on renal hemodynamics and blood pressure. Increased water intake suppresses its production, according to the investigators. The findings also were published recently in the American Journal of Nephrology (2013;37:434-442). The study focused on 3,426 people who completed a dietary interview and physical examination. The median total water intake was 5.4 L/day in the highest tertile, while it was 2.9 L/day in the middle tertile, and 1.6 L/day in the lowest tertile. Subjects in the lowest tertile had a higher average age than those in the highest tertile (mean 47 vs. 42 years), a higher percentage of females (69% vs. 35%), lower per-

BPH drugs continued from page 1

Prior to the introduction of tamsulosin in 1996, urologists were no more likely to prescribe alpha blockers than primary care physicians; after tamsulosin became available, urologists were nearly twice as likely to prescribe alpha blockers, a finding that suggests urologists may adopt novel medications more readily than primary care providers, according to the investigators. This finding is important because primary care physicians provide a large portion of BPH care in the U.S, said Dr. Filson, who is a research fellow. “Understanding these [prescribing] differences may help reveal educational barriers or differences in severity of disease in terms of the patients that primary care providers and urologists treat,” he told Renal & Urology News. The other study examined trends in the medical management of BPH/LUTS in the Veterans Affairs Healthcare System. The study, by Bradley Erickson, MD, MS, and collaborators at the University of Iowa Carver College of Medicine in Iowa City, included 505,314 veterans with newly diagnosed with BPH/ LUTS. Results showed that the proportion of men who were prescribed pharmacotherapy within 90 days of diagnosis increased from 32.2% in 2003-2004 to 44.8% in 2009-2010. The increase was greater among men aged 40-59 than men aged 60 or older, the researchers reported. Alpha blockers

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centage of non-Hispanic whites (57% vs. 83%), were less likely to have gone beyond a high school education (48% vs. 65%), had a lower percentage of obese subjects (28% vs. 32%), were less likely to be currently smoking (22% vs. 38%), and were more likely to be sedentary (76% vs. 50%) or to have high blood pressure (31% vs. 26%) or diabetes (11% vs. 8%). They also had a considerably lower mean sodium intake (2,595 vs. 4,697 mg/day). The lowest-tertile group had the highest percentage (8.4%) of individuals with an eGFR of 30-60 (stage 3 CKD). The proportion of subjects with stage 3 CKD in the middle and highest tertiles was 3.7% and 1.3%, respectively. Compared with those in the highest tertile, those in the lowest tertile had a 2.5 times increased risk for CKD after adjusting for age, gender, ethnicity, body mass index, dietary sodium, smoking, hypertension, and

Key Points ■■ From 1993 to 2010, the

proportion of visits in which alpha blockers alone were prescribed increased from 8.3% to nearly 20%. ■■ In the modern era, tamsulosin

has accounted for the majority of alpha blocker prescriptions. ■■ Prescriptions for 5-alpha-

reductase inhibitors rose from 3.2% of visits in 1993 to 7.5% of visits in 2009-2010.

were the most commonly prescribed drugs, and their use remained stable during the study period (86.4% and 85.8% of prescriptions in 2003-2004 and 2009-2010, respectively). From 2003 to 2010, 5-ARI use increased from 12.9% to 17% of prescriptions, while the use of anticholinergic drugs decreased from 6.6% to 4.4% of prescriptions. In addition, from 2003 to 2010, the mean age at diagnosis decreased significantly from 65.8 to 60 years and the percentage of white patients decreased significantly from 70.2% to 65.8%. Dr. Erickson and his colleagues concluded that “earlier age at BPH/LUTS diagnosis combined with earlier initiation of pharmacotherapy is likely to expose more men to a longer duration of treatment with uncertain long-term consequences.” n

diabetes. Subjects in the middle tertile had a 48% increased risk. The protective effect was almost entirely from plain water rather than water from other types of drinks.

Drinking more than 4.3 liters a day found to have a protective effect. Participants in the lowest tertile of water intake had more cardiovascular disease (CVD), but the investigators’ analyses did not turn up a statistically significant association between low water intake and CVD. The team also has completed a pilot prospective study that shows it is safe to hyperhydrate patients with an estimated glomerular filtration rate of

RP and LUTS continued from page 1

of what would be expected in the general population,” he said. The long-term impact of RP on men with baseline clinically significant LUTS who completed the AUASI at baseline and 10 years was a statistically significant decline in mean symptom score from 13.5 to 8.8. “This is a remarkable five-point improvement that remains durable at long-term follow-up,” he said. The new findings echo those of a longitudinal study published in April in Urology (2013;81:787-793), which found significant gradual improvement in

30 -60 mL/min/1.73 m2, and that participants can be successfully coached to hyperhydrate, said lead investigator William F. Clark, MD, Professor of Medicine at Western University in London, Ontario. The results will be presented at the American Society of Nephrology’s annual meeting in October, he said. Based on the success of the pilot study, Dr. Clark and his team launched a randomized, controlled trial of hyperhydration in April. They are enrolling the first of 700 participants with an eGFR of 30-60, Dr. Clark said. Adult participants are being randomized to drink between 1.0 and 1.5 litres of water a day in addition to their usual fluid intake for one year. Dr. Clark’s team will measure subjects’ eGFRs every three months and compare their renal function changes with those of controls who have usual fluid intake without drinking extra water. n

moderate-to-severe LUTS over a oneyear period following robotic-assisted RP. The study, by Jeong Hyun Kim, MD, and colleagues at the Cancer Institute of New Jersey, included 127 men who underwent RARP and completed the AUASI questionnaire preoperatively and at three, six, and 12 months postoperatively. Patients with mild LUTS had a significant increase in AUASI score at three months after surgery, but LUTS began to improve at six months postoperatively. Increased BMI was associated with a lack of improvement in LUTS, and early recovery of urinary incontinence after surgery predicted better symptomatic improvement in LUTS. n

Study: Silodosin Improves Management of AUR Silodosin treatment significantly increases the likelihood of successful trial without catheter (TWOC) after acute urinary retention (AUR) in men with benign prostatic hyperplasia, according to a new study. Researchers randomized 60 men older than 50 years with AUR to receive silodosin 8 mg once daily or placebo for three days followed by TWOC. Patients who had recurrent urinary retention or post-void residual urine volume greater than 150 mL were re-catheterized and considered to have a failed TWOC. All patients with a successful TWOC on day 3 were started on silodosin regardless of which arm they had been assigned to initially. The two treatment arms were similar with respect to demographics and clinical characteristics. The TWOC success rate was significantly greater in the silodosin than the placebo arm (76.7% vs. 36.7%), Santosh Kumar, MS, MCh, FRCS, and colleagues at the Postgraduate Institute of Medical Education and Research in Chandigarh, India, reported online ahead of print in Urology. The researchers reported no significant adverse effects with silodosin use. n

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Renal & Urology News 17

Reports from the American Urological Association annual meeting, San Diego

aua 2013 ■

BY JODY A. CHARNOW Physical activity and greater intake of dietary fiber, fruits, and vegetables may lower the risk of kidney stones in postmenopausal women, researchers reported. “Even mild to moderate amounts of exercise appear to protect against kidney stone formation,” said lead investigator Mathew D. Sorensen, MD, of the University of Washington Medical Center in Seattle. “It is not the intensity of the activity that appears to matter; it’s the amount of activity.” He and his colleagues analyzed data from 84,225 postmenopausal women aged 50-79 enrolled 1993-1998 in the Women’s Health Initiative (WHI) Observational Study who had no history of kidney stones and had filled out the WHI food frequency questionnaire. Women reported kidney stone development annually. The median follow-up was eight years. Incident kidney stones were reported by 2,392 women (2.8%). Women in the lowest physical activity category

Lithotripsy May Raise Risk of HTN Extracorporeal shock wave lithotripsy (SWL) is an independent risk factor for hypertension (HTN) in patients without chronic kidney disease (CKD). The new findings come from a study of 24,461 Taiwanese patients diagnosed with upper urinary tract stones and who did not have HTN. The patients had a minimum follow-up of eight years. Among patients without CKD, patients who underwent SWL for kidney stones

had a 14% decreased risk of kidney stones compared with sedentary women in adjusted analyses. Moreover, as weekly activity increased, Dr. Sorensen’s team observed up to a 31% decreased risk of kidney stones. Intensity of activity was not associated with stone formation, according to the researchers. The study also showed that greater dietary energy intake was associated with up to a 42% increased risk of incident kidney stones. Lower dietary energy intake, however, did not protect against stone formation. Greater body mass index increased the risk of incident stones. For women to get the maximum benefit in terms of lowering stone risk, they would need to engage in a modest amount of physical activity, such as three hours of leisurely walking at about two to three miles per hour or four hours of gardening in a week, Dr. Sorensen said. “We’re not talking about running a marathon,” he said.

More Activity May Cut Stone Risk

Leisurely walking could lower a women’s stone risk.

Using the same study population, Dr. Sorensen’s team examined the effect of diet on kidney stone risk. Greater intake of total fiber, fruits, and vegetables was associated with up to a 28%, 26%, and 26% decreased risk

of kidney stones, respectively. These protective factors did not exist in an exploratory analysis of women with a history of kidney stones, Dr. Sorensen and his colleagues reported. These new findings add to the growing medical literature on the association between lifestyle factors and kidney stone risk. A recent study published online ahead of print in The Journal of Urology by Eric N. Taylor, MD, MSc, and Gary C. Curhan, MD, ScD, both of Harvard Medical School in Boston, showed that higher dietary calcium intake is independently associated with a significantly decreased risk of symptomatic kidney stones. Other investigations, however, suggest that higher intake of some dietary nutrients may increase kidney stone risk. For example, a study published in the American Journal of Nephrology (2012;36:549-553) found that subjects with the highest intake of dietary zinc had a significant 70% increased risk of kidney stones compared with those who had the lowest intake. n

AUA Updates PCa Screening Guidelines Updated American Urological Association (AUA) guidelines for prostate cancer screening recommend that men aged 55-69 who are considering PSA screening talk with their doctors about the benefits and harms of testing and proceed based on their personal values and preferences. The new guidelines, which update the AUA’s 2009 Best Practice Statement on Prostate-Specific Antigen, do not recommend screening among men younger than age 40 and routine screening among men aged 40 to 54 at average risk.

The new guidelines were announced at the 2013 AUA annual meeting. To reduce the harms of screening, a routine screening interval of two years or more may be preferred over annual screening in men who have participated in shared decision-making and decided to be screened. Compared with annual screening, it is expected that screening intervals of two years preserve the majority of benefits and decrease overdiagnosis and the number of false positives. Routine PSA screening also is not recommended for men older than 70 years

or any man with less than a 10-15 year life expectancy. According to AUA, the new guidelines differ significantly from previous statements in that they were developed using evidence from a systematic literature review rather than consensus opinion. The highest-quality evidence for screening benefit (lower PCa mortality) was for men aged 55-69 years screened at two- to four-year intervals. Data showed that one man per 1,000 screened will prevent a PCa death over a decade. n

NSS Offers Better Renal Function Preservation

had a significant 13.4% increased risk of HTN than those who did not, HsiaoJen Chung, MD, of Taipei Veterans General Hospital, and colleagues reported. SWL for ureteral stones was not associated with an increased risk of HTN. n

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Nephron-sparing surgery (NSS) for small renal masses may be more effective in reducing serum creatinine levels compared with radical nephrectomy (RN), data show. Using data from the European Organization for Research and Treatment of Cancer trial 30904,

Emil Scosyrev, PhD, and colleagues at the University of Rochester Medical Center studied 258 patients who were randomized to undergo RN and 254 were randomized to undergo NSS. The mean serum creatinine level after surgery was 1.411 mg/dL in RN patients and 1.153 in NSS, a signifi-

cant difference of 0.258 mg/dL. Over 15 years of follow-up (median 6.7 years for serum creatinine), researcher found an estimated average rate of change of -0.008 mg/dL per year with RN and 0.004 mg/dL per year with NSS, a significant difference between the treatment arms. n

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Postpartum Diabetes Risk Factors ID’d Preeclampsia and gestational hypertension each increase the risk of diabetes twofold, study finds BY ROSEMARY FREI, MSc Having preeclampsia (PEC) or gestational hypertension (GH) doubles women’s risk of developing postpartum diabetes compared with those who do not have either condition, a new study has revealed. Furthermore, gestational diabetes (GDM) is associated with a nearly 13 times increased risk of developing postpartum diabetes, according to an analysis of health information from more than one million women who delivered babies in Ontario, Canada, from April 1994 to March 2008. The investigators, who reported their findings in PLoS Medicine (2013;10:e1001425), were surprised at the magnitude of increased risk for diabetes conferred by these conditions. They recommend that health care providers screen their pregnant patients for a history of preeclampsia or gestational hypertension. “Also, they should screen their female patients regularly for diabetes, and counsel them to maintain a normal weight and exercise regularly because this may prevent the onset of diabetes,”

Hyponatremia Linked to Thiazide Use Thiazide use is associated with an increased risk of hyponatremia, and this risk is greater for younger individuals and those with lower body mass index, according to a population-based study. Compared with individuals not exposed to thiazides, those who took the medications had a nearly fivefold

lead investigator Denice Feig, MSc, told Renal & Urology News. Feig is a scientist with the Institute for Clinical Evaluative Sciences in Toronto, and the head of the Mount Sinai Hospital’s Diabetes & Endocrinology in Pregnancy Program. Her team conducted the study because previous research showed women with PEC and GH also have insulin resistance, and PEC/GH is associated with other disorders linked to intrapartum insulin resistance. The team identified women with PEC, GH, or GDM from the Canadian Institute for Health Information Discharge Abstract Database and excluded those with pre-existing diabetes or hypertension. They analyzed the resulting 1,010,068 women’s records. The available information did not include obesity level or other factors known to be associated with the development of diabetes such as family history and amount of physical activity. It also did not indicate whether the cases of postpartum diabetes were type 1 or type 2; however, the investigators

Risk Factors for Postpartum Diabetes A Canadian population-based cohort study found that the presence of preeclampsia (PEC), gestational hypertension (GH), or gestational diabetes (GDM) during pregnancy increases the risk of developing postpartum diabetes. The magnitude of these increased risks is shown here. 12.8 gdm

20 15 10 5

2.0 PEC

15.7 gdm & pec

18.5 gdm & gh

2.0 gh

The number of times by which the risk of postpartum diabetes increases Source: Feig D, et al. Preeclampsia as a risk factor for diabetes: a population-based cohort study. PLoS Med 2013;10:e1001425.

believe most cases were likely to be type 2 because of the age of the women in the study. The number of women who would have to be followed for five years to detect one case of diabetes was 4,511 with GH alone, 123 for PEC alone, 68 for GDM alone, 31 for GDM plus PEC and 105 for GDM plus GH. The 30,852 women with GDM were significantly older than those without this condition, and also had lower

incomes. Moreover, they were more likely to have pre-existing hypertension and comorbidities. The researchers found that PEC alone and GH alone are associated with a twofold higher risk of developing diabetes. GDM alone was associated with a 12.8 times increased risk. GDM plus PEC was associated with a 15.7 times increased risk and GDM plus GH was associated with an 18.5 times increased risk. n

LVH Tied High Dietary Phosphorus Higher dietary phosphorus intake is associated with greater left ventricular mass (LVM) and an elevated risk of left ventricular hypertrophy (LVH) in women, but not men, new findings suggest. A team led by Bryan Kestenbaum, MD, of the University of Washington in Seattle, investigated the link between dietary phosphorus and left ventricular mass (LVM) in a group of 4,494 participants in the Multi-Ethnic Study of Atherosclerosis, a community-based study of individual free of known car-

diovascular disease. The researchers estimated dietary phosphorus intake using a 120-item food frequency questionnaire. LVM was measured using magnetic resonance imaging. The mean dietary phosphorus intake was 1,167 mg/day among men and 1,017 mg/day among women, the investigators reported online ahead of print in Kidney International. Each quintile increase in the estimated dietary phosphorus intake was associated with an estimated 1.1 gram increment in LVM, after adjusting for demographic fac-

tors, dietary sodium, total calories, comorbidities, lifestyle factors, and known LVH risk factors, accorsing to the researchers. The highest genderspecific dietary phosphorus quintile was associated with an estimated 6.1 gram greater LVM compared with the lowest quintile. Compared with the lowest quintile of dietary phosphorus intake, the highest quintile was associated with a threefold increased risk of LVH among women, but no increased risk among men in adjusted analyses, the researchers found. n

increased risk of hyponatremia, researchers reported online ahead of print in the American Journal of Kidney Disease. The study, by Eline M. Rodenburg, MD, of Erasmus Medical Center in Rotterdam, the Netherlands, and colleagues, included 13,325 individuals aged 45 years and older living in a suburb of Rotterdam. Hyponatremia developed in 522 subjects. n

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Study: Heparin-Free Hemodialysis Not Safer Heparin-free hemodialysis (HD) is not significantly associated with decreased likelihood of death, bleeding or thrombosis, according to a recent study. The finding suggests that HD without heparin may be no safer than HD with heparin, researchers concluded.

Jenny I Shen, MD, and colleagues at the Stanford University School of Medicine in Palo Alto, Calif., identified 12,468 patients aged 67 years or older with no recent history of warfarin use who initiated maintenance HD from 2007-2008. Of these patients, 836 (6.7%) were dialyzed without heparin.

The researchers found no significant difference between heparin-free HD and HD with heparin with respect to all-cause mortality, bleeding, atherothrombosis, or venous thromboembolism, according to findings published online ahead of print in Nephrology Dialysis Transplantation. n

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Renal Nutrition Update Zinc supplementation may benefit dialysis patients by protecting them from inflammation, malnutrition, and oxidative damage By GRISSIM CLARK CONNERY, MS, RD, LD

Improved immunity Subsequently, multiple markers of inflammatory and oxidative stress have been shown coincide with low zinc, selenium, and iron levels (Perit Dial Int 2011;31:583-591). In a twoyear prospective trial involving dialysis patients, low serum zinc was an independent predictor for increased risk of infection and overall mortality for those with a serum value less than the median of 72.2 μg/dL (Clin Nutr 2012;31:630-636). A possible future evaluation parameter for zinc status in kidney disease populations involves metallotheionein (MT), a protein involved in heavy metal and free radical protection in

On The Web RUN0613_RenalNut.indd 23

renal tissues. In rodent studies, zinc depletion has been shown to decrease zinc and MT levels, whereas repletion upregulates MT concentration without changing zinc levels. These results could indicate that MT is a more sensitive marker for changes in zinc concentration (J Trace Elem Biol 2009;23:176-182). Renal populations are at increased risk for accumulations of toxic metals, and thus the combined benefit of zinc on immune function and MT function may increase future focus on zinc supplementation for improved health outcomes.

Lead, aluminum protection Zinc supplementation has been shown to decrease renal lead concentrations while upregulating MT concentrations. Lead is a renal toxicant, and zinc supplementation appears to offer protective effects against this metal (Biometals 2008;21:29-40). Other metals such as elevated plasma aluminum also present risk factors for oxidative stress in dialysis populations (Clin Biochem 2011;44:1309-1314). In a recent study of zinc-deficient dialysis patients (Nutrients 2013;5:1456-1470), zinc supplementation significantly decreased levels of plasma aluminum and reactive oxygen species and increased plasma zinc and selenium concentrations. Additionally, zinc supplementation was associated with elevated levels of superoxide dismutase, albumin, and hemoglobin, and reduced levels of the oxidative product malondialdehyde. Improved protein catabolic rate Zinc supplementation has been shown to correlate with other beneficial parameters, such as improved protein catabolic rate (PCR). In a study of a group of dialysis patients supplemented with zinc, PCR improved without a change in dietary protein intake (J Ren Nutr 2000;10:148-153). Another

inc is an essential trace mineral in the human diet that is an important cofactor in the body’s natural antioxidant machinery. It is necessary for anti-inflammatory activity and proper immune function. Zinc deficiency is associated with malnutrition, whereas increased concentrations have been shown to improve inflammation and malnutrition in dialysis patients (Nutrients 2013;22;5:1456-1470). In dialysis populations, dietary intake of zinc is often low (Perit Dial Int 2012;32:183-191; Am J Clin Nutr 2002;76:569-576). Hemodialysis (HD) patients exhibit reduced zinc levels when malnourished (Biol Trace Elem Res 2009;127:191-199), but the etiology of kidney disease affects the magnitude of zinc deficiency. Interestingly, one study demonstrated that zinc concentrations correlated with uric acid and parathyroid hormone (PTH) (Biol Trace Elem Res 2006;113:209-222). Zinc is a necessary cofactor in superoxide dismutase, an enzyme necessary for protection against oxidative damage. Studies have found the activity of superoxide dismutase to be lower in dialysis patients (Nutr Hosp 2011;26:1456-1461).

Oysters are the most concentrated food source of zinc, according to the USDA.

study found that, in zinc supplemented HD patients, serum zinc positively correlated with LDL cholesterol levels. Of note, though, energy intake increased significantly in the zinc supplemented group compared with controls. The changes in cholesterol may be explained by caloric intake alone, and this study leads to further questions regarding the effect of zinc on appetite (J Ren Nutr 2002;12:183-189). In diabetic patients with albuminuria, a combination of magnesium, zinc, vitamin C, and vitamin E was shown to decrease urinary albumin excretion, blood pressure, fasting serum glucose, and malondialdehyde while increasing HDL and apolipoprotein A1. These effects were not significant when the vitamins were not supplemented with the minerals (Diabetes Care 2005;28:2458-2464). It is important to note that benefits from zinc supplementation can be seen in as little as two months; two weeks has not been shown to be beneficial (Nutrients 2013;5:1456-1470; Rev Invest Clin 2003;55:519-527). Dietary interventions focusing on education

have been shown to reduce hypozincemia in patients with chronic renal failure amidst protein restriction (Magnes Res 2009;22:72-80). Furthermore, choice of phosphate binder does not appear to affect zinc concentrations (Nephrol Dial Transplant 2011;26:1006-1010.

Oysters the richest source According to the U.S. Department of Agriculture food and nutrient database, the most concentrated food source of zinc is oysters, providing 74 mg in a 3 oz cooked portion. Enriched cereals and beef provide the next highest sources, but these typically range from 4-9 mg per serving. Oysters are not excessively high in potassium and have a 10.9 ratio phosphorus/protein. For future studies on zinc intervention in dialysis patients, oysters could be used as a food source much like recent studies using Brazil nuts as a rich source of selenium. n 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 helping patients manage sodium and phosphorus intake. See us at www.renalandurologynews.com/nutrition.

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24 Renal & Urology News

■ NKF 2013

june 2013 www.renalandurologynews.com

Reports from the National Kidney Foundation’s 2013 Spring Clinical Meetings, Orlando, Fla.

Elderly Have More Drug-Induced AIN Proton pump inhibitors are a major cause of acute interstitial nephritis in this population Elderly patients have a higher incidence of drug-induced acute interstitial nephritis (AIN) than younger patients, new findings suggest. The study, led by Angela K. Muriithi, MB, ChB, of Mayo Clinic in Rochester, Minn., revealed that proton pump inhibitors (PPIs) are a major cause of AIN in the elderly. In fact, it was the second most common cause of druginduced AIN behind antibiotics. “Previous studies have suggested that patients over age 65 years may have higher risk of developing AIN, especially from drugs,” Dr. Muriithi told Renal & Urology News. “We were able to show that in fact in the elderly, drugs are more likely to be the cause of AIN than in younger patients. Autoimmune causes are rare in this age group.”

PCa Need Not Preclude Transplants Early kidney transplantation in patients with prostate cancer (PCa) is associated with improved survival compared with remaining on hemodialysis (HD), researchers reported. Thet Zaw, MD, and colleagues at Newark Beth Israel Medical Center in Newark, N.J., noted that for patients on HD to be eligible for a kidney transplant, they must have a two-year cancer-free period immediately preceding transplantation. The purpose of their study was to determine if some patients with PCa would be better served by undergoing kidney transplantation rather than waiting for two years to be declared cancer-free. Dr. Zaw’s group studied 30 kidney transplant recipients diagnosed with PCa prior to transplantation. They assumed that patients incidentally diagnosed with PCa within six months of transplantation likely had PCa prior to transplantation. The patients had a five-year mortality rate of 3.3%. By comparison, HD patients overall have a five-year mortality rate of 73.6%, according to 2000-2007 data from the U.S. Renal Data System.

RUN0613_NKF2.indd 24

Dr. Muriithi’s group cited a recent registry study published in Nephrology Dialysis Transplantation (2013;28:112115) showing that the prevalence of AIN has increased about threefold in all patients from 1994-2009 and eightfold among elderly patients. Dr. Muriithi and her colleagues retrospectively studied 133 patients with biopsy-proven AIN. Of these, 45 were elderly (older than 65 years). Drug-induced AIN occurred significantly more frequently in the elderly patients than the younger patients (87% vs. 64%). Antibiotics were the single biggest cause of drug-induced AIN in both the elderly and younger patients (47% and 30% of cases, respectively). Of the 13 cases of AIN caused by PPIs, eight (18%) occurred

The researchers concluded that PCa should not preclude kidney transplantation “since slow growth and early detection carries a good prognosis.” Surgery and radiation therapy may be curative treatments for localized tumors, they noted. In a separate study also presented at the meeting, Dr. Zaw and collaborators found that surgery and radiation treatment for PCa in kidney transplant patients are associated with similar survival. In a retrospective analysis of the United Network of Organ Sharing (UNOS) database from January 2000 to June 2012, the investigators identified 396 kidney transplant patients who had received surgery or radiation therapy for PCa. Patients were classified according to choice of treatment and treatment outcomes. A total of 156 patients underwent surgery, 211 had radiation therapy, and 29 had both. By the end of the study period, the surviving patients included 150 (96%) of 156 who had undergone surgery, 206 (98%) of 211 who had received radiation therapy, and 27 (93%) of 29 who had both, Dr. Zaw’s group reported. The authors noted that both studies were limited by the unavailability of histopathologic staging, and that a larger study with longer follow up is needed to confirm the findings. n

in the elderly and five (6%) occurred in the younger patients, a significant difference in AIN incidence. Only three (7%) of the elderly patients had autoimmune AIN compared with 24 (27%) of the 88 younger patients. Compared with younger patients, elderly patients were significantly more likely to have pyuria and a significantly higher prevalence of chronic kidney disease at baseline. Additionally, the elderly patients had significantly higher degrees of interstitial fibrosis and glomerulosclerosis. All of the elderly patients with drug-induced AIN except one were treated with steroids. Of the 30 elderly patients with available follow-up information, 25 (83%) showed partial or complete recovery within six months.

“For clinicians seeing elderly patients with unexplained changes in kidney function, even over long periods of time, look into the drugs they are on, with special attention to the PPIs,” Dr. Muriithi said. “We found that these drugs are typically used for long durations and [patients] do not present with dramatic changes in kidney function, which may cause physicians to have a low index of suspicion and cause delays in making the diagnosis. As biopsy remains the gold standard test for the diagnosis for AIN, delays in performing biopsy, with subsequent prolonged exposure to the drug, may have been responsible for lower rates of recovery in elderly patients with AIN due to PPIs as compared to antibiotics.” n

Restarting Warfarin Not More Risky in CKD/ESRD Patients Most physicians tend not to restart

patients who had normal kidney func-

warfarin treatment after a gastrointesti-

tion, the difference was not statistically

nal hemorrhage in patients with chronic

significant. In addition, the risk of GIB

kidney (CKD) or end-stage renal disease

among the CKD and ESRD patients

(ESRD), even though the risk of recur-

restarted on warfarin was similar to

rent hemorrhage is not significantly dif-

that of CKD and ESRD patients who did

ferent from that of patients with normal

not restart warfarin.

kidney function, data show. Fatima Khalid, MD, and her col-

The investigators defined GIB as visible bleeding, hematemesis, melena,

leagues at the Henry Ford Health

endoscopic evidence of bleeding, and

System in Detroit analyzed retrospec-

bright red bleeding from the rectum.

tive data from warfarin-related insur-

The researchers concluded that, as

ance claims and chart reviews. The

with patients who have normal kidney

study included 94 patients with ESRD

function, warfarin should be restarted

and 159 with CKD who experienced

in ESRD and CKD patients who had

gastrointestinal bleeding (GIB) while on

the drug discontinued following an

warfarin and had the drug discontinued.

episode of GIB.

Thirty-two ESRD patients and 89 CKD

“Renal disease is a known risk factor

patients were restarted on warfarin

for atrial fibrillation,” Dr. Khalid told

within 180 days of discontinuation. The

Renal & Urology News. “Although anti-

major reason for not restarting war-

coagulation in atrial fibrillation has been

farin was primary GIB in 69% of ESRD

extensively studied, patients with renal

patients and 56% of CKD patients,

disease are frequently not included in

Dr. Khalid’s team found. Although the

clinical trials of anticoagulant drugs.”

researchers observed a trend towards

This study is one of the first involving

a higher risk of recurrent GIB in CKD

renal disease patients who experienced

and ESRD patients compared with

GIB while on anticoagulation. n

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Renal & Urology News 25

RLS May Increase Risk of Erectile Dysfunction Restless legs syndrome (RLS) may place men at higher risk for erectile dysfunction (ED), new findings suggest. Researchers led by Xiang Gao, MD, of the Channing Laboratory and Harvard Medical School in Boston, prospectively studied 10,394 men in the Health Professionals Follow-up Study (HPFS). In 2002, RLS was found in 331 men. From 2005-2008, researchers identified 1,633 new cases of ED. During this period, ED developed in 23.4% of men who had RLS at baseline compared with 15.4% among those without RLS, Dr. Gao’s group reported online ahead of print in the American Journal of Epidemiology. Men with RLS had a 38% increased risk of ED compared with men without RLS, after

PCa Severity Not Linked to Obesity Prostate cancer (PCa) patients

adjusting for age, smoking status, and other potential confounders. In addition, the risk of ED increased with a higher frequency of RLS symptoms. Compared with men who did not have RLS, those who experienced RLS 5-14 times per month had a 34% increased risk of ED, whereas men who

had RLS 15 or more times per month had a 45% increased risk. The study showed that 9.8% of men with RLS at baseline rated their erectile function as “very poor” in 2008 compared with 5.8% of those without RLS. The HPFS was established in 1986, when 51,529 male U.S. health profes-

sionals aged 40-75 years completed a mailed questionnaire asking about their medical history and lifestyle. Every two years, participants received follow-up questionnaires to obtain updated information on potential risk factors and to identify newly diagnosed diseases. n

He had normal kidney function. He became critically ill. He was diagnosed with AKI.

who are obese are no more likely than those of normal weight to have a higher prebiopsy PSA level or higher-risk disease, according to researchers. Consequently, obese PCa patients might not benefit from more aggressive treatment options, they concluded. Karim Chamie, MD, and colleagues at the University of California Los Angeles reviewed data on 573 men with a mean age of 61.5 years and median prebiopsy PSA level of 6.7 ng/mL. More than 70% of the men were overweight. On multivariate analysis, the investigators found no association between BMI and prebiopsy PSA level, Gleason score, clinical T stage, or D’Amico risk, researchers reported online ahead of print in Urology. Advancing age was associated with a greater risk of a higher prebiopsy

He 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.

PSA level, Gleason score, and D’Amico tumor risk. In a discussion of study limitations, Dr. Chamie’s team noted that their study was retrospective and thus subject to omitted variable bias. n

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.

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26 Renal & Urology News

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Practice Management S

tudies have shown that group therapy can be at least as effective as individual treatment for conditions such as depression, anxiety, and personality disorders. In recent years, however, group treatment has begun making its way into physicians’ offices. Shared medical appointments are visits in which a small group of patients meet for a check up, talk about their experiences, and receive education. These appointments are typically used to treat chronic conditions like diabetes and pediatric asthma, and they are increasingly and successfully being offered to patients with erectile dysfunction (ED) and kidney disease in nephrology and urology practices. “There are few nephrologists in the country, but 26 million people with chronic kidney disease,” said Micah Chan, MD, clinical chief of the division of nephrology at the University of Wisconsin School of Medicine and Public Health in Madison, which offers group appointments in the kidney stone clinic and for patients with chronic kidney disease. “It is hard to see all of these patients and at same time give them enough education to keep their kidney disease from getting worse.”

Creating a community Charles Modlin, MD, Director of the Minority Men’s Health Center at the Cleveland Clinic, said his center uses shared medical appointments for a number of conditions, but one of the most popular is ED. It might seem like a topic men would not want to discuss in the presence of others, but it is the community environment that makes it such a success, Dr. Modlin said. “It is becoming more and more acceptable for men to admit they have

On The Web RUN0613_PracManage.indd 26

ED, and it is really quite beneficial for men to hear that other men are going through this and it isn’t just them,” Dr. Modlin said. “It gives them an opportunity to talk amongst themselves and learn from one another.” Men with all stages of ED are in the class and those considering treatments can talk with others who have already experienced it, Dr. Modlin said. He said the men open up much more in group visits than with him in a one-onone appointment. “It allows us to address issues that are relevant to a partner or caregiver,” said Ryan Terlecki, MD, a urologist at Wake Forest Baptist Health, which has been offering shared visits for more than a year. “If they bring spouses, it allows a lot of ground to be covered – more so than if it is just the men.”

How it works If you are considering offering shared medical appointments, the first thing to take into account is whether you will be comfortable heading a class. Dr. Chan, who admits he is an introvert, said it is not for everyone. If you are willing to lead a group, Dr. Terlecki said, the topic needs to be on conditions that you have a good handle on. You have to be able to give a comprehensive overview and be ready to answer any questions patients might have. Conditions that work well for shared appointments are those that follow a protocol and require regular follow up, Dr. Chan said. He provides visits for late-stage kidney disease patients, a group he sees regularly. The classes allow him to cover topics such as anemia, cardiovascular risks, and dialysis all in one visit. For kidney stones, classes works well with newer patients,

Group visits can cut down on patient wait times for appointments and increase provider income By Tammy Worth

With shared medical visits, patients can talk with each other about their experiences.

all of whom need advice on diet, urine measurements, and recurrence rates. When you start booking the appointments, Dr. Terlecki said, it is good to start small until you get used to running the visits. An ideal group can run anywhere from about eight to 12 individuals. You have to work with patients who think they would be comfortable in a group setting. Finally, Dr. Terlecki said you have to schedule the appointments regularly to make them successful. Plan one half day a week to start with and expand the offerings based on demand.

Time and reimbursement Shared medical appointments are not only good for patients, but they can be profitable for your office as well. For instance, Dr. Terlecki said new-patient visits are scheduled for 30 minutes. In an hour and a half, he can see three people in traditional appointments;

he can see 10 in the same amount of time at a shared visit. Dr. Chan said he sees about six to eight patients in a half day in the clinic, but 12 to 14 in a half day allotted to a shared appointment. Billing is the same as it would be for a typical physical exam. All three physicians say shared appointments cut down on wait times for patients, increase income for the providers and improve patient satisfaction. They are all planning to expand the conditions for which they offer group visits. “In an era of healthcare reform where you are told to provide patient-valued care—the best quality of care with the least amount of cost—I feel this is the ideal way to do that,” Dr. Chan said. “You can provide the educational benefit to lots of people at one time.” n Tammy Worth is a freelance medical journalist based out of Blue Springs, MO.

Want to improve your practice? Look for our tips on how to handle equipment issues, adjust to EHRs, comply with HIPAA, and more at www.renalandurologynews.com/practice.

5/24/13 2:30 PM

28 Renal & Urology News

JUNE 2013 www.renalandurologynews.com

Kidney Tumor Ablation Benefits Cited British radiologist calls ablation a particularly good option for patients unfit for surgery BY NAYANAH SIVA LONDON—Ablation techniques are an ideal treatment option for some patients with kidney cancer, said Alice Gillams, MRCP, FRCR, Consultant Radiologist, The London Clinic, Harley Street. Dr. Gillams told attendees at the Renal and Bladder Cancer 4th National Conference about about her experience with ablation techniques for renal cancer. Having performed cryotherapy and radiofrequency ablation (RFA) on hundreds of patients since 1996, Dr. Gillams said she thinks these are promising and well-established treatment options for select patients. Ablation therapies are a particularly good option for patients who are not fit for surgery. The ideal tumor is small (less than 5 cm), peripheral, and exophytic. Ablation also is safer than surgery. The complication rate for laparoscopic partial nephrectomy is 30%, compared with less than 10% for cryotherapy and 2%-7% with RFA. “Cryotherapy is injury by ice forma-

PSA Testing of Men Aged 75+ Declines Annual PSA screening rates among men aged 75 and older declined by 7.9 percentage points since the U.S. Preventive Services Task Force in 2008 recommended against such screening among men in this age group, researchers reported in Health Affairs (2013;32:596-602). The finding is based on a study

tion, and this causes cellular disruption. The standard is a double freezethaw cycle: You freeze again and you thaw again. You really need that double freeze-thaw cycle to get good cell injury,” Dr. Gillams explained. “Originally, the cryoprobes were very big, and [the procedure] could only be done only at open surgery, but now we have 17-gauge percutaneous probes.” RFA is “very very different,” Dr. Gillams said. “It is an alternating current that alternates within the 375480 kHz range, and that causes ionic agitation so the probe itself does not get hot. The ions in the tissue around the probe agitate and get hot with frictional heating.” Dr Gillams said she predominantly uses a cool tip device, which gives clinicians the option of using a single needle or three needles mounted on one handle. The procedure can be laparoscopic and ultrasound guided, but a percutaneous approach is another option. It is much more minimally invasive

Key Points ■ The ideal tumor for ablation

treatments is smaller than 5 cm, peripheral, and exophytic. ■ Complication rates are

less than 10% for cryotherapy and 2%-7% for radiofrequency ablation. ■ Percutaneous biopsies can

be performed on patients undergoing ablation.

and a good technique for anterior tumors, Dr. Gillams said. She said she typically performs a contrast-enhanced imaging study immediately after each RFA procedure to evaluate what has been achieved. “Dead tissue does not enhance with RFA, so absent enhancement denotes cell death.” A criticism of ablation is that it is not possible to get a biopsy or sample of tis-

sue to stage the cancer, but Dr. Gillams said that she routinely does a percutaneous biopsy on her ablation patients. “Percutaneous biopsy has now come of age,” she said. Tumor size and location are important, she noted. “We are very good at peripheral tumors, but not very good at central tumors; they tend to come into the center of the kidney, sitting next to blood vessels, and blood vessels are a problem for ablation.” The blood flowing in the vessels acts “like a sort of fan, gently cooling the tumor and potentially protecting it.” Although it is possible to treat tumors sitting on blood vessels, there is a greater likelihood of incomplete ablation, she said. “I don’t think there is much question that the percutaneous approach is safer,” Dr. Gillams said. “It really is a very simple, uncomplicated procedure, it’s quite short, there is a very limited hospital stay, there is a very quick convalesce, and the laparoscopic approach carries some trocarspecific complications.” n

Lithotripsy Okay for Lower Pole Stones Extracorporeal shockwave lithotripsy (ESWL) has favorable efficacy in the treatment of lower pole renal stones, according to researchers. Helen Cui, MD, and colleagues at The Churchill Hospital in Oxford, U.K., evaluated the use of ESWL in 50 patients with lower pole kidney stones 15 mm or less in diameter. The researchers defined clinical success as stone-free status or asymptomatic clinically insignificant residual fragments (CIRFs) at radiological follow-up. Subjects had a mean stone size of 7.8 mm, with 66% of the stones 5-10 mm

in diameter and 28% of stones 10-15 mm in diameter. For solitary lower pole stones, complete stone clearance was achieved in 63% of cases, the investigators reported online ahead of print in Urolithiasis. Total stone clearance (either complete clearance or CIRFs) was achieved in 81% of patients. Among patients with multiple stones, success rates were lower: complete clearance occurred in 54% of patients and total stone clearance was achieved in 72%. The researchers noted that lithotripsy is believed to have poor

efficacy at treating lower pole renal stones. Dr. Cui’s group commented that their outcome data for the treatment of lower pole renal stones 15 mm or smaller compare favorably with the literature. “With this level of stone clearance, a non-invasive, outpatient-based treatment like lithotripsy should remain the first-line treatment option for lower pole stones,” the authors concluded. “Ureteroscopy must prove that it is significantly better in terms of clinical outcome or patient satisfaction to justify replacing lithotripsy.” n

of data from the Medicare Current Beneficiary Survey Access to Care files and linked claims. n addition, the study found that 42% of men aged 75 and older continue to receive PSA tests. The researchers said their results “highlight the potential of guidelines with negative recommendations to reduce the use of low-value medical care.” n

RUN0613_Gillams.indd 28

Allopurinol AEs Linked to Colchicine, Statins Patients taking allopurinol are at increased risk for adverse effects (AEs) from the drug if they also use either colchicine or statins, according to Korean researchers. Eun Bong Lee, MD, PhD, and colleagues at Seoul National University College of Medicine, enrolled 94

patients who experienced allopurinolinduced AEs and 378 controls randomly chosen from 1,934 patients who used allopurinol but did not experience AEs. In multivariate analysis, colchicine or statin use was associated with a threefold and twofold increased

risk of allopurinol-related AEs, respectively, according to an online report in The Journal of Clinical Pharmacology. “A cautious approach should be taken when prescribing allopurinol to these high-risk groups,” the authors concluded. n

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Renal & Urology News 29

High-Potency Statins Pose AKI Risk The benefit/harm profile in younger patients or harm in the frail elderly, should be considered BY ROSEMARY FREI, MSc New data strengthen the evidence linking high-potency statins to acute kidney injury (AKI) in a small fraction of patients with kidney disease, whether chronic or not, although the danger is low for most individuals. Patients with non-chronic kidney disease had a 34% greater chance of being hospitalized for AKI if they started taking high-potency statins in the previous 120 days than if they began using low-potency statins in that period. Patients with chronic kidney disease (CKD) had a 10% increased risk. The investigators calculated that 1,700 patients with non-chronic kidney disease would need to be treated with a high-potency rather than a lowpotency statin for 120 days to result one additional hospitalization for AKI. “The absolute risk increase in AKI with high vs. low dose statin is small, and the associated number needed to harm—that is the number of patients

High P Levels May Raise ESRD Risk High serum phosphorus levels in patients with normal renal function are associated with a greater risk of endstage renal disease (ESRD) and death. In a retrospective study of adults in a vertically integrated health plan, a team led by John J. Sim, MD, of Kaiser Permanente Los Angeles Medical Center in Los Angeles, identified 94,989 individuals without kidney disease (estimated glomerular filtration rate of 60 mL/min/1.73 m2 or higher). The study population had a mean age of 50 years and was 61% female, 38% white, 14% black, and 25% Hispanic. ESRD developed in 130 subjects (0.1%). Each 0.5 mg/dL increment in phosphorus level was associated with a 40% increased risk of ESRD and 9% increased risk of death in adjusted analyses, the investigators reported online ahead of print in the American Journal of Medicine. Compared with patients who had baseline phosphorus levels in the first quartile (1.9-3.0 mg/dL), those with baseline levels in the fourth quartile (3.9-5.7 mg/

RUN0613_Statins.indd 29

who would need to receive a high vs. low dose to realize one additional AKI event—is large,” said co-investigator Amit Garg, MD, PhD, Director of the London Kidney Clinical Research Unit and a professor in the departments of medicine and epidemiology at the University of Western Ontario in London. The study’s use of an administrative database, however, likely underestimates the true AKI incidence, and also “many millions of patients worldwide receive a statin each year,” Dr. Garg said. “So it remains prudent to be cognizant of this risk.” Lead i nvest igator Colin Dormuth, ScD, MSc, chair of the University of British Columbia’s PharmacoEpidemiology Working Group, added that statin use must be individualized. “Expected benefits of treatment should be placed in context of suspected harms, including AKI and diabetes,” Dr. Dormuth said. “To

dL) had a significant 48% increased risk of ESRD in adjusted analyses. Timeaveraged serum phosphorus showed a similar relationship across quartiles and as a continuous variable. In addition, ESRD was 2.4 times more likely to develop in men than women, 2.7 times more likely to develop in blacks than whites, and 2.2 times more likely to develop in Hispanics than whites. “High serum phosphorus levels may represent a mechanism, intermediary step, or a surrogate marker for chronic kidney disease onset and advancement,” the authors wrote. A potential mechanism underlying serum phosphorus levels and kidney disease onset or progression is increased nephrocalcinosis, Dr. Sim’s team noted. It has been postulated that higher serum phosphorus levels directly promote vascular injury and calcifications. Another possible mechanism may be related to serum fibroblast growth factor-23 (FGF-23), which is a key regulator of serum phosphorus in patients with chronic kidney disease (CKD), according to the investigators. FGF-23 levels have been found to increase early in the course of CKD, before development of overt hyperphosphatemia, the researchers pointed out. n

this end, one would want to consider the benefit/harm profile in younger healthier patients, or harm in the frail elderly who probably should not be on a statin anyway.” The team focused on the records of 2,067,639 patients who were participat-

Risk is increased 34% in patients with non-chronic kidney disease. ing in Canadian, American and U.K. health care databases and were newly exposed to statins between January 1, 1997 and April 30, 2008. They defined high-potency statin treatment as at least 10 mg rosuvastatin/day, at least 20 mg atorvastatin/day, and at least 40 mg/day of simvastatin. A total of 59,636 patients had CKD and used

statins within the three-year period before they entered the database; 2,008,003 had non-chronic kidney disease and used statins within three years of entering the database. The patients were equally split between the two sexes and had an average age of 68 years. The rates of hospitalization for AKI in patients with non-chronic kidney disease and who were younger than 65 ranged from 1.0-3.5/1,000. The corresponding range in those 65 and older was 3.1-4.0/1,000. Furthermore, the rates were much higher in those with CKD, ranging from 10-63/1,000. In an accompanying editorial, Robert Fassett, MD, and Jeff Coombes, MD, of the University of Queensland in Brisbane, Australia, concluded that “clinicians should use low-potency statins whenever possible to provide cardiovascular benefits without the increased risk of acute kidney injury.” n

Low UACR Predicts Better Kidney Disease Outcomes By comparison, the risk of

Patients with moderate and advanced chronic kidney disease

eGFR decline associated with

(CKD) who have a very low

a UACR of 10-19 versus less

urine microalbumin-creatinine ratio

than 5 was increased by 9%,

(UACR) experience worse CKD

19%, and 7% among subjects with an

progression and higher mortality,

eGFR of 90 or higher, 60-89,

according to a study.

and 45-59, respectively. The researchers, led by Csaba P.

In contrast, a very low UACR is associated with decreased

Kovesdy, MD, of Memphis VA

likelihood of renal function decline

Medical Center, observed a similar

and death among individuals

pattern with respect to mortality.

without CKD, the study of nearly

Compared with a UACR less

300,000 U.S. veterans found.

than 5, a UACR of 10-19 was associated with a 19% decreased

Compared with a UACR less than 5 µg/mg, a UACR of 10-19

risk of death among subjects

was associated with a 23%

with an eGFR of 15-29 compared

and 62% decreased risk of

with a 19%, 32%, and 11% increased

CKD progression among

risk of death among individuals with

subjects with an estimated

an eGFR of 90 or higher, 60-89, and 45-59, respectively.

glomerular filtration rate (eGFR) of 30-44 and 15-29 mL/min/1.73 m , 2

“Proteinuria-lowering interventions

respectively, investigators

in patients with advanced CKD should

reported online ahead of print in

be implemented cautiously, consider-

the Journal of American College

ing the potential for adverse out-

of Cardiology.

comes,” the authors concluded.n

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Malpractice News

Photos courtesy of Tim Bommel and the House Communications Office

Over the last few years, the highest courts in several states have heard challenges to caps on medical malpractice damages for non-economic injuries, such as pain and suffering. These sorts of caps on damages have been ruled unconstitutional in several states based on the fact that the caps deprive a person of the constitutional right to have the jury make a decision. In an interesting twist, the Missouri House has just endorsed the reinstatement of medical malpractice caps. The state originally passed a cap on damages in 2005, but last year the cap was struck down by the state Supreme Court. Now it looks like it may be reinstated. The proposal is sponsored by Rep. Eric Burlison, and puts a $350,000 limit on non-economic damages. “Without these limits, Missouri’s health care industry is subject to erratic and excessive jury awards that will raise the cost of care,” Burlison said. His solution to solving the issue of unconstitutionality is to put the right to sue for malpractice into statutory law, rather than have it as part of common law. During the House debate about the issue, Burlison said that since the original cap was put in place in 2005, “the cost for health

Missouri legislators are mulling a $350,000 limit for non-economic damages.

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insurance—medical malpractice premiums—have gone down and the volume of lawsuits have gone down, until this year when the caps were thrown out by the courts.” He also noted that the state has been gaining physicians since the caps were put into place. An analysis conducted last year by the Missouri Foundation for Health found that claims again doctors had dropped about 24% since caps were put into place in 2005. The bill to reinstate caps passed in the Missouri House by a 93-62 vote and is now headed to the state Senate.

Malpractice Award Caps May be Reinstated in Missouri

By ANN W. LATNER, JD

Florida Moves Towards Malpractice Reform A new medical malpractice bill is slowly gaining traction in Florida. Senate Bill 1792 was approved by the Florida Senate Rules Committee and will now be considered by the state Senate. The House is considering a similar bill simultaneously. The bill, which has been strongly pushed by the Florida Medical Association (FMA), contains three changes that the FMA has considered top priority for years. The first limits who qualifies as an expert witness in a medical malpractice case. Currently, a physician who specializes in a similar specialty and who has treated the patient in the past would qualify as an expert witness in the case. The proposed change would allow only physicians with the same specialty to act as experts. The second change, and one that is hotly contested, would allow the defendant or the defendant’s attorney to interview physicians who are not part of the suit but who have treated the plaintiff without notifying the plaintiff, or having the plaintiff’s attorney present. These “ex parte” communications (meaning for one side only) are not typically how things are done in legal cases, but also bring up a bigger issue, which is patient privacy. Sen. Joe Negron expressed his concern about the provision, stating that, “there is a reason they shut the door when you go see the doc-

A Florida malpractice reform bill would limit who qualifies as an expert witness.

tor, because those are private things.” Negron said he would work to have that provision removed, however the bill’s sponsor, Sen. Tom Lee said that the provision was the “heart of the bill” and it might not pass without it. The third proposed change involves laws regarding medical information, and specifies that if subpoenaed in a medical malpractice or administrative hearing, a doctor must provide a patient’s medical records to an attorney as long as the patient agreed in writing beforehand.

describes the hospital’s response to improve care and avoid errors in the future. To protect privacy, patients’ real names are not used, nor are healthcare practitioners named because the hospital does not want to discourage staff from reporting issues. The driving force behind “Safety Matters” is Dr. Elizabeth Nabel, Brigham’s chief executive, who, last fall, described her own experience making a medical error, and how in the aftermath she felt afraid to discuss it with anyone for fear of being shunned by her colleagues. The newsletter, rather than placing blame, focuses on possible improvements and helps healthcare practitioners understand the error from the patient’s perspective. The hospital plans to start distributing paper copies of “Safety Matters” in staff lounges, conference rooms, and other high-traffic areas. While some hospital administrators were initially concerned that leaving the newsletter in places where patients might see it could potentially scare patients, the consensus is that the transparency about errors and implementation of better safety procedures makes it worthwhile. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

Boston Hospital Divulges Medical Errors to Improve Care To improve care and avoid errors, Brigham and Women’s Hospital in Boston is revealing its mistakes in a newsletter called “Safety Matters.” The newsletter, which is electronically sent to the hospital’s 16,000 employees, was started to encourage staff to speak openly about mistakes and possible solutions in an effort to prevent future errors. Although some hospitals post information about infection rates and falls, medical errors are rarely discussed publicly or candidly. The Brigham newsletter however, recounts stories of healthcare gone wrong via interviews with patients and caregivers and then

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A hospital reveals medical mistakes to staff via electronic newsletter.

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

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CME feature

Managing Bone Loss Associated with Androgen Deprivation Therapy While bone loss and reduction in bone mineral density are well known consequences of ADT, the main concern is increased risk of osteoporotic fractures.

Release Date: June 2013 Expiration Date: June 2014 Estimated time to complete the educational activity: 1 hour This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education. Statement of Need: Although ADT has been shown to improve outcomes in men with advanced prostate cancer (PCa), it does not come without significant adverse effects. ADT is well known to accelerate bone loss and to increase risk of fractures. Since urologists are often the first practitioners to treat their patients with ADT and to diagnose bone metastases, they should be aware of appropriate bone protective agents that should be prescribed. Target Audience: This activity has been designed to meet the needs of urologists, and allied healthcare clinicians who treat prostate cancer patients with ADT. Educational Objectives: After completing the activity, the participant should be better able to: • Assess fracture risk for men undergoing androgen deprivation therapy. • Discuss treatment options for prostate cancer patients with ADT-induced bone loss and bone metastases. 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 Credit TM. 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 our 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 J. Bryant Byrd, MD William J. Aronson, MD

Reported Financial Relationship No financial relationships to disclose Grants/Research Support: NIH/NCI P50CA92131 Consultant: Amgen, Dendreon, Janssen, Medivation Speakers’ Bureau: Amgen, Janssen, Medivation

by J. Bryant Byrd, MD, and William J. Aronson, MD

rostate cancer (PCa) is extremely common in the male population. It is estimated that 238,590 men will be diagnosed and 29,720 will die from the disease in 2013.1 Of the roughly 2.5 million men in the U.S. living with PCa, 2 one-third or more are treated with androgen deprivation therapy (ADT).3 ADT is now routinely used in patients in combination with radiation for intermediate- and highrisk disease, in men with a rising PSA after primary therapy, and in men with metastatic disease. Furthermore, ADT is often given continuously or intermittently for the lifetime of the patient once it is initiated. Although ADT has been shown to improve outcomes in men with advanced PCa, its use does not come without significant adverse effects (AEs) including sexual, loss of cognitive function, depression, fatigue, hot flashes, increased body fat, and decreased muscle mass. ADT is also well known to accelerate bone loss and to increase the risk of fractures.4 Furthermore, men with PCa often

have preexisting conditions that put them at increased fracture risk, such as advanced age, increased risk of falling, and preexisting osteopenia or osteoporosis.5,6 Men with metastatic PCa are also at risk for developing AEs on bone health (skeletal-related events [SREs]). In this article, we review some of the key aspects of bone health that urologists should take into consideration when managing PCa patients. For a more detailed review, we would suggest a review article by Saylor P.J., et al.7 Another useful reference that addresses ADT-induced osteoporosis and prevention of SREs is the 2013 National Comprehensive Cancer Network (NCCN) Guidelines for PCa available at http://www.nccn.org/clinical.asp.

Bone health and ADT In longitudinal studies of men, aging is associated with a rate of bone loss of up to 0.5% to 1% per year starting from middle age.8 Several factors accelerate bone loss in the aging male, including physical inactivity, insufficient dietary

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 June 2013 through June 2014, 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/ renalandurologynews, 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.

J. Bryant Byrd, MD (left), is a resident in the Department of Urology at the David Geffen School of Medicine at the University of California Los Angeles (UCLA). William J. Aronson, MD (right) is Clinical Professor, UCLA Department of Urology, Chief of Urology at Olive View UCLA Medical Center, and Chief of Urologic Oncology at the VA Greater Los Angeles Healthcare System.

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CME feature calcium intake, reduced intestinal calcium absorption, vitamin D deficiency, and a gradual decline in gonadal androgen production.9 Osteoporosis is a common consequence of ADT due to accelerated bone loss from treatmentinduced reduction in androgen and estrogen levels impacting on osteoclast and osteoblast function. The key pathophysiologic event leading to ADT-induced accelerated bone loss is increased osteoclast activity, as evidenced by elevated urinary markers of bone turnover.10 Numerous crosssectional and longitudinal studies of men with PCa treated with ADT demonstrate a progressive decline in bone mineral density (BMD),11,12 and bone loss occurs most rapidly during the first year of therapy.13 This early and acute loss of BMD underlies the need for monitoring and possibly early preventive therapy in men at risk for fractures treated with ADT. Likewise, urologists should consider BMD studies in PCa patients undergoing radiotherapy who receive ADT. While bone loss and reduction in BMD are well known consequences of ADT, the main concern is increased risk of osteoporotic fractures. Whereas urologists typically do not report numerous examples of ADT-induced osteoporotic fractures in their clinical practice, the data from observational studies suggests a markedly increased risk of clinical fractures with increased duration of ADT.14 Perhaps the best evidence comes from the placebo arms of large prospective, double-blind, randomized trials in men receiving ADT for nonmetastatic PCa. In a trial of denosumab to assess its effects on BMD and fracture risk, the placebo group had a 3.9% cumulative incidence of a new vertebral fracture at 36 months and a 7.2% incidence of fracture at any site.15 Another study evaluating toremifene for preventing new fractures in men with PCa on ADT found a two-year incidence of new vertebral fracture of 4.9% in the placebo group.16 In a large populationbased review from the Surveillance, Epidemiology and End Results (SEER) database, 19.4% of men surviving five years after a diagnosis of PCa who were receiving ADT suffered from a fracture compared with 12.6% of men not receiving ADT. Furthermore, the relative risk of fracture increased steadily with increasing duration of ADT.14

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Fractures are well known to have significant consequences, with up to 31% of elderly men dying within one year of suffering a hip fracture.17

Assessing fracture risk in men on ADT Patients receiving ADT should be fully apprised of all the potential AEs. We suggest that clinicians should put together an educational handout distributed by the office staff that includes all the potential AEs and therapies to prevent and treat these AEs. We consider this extremely important, as ADT will significantly alter numerous aspects of the patient’s quality of life, some of which can be potentially obviated by changes in lifestyle and medical therapies. Furthermore, the patient’s primary care physician should be alerted to the AEs of ADT—including an increase in serum lipids, insulin resistance, cardiovascular risks, and osteoporosis—so the primary care physician can participate in limiting these risks. We will focus our subsequent discussion on bone health in men on ADT. When initiating ADT, a focused history and physical examination should evaluate the risk factors for osteoporosis and fracture, including prior

fracture history, smoking, alcoholism, chronic glucocorticoid therapy, age, risk for falling, and BMI.18 A BMD study (dual-energy X-ray absorptiometry [DEXA] scan) should be obtained at baseline for men suspected of having osteopenia or osteoporosis, after one to two years of ADT, and then possibly every two to three years depending on risk factors and results of prior studies. Likewise, a BMD study should be performed on men on long-term ADT who have never had one. As defined by the World Health Organization (WHO), osteoporosis exists when the BMD value is 2.5 or more standard deviations below normal values of a healthy young male (T-score <-2.5), and osteopenia is defined as a T score ranging between -1.0 and -2.5.19 In elderly men, spinal BMD, as measured by a DEXA scan, may be falsely elevated as a result of osteoarthritis; therefore, femoral neck bone density in elderly men is used routinely for the diagnosis of osteoporosis.20 Fracture risk can be assessed clinically by the practitioner based on the history, physical, and BMD results. Alternatively, the 10-year risk of a major osteoporotic fracture or a hip fracture can readily be obtained using the WHO Fracture Risk Assessment calculator found at

http://www.shef.ac.uk/FRAX/. This tool takes into account multiple risk factors for fracture such as age, BMI, prior fracture, prior steroid use, and femoral neck BMD. The tool requires weight and height in kilograms and centimeters. There is a user friendly accompanying metric conversion calculator, which directly inputs the results into the FRAX calculator. Recommended thresholds for treatment from the National Osteoporosis Foundation (NOF) are a >3% 10-year risk for hip fracture and a >20% 10-year risk for major osteoporotic fractures.21 When using the FRAX tool to assess fracture risk for men on ADT, for question 10 check “yes” for “secondary osteoporosis,” and we would suggest the easiest way to list the femoral neck BMD would be to use the “T-score” option. An example of the FRAX score for a 71-year-old male with a height of 5 foot 8 inches weighing 155 pounds on ADT with a T-score of -2 at the femoral neck is shown in Figure 1 below.

Fracture prevention and osteoporosis treatment For all patients on ADT, a daily 30-minute weight-bearing exercise program

Figure 1. Example FRAX score for a 71-year-old male with a height of 5 foot 8 inches weighing 155 pounds on ADT with a T-score of -2 at the femoral neck.

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should be recommended. Walking is an ideal and simple weight-bearing exercise. Likewise, strength training and balance exercises will also reduce fall risk. Gralow et al suggest that Tai Chi and dancing are examples of activities to improve balance and strength to potentially lower fracture risk.22 Modifiable risk factors for osteoporosis should be addressed; patients who smoke should be counseled to quit tobacco and men with excessive alcohol intake should be counseled as well. Given that the majority of men over 50 have inadequate calcium and vitamin D intake, it is reasonable in all patients to follow the NOF Guidelines and recommend 1,200 mg of calcium (from food and supplements) daily and 800 to 1,000 units of vitamin D (cholecalciferol).21 The least expensive calcium supplement is calcium carbonate and this is best absorbed in an acidic environment. Therefore, it should be taken with meals. Patients should be counseled about the risk of constipation with calcium carbonate, and if not well tolerated (or the patient is on a proton pump inhibitor) then calcium citrate is recommended. Non-prescription preparations of vitamin D are widely available and inexpensive and can be taken daily. For patients at a high risk for fracture, consider obtaining a serum 25-hydroxyvitamin D level. If the value is below the lower limit of normal, we suggest consulting the patient’s primary care physician for appropriate vitamin D supplementation. Men with a >3% 10-year risk for hip fracture and a >20% 10-year risk for major osteoporotic fractures as measured by the FRAX calculator, and/or with osteoporosis by DEXA scan should be strongly considered for pharmacologic therapy. Alternatively, the practitioner can assess fracture risk based on the history, physical, and BMD results. In addition, pharmacologic therapy should be considered in men with severe osteopenia (T-score approaching -2), especially given that these patients are on ADT and are at risk for further loss in BMD. As per NCCN guidelines, therapy options include alendronate, zoledronic acid, and denosumab. Bisphosphonates act as pyrophosphate analogues, adhere to the bone matrix, and are internalized by osteoclasts during active bone resorption. This results in inhibition of osteoclast

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ADT is well known to accelerate bone loss, thereby increasing fracture risk, as shown above in this colored SEM displaying a fractured femur resulting from osteoporosis.

activity and survival. 23 The oral bisphosphonate alendronate is FDA approved for the treatment of osteoporosis in men. In a randomized, placebo controlled trial of men with osteoporosis (not ADT-induced osteoporosis), the alendronate group had an increase in BMD, a decrease in loss of height, and a decrease in the incidence of vertebral fractures.24 In a randomized, placebocontrolled trial that enrolled men with osteoporosis (not ADT-induced), those receiving 5 mg of zoledronic acid (a more potent bisphosphonate than alendronate) at baseline and at 12 months had a 67% risk reduction of incurring a new vertebral fracture.25 Zoledronic acid is administered as a once yearly intravenous infusion of 5 mg, making its use appealing for compliance reasons. Denosumab, a human monoclonal antibody against receptor activator of nuclear factor-κB ligand, was tested in a randomized, placebo-controlled trial of 1,468 men receiving ADT for nonmetastatic PCa. Denosumab increased bone density in the spine, hip, and forearm, reduced markers of bone turnover, and reduced the number of new vertebral fractures.15 Denosumab (60 mg subQ every six months) was FDA approved in 2010 as a treatment to increase bone mass in patients who are at high risk for fracture, including those receiving ADT for nonmetastatic PCa. Once patients initiate pharmacologic therapy, bone densitometry should be performed at one year and every two to three years thereafter. If bone density continues to decline, then referral should be made to an endocrinologist or osteoporosis specialist.

Delaying skeletal-related events in men with metastatic PCa Skeletal-related events (SREs) are one of the main sources of morbidity in men with metastatic castration-resistant prostate cancer (CRPC). SREs are defined as palliative radiation to bone, pathologic fractures, spinal cord compression, and surgery to bone. The natural history of untreated bone metastases in men with metastatic CRPC has been elucidated from the placebo arm of a prospective, randomized trial comparing zoledronic acid with placebo.26 In the placebo arm, patients had a 49% chance of having at least one SRE within two years, and the median time to first SRE was 10.7 months. In this trial, zoledronic acid significantly prolonged the time to SREs and reduced the incidence of SREs compared with placebo and became the first agent FDA approved for the prevention of SREs in PCa patients.26 In a more recent, large-scale, randomized, controlled trial comparing denosumab and zoledronic acid in men with metastatic CRPC, denosumab had improved efficacy in delaying time to first and subsequent SRE compared with zoledronic acid, with a median time to first SRE of 20.7 months compared to 17.1 months with zoledronic acid.27 Per NCCN guidelines, men with metastatic CRPC should be prescribed either zoledronic acid or denosumab. Osteonecrosis of the jaw is a rare AE of both agents (occurring in 1%-2% of patients). Prior to initiating either therapy, a dental history should be taken and a brief oral exam performed. If the patient had recent dental procedures or has planned procedures,

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therapy should be delayed until complete healing has occurred, approximately three months (consult with patient’s dentist/orthodontist). Renal failure is a complication of zoledronic acid, so creatinine levels should be monitored before each dose, and dose adjustment or drug discontinuation is required if the creatinine rises. Denosumab is not metabolized by the kidneys and creatinine levels do not need to be monitored during therapy, although denosumab has not been evaluated in PCa patients with a creatinine clearance of <30cc/min or on dialysis. In the clinical trial, severe hypocalcemia occurred in 5% of patients on denosumab and 1% on zoledronic acid. Therefore, calcium levels should be normalized at baseline and followed monthly for several months and then periodically.27 Likewise, calcium and vitamin D should be given to all patients on denosumab and zoledronic acid. Two recently approved therapies that play a critically important role in treating advanced PCa (abiraterone and enzalutamide) have also been reported to delay time to SREs.28,29 Radium-223 is an alpha-emitting pharmaceutical targeting bone metastases with high energy, short range, alpha particles. Radium-223 improved overall survival in CRPC patients with bony metastasis by 3.6 months compared with placebo.30 In patients receiving six q4wk injections of radium-223, time to first SRE was delayed by 5.8 months compared with placebo.31 Radium-223 was approved by the FDA in May 2013 for CRPC and symptomatic bone metastases. Cabozantinib, an oral tyrosine kinase inhibitor with activity against hepatocyte growth factor receptor and vascular endothelial growth factor receptor 2, has also shown promising results in men with metastatic CRPC.32 In a phase 2 trial, 72% of patients had regression in soft tissue lesions and 68% had improvement on bone scans, including complete resolution of bone scan lesions in 12% of patients. Bone pain also improved in 67% of patients with a decrease in narcotic use in 56% of subjects.30 Phase 3 trials of cabozantinib are ongoing.

Conclusion Urologists hold a unique clinical position in managing bone health as most of their patients are aging men, many of whom suffer from PCa and require ADT. When a urologist prescribes

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CME feature ADT, osteoclast activity is increased and bone loss is accelerated, thereby increasing fracture risk. As a central caregiver for aging men, it is critically important that the urologist either evaluates and appropriately treats these patients to preserve bone health and lower fracture risk, or refers these patients to their primary care doctor for appropriate therapy. Likewise, urologists are often the first practitioners to diagnose their PCa patients with bone metastases, and appropriate bone protective agents should be prescribed or the patients should be referred to a medical oncologist to obtain these therapies. n References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin, 2013;63:11-30. 2. Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2009. 3. Shahinian V, Kuo Y, Gilbert S. Reimbursement policy and androgen-deprivation therapy for prostate cancer. N Engl J Med 2010:363:1822-1832. 4. Diamond T, Higano C, Smith M, et al. Osteoporosis in men with prostate carcinoma receiving androgendeprivation therapy: recommendations for diagnosis and therapies. Cancer 2004;100:892-899. 5. Elliott M, Wilcox A, Carnes M, et al. Androgen deprivation in veterans with prostate cancer: implications for skeletal health. Ann Pharmacother 2006;40:2107-2014. 6. Conde F, Sarna L, Oka R, et al. Age, body mass index, and serum prostate-specific antigen correlate with bone loss in men with prostate cancer not receiving androgen deprivation therapy. Urology 2004;64:335-340. 7. Saylor P, Lee R, Smith M. Emerging therapies to prevent skeletal morbidity in men with prostate cancer. J Clin Oncol 2011;29:3705-3714. 8. VanderWalde A, Hurria A. Aging and osteoporosis in breast and prostate cancer. Ca Cancer J Clin 2011;61:139-156.. 9. Kaufman J, Johnell O, Abadie E, et al. Background for the studies on the treatment of male osteoporosis: state of the art. Ann Rheum Dis 2000;59:765–772. 10. Smith M, McGovern F, Zietman A, et al. Pamidronate to prevent bone loss during androgen deprivation therapy for prostate cancer. N Engl J Med 2001;345:948-955. 11. Stoch S, Parker R, Chen L, et al. Bone loss in men with prostate cancer treated with gonadotropinreleasing hormone agonists. J Clin Endocrinol Metab 2001;86:2787–2791. 12. Berruti A, Dogliotti L, Terrone C, et al. Changes in bone mineral density, lean body mass and fat content as measured by dual energy X-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. J Urol 2002;167:2361–2367. 13. Greenspan S, Coates P, Sereika S, et al. Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. J Clin Endocrinol Metab 2005;90:6410-6417.

14. Shahinian V, Kuo Y, Freeman J, et al. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352:154-164 15. Smith MR, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361:745-755. 16. Smith MR, Morton RA, Barnette KG, et al. Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer. J Urol 2010;184:1316-1321. 17. Campion J, Maricic M. Osteoporosis in men. Am Fam Physician 2003;67:1521-1526. 18. Ryan C, Petkov V, and Adler R. Osteoporosis in men: the value of laboratory testing. Osteoporos Int 2011; 22(6):1845-1853. 19. WHO Study Group on Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Geneva: World Health Organization, 1994. 20. Faulkner K. Bone densitometry: choosing the proper skeletal site to measure. J Clin Densitom 1998; 1:279-285. 21. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington,DC: National Osteoporosis Foundation; 2010. 22. Gralow J, Biermann J, Farooki A, et al. NCCN Task Force Report: Bone Health in Cancer Care. J Natl Compr Canc Netw 2009;7 Suppl 3:S1-S32. 23. Higano C. Bone loss and the evolving role of bisphosphonate therapy in prostate cancer. Urol Oncol 2003;21:392-398. 24. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000;343:604-610. 25. Boonen S, Reginster J, Kaufman J, et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med 2012;367:1714-1723. 26. Saad F, Gleason D, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormonerefractory prostate cancer. J Natl Cancer Inst 2004 Jun 2;96:879-882. 27. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomized, double-blind study. Lancet 2011;377(9768):813-822. 28. Scher H, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187-1197. 29. Logothetis C, Basch E, Molina A, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol 2012;13:1210-1217. 30. Parker C, Nilsson S, Heinrich D, et al. Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castrationresistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA). J Clin Oncol 2012 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2012 Jun 20 supplement: LBA4512. 31. Vogelzang N, Parker C, Nilsson S, et al. Updated analysis of radium-223 dichloride (Ra-223) impact on skeletal-related events (SRE) in patients with castration-resistant prostate cancer (CRCP) and bone metastases from the phase III randomized trial (ALSYMPCA). J Clin Oncol 2013;31 abstr 11. 32. Smith D, Smith M, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 2013;31:412-419.

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

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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: June 2014 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. What factor(s) accelerate bone loss in the aging male? a. Physical inactivity b. Insufficient calcium intake c. Decline in gonadal androgen production d. All of the above 2. All of the following are risk factors for osteoporosis EXCEPT: a. Prior fracture history b. Smoking c. Finasteride therapy d. Chronic glucocorticoid therapy 3. The T-score that defines osteoporosis is: a. 0 to -1 b. <-2.5 c. -1 to -1.5 d. <-1 4. Men on ADT should be counseled to: a. Quit smoking b. Consume 1,200 mg of calcium daily c. Consume 800 to 1,000 units of vitamin D daily d. Do weight bearing exercises for 30 minutes daily e. All of the above 5. Pharmacologic therapy options for ADT-induced osteoporosis include: a. Alendronate b. Zoledronic acid c. Denosumab d. All of the above 6. Which agent is FDA approved to increase bone mass in men at high risk for fracture on ADT? a. Alendronate b. Zoledronic acid c. Denosumab d. None of the above 7. The 2013 NCCN Guidelines recommend which agent(s) to delay SREs in men with metastatic castrate-resistant prostate cancer? a. Denosumab b. Zoledronic acid c. Abiraterone d. Enzalutamide e. A and B

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