Renal & Urology News October 2012 Issue

CONVENTIO N ISSUE

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VOLUME 11, ISSUE NUMBER 10

MHD Patient Death Rate Lower in China

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Hemodialysis Mortality Rates in China vs. the U.S. Regardless of race, mortality rates among maintenance hemodialysis patients are higher in the United States than in China, according to a Chinese study.

Shown here are the raw mortality rates per 1,000 patients at risk each year.

Whites African-Americans 236.3%

Racial and practice pattern differences suspected

Asian-Americans

156.7%

BY JODY A. CHARNOW MORTALITY RATES among maintenance hemodialysis (MHD) patients in China are lower than those among MHD patients in the United States, and the reason may be differences in race or practice pattern, according to a new study.

The study, by Li Zuo, MD, of Peking University First Hospital in Beijing, China, and colleagues, included 11,675 MHD patients from 104 dialysis centers in Beijing and 1,937,819 MHD patients in the U.S. Renal Data System (USRDS). The raw mortality for the

IN THIS ISSUE 5

Smoking hikes bladder cancer recurrence risk

13

Sex satisfaction often declines after prostate surgery

18

Preoperative hyponatremia increases death risk

20

Periodontitis linked to arterial stiffness in CKD patients

22

Q&A: Frequent dialysis and physical health concerns

Ultra-low CT dose for renal stone imaging PAGE 14

Beijing cohort (per 1,000 patient-years) increased from 47.8 in 2007 to 76.8 in 2010, the study showed.

In the USRDS cohort, the raw mortality rate (per 1,000 patient-years) for white patients decreased from 250.7 in 2007 to 236.3 in 2009. For African Americans, the rate decreased from 167.8 in 2007 to 156.7 in 2009. For Asian Americans, the rate was 157.6 and 147.9 for those years, respectively.

In adjusted analyses, the Beijing cohort had a survival benefit compared with each of the U.S. race groups. The annual mortality rates for the Beijing patients

PCa Diagnosis Alone Raises Risk of ED

BY JODY A. CHARNOW CHICAGO—A prostate cancer (PCa) diagnosis, by itself, has a negative psychological impact on men that may result in erectile dysfunction, according to a study.

Most clinicians evaluate a man’s erectile function following a prostate biopsy, but study findings suggest that erectile function should be evaluated prior to biopsy because a positive diagnosis may influence the results of the evaluation, said investigator Brian T. Helfand, MD, PhD, of NorthShore University Healthsystem in Evanston, Ill. He presented study findings at the World Meeting on Sexual continued on page 12

147.9%

76.8%

China (2010 data)

United States (2009 USRDS data)

Source: Cheng X, Nayyar S, Wang M, et al. Mortality rates among prevalence hemodialysis patients in Beijing: a comparison with USRDS data. Nephrol Dial Transplant 2012; published online ahead of print.

were 99.4, 80.6, and 94.3 when adjusted to whites, African Americans, and Asian Americans, respectively, in 2009.

In an online report in Nephrology Dialysis Transplantation, Dr. Zuo’s group noted that the Beijing cohort was relatively younger than the USRDS

© PHOTO RESEARCHERS, INC. / AJPHOTO / HÔSPITAL AMÉRICAIN

OCTOBER 2012

cohort and had a lower prevalence of diabetic end-stage renal disease (ESRD). Regardless of age group, U.S. patients suffered from relatively higher mortality compared with their Beijing counterparts. The survival advantage continued on page 12

Kidney Stones Increase CKD Risk KIDNEY STONES increase the risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD), according to findings published online in the British Medical Journal.

Marcello Tonelli, MD, of the University of Alberta in Edmonton, and colleagues studied more than 1.9 million adults without ESRD at baseline or a history of pyelonephritis and who had outpatient serum creatinine measurements. A total of 23,706 individuals had at least one kidney stone.

Over a median follow-up of 11 years, ESRD developed in 5,333 (0.2%) individuals, late stage chronic kidney disease (CKD) developed in 68,525 (4%),

CME FEATURE

sustained doubling of serum creatinine occurred in 6,581 (0.3%).

In adjusted analyses, one or more stone episodes during follow-up was associated with a significant twofold increased risk of ESRD, a 1.7 times increased risk of late stage CKD, and a 1.9 times increased risk of a doubling of serum creatinine compared with individuals who did not have kidney stones. However, the investigators pointed out that the increases were small in absolute terms.

The magnitude of the association between kidney stones and adverse renal outcomes was larger for women continued on page 12

Earn 1 CME credit in this issue

The Evaluation and Treatment of Resistant Hypertension PAGE 42

4 Renal & Urology News

OCTOBER 2012

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Predictors of Post-RC Cancer Death Identified SHORTER INTERVALS between radical cystectomy (RC) for urothelial carcinoma of the bladder and disease recurrence are associated with an increased risk of cancer-related death, as is the presence of common clinical and pathologic factors, according to a study.

Of 1,545 patients who experienced disease recurrence following RC and bilateral lymphadenectomy, 1,254 died from urothelial carcinoma of the bladder and 47 died from other causes. The median cancer-specific survival (CSS) time after recurrence was 6.9 months. The actuarial CSS estimate at 12 months after

recurrence was 32%, researchers led by Shahrohk F. Shariat, MD, of Weill Cornell Medical College in New York, reported online in BJU International.

In a multivariable analysis, the presence of non-organ-confined tumor stages, lymph node metastases, and positive soft tissue surgical margins increased the risk

of cancer-specific mortality by 38%, 25%, and 32%, respectively. Female gender was associated with a 21% increased risk. The adjusted risk of cancer-related death within one year after recurrence for patients who recurred 6, 12, and 24 months after surgery was 70%, 64%, and 60%, respectively. â–

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

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

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

--------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@.

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

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

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

--------------------------------- ADVERSE REACTIONS ------------------------------Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ€HFW WKH UDWHV REVHUYHG in practice.

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

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

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

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

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

9.0 44.4 9.3 Peripheral Edema

1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4

24.3 4.0 Arthralgia

17.3 1.8 Musculoskeletal Pain

1.3

0.3 Muscular Weakness 9.8

6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

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

Gastrointestinal Disorders Diarrhea 21.8 1.1

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

0.0

Dizzinessb Spinal Cord 7.4 6.6

3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0

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

0.3 Upper Respiratory Tract Infectiond Lower Respiratory

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

Anxiety

0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8

1.0 Pollakiuria 4.8 0.0

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

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

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

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

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

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

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

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OCTOBER 2012

Renal & Urology News 5

Bladder Cancer Recurrence Linked to Smoking CURRENT AND former cigarette smokers are at increased risk for adverse oncologic outcomes following surgery for non-muscle-invasive bladder cancer (NMIBC), but long-term smoking cessation may attenuate that risk.

The study included 2,054 patients with NMIBC who underwent transurethral

resection of the bladder (TURB). The study, led by Shahrokh F. Shariat, MD, of Weill Medical College of Cornell University in New York, showed that compared with patients who never smoked, current and former smokers have a 22% and 12% increased risk of disease recurrence, respectively, and

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

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

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

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

-------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

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

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

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

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

a twofold and 29% increased risk for disease progression, respectively.

Former smokers who had stopped smoking 10 or more years prior to surgery had a 34% decreased risk of disease recurrence and a 58% decreased risk of progression compared with current smokers.

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

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

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

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

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

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

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

ONCOLOGY

The study findings, which were published online ahead of print in European Urology, underscore the need for integrated smoking cessation and prevention programs in the management of NMIBC patients, according to the investigators.

Dr. Shariatâ&#x20AC;&#x2122;s group also found that as smoking intensity decreased, so did the risk of adverse oncologic outcomes.

Compared with â&#x20AC;&#x153;heavy longâ&#x20AC;? smokersâ&#x20AC;&#x201D; those who smoked 20 or more cigarettes per day (CPD) for at least 20 yearsâ&#x20AC;&#x201D; â&#x20AC;&#x153;heavy shortâ&#x20AC;? smokers (20 or more CPD for 19.9 or fewer years and â&#x20AC;&#x153;light shortâ&#x20AC;? smokers (19 or fewer CPD for 19.9 or fewer years) had a 57% and 65% decreased risk of disease recurrence, respectively, and an 88% and 95% decreased risk of progression. â&#x20AC;&#x153;Light longâ&#x20AC;? smokers (19 or fewer CPD for 20 or more years) had a 9% decreased risk disease recurrence and a 57% decreased risk of disease progression.

Long-term smoking cessation found to decrease the risk of adverse outcomes.

Based on the study findings, the authors concluded: â&#x20AC;&#x153;General health practitioners and urologists may play an important role in informing smokers regarding their risk of UCB [urothelial carcinoma of the bladder] development and progression as well as the benefits of smoking cessation.â&#x20AC;?

The study by Dr. Shariatâ&#x20AC;&#x2122;s group corroborates findings by researchers at National Taiwan University Hospital in Taipei, who analyzed data from 265 NMIBC patients who underwent TURB, including 64 nonsmokers, 64 ex-smokers (those who stopped smoking more than a year before cancer diag nosis), 59 quitters (those who stopped smoking within a year before and three months after cancer diagnosis), and 78 continued smokers.

The median follow-up was 38 months.

The three-year recurrence-free survival rates for continued smokers, non-smokers, ex-smokers, and quitters was 45%, 57%, 62%, and 70%, respectively, according to a report in BJU International (2007;100:281286). The researchers concluded that smoking cessation might be associated with a lower recurrence rate for NMIBC patients. â&#x2013;

6 Renal & Urology News

OCTOBER 2012

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FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

A Rising Epidemic of Foamy Urine

H

istorically, foamy urine is considered a warning sign for probable kidney disease. Nephrologists and urologists traditionally refer to it as a marker of proteinuria. Upon history and physical examination, many clinicians ask whether the patient has noticed foamy urine, and some even document a lack of it as a significant negative finding.

I travel frequently, and upon going to public bathrooms in different domestic airports I cannot help but noticing residues of foamy urines in many urinals. Indeed, my anecdotal observation of frequent urinary bubbles in public bathrooms is not restricted to the airports. I also have noticed it in the bathrooms of restaurants, coffee shops, and even the bathrooms the staff use at my workplace. Am I observing a fast-growing epidemic of proteinuria in an increasingly unhealthy nation with metabolic syndrome and chronic kidney disease?

Foamy urine can also be caused by factors other than protein in the urine. Rapid urination can create bubbles in the urine, so maybe people in airport bathrooms are in a rush, but then the foam should not persist for more than a few seconds, so that when a curious visitor like me inspects the urinals, I should really not see long-lasting foams.

Concentrated urine in hot weather can also lead to foamy urine, but the foamy urines I have observed in public bathrooms are not restricted to summer time. Kidney stones can lead to foamy urine as can urinary tract infections by virtue of pyuria. Similarly, we may observe frothy urine when there is leukocyturia, for example, due to acute interstitial nephritis or prostatitis. Would other bladder or prostate disorders also lead to foamy urine? Other rare causes of foamy urine include vesico-intestinal fistula such as in Crohn’s disease or ulcerative colitis.

The presence of semen as a result of retrograde ejaculation or even after sexual intercourse may lead to foamy urine.

Upon looking up this “foamy urine” in PubMed and Google Scholar I was disappointed to find very limited literature about this topic and essentially no systemic study about causes and consequences of foamy urine. There are many unanswered questions. For example, is the size or intensity of foam a helpful feature for the differential diagnoses?

Would the presence of micro-hematuria confound the appearance of foamy urine? Can different types of protein lead to different foam formation or threshold? Is a simple urinalysis the first step in the workup of foamy urine? I think nobody really knows answers to any of these questions. I always thought that any degree of proteinuria can cause foamy urine. However, it is not clear what minimum amount is needed. Undoubtedly, more research is needed.

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

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 Chairman Department of Regional Urology Cleveland Clinic Glickman Urological & Kidney Institute Professor of Surgery Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California, Irvine James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

Anthony J. Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C. Suphamai Bunnapradist, MD Director of Research Department of Nephrology Kidney Transplant Research Center The David Geffen School of Medicine at UCLA R. Michael Hofmann, MD Associate Professor and Medical Director, Living Kidney Donor Program University of Wisconsin School of Medicine and Public Health, Madison Csaba P. Kovesdy, MD Associate Professor of Clinical Medicine University of Virginia, Charlottesville Chief of Nephrology Salem VA Medical Center Salem, Va. Edgar V. Lerma, MD, FACP, FASN, FAHA Clinical Associate Professor of Medicine Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine, Chicago Allen Nissenson, MD Emeritus Professor of Medicine The David Geffen School of Medicine at UCLA, Chief Medical Officer, DaVita Inc. Rulan Parekh, MD, MS Associate Professor Johns Hopkins Children’s Center, Baltimore Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J. Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.

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

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

Renal & Urology News (ISSN 1550-9478) Volume 11, Number 10. Published monthly by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. For reprints, contact Wright’s Reprints at 1.877.652.5295. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2012.

INHIBIT ANDROGEN PRODUCTION

BLOCK THE ANDROGEN RECEPTOR

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

References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelineÂŽ ): Prostate Cancer v3.2012.

Fort Washington, PA: National Comprehensive Cancer Network; 2012. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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Contents

OCTOBER 2012

■

VOLUME 11, ISSUE NUMBER 10

Urology 5

14

this month at renalandurologynews.com Expert Q&A

19

Pan-Fried Meat May Raise Risk of Advanced PCa Red meat cooked at high temperatures, especially in a frying pan, may increase the risk of advanced prostate cancer.

27

ED Risk Less with Partial Nephrectomy Erectile dysfunction is less likely to develop postoperatively in men who undergo partial rather than radical nephrectomy.

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

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 August winner: Martin Gregory, MD

News Coverage Visit our website for comprehensive coverage of Kidney Week in San Diego, October 30-November 4.

“

42

CME Feature 42

The Evaluation and Treatment of Resistant Hypertension Raymond V. Oliva, MD, Clinical Associate Professor of Medicine at the University of the Philippines, and George L. Bakris, MD, Professor of Medicine at the University of Chicago, discuss the prognosis, predictors, and etiology of resistant hypertension.

Nephrology 16

Size Matching Important in Pediatric Renal Tx Donor/recipient body surface area ratio should be taken into account when matching living donors with children who need a kidney transplant.

17

ACE Inhibitor Plus ARB Not More Renoprotective The combination is no more effective than either drug alone in slowing the rate of decrease in glomerular filtration rate in patients with diabetic nephropathy.

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

Our latest include: • Grapefruit Juice May Aid Sirolimus Therapy • PCa Less Likely than CVD to Cause Death • Rituximab May Ease Idiopathic Membranous Nephropathy

Study: Ultra-Low CT Dose Accurately Detects Stones This approach has a sensitivity and specificity of 92% and 100%, respectively, according to researchers.

21

Departments 6

From the Medical Director Epidemic of foamy urine

18

Hyponatremia Before Surgery Raises Death Risk Preoperative hyponatremia increases the risk of death within 30 days of surgery.

10

News in Brief Lifetime ESRD risk higher for men

35

Statins Lower Death Risk in ACS-CKD Patients Study of chronic kidney disease patients with acute coronary syndromes show benefit with statins alone or in combination with aspirin.

21

Renal Nutrition Update All fish not the same for CKD patients

26

Practice Management Buying versus leasing expensive equipment

36

Malpractice News Missouri court strikes down damages cap

41

Your Money Cash assets may stem losses

“

ONLINE

Bladder Cancer Recurrence Linked to Smoking Smoking increases the risk for adverse oncologic outcomes following surgery for nonmuscle-invasive bladder cancer, but long-term smoking cessation may attenuate that risk.

Active surveillance for low risk prostate cancer is associated with minimal risk for progression and good 10-year cancer-specific survival.

See our story on page 15

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

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

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

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www.renalandurologynews.com

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

Short Takes Aspirin May Lower PCa Mortality

As Virginia A. Moyer, MD, MPH, and

Anticoagulant use may lower the risk

line ahead of print in Annals of Internal

of death from prostate cancer (PCa),

Medicine, evidence that routine screen-

according to a study of men who

ing of CKD improves clinical outcomes

underwent radical prostatectomy (RP)

for asymptomatic adults is inadequate,

or radiotherapy (RT).

and evidence on the harms of such

fellow USPSTF members reported on-

After a median follow-up of 70

screening is inadequate. Convincing

months, the likelihood of prostate

evidence, however, shows that medi-

cancer-specific mortality (PCSM) was

cations used to treat early CKD may

significantly lower among 2,175 men

have adverse effects.

receiving anticoagulants (warfarin, than among 3,780 who were not

RP Outcomes Found to Differ by Race

receiving anticoagulants (3% vs. 8%

Black men undergoing radical pros-

at 10 years). Both RP and RT patients

tatectomy (RP) were 33% less likely to

experienced the benefit of anticoagu-

use a high-volume surgeon and 27%

lation therapy, Kevin S. Choe, MD,

less likely to undergo the operation

and colleagues reported online in

in a high-volume hospital than were

the Journal of Clinical Oncology. In

white men in an analysis of data from

multivariate analysis, aspirin use was

105,972 RP patients in all nonfederal

independently associated with 57%

hospitals in Florida, Maryland, and

decreased risk of PCSM.

New York from 1996 to 2007. Daniel

clopidogrel, enoxaparin and/or aspirin)

A. Barocas, MD, MPH, and co-investi-

Panel Nixes Routine CKD Screening

gators also noted in an online report in

Insufficient evidence exists to recom-

also had a 1.7 times increased risk of

mend routine screening for chronic

dying in the hospital compared with

kidney disease (CKD) in asymptomatic

whites. They also were more likely to

adults, the United States Preventive

require blood transfusions and to have

Task Force (USPSTF) has concluded.

longer hospital lengths of stay.

The Journal of Urology that black men

Shock Wave Delivery Preferences A recent study of shock wave lithotripsy (SWL) found that 60 rather than 120 shock waves per minute resulted in significantly better treatment outcomes. In an online poll, Renal & Urology News asked urologists which shock wave delivery rate they prefer when using SWL to treat kidney stones. Here are the results based on 106 respondents.

60 shocks per minute 45.37%

120 shocks per minute 28.7%

Neither 25.93% 0

10

20

30

40

50

Lifetime ESRD Risk Higher For Men, Study Finds M

en have a greater lifetime risk for end-stage renal disease (ESRD) than women, according to a Canadian study.

In a study more than 2.8 million Alberta adults without ESRD, researchers found that, among individuals without ESRD at age 40, the lifetime risk of ESRD for men and women living into their 90s was 2.66% and 1.76%, respectively. This translates into approximately one in 40 men and one in 60 women, Brenda Hemmelgarn, MD, of Foothills Medical Centre in Calgary, Alberta, and colleagues reported online ahead of print in the Journal of the American Society of Nephrology.

The risks were higher among those with reduced kidney function. For subjects with an estimated glomerular filtration rate (eGFR) of 44-59 mL/min/1.73 m2, the lifetime risk for ESRD was 7.51% for men versus 3.21% for women. For individuals with relatively preserved kidney function (eGFR 60-89), the lifetime risks for men and women were 1.01% and 0.63%, respectively.

Greater Miconutrient Intake May Improve Sperm DNA A

survey of micronutrient intake (vitamins C and E, beta-carotene, zinc, and folate) among 80 nonsmoking men aged 22 to 80 years with no reported fertility problems demonstrated that those with the highest intake of vitamin C had approximately 16% less sperm DNA damage than those with the lowest intake. Similar findings were noted for vitamin E, folate, and zinc, but not for beta-carotene, according to findings published online in Fertility and Sterility. Andy J. Wyrobek, PhD, of the Lawrence Berkeley National Laboratory in Berkeley, Calif., and colleagues also found that among men older than age 44 years, those with the highest vitamin C intake had approximately 20% less sperm DNA damage than those with the lowest intake, with similar findings for vitamin E and zinc. Members of this age group with the highest intake of thee micronutrients showed levels of sperm damage similar to those of men younger than age 44 years. The younger men, however, did not benefit from higher intakes of the micronutrients surveyed.

Hospitalization Costs Higher With Robotic Prostatectomy R

obot-assisted radical prostatectomy (RARP) is associated with fewer complications and shorter hospital stays compared with open radical prostatectomy (ORP), but total hospitalization costs are approximately $2,500 higher on average for RARP patients. A new study examined total hospitalization costs for both surgical approaches using data from a population-based cohort of 29,837 prostate cancer patients who underwent either RARP (20,424 patients) or ORP (9,413 patients). Compared with ORP patients, RARP patients were significantly less likely to experience postoperative complications (8.2% vs. 11.3%) and they had a significantly shorter stay in the hospital (1 vs. 2 days), investigators led by Simon P. Kim, MD, of Mayo Clinic in Rochester, Minn., reported online ahead of print in European Urology. After adjusting for patient and hospital characteristics, the median hospitalization costs were was significantly higher for the RARP compared with ORP ($11,932 vs. $9,390).

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

References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelineÂŽ): Prostate Cancer v3.2012. Fort Washington, PA: National Comprehensive Cancer Network; 2012. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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12 Renal & Urology News

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MHD patient death rates

PCa diagnosis and ED

continued from page 1

continued from page 1

of the Beijing cohort still persisted even after adjusting for age, gender, and primary cause of ESRD. Although the possibility of baseline comorbidity differences could not be ruled out as an explanation for survival difference, practice pattern variations (such as time spent by physicians on patients) or race are the main explanations, according to the investigators.

Researchers pointed out that, according to the Dialysis Outcomes and Practice Patterns Study (DOPPS), better care was not explained by doses of erythropoiesis-stimulating agents or urea kinetics, but by the number of minutes physicians spent with their patients.

In Beijing, the authors explained, it is mandatory for physicians to be present in the dialysis facility while patients are undergoing dialysis. Physicians are asked to see patients before dialysis starts and to change their dialysis prescription if necessary. They are also asked to make rounds—seeing each patient during dialysis—and to follow up with the patient once the treatment is finished in order to evaluate and make necessary prescription changes for the next dialysis session.

“To our knowledge, whether this practice pattern of intensive patient care favored better patient outcomes has not been explored adequately,” the authors observed.

Commenting on the study, Dorry Segev, MD, PhD, Associate Professor of Surgery and Epidemiology at Johns Hopkins Medical Institutions in Baltimore, said it is likely that a substantial part of the difference in outcomes is related to residual confounding.

The United States has a much older dialysis population, yet the study “very coarsely” accounted for age with only three categories, said Dr. Segev, who also is Director of Clinical Research in the Division of Transplantation at Johns Hopkins. The difference in outcomes also may be due to unmeasured confounding. The U.S. dialysis population, he observed, has a higher burden of cardiovascular disease and other comorbidities that increase the risk of death, but the Chinese study did not account for comorbidities.

“However, our dialysis care in the United States is not optimal,” Dr. Segev told Renal & Urology News, “and in some areas, far from optimal, so this study certainly serves as a wakeup call to re-examine and improve our practices at both the patient and provider level.” ■

Medicine, which was cosponsored by the Sexual Medicine Society of North America and the International Society for Sexual Medicine.

Dr. Helfand and collaborators at Northwestern University’s Feinberg School of Medicine in Chicago studied 85 men undergoing a single 12-core prostate biopsy. They filled out International Index of Erectile Function (IIEF), American Urological Association Symptom Index (AUA-SI), and Quality of Life (QoL) questionnaires. Pre- and post-biopsy IIEF scores did not differ significantly in the study population overall, but the subgroup of 23 men found to have PCa on biopsy had a significantly greater adverse change in post-biopsy IIEF scores compared with the subgroup of 62 men who did not have PCa found (mean change -10.1 vs.

-1.1). The men with PCa experienced significant adverse changes in all IIEF domains, including erectile function (mean change -4.3 vs. 10.8). Multivariate analysis showed that men had threefold

Stones raise CKD risk continued from page 1

than men and for those younger than 50 years than for those aged 50 years and older.

The investigators said their findings “suggest that kidney stones are an important potential contributor to the risk of ESRD and that patients with prior kidney stones should be considered at increased risk for adverse renal outcomes—especially younger women or those with multiple symptomatic episodes.”

“In conclusion,” Dr. Helfand told meeting attendees, “we found that prostate cancer diagnosis does not influence lower urinary tract symptoms following a prostate biopsy. However, the diagnosis in itself does…influence erectile function.”

In addition to being presented at the meeting, study findings were published online ahead of print in BJU International.

Previous studies have suggested that PCa diagnosis is associated with psychological distress. For example, a study published in the Journal of the National Cancer Institute (2010;102:307-314) found that a PCa diagnosis raises a man’s risk of suicide or cardiovascular death, especially in the first few months after learning about the diagnosis. The study, which included 342,497 PCa patients, showed that 148 men committed suicide and 6,845 died of cardiovascular disease, yielding mortality rates of 0.5 and 21.8 per 1,000 person-years, respectively. The mortality rate for PCa patients during the first year following diagnosis was 40% greater than for men not diagnosed with PCa. It was 90% greater during the first three months.

In addition, findings from a Swedish study presented at the 2008 Genitourinary Cancers Symposium showed that men diagnosed with PCa had a 2.6 times increased risk of suicide and a 50% increased risk of cardiovascular death compared with men not diagnosed with the malignancy. ■

The researchers noted that their study is limited by the fact that individuals with kidney stones were identified by their presentation to health services, meaning that their findings do not apply to those who did not seek medical attention for a stone episode. “Consequently, we cannot comment on the association between asymptomatic kidney stones and adverse renal outcomes.”

In addition, Dr. Tonelli’s team was unable to determine the kidney stone composition and therefore could not assess the specific risk associated with different stone types.

The new findings are consistent with those of prior research. For example, a study of residents of Olmsted County, Minnesota—which included 4,774 stone formers and 12,975 controls— showed that stone formers had a 56% increased risk of a clinical diagnosis of CKD compared with controls, after adjusting for age, gender, and all comorbidities, according to a report in the Clinical Journal of the American Society of Nephrology (2009;4:804811). Researchers also noted that stone formers did not have a significantly increased for ESRD. ■

increased risk of a significant negative change in erectile function, defined as a greater than five-point drop in total ILEF score, after being told of a position result on biopsy.

The investigators observed no significant differences in AUA-SI or QoL scores in the overall cohort or in the subgroups.

Researcher says erectile function should be evaluated before biopsy.

Peripheral Renal Tumors Likely to Be Benign TUMOR LOCATION and body mass index

whose tumors were in a peripheral loca-

in the study, 52 (38%) had benign histol-

(BMI) may be useful for identifying which

tion had a twofold increased likelihood of

ogy and 85 (62%) had malignant disease.

renal tumors are likely to be benign prior

having benign histology, Bruce R. Kava,

In contrast, among the 188 men in the

to surgery. In a study of 316 patients

MD, Associate Professor of Urology at

study, only 27 (14%) had benign disease

who underwent nephron-sparing surgery

the University of Miami Miller School

and 161 (86%) had malignant disease.

(NSS), investigators found that peripheral

of Medicine, and colleagues reported

tumor location on the kidney and lower

online in International Urology and

[tumor location and BMI] with previously

BMI were independently associated with

Nephrology. Those with a BMI below

validated clinical variables is likely to

benign tumor histopathology at the time

25 kg/m2 were 50% more likely to have

improve the performance of any

of surgical resection.

benign histology than patients with a BMI

future nomograms in predicting which

of 25 or greater.

renal tumors are likely to be benign,”

Patients in the study underwent NSS for suspicious renal masses measuring

Additionally, women were nearly four

“Incorporation of these variables

Dr. Kava’s group said. “Select patients

less than 7 cm. Of the 316 patients,

times more likely than men to have

may ultimately avoid surgical resection

76 (24%) had benign tumors. Patients

benign histology. Among the 137 women

as a result.” ■

www.renalandurologynews.com

OCTOBER 2012

Renal & Urology News 13

Sex Satisfaction Frequently Declines Post-RP CHICAGO—Intercourse satisfaction decreases for most men after radical prostatectomy (RP) even if they recover the penetration-hard erections they had before surgery, researchers reported at the World Meeting on Sexual Medicine.

The findings may assist clinical in counseling patients prior to undergoing RP, investigators concluded.

Christian J. Nelson, PhD, and colleagues at Memorial Sloan-Kettering Cancer Center in New York evaluated 166 men prior to undergoing RP and at 24 months post-RP using the erectile function domain (EFD) and intercourse satisfaction domain (ISD) of the International Index of Erectile Function (IIEF) questionnaire.

They also asked subjects whether or not they used phosphodiesterase type 5 (PDE-5) inhibitors. Of the 166 patients, 77 had penetration hardness erections (PHE) at baseline (those with an EFD score of 24 or higher).

Dr. Nelson’s group defined erection recovery in two ways: PHE at 24 months and EFD score that returned “back to baseline” (BTB)—a

ED Drug May Work Within 15 Minutes CHICAGO—Avanafil may enable men with mild to severe erectile dysfunction (ED) to engage successfully in sexual intercourse within 15 minutes after dosing, new findings show.

John P. Mulhall, MD, of Memorial Sloan-Kettering Cancer Center in New York, and colleagues studied 597 men with mild to severe ED: 85 with diabetes, 391 without diabetes, and 121 who underwent bilateral nerve-sparing radical prostatectomy (RP). On a perattempt basis, 59.7% of diabetic and non-diabetic patients and 36.4% of post-RP patients experienced one or more successful intercourse attempts in 15 or minutes or less after avanafil dosing, compared with 27.6% and 4.5%, respectively, among placebo recipients, findings reported at the World Meeting on Sexual Medicine suggest.

Avanafil, which is a phosphodiesterase type 5 inhibitor, was approved for treating ED on April 27. It is marketed by Vivus Inc. under the trademark name Stendra. ■

score within one point or higher of baseline—at 24 months.

Subjects had a mean age of 58 years. Their mean baseline and 24-month EFD was 29 and 19.7, respectively, a significant difference in score, the researchers reported.

Overall, ISD score decreased sig-

nificantly from 12 at baseline to 8.3 at 24 months. It even decreased significantly among men with PHE at 24 months (from 12.3 to 11.3).

The researchers also observed a significant decrease (from 12.1 to 10.8) in men not using PDE-5 inhibitors and those using the

medications (from 12.5 to 11.7). On multivariable multivariate analysis, only baseline ISD remained a significant predictor of 24-month ISD. This meeting is cosponsored by the International Society for Sexual Medicine and the Sexual Medicine Society of North America. ■

It’s time to turn OAB on its head.

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

Why are many patients suffering despite current therapeutic options?

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

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

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

All rights reserved.

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012F-500-5743

July 2012

14 Renal & Urology News

OCTOBER 2012

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Study: Ultra-Low CT Dose Accurately Detects Stones This approach yielded no false-positive findings, researchers say we are still performing them under the study protocol.”

The American Urological Association and the European Association of Urology have both adopted recommendations for the use of low-dose CT for renal colic. The new study takes this a step further by focusing on ultralow-dose CT, which gives a radiation dose of just 20 mA. This translates into a greater than 95% reduction in radia-

© PHOTO RESEARCHERS, INC. / ZEPHYR

BY ROSEMARY FREI, MSc BANFF, ALBERTA—Ultra-low-dose computed tomography (CT) can accurately discriminate between true cases of renal colic and pathologies with symptoms due to other causes, according to a study presented at the Canadian Urological Association (CUA) annual meeting.

In a prospective study of 56 patients with suspected renal colic, ultra-low-

Ultra-low-dose CT compares favorably with standard CT for renal stone imaging.

dose CT had a sensitivity of 92% and a specificity of 100% for detecting renal stones. The sensitivity increased to more than 97% when the stones were larger than 2 mm in diameter.

“Once we publish a manuscript on our results, our plan is to come up with guidelines between urology, radiology, and emergency medicine for the use of the ultra-low-dose protocol,” said Iain Kirkpatrick, MD, Associate Professor of Diagnostic Radiology at the University of Manitoba in Winnipeg and Adjunct Clinical Instructor in Diagnostic Radiology at Stanford University in Palo Alto, Calif. “We would want to target it at patients who have a high pretest probability of calculi and obstructive uropathy, since the ability to detect other pathology is hindered. For now,

Sensitivity and specificity are 92% and 100%, respectively. tion dose compared with standard CT when the length of the scans is taken into consideration.

Jason Archambault, MD, a senior urology resident at the University of Manitoba, led the study under Dr. Kirkpatrick’s supervision. The study began in November 2010 and is ongoing. The analysis presented at the CUA meeting included 56 emergency-department patients with suspected renal colic who underwent a standard CT of the kidneys, ureters, and bladder.

An ultra-low-dose CT scan was also performed on each patient, taking less than one additional minute. The two sets of CT scans from each patient were each interpreted by four blinded radiologists.

The subjects had a mean age of 58 years and a mean body mass index (BMI) of 29 kg/m2.

Thirty-six of the patients were found on standard CT to have an obstructing stone and 33 of these were also found to have a stone on ultra-low-dose CT. There were no false positives with the ultra-low-dose approach. There was a high inter-observer agreement between the four radiologists who read the CT scans. This included a high level of agreement about the presence of hydronephrosis, which was a secondary outcome measure.

The average size of the stones in patients with false negatives—that is, in whom ultra-low-dose CT did not show a stone—was 2.4 mm. In comparison, the true positives’ average stone size was 3.8 mm. There was not a significant difference in BMI between the truepositive and false-negative groups.

The investigators found that image quality was worse in high-BMI patients, but the study was not large enough to show a statistically significant difference.

“We did not find that there was a significant difference in diagnostic utility of the scan by BMI, but again this could be because of the low patient numbers,” Dr. Kirkpatrick noted.

“Once all the data are in we may end up recommending a modified protocol for high-BMI patients, but this is still to be worked out.”

The radiologists had an average 75% rating of being “very confident” in diagnosis with standard CT and an average 48% rating of this level of confidence with ultra-low-dose CT. “One of the things we intend to look at is whether tests interpreted at the end of the study tend to be read with more confidence than those at the beginning,” Dr. Kirkpatrick said.

“The relatively low observer confidence with ultra-low-dose CT that we found overall does not reflect low enthusiasm at all for the protocol.” ■

HoLEP Okay For Treating Big Prostates

BY ROSEMARY FREI, MSc BANFF, ALBERTA—Holmium-laser enucleation of the prostate (HoLEP) combined with mechanical morcellation is a safe and effective treatment for benign prostatic hyperplasia (BPH) involving glands weighing 200 grams or more, a study has confirmed.

The study examined 58 cases in which HoLEP was performed on prostates weighing at least 200 grams (mean 218 grams). The mean PSA level decreased from 19.9 ng/mL before surgery to 0.85 ng/mL six months after surgery. The mean preoperative American Urological Association Symptom Score decreased from 18.9 before surgery to 3.85 at 12 months. Furthermore, mean post-void residual volume decreased from 237.6 cc preoperatively 34.9 cc at 12 months. The procedure was associated with a 3.4% complication rate.

The researchers believe the combination of HoLEP enucleation and morcellation is one of the best surgical treatments for BPH. “It offers at least an equivalent if not superior result to transurethral prostatectomy and open prostatectomy in terms of length of catheterization, length of stay, lower rate of transfusion and has a very low re-intervention rate,” said primary investigator Naeem Bhojani, MD, who is presenting the results at the Canadian Urological Association’s 2012 annual meeting. “Using HoLEP also allows for the acquisition of a pathological tissue specimen. Most importantly, these results are durable, reproducible and can be applied to any prostate gland size.”

Dr. Bhojani agrees with other clinicians that HoLEP’s complexity limits its use to only a handful of centers. The learning curve is 15 to 20 cases when taught by a mentor and approximately double that without one, he said.

An average of 213.4 grams of tissue was removed. Enucleation took an average of 86.7 minutes and morcellation averaged 49.3 minutes. The mean length of post-operative catheterization was 19.9 hours (range 8-96 hours). The average post-operative hemoglobin was 11.5 g/ dL. All 58 cases experienced spontaneous voiding after catheter removal.

Two post-operative complications occurred and both required transfusion.

One patient was treated the same day for bleeding, and the other was brought back 48 hours later for completion of morcellation. ■

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OCTOBER 2012

Renal & Urology News 15

AS Benefits for Low-Risk PCa Confirmed Active surveillance for selected patients is associated with a small risk of disease progression

BY ROSEMARY FREI, MSc BANFF, Alberta—Active surveillance (AS) for low-risk prostate cancer (PCa) is associated with a low risk for progression and good 10-year cancer-specific survival, according to new findings.

A study presented at the Canadian Urological Association’s 2012 annual meeting by Mark Preston, MD, a urologic oncology fellow at Massachusetts General Hospital (MGH) and Harvard Medical School in Boston, showed that 77% of patients remained intervention-free after five years and 62% had this status after a decade. Furthermore, a systematic review published online on June 7th in European Urology indicated PCa-specific mortality is only about 1% with AS and that just one-third of patients receive secondary therapy after a median of approximately 2.5 years of surveillance.

Dr. Preston, the lead investigator of the MGH study, said the results of both studies are surprisingly similar. “Our collective work shows that extremely lowrisk disease can be safely managed with active surveillance,” he said. “The caveat is that there remains a very small risk of developing metastatic or lethal disease, and so further research is needed to solidify inclusion criteria and indicators for timely intervention.”

The researchers examined the outcomes of 469 men diagnosed with PCa at the MGH between January 1997 and October 2009. The hospital’s AS criteria are that a patient be a candidate for curative treatment, have a Gleason score of 6 or less—although a score of 7 is acceptable for some low-tumor-volume patients— have no more than three positive cores with less than 20% of each core containing tumor and have a PSA level below 10 ng/mL. The center’s AS protocol which was formalized in 2008 involves PSA testing and a digital rectal examination every four months for one year, followed by these procedures once every six months for two years, then annually. Those on AS also have a repeat 12-core biopsy 12-18 months after diagnosis and additional biopsies at the discretion of the doctor.

The mean follow-up was 5.6 years and the patients had a mean of 1.5 post-diagnosis biopsies. Three hundred and eight (65.7%) had at least one prostate re-biopsy and 132 (28.1%) had more than one. On first re-biopsy, Fifty-five (17.9%) experienced an increase in their Gleason score. Fiftytwo (16.8%) experienced cancer-volume progression, defined as an increase from less than 33% to 33% or more.

A total of 116 patients (24.7%) had an intervention during follow-up. Of

Active Surveillance Safe New data show that selected men with low-risk prostate cancer have very good outcomes as indicated by five- and 10 -year rates of intervention-free, cancer-specific, and overall survival.

Intervention-free survival Cancer-specific survival

77% 100% 95%

Five years

62% 100%

88%

Overall survival

Ten years

Source: Preston, MA et al. Need for intervention and survival in a cohort of patients on active surveillance for low-risk prostate cancer. Presented at the Canadian Urological Association 2012 annual meeting, Banff, Canada. Abstract POD-05.02.

these, 52 (44.8%) had an intervention due to pathologic progression, whereas 35 (30.2%) had a PSA increase and 14 (12.1%) chose to have an intervention because of their own preference.

Fifty-four patients (46.6%) underwent external beam radiation therapy.

Another 26 patients (22.4%) underwent radical prostatectomy, 19 (16.4%) received androgen deprivation therapy, and 17 (16.4%) had brachytherapy, the study showed.

At five years post-diagnosis, 77% of the cohort was free from intervention, as was 62% at 10 years. At both five and 10 years, the cancer-specific survival rate was 100%. The overall survival rate was

95% at five years and 88% at 10 years, the researchers noted.

The systematic review, by Marc A. Dall’Era, MD, of the University of California-Davis Medical Center in Sacramento, and colleagues included the results of seven large AS series published between 1980 and 2011. The longest median follow-up was 6.8 years.

PCa-specific mortality was 0%-1% and up to one-third of the patients received secondary therapy after a median of approximately 2.5 years of surveillance.

Most patients were treated for histologic reclassification or rapid increase in PSA, whereas 7%-13% were treated despite no evidence of progression. ■

PCNL Suitable for Elderly Kidney Stone Patients

BY ROSEMARY FREI, MSc BANFF, Alberta—Older adults can safely undergo percutaneous nephrolithotomy (PCNL), researchers reported at the Canadian Urological Association annual meeting.

In a study, the average operative time, post-procedure stone-free rate, complication rate, and hospital length of stay were similar for patients aged 70 and older and for young patients.

“We look at surgical management of stones more favorably in the elderly population than we did before conducting our study,” said lead investigator Shubha De, MD, after presenting the findings. “We also continue to manage older patients in the same way we do younger patients, including using two general anesthetics and one conscious sedative, and using prone positioning.”

The aging population brings with it more patients with several medical

comorbidities, including those with kidney stones, sepsis, and renal deterioration. Hence, Dr. De and his colleagues retrospectively compared 28 patients over 70 years of age to 20 stone-sizematched and age-adjusted controls to examine whether older patients have worse outcomes.

They drew the two groups of patients from 231 patients who underwent PCNL by Dalhousie University urologists in Halifax, Nova Scotia.

The older patients had an average age of 78.6 years and the younger patients’ average age was 47.1. The older group had a higher average American Society of Anesthesiologists score and more comorbidities than the younger group (2.86/patient vs.

1.10/patient). Furthermore, more of the elderly individuals had cardiac disease and cancer.

The two groups’ rates of urosepsis and recurrent urinary-tract infections were

similar. The average stone diameter in the elderly and younger patients also was comparable, at 1.73 and 1.89 cm, respectively, as was the average number of stones, at 2.16 and 1.60, respectively.

Age alone should not be an exclusion criterion for PCNL, a researcher said.

The stone composition also was similar in both groups, with the majority being made of calcium oxalate.

Intraoperatively, the majority of patients in both groups had PCNL performed on their right side and a similar, low rate of dual access. The average operating-room time was also similar, at 72.5 minutes among the elderly and 84.9 minutes in the controls. For post-

operative drainage, more patients in both groups had a nephrostomy tube and a urethral catheter than either a urethral catheter alone or a nephrostomy tube and a urethral stent.

The elderly group’s stone-free rate was 63.3% and that in the control group was 74%; this is a non-statistically significant difference. The lengths of stay also were similar, at 2.37 days and 3.21 days, respectively. The 30-day complication rates also were statistically similar, at 33%and 15%, respectively.

“Age alone should not be an exclusion criterion for PCNL,” concluded Dr. De, who was a urology resident at Dalhousie and started a fellowship at the Cleveland Clinic at the beginning of July 2012. “Concerns regarding multiple anesthetics, prone positioning, bleeding, and hospitalization should be considered individually, rather than in terms of second-line management based on advanced age.” ■

16 Renal & Urology News

OCTOBER 2012

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Size Matching Important in Pediatric Renal Tx

BY ROSEMARY FREI, MSc BERLIN—Donor/recipient body surface area (BSA) ratio should be taken into account when matching living donors with children who need a kidney transplant, investigators from Seattle Children’s Hospital concluded.

The team used data from the United Network of Organ Sharing’s Standard Transplant Analysis Research (UNOS STAR) files to show that a donor/recipient BSA ratio below 0.9 is associated with a 59% increased risk of graft loss by 10 years after kidney transplant in the pediatric population (younger than 18 years).

more likely to have glomerulonephritis as the cause of their renal failure and less likely to have a cystic, congenital, or hereditary cause. This is consistent with the causes of renal disease in the adolescent population. The clinical characteristics of the two groups were similar, including similar cold or warm ischemia

André Dick, MD, MPH

“When kids get a kidney transplant, at some point in their lives they’re going to need another, so the goal is to maximize the longevity of that graft,” said lead investigator André Dick, MD, MPH, after presenting the results at the 24th International Congress of The Transplantation Society. Dr. Dick is Assistant Professor of Surgery in the Division of Transplantation at the University of Washington and Seattle Children’s Hospital.

Using the UNOS STAR database, he and his colleagues identified 3,089 living donor-pediatric recipient pairs with a donor/recipient BSA ratio of 0.9 or greater and another 112 pairs with a ratio below 0.9. The donor demographics were similar in the two groups of subjects. The average age was 37-40 years and 66%71% of subjects were white. In the lower donor/recipient BSA ratio group 83.9% of donors were female compared with 54.7% in the other group.

The recipients in the lower-BSA ratio group were significantly older (16.7 vs.

11.0 years), and the respective proportion of males was 78.6% and. 59.3%.

Lower-BSA-ratio recipients also were 3744_takpeg_fa2_run_2pg.indd 1

times. He added that in the lower donor/ recipient BSA ratio group, the donor organs often were transplanted from relatively small females into larger older male recipients. Fifty percent of the grafts were lost after 6.8 years in the donor/ recipient body surface area ratio group below 0.9 while this occurred after 10.8

years in the group with a donor/recipient body surface area ratio of 0.9 or higher.

“One hypothesis is that with small ratios the small kidney has to compensate for the metabolic demands of the larger recipient, leading to progressive injury, which in turn affects long-term graft survival,” Dr. Dick said. ■

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OCTOBER 2012

Renal & Urology News 17

ACE Inhibitor Plus ARB Not More Renoprotective USING AN ACE inhibitor in combination with an angiotensin receptor blocker (ARB) is no more effective than either drug alone in slowing the rate of decrease in glomerular filtration rate in patients with diabetic nephropathy.

Gema Fernandez Juarez, MD, of Hospital Fundación de Alcorcón in

Madrid, and colleagues enrolled 133 patients with diabetic nephropathy who were randomly assigned to receive the ACE inhibitor lisinopril alone (35 patients), the ARB irbesartan alone (28 patients), or a combination of both (70 patients). The primary composite outcome was a greater than 50%

increase in serum creatinine level, endstage renal disease, or death.

After a median follow-up of 32 months, 21 patients (30%) in the combination arm, 10 (29%) in the lisinopril arm, and eight (29%) in the irbesartan arm reached the primary outcome, the researchers reported online ahead of print in the

Reducing the burden of

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

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

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

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

IMPORTANT SAFETY INFORMATION

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

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

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

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

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

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

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

Contraindications OMONTYS is contraindicated in patients with uncontrolled hype ertension.

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

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

•

•

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

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

Please see accompanying Brief Summary.

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

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

9/24/12 3:23 PM

American Journal of Kidney Diseases.

No significant differences in proteinuria reduction or blood pressure control were observed among the groups.

With regard to study limitations, the authors noted that the study was not double blind and it included a small sample size. ■

18 Renal & Urology News

OCTOBER 2012

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Hyponatremia Before Surgery Raises Death Risk PREOPERATIVE hyponatremia increases the risk of death within 30 days after surgery, according to a new study.

The study of 964,263 adults who underwent major surgery showed that the 30-day mortality risk was 5.2% for patients with preoperative hyponatremia compared with 1.3% for patients

without preoperative hyponatremia, a difference that translated into a 44% increased risk, after adjusting for potential confounders.

Preoperative hyponatremia was associated with an increased likelihood of perioperative major coronary events (1.8% vs. 0.7%), wound infections

(7.4% vs. 4.6%), and pneumonia (3.7% vs. 1.5%). Of the 964,263 subjects, 75,423 (7.8%) had preoperative hyponatremia, which the investigators defined as a sodium level below 135 mEq/L. The study, by Alexander A. Leung, MD, of Brigham and Women’s Hospital in Boston, and colleagues,

was published online in Archives of Internal Medicine. Although this study provides evidence that preoperative hyponatremia is associated with perioperative morbidity and mortality, further research is needed to establish whether correcting preoperative hyponatremia will mitigate risks. ■

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

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

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

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

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

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

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

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

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

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

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

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

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

3744_takpeg_fa1_run_2pg.indd 3

NHS (N = 1265) 1993 to 1996

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

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

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

12.5 (12.0, 12.8) vs.

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

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

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

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

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

Hypertension OMONTYS is contraindicated in patients with uncontrolled hypertension.

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

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

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

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

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

9/14/12 2:49 PM

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OCTOBER 2012

Renal & Urology News 19

Pan-Fried Meat May Raise Risk of Advanced PCa RED MEAT cooked at high temperatures, especially in a frying pan, may increase the risk of advanced prostate cancer (PCa), a study found.

Men who ate more than 1.5 servings of pan-fried red meat per week increased their risk of advanced PCa by 30%, according to lead investiga-

tor Mariana Stern, PhD, Associate Professor of Preventive Medicine at the University of Southern California’s Keck School of Medicine.

Men who ate more than 2.5 servings per week of red meat cooked at high temperature were at 40% increased risk. Study findings were published

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

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

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

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

Dialysis Patients Treated with OMONTYS (N = 1066)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

14.0%

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

11.8%

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

12.4%

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

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

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

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

3744_takpeg_fa1_run_2pg.indd 4

online ahead of print in Carcinogenesis.

Dr. Stern and her colleagues examined pooled data from about 2,000 men who participated in the California Collaborative Prostate Cancer Study.

Study subjects completed a comprehensive questionnaire that evaluated the amount and type of meat intake,

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

9/14/12 2:49 PM

Mariana Stern, PhD

including poultry and processed red meat. Information about cooking practices (pan frying, grilling, oven broiling) was obtained using color photographs that displayed the level of doneness.

Hamburgers, but not steak, were linked to an increased risk of PCa, especially among Hispanic men, according to the investigators.

The researchers found that pan frying, regardless of meat type, was associated with an increased risk of PCa. They do not know why, but suspect that it is due to the formation of heterocyclic amines, which can damage DNA. Other carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) are formed during the grilling or smoking of meat.

Study findings are consistent with those of previous studies. A study of 470 cases of aggressive PCa and 512 controls demonstrated that higher consumption of any ground beef or processed meats was associated with an increased risk of aggressive PCa, particularly when the meat was grilled or barbecued and when well-done.

The study, by Sanoj Punnen, MD, of the University of California in San Francisco, and colleagues found that high consumption of well-cooked/ very-well-cooked ground beef was associated with a twofold increased risk of aggressive PCa compared with no consumption. Low consumption was associated with a 51% increased risk, according to findings published in PLoS One (2011;6:e27711). In contrast, consumption of rare or medium-cooked ground beef was not associated with aggressive PCa. In addition, the investigators observed an increased risk associated with two meat mutagens produced by high-temperature cooking when comparing highest to lowest quartiles of intake. ■

20 Renal & Urology News

OCTOBER 2012

www.renalandurologynews.com

Arterial Stiffness, Periodontitis Linked In a recent study of CKD patients, pulse wave velocity increased along with inflammation severity

BY JILL STEIN PARIS—Increasing severity of periodontitis is associated with increasing arterial stiffness in patients with chronic kidney disease (CKD) .

“Increased arterial stiffness typically occurs with CKD and may alter cardiac structure and function and ultimately increase the risk of cardiovascular death, which is a significant cause of morbidity and mortality in patients with CKD,” Stephanie Stringer, MD, renal research fellow at the University of Birmingham, said in an interview at the 49th Congress of the European Renal Association-European Dialysis and Transplant Association.

“If we eventually show from our prospective observational study that periodontitis in CKD patients is a risk factor for cardiovascular disease and renal progression,” Dr. Stringer continued, “this would lead to the development of studies to test whether treatment of periodontitis alters renal and cardiovascular outcomes.

Thus, it may be that interventions aimed

at improving periodontal health may play an important role in reducing the cardiovascular burden in patients with progressive CKD.” The researchers measured arterial stiffness noninvasively using carotid-femoral pulse wave velocity (PWV) in 198 CKD patients recruited into the prospective observational Renal Impairment In Secondary Care (RIISC) study.

Periodontitis is characterized by chronic, low-grade inflammation of the gums and occurs in about 15% of patients with CKD, but the prevalence varies widely depending upon the population studies and the classification of periodontitis used, Dr. Stringer said.

Although a lot of research has been done on inflammation in rheumatology and cardiology cohorts, limited data exist on the periodontal health of patients with CKD and how this might influence their outcomes.

The prevalence of normal periodontal health, gingivitis, periodontitis,

Data Support the Use of Salvage RALP

The median time from primary therapy to salvage treatment was 48.5 months.

Subjects had a median PSA level of 3.86 ng/mL prior to salvage treatment. The median operative time was 176 minutes and 94% of patients were discharged on the first post-operative day.

After a median follow-up of 16 months, biochemical failure occurred in 18% of patients and 39% had achieved urinary continence (use of 0-1 pad per day).

Salvage radical prostatectomy, performed in an open or robotic-assisted fashion, is a difficult surgery with a higher rate of potential complications than a prostatectomy performed in the primary setting, Dr. Kaffenberger told Renal & Urology News. However, previous studies have shown that salvage radical prostatectomy can improve survival in patients with locally-recurrent prostate cancer.

“We think that the use of the robotic platform is the way to go for performance of radical prostatectomy in the salvage setting, especially due to the improved visualization,” Dr. Kaffenberger said. “Our work shows that salvage robotic-assisted radical prostatectomy can be performed safely with excellent early oncologic results, low blood loss, short length of stay, and low rates of bladder-neck contractures.

However, problems with incontinence and erectile dysfunction remain a significant concern in these patients.” ■

SALVAGE robotic-assisted laparoscopic prostatectomy (RALP) for recurrent prostate cancer (PCa) appears to be safe, with outcomes comparable to open salvage radical prostatectomy, according to new findings.

The primary advantages of salvage RALP are improved visualization of the posterior prostatic plane, low complication rates, and short length of stay, according to investigators who reported on what is possibly the largest single-institution series of salvage RALP. Samuel D. Kaffenberger, MD, and collaborators, including Kirk A. Keegan, MD, and Joseph A Smith, MD, at Vanderbilt University in Nashville, Tenn., evaluated 34 consecutive patients who underwent salvage RALP from 2006 to mid-2011.

Initial therapy was brachytherapy (14 patients), external beam radiotherapy (11 patients), combined brachytherapy/ external beam radiotherapy (five patients), and high-intensity focused ultrasound (four patients). All patients had biopsyproven recurrent PCa and no evidence of metastatic disease.

Periodontitis and PWV As the severity of periodontitis increases in patients with chronic kidney disease, so does carotid-femoral pulse wave velocity (PWV), a study found. The PWV values, in m/sec, are shown here.

12 10 8 6

9.48

10.53

11.35

Mild

Moderate

Severe

4 2 0

Periodontitis severity SOURCE: Ng KP, Sharma P, Stringer S, et al. Severity of periodontitis is associated with increased arterial stiffness in progressive chronic kidney disease (CKD) patients. Data presented at the ERA-EDTA 49th Congress, Paris. Abstract FP136.

and absence of teeth was 3.8%, 10%, 65.4% and 13.7%, respectively. Of the subgroup with periodontitis, the condition was classified as mild in 79, moderate in 41, and severe in 18 patients. The data showed that increasing periodontitis severity was significantly associated with increasing PWV. PWV values in patients

with mild, moderate and severe periodontitis were 9.48, 10.53, 11.35 m/sec, respectively. After adjusting for potential confounders, including gender, age, blood pressure, and estimated glomerular filtration rate in the three different periodontal severity groups, the findings remained statistically significant. ■

RCC Mortality Risk Greater With Ablation than NSS PATIENTS WITH small kidney cancer

94.4% in the ablation group. For the

tumors may be more likely to die from

study, the researchers used data from

the malignancy if they are treated with

the Surveillance, Epidemiology and End

ablation rather than nephron-sparing

Results (SEER) cancer registry. The study

surgery (NSS).

included patients with RCC tumors smaller

In a retrospective study of 8,818

than 4 cm and who had no evidence of

patients with clinical stage T1a renal cell

distant metastases. Of the 8,818 sub-

carcinoma (RCC), investigators found that

jects, 7,704 were treated with NSS and

those treated with ablation had a twofold

1,114 underwent ablation.

increased risk of RCC-related death com-

Dr. Whitson’s group noted that their

- pared with patients treated with NSS,

study is the first well-powered investiga-

after adjusting for multiple potential con-

tion to compare the effectiveness of NSS

founders. Despite the increased relative

and ablation. The study, however, had

risk of a kidney cancer death associated

limitations, including a relatively short

with ablation, the researchers noted that

follow-up in the ablation group (me-

at five years, the absolute difference in

dian 1.6 years vs. 2.8 years in the NSS

risk is small, Jared M. Whitson, MD, and

group). The authors pointed out, though,

colleagues at the University of California

that in more than 100 patients in the abla-

San Francisco reported in BJU Internation-

tion group who had more than five years

al (2012; published online ahead of print).

of follow-up, the kidney cancer death risk

A total of 716 subjects (8.1%) died during follow-up; of these, 110 (15%) died

appeared to increase relative to NSS. Among the 1,114 patients who

from RCC: 91 (1.2%) in the NSS group

underwent ablation, 662 (59%) had

and 19 (1.7%) in the ablation group.

cryoablation, 239 (21%) had ablation

The disease-specific survival rate at five

“not otherwise specified,” and 213 (19%)

years was 98.2% in the NSS group and

had radiofrequency ablation. ■

www.renalandurologynews.com

OCTOBER 2012

Renal & Urology News 21

Renal Nutrition Update Fish can be a beneficial protein source for CKD patients, but the species of fish to recommend varies BY GRISSIM CLARK CONNERY, MS, RD, LD • Oilfish had the highest total fat content (12.98 g/100 g portion). Round herring and longjaw leatherjacket had the second and third highest total fat content (6.37 and 3.99 g/100 g portion.

• Spotted scorpionfish, black bullhead, and American harvestfish had the most vitamin D per gram of protein.

• The black bullhead, American harvestfish, and round herring had the most vitamin E per gram of protein.

The primary purpose of this paper was to consider the content of beneficial n-3 fatty acids in relation to typical nutritional restrictions that renal patients must follow.

Various studies have shown that n-3 fatty acids possible confer a number of positive health benefits. The two primary n-3 fatty acids studied, EPA and DHA, appear to have different individual effects on mitigating the pathophysiology of inflammatory pathways, and DHA is often regarded as more beneficial due to its ability to reduce collagen aggregation. Some trials using high doses suggest that possible benefits include reductions in proteinuria and blood pressure. Population studies tend to indicate that regular intakes of actual fish instead of n-3 fatty acid supplements tends to produce favorable outcomes, such as reduced incidence of chronic kidney disease (CKD) and 50% reduced mortality risk in dialysis patients. Based on the study’s findings, the primary goal should be to maximize intake of n-3 fatty acids while reducing the intake of restricted nutrients. Each patient’s needs must be considered on an individual basis.

Before making recommendations, however, some characteristics of the following fish need to be considered: • Round herring has the highest content of n-3 fatty acids, but its main drawback is that it has the highest sodium content (192.9 mg/100 g portion) of any other fish in this study.

• Oilfish, which has the highest total fat content, is a great source of calories for CKD patients, who simultaneously need to increase calories while restricted

© THINKSTOCK

F

ish should not be overlooked as a beneficial protein source for patients adhering to a renal diet.

When considering how fish can play a role in helping a patient follow dietary guidelines, it is important to consider both beneficial nutrients and those that should be limited.

A recent study by Castro-González et al published online ahead of print in the International Journal of Food Sciences and Nutrition evaluated 14 fish species (oilfish, round herring, longjaw leatherjacket, broadbill swordfish, black bullhead, gray snapper, spotted weakfish, yellowfin tuna, longjaw silverside, American harvestfish, Atlantic tripletail, Atlantic blue marlin, parrot sand bass, and spotted scorpionfish) and their nutrient compositions in relation to renal diet recommendations. The researchers evaluated protein, phosphorus, potassium, sodium, fat, and cholesterol, and quantified content of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as well as vitamin D and vitamin E. The study revealed the following: • The three fish with the highest content of EPA and DHA were round herring, oilfish, and longjaw leatherjacket, which contained 1667.35, 646.12, and 606.12 g n-3 fatty acids/100 g portion of fish, respectively.

• All fish contained the recommended protein content for renal disease patients (less than 25 g/80 g portion).

• All but three fish (broadbill swordfish, black bullhead, and spotted scorpionfish) had a phosphorus content within the recommended range of less than 10 mg/g protein.

• All fish had a cholesterol content within the range of 44.70-68.45 mg/ 100 g portion.

• The fish with a sodium content of more than 100 mg/100 g portion included round herring, parrot sand bass, and the gray snapper.

• The fish with a potassium content greater than 300 mg/100 g portion included (in order of content) the spotted scorpionfish, yellowfin tuna, Atlantic tripletail, broadbill swordfish, and gray snapper.

In a study, round herring (shown above) had the highest content of n-3 fatty acids.

protein. It is low in potassium, sodium, and phosphorus, but interestingly, it has the lowest vitamin D content of any fish in this study.

• Longjaw leatherjacket has the thirdhighest content of n-3 fatty acids among the fish studied, but it is closer to the median ranges regarding mineral content. It has the second-lowest vitamin D content of the fish in the study.

• Atlantic tripletail has a more moderate n-3 fatty acid content (390.32 mg/100 g portion) compared with some of the other fish, but it is an adequate source that has the lowest phosphorus content of the fish studied (50.86 mg/100 g

This study took place in Mexico, and thus the fish examined were primarily available to that region. Because the availability of different species is geographically limited, following these same guidelines may not be possible if located in other regions such as the northern regions of the continental U.S. Of note though, cold water fish are more commonly associated with higher concentrations of n-3 fatty acids, and thus local fish from northern climates may have similar ratios of nutrients to that of the round herring found in this study. In general, most of the fish in this study proved to be beneficial, high-quality protein sources that are within or close

Most of the fish studied were high-quality protein sources that are within or close to the appropriate phosphorus/protein ratios. portion). It also has the highest protein content (30.06 g/100 g portion).

When considering an 80 g serving as the typical serving size, this species will fall within the appropriate protein guidelines, but it could potentially be advantageous in renal disease patients who need to control phosphorus while maximizing protein.

to the appropriate phosphorus/protein ratios. Repeating this research for a wider range of fish species in the continental U.S. would be of benefit for dietitians and physicians. ■ Mr. Connery is Research Coordinator at Case Western Reserve University in Cleveland.

22 Renal & Urology News

OCTOBER 2012

www.renalandurologynews.com

Frequent Dialysis and Physical Health & QA

The Frequent Hemodialysis Network Trial Group found that frequent (six times a week) in-center hemodialysis

(HD) improved self-reported physical functioning for patients with end-stage renal disease (ESRD) when compared with conventional HD (three times a week).

Frequent HD, however, had no significant effect on objective physical performance. Frequent nocturnal dialysis, for its part, showed no significant effects on any of these physical metrics. Nephrologist Yoshio Hall, MD, Assistant Professor of Medicine at the University of Washington, Seattle, discusses his team’s findings with Renal & Urology News.

Were you surprised and/or disappointed by these findings?

Dr. Hall: We hypothesized that increasing the frequency of HD might further improve overall physical capacity through perhaps better control of uremia, preservation of nutritional status and muscle mass, correction of acidbase imbalances, and reduction of interdialytic weight gain and volume overload in patients.

Overall, our results were mixed.

The lack of demonstrable effects of frequent nocturnal home HD on all physical measures was perhaps unsurprising due to limited sample size (87 patients) of the Frequent Hemodialysis Network nocturnal trial. The modest effects of frequent HD on self-reported physical health and functioning were consistent with those demonstrated in the HEMO study [Kidney International 2004;66:355-366], in which increasing the per-session dose of dialysis led to better preservation of self-reported physical health and functioning among patients receiving HD three times per week. These results deserve attention, as self-reported physical health and functioning are important predictors of subsequent morbidity and mortality.

Unfortunately, no prior randomized studies have demonstrated significant improvements in physical performance by increasing dialysis dose. The lack of effect of frequent HD on physi-

cal performance suggests that the potential benefits of frequent dialysis (in terms of dietary intake or body composition) will likely only be realized if the person engages in concurrent physical activity. Simply increasing the dialysis frequency (and thereby dose) appears to have little measurable effect on physical performance, at least in this trial population.

Did your study findings change your opinion regarding more frequent HD? Dr. Hall: Our study results align with those from clinical trials that have been conducted over the past three decades to test the effects of increased dialysis dose (as calculated by ureakinetic modeling) on important clinical outcomes—namely that dialysis sustains life, but generally does not restore health.

In this respect, frequent HD may improve the lives of some, but is not a cost-effective or practical solution to improving the physical capacity of most patients with ESRD.

Would these findings cause you to dissuade proponents of frequent HD or nocturnal dialysis from advocating these treatments?

Dr. Hall: Not necessarily, but in terms of overall physical health, it remains uncertain as to which patients might actually benefit from more frequent treatments.

Frequent HD may yet improve the physical health of some patients with ESRD, for example, in those individuals who have little residual kidney function and who struggle with large, interdialytic weight gains.

What else should nephrologists know about these results?

Dr. Hall: Difficulty in recruitment reduced the sample size of the nocturnal trial and precluded detection of smaller but potentially meaningful effects of frequent nocturnal HD on physical performance, health, and functioning. In addition, the characteristics of the study participants differed substantially between the two trials.

It is important to note also that mean scores for self-reported physical health increased in both groups receiving nocturnal home HD, suggesting that changing the dialysis venue (in-center to home) may have also influenced self-perceived physical health.

Alternatively, the presence of substantial residual kidney function among subjects enrolled in the nocturnal trial may have reduced the potential effect of HD frequency on physical health and functioning, and perhaps on physical performance.

What do you see as the main drawbacks or dangers of frequent HD or nocturnal dialysis?

Dr. Hall: Overall, relatively few adverse events attributable to the intervention were observed during the trials. Besides the added time commitment, support, and costs associated with more frequent in-center treatments, the primary drawback observed during the trials was that patients randomly assigned to frequent HD were more likely to undergo interventions related to vascular access than were patients assigned to conventional HD.

Do these findings have any bearing on peritoneal dialysis?

Dr. Hall: Our study findings have little bearing on the management of patients receiving peritoneal dialysis.

These modalities for renal replacement therapy (HD and peritoneal dialysis) are quite different. In addition, the characteristics of the patients who elect to perform them, at least in the United States, also differ substantially. That being said, the ADEMEX [Adequacy of Peritoneal Dialysis in Mexico; Journal of the American Society of Nephrology 2002;13:1307-1320] trial found no significant effects of increasing the dose of peritoneal dialysis on important outcomes such as patient survival and health-related quality of life.

What strategies will help improve or preserve the physical capacity of ESRD patients?

Dialysis sustains life, but generally does not restore physical health.

—Yoshio Hall, MD

Dr. Hall: The rising incidence and associated disability of ESRD warrant more attention to the assessment of physical measures and interventions to improve these measures as a part of the routine care of patients requiring dialysis. In terms of improving physical capacity, several smaller studies have reported favorable changes in muscle strength and composition in subjects on HD using a combined program of cardiovascular and strengthening exercises.

The nephrology community may benefit by evaluating the effects of similar exercise programs on a larger scale. For many patients on HD, preservation of these physical parameters may be as important as, if not more important than, marginal increases in longevity with poorer functional capacity. ■

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

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

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

10851ALT_653737_ZYT_King_v1 1

9/12/12 11:02 AM

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

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information).

Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

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

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

08Z11121R3

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

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

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

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

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9/12/12 11:02 AM

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

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

CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter.

In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

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

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

Adrenocortical insufficiency [see Warnings and Precautions].

Hepatotoxicity [see Warnings and Precautions].

Food effect [see Warnings and Precautions].

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

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

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

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

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

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

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

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

4.1 2.3

18.3

0.8

16.8 6.9

0.3 0.3

13.5 3.3

1.3 0

7.1 2.5

0.5 0

7.6

0

5.1 4.1

0.3 0

2.3

0

4.6 2.8 1.0

1.0 0 0.3

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

10851ALT_653737_ZYT_King_v1 2

ZYTIGA® (abiraterone acetate) Tablets 4 5 6

Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms.

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

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

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

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

Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8.

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

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

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: ZYTIGA is not indicated in children.

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

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

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

If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

Manufactured by: Patheon Inc. Mississauga, Canada

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

© Janssen Biotech, Inc. 2012

Revised: July 2012

08Z12237B

9/12/12 11:02 AM

26 Renal & Urology News

OCTOBER 2012

www.renalandurologynews.com

Practice Management O

ffice and medical equipment can be one of the major expenses in your practice and how you manage it can greatly affect your cash flow.

One of the biggest questions for many is whether to bite the bullet and purchase medical and office equipment or to lease it. The answer to that is different for each practice and depends upon a wide variety of considerations including cash flow, frequency of use, and the current cost of borrowing money.

There may be no right or wrong way to deal with your equipment needs, but there are a host of questions to mull over when figuring out what would work best for your office.

Should you lease?

When deciding whether to purchase or lease equipment, you should not make a snap decision, said Judy Aburmishan, the partner in charge of healthcare industry services with FGMK, LLC, a Chicagobased accounting firm. Initially, you should consider both options.

Doane, Director of Reimbursement for Dallas Nephrology Associates. “If you have it for too long, you can live through one to two generations of equipment.”

One downside of these leases is that they are often more expensive than leaseto-own contracts. The leasing company must build profit into the lease and make up for damage to the equipment, so the payments will likely be higher.

A benefit of leasing is that you don’t have the responsibility of owning the equipment. If it breaks, it’s not your problem.

If an image tube goes out, you don’t have to replace it. If you are looking at equipment that has to be serviced frequently, like electronic monitoring equipment, it might be better to lease.

“Almost every time you lease, it will include a service contract for the length of the lease, so you have a fixed cost for equipment,” Mr. Doane said.

Lease-to-own contracts A lease-to-own contract is better for expensive equipment that has a longer

A lease-to-own contract can be beneficial for tax purposes, as you can deduct the full cost of the equipment upfront.

Some of the main things to factor into the equation when thinking about leasing equipment include: • How long is the lease?

• Is the lease long enough to cover the life of the equipment or the time you need it?

• What will be the cost if you want to purchase the equipment at the conclusion of the lease?

Short-term leases would likely be best for high-cost technology that changes frequently. “Imaging and lab equipment have relatively short technology life spans, usually fewer than three years,” said David

lifespan that you cannot or do not want to purchase outright. With this, you lease the equipment for a period of time without paying anything upfront. At the end of the lease, you pay a fixed amount of money to purchase the equipment.

This strategy can be beneficial in that it works in the same way a loan does, Ms. Aburmishan noted. For tax purposes, you can deduct the full cost of the equipment with this lease, even though you haven’t fully paid for it. With a short-term lease, you deduct payments the way you would for immediate expenses like rent.

Other options for very expensive technology include daily or pay-per-click

© THINKSTOCK

Should you buy or lease expensive medical equipment for your practice?

That depends on a number of factors BY TAMMY WORTH

Short-term leases are advised for sophisticated imaging equipment, like the MRI shown here.

rentals. If you don’t frequently use a sophisticated piece of equipment—like a magnetic resonance imaging scanner or a laser—you can just rent as needed.

“A per-day basis will be more expensive, but if you decide you don’t need the equipment five days a week, if would be more cost efficient overall,” Ms. Aburmishan said. If you find these options cost more than what the equipment is worth, it makes sense to outsource.

Making the decision to buy An obvious impetus to buy is need and frequency of use, Mr. Doane observed.

“But the purchasing threshold will be different in every practice—based on solvency.” If you want to buy, first look at the interest rates to make sure they are going to be better than what you would pay for a lease-to-own plan. The interest rates are often comparative right now, so that getting a loan from a bank “is like free money,” Mr. Doane noted. Next, you must determine how quickly the technology will be obsolete; if it’s soon, a short-term lease might be your best option.

If you do choose to buy, a main consideration is to decide whether you want to expend your capital or take out a loan. Ms. Aburmishan recommends keeping your money out of the practice when possible.

“I generally advise that you have someone else pay for practice-related equipment,” she said. “That way, you are not putting personal funds into the practice, where they could would subject to a lien in a malpractice suit.”

How you get rid of antiquated equipment must also be a factor. If you know you will need the machinery beyond a certain lease period, it is best to purchase. When figuring out the value of buying, it’s good to think of what it might resell for when you are finished with it.

Weighing your choices Individual practices have a host of considerations for leasing-versus-buying equipment. Mr. Doane said he knows of some groups that lease all equipment in bundle packages. Physicians in private practice should always consult with their financial officers before making major purchases.

Finally, don’t let your practice get in a rut because you made the wrong initial choice. Just because you leased something last year, doesn’t mean you shouldn’t purchase it or change the contract the following year. ■ Tammy Worth is a freelance medical journalist based out of Blue Springs, MO.

www.renalandurologynews.com

OCTOBER 2012

Renal & Urology News 27

ED Risk Less with Partial Nephrectomy Researchers hypothesized that renal function preservation would play an important protective role ERECTILE DYSFUNCTION (ED) is less likely to develop postoperatively in men who undergo partial rather than radical nephrectomy a study found.

The study, which involved 432 men, is the first to demonstrate a decreased risk of ED following partial nephrectomy (PN) versus radical nephrectomy (RN), researchers reported online in BJU International.

After a mean follow-up of 5.8 years, the 264 men who underwent RN had a 3.5 times increased risk of new-onset ED after surgery compared with the 168 men in the PN group. Preoperatively, 18.6% of the RN group and 27.4% of the PN group had ED. After surgery, ED was present in 48.1% of the RN group and 36.9% of the PN group.

The researchers, led by Ithaar H. Derweesh, MD, of the University of California-San Diego Medical Center in La Jolla, explained that ED is a manifestation of endothelial dysfunction.

ED may be the first sign of underlying systemic endothelial disease. Many patients with ED have pre-existing chronic kidney disease (CKD), which also is associated with an increased risk of cardiovascular morbidity and mortality. About 70% of men with CKD have concurrent ED. Dr. Derweesh and his

colleagues hypothesized that PN would limit development of ED primarily due to renal function preservation.

Preoperatively, 11.7% of RN patients and 16.7% of PN patients had CKD, defined as an estimated glomerular filtration rate (eGFR) below 60 mL/ min/1.73 m2. The difference between the groups was not statistically significant. Postoperatively, however, a statistically significantly higher proportion of RN than PN patients had CKD (44.7% vs. 26.2%). The authors pointed out that the proportion of de novo ED was “strikingly similar” to the proportion of de novo eGFR below 60 (33% in the RN group and 9.76% in the PN group). Both preoperative and postoperative CKD were strong predictors of new-onset ED. Patients with preoperative CKD had a nearly ninefold increased likelihood of de novo ED compared with those without CKD before surgery. Postoperative CKD was associated with a 2.6 times increased risk of de novo ED. “This supports that PN and renal function preservation limit the risk of at least one endothelial disease, and suggests it may reduce the risk of other cardiovascular disease compared with RN,” they wrote.

Partial vs. Radical Nephrectomy In a study, men who underwent radical nephrectomy had a higher rate of new-onset erectile dysfunction (ED) than those who underwent partial nephrectomy (29.5% vs. 9.5%). Shown here are the proportions of men in each treatment arm who had ED before and after surgery.

Radical nephrectomy

27.4%

Partial nephrectomy

50

36.9%

40 30

48.1% 18.6%

20 10 0

Before Surgery

After Surgery

Source: Kopp RP, Dicks BM, Goldstein I, et al. Does radical nephrectomy increase the risk of erectile dysfunction compared with partial nephrectomy? A cohort analysis. BJU Int. Published online ahead of print.

The investigators evaluated sexual function preoperative and postoperatively with the five-item Sexual Health Inventory for Men questionnaire. They defined ED as a SHIM score less than 22. The researchers excluded from their analyses patients who were not sexually active.

Dr. Derweesh’s group observed that PN is now the preferred option for treating small renal masses, and noted that it confers equivalent oncologic outcomes and superior renal function outcomes. Data also show that that

PN is associated with improved overall survival compared with RN, possibly because of a decrease in cardiovascular events.

The men in the study had a mean age of 58 years. The mean tumor size was larger in the RN than the PN patients (7.2 vs. 3.8 cm). The RN and PN groups were similar with respect to mean body mass index (27.9 and 28.2 kg/ m2, respectively), and the proportion of men with a history of hypertension (67.4% and 73.8%) and diabetes mellitus (23.9% and 29.2%). ■

Reduced Sodium Intake Enhances ARB Effects LOWER SODIUM intake boosts the renal and cardiovascular (CV) protective effects of angiotensin receptor blockers (ARBs) in patients with type 2 diabetic nephropathy, according to a post-hoc analysis of data from two randomized clinical trials.

Among patients in the lowest tertile of sodium intake, those treated with an ARB (either losartan or irbesartan) experienced a significant 43% decreased risk of a renal event and a significant 37% decreased risk of a CV event compared with subjects treated with drugs that do not block the renin-angiotensinaldosterone system (RAAS), investigators reported in Kidney International (2012;82:330-337).

Until further data are available, the researchers noted, they advocate that patients on RAAS-blocking drugs avoid high dietary sodium intake and recommend adherence to a guideline-suggested target of salt intake of 5-6 grams per day.

The investigators, led by Hiddo J. Lambers, MD, of University Medical Center Groningen, The Netherlands, defined a renal event as a composite of a confirmed doubling of serum creatinine from baseline or end-stage renal disease. They defined a CV event as

Improved renal and CV protection in patients with type 2 diabetic nephropathy. a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, or revascularization procedures.

The researchers studied 1,117 patients with type 2 diabetic nephropathy who participated in the Angiotensin II Antagonist Losartan (RENAAL) trial

and the Irbesartan Diabetic Nephropathy Trial (IDNT). During follow-up, 372 patients experienced a renal event and 392 experienced a CV event.

For patients in the second tertile of sodium intake, the risk of renal events was similar for both ARBs and nonRAAS treatment, whereas ARB treatment increased CV event risk by 2% compared with non-RAAS intervention. Among those in the highest tertile, ARBs were associated with a significant 37% increase in risk in renal event risk and a significant 25% increased CV event risk.

Sodium intake was determined by measuring 24-hour urinary sodium excretion. Urinary sodium excretion is a proxy for sodium intake, but is considered more reliable than food questionnaires, Dr. Lambers’ group stated.

“Our study demonstrates that the renal and cardiovascular protective effects of ARBs are blunted in subjects with type 2 diabetes and nephropathy

in whom dietary sodium intake is excessively high,” the authors wrote.

The authors acknowledged that their study had the limitation of being a retrospective analysis, so the results can only be interpreted as hypothesis generating.

“It could be possible that the differences in patient’s characteristics across tertiles of sodium intake have contributed to the enhanced effects of ARBs in the lower tertile of urinary sodium excretion.”

The researchers noted that several pathophysiological mechanisms may explain the blunted treatment effect of ARBs in patients with high dietary sodium intake. For example, they noted that experimental and human studies “have shown that a high sodium intake increases angiotensin-converting enzyme (ACE) activity in renal and vascular tissues, despite decreased plasma renin and angiotensinogen concentrations, which in turn attenuates the effect of ACE inhibition at a tissue level.” ■

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI.

Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information).

Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring.

If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Food Effect—ZYTIGA® must be taken on an empty stomach.

Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC 0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

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ZYTIGA® is converted in vivo to abiraterone, an androgen biosynthesis inhibitor (ABI) that directly affects the androgen biosynthesis pathway by inhibiting CYP17 (17␣-hydroxylase/C17,20-lyase) — Consequently, androgen biosynthesis is inhibited at 3 sources of testosterone production: the testes, adrenal glands, and prostate tumor tissue Androgen biosynthesis inhibition with ZYTIGA® results in decreased levels of serum testosterone and other androgens

Proven survival benefit Results of the interim analysis of the pivotal phase 3 study*† showed a statistically significant improvement in overall survival (OS) in patients treated with ZYTIGA® plus prednisone compared with patients who received placebo plus prednisone (median OS: 14.8 months vs 10.9 months [hazard ratio (HR) = 0.646; 95% confidence interval (CI): 0.543, 0.768; P < 0.0001]) — This represents a 3.9-month difference/improvement in median OS In an updated analysis,‡ results were consistent with the interim analysis, with a 4.6-month difference/improvement in median OS with ZYTIGA® plus prednisone compared with placebo plus prednisone (median OS: 15.8 months vs 11.2 months [HR = 0.74; 95% CI: 0.638, 0.859])

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

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

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

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

These patients should not receive ZYTIGA®. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 3/12 08Z12069B

ORAL THERAPY

study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398).

Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival. †552 events. ‡775 events.

08Z11121R3

and

Mechanism of action

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

Please see adjacent pages for brief summary of full Prescribing Information.

www.zytiga.com

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

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

CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter.

In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

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

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

Adrenocortical insufficiency [see Warnings and Precautions].

Hepatotoxicity [see Warnings and Precautions].

Food effect [see Warnings and Precautions].

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

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

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

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

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

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

Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Prednisone (N=791) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % Musculoskeletal and connective tissue disorders 29.5 4.2 Joint swelling/discomfort2 26.2 3.0 Muscle discomfort3 General disorders 26.7 1.9 Edema4 Vascular disorders Hot flush 19.0 0.3 Hypertension 8.5 1.3 Gastrointestinal disorders Diarrhea 17.6 0.6 Dyspepsia 6.1 0 Infections and infestations Urinary tract infection 11.5 2.1 Upper respiratory tract infection 5.4 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 Nocturia 6.2 0 Injury, poisoning and procedural complications 5.9 1.4 Fractures5 Cardiac disorders Arrhythmia6 7.2 1.1 Chest pain or chest discomfort 7 3.8 0.5 Cardiac failure8 2.3 1.9 1 2 3

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

4.1 2.3

18.3

0.8

16.8 6.9

0.3 0.3

13.5 3.3

1.3 0

7.1 2.5

0.5 0

7.6

0

5.1 4.1

0.3 0

2.3

0

4.6 2.8 1.0

1.0 0 0.3

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

ZYTIGA® (abiraterone acetate) Tablets 4 5 6

Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms.

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

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

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

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

Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8.

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

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

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: ZYTIGA is not indicated in children.

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

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

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

If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

Manufactured by: Patheon Inc. Mississauga, Canada

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

Issued: May 2012

08Z12155B

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OCTOBER 2012

Renal & Urology News 31

Legal Issues in Medicine A nurse thinks she is HIPAA compliant when accessing the medical records of family members while on duty BY ANN W. LATNER, JD would periodically look up her mother’s and sister’s health records on the hospital computer to get information or to access their treatment plans. She didn’t see anything wrong with this—after all, it was her own family.

HIPAA violations One of her colleagues, however, had noticed Ms. P looking at the records on more than one occasion, and anonymously reported her. The hospital’s HIPAA compliance officer began an investigation, which revealed that Ms. P had accessed her mother’s charts on forty-four separate occasions and her sister’s charts on twenty-eight occasions. When the human resources director confronted her with the results of the investigation, Ms. P admitted that she had accessed the records, but they were family records and she didn’t see anything wrong with it.

“Did you need to access information from their medical records in order to do your job as a clinical affiliate in the cardiology department?” asked the human resources director, sternly.

“No…” replied Ms. P. “They were not cardiology patients.”

She was terminated from her employment that day.

Angered by the loss of her job, Ms. P sought the advice of an attorney to see if

The privacy rule is balanced so that it permits the disclosure of personal health information needed for patient care and other important purposes.

Accessing patient records Ms. P understood the importance of patient confidentiality and would never look in the records of patients that weren’t hers… with two exceptions. Ms. P’s mother and sister both had serious chronic conditions, which frequently resulted in hospital visits over the years. Ms. P’s mother had Parkinson’s disease, was on numerous medications and was prone to falls. Ms. P’s older sister, who lived with her, had Down syndrome. Ms. P

she could sue the hospital for wrongful termination. The attorney was skeptical.

“HIPAA violations are taken very seriously,” he said. “Did they give you training about patient privacy? And were you asked to sign anything?” inquired the attorney.

“Well, yes…” said Ms. P. “I did sign a confidentiality agreement, and the hospital does have a policy that you could lose your job for violating it. But these were my mother and sister’s records only.”

© THINKSTOCK

M

s. P, 45, was a nurse working in the cardiology department of a large hospital. Her duties included accessing patient medical records, reviewing lab values and other diagnostic tests ordered by physicians, and writing progress notes in patients’ charts.

When she was hired by the hospital, the human resources department stressed the fundamentals of patient confidentiality. Ms. P was required to sign a patient confidentiality agreement, stating that she would only seek or obtain information regarding a patient, in the course of performing her duties.

Later, when the U.S. Health Insurance Portability and Accountability Act (HIPAA) went into effect, Ms. P went to another mandated human resources seminar and sign a revised confidentiality agreement. The revised agreement stated that she would not access or view information other than what was required for to do her job, and that she would immediately ask her supervisor for clarification if she had any questions about whether information was required for her job. Finally, the agreement contained a section saying that Ms. P acknowledged that violation of the facility’s confidentially policy could result in disciplinary action up to and including termination.

HIPAA violations are taken very seriously and are grounds for immediate termination.

“That’s irrelevant,” said the attorney. “It doesn’t matter if they are family or not.

You still didn’t have the right to look at the records…I don’t think we have a leg to stand on, unless…” the attorney trailed off, thinking.

“How old are you?” he suddenly asked.

When she told him, he smiled. “I think we may have an angle. We can try suing the hospital for age discrimination. We can claim that the privacy violation was merely a pretext to get rid of you—a higher paid, experienced nurse—and replace you with a less expensive junior person.”

The attorney filed the papers against the hospital. The hospital’s attorney promptly filed a motion to dismiss. After review, the court dismissed Ms. P’s case.

Legal background People who are over 40 years of age can allege age discrimination if it appears that the employer is using another excuse to fire an older employee and replace them with someone younger and cheaper. In this case, however, the hospital had a clear policy, in writing, which Ms. P was familiar with and had signed. In addition, the hospital had a history of terminating employees for HIPAA violations, and over half of those who were fired were under 40-years-old at the time.

If an employer has a policy on the books that is being enforced uniformly across all age groups, then a cause of action

alleging age discrimination will fail—as it did here.

Protecting yourself The HIPAA Privacy Rule provides federal protections for personal health information. At the same time, the rule is balanced, so that it permits the disclosure of personal health information needed for patient care and other important purposes. Ms. P had no valid reason to be looking at family medical records.

HIPAA is taken very seriously, and numerous jobs have been lost based on violations of the rule. A hospital or medical practice cannot afford to have violations, as the Federal government strictly enforces HIPAA. It is essential to remember that a patient’s privacy—whether it is someone you know or not—is of paramount importance. Also, pay attention to the policies of your employer. Had Ms. P considered the training she’d had, or the agreement she signed, she might have realized what the consequences would be of looking at unauthorized medical records. Err on the side of caution. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y. Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended.

32 Renal & Urology News

OCTOBER 2012

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Testosterone Replacement Health Benefits Shown Patients experienced weight loss, reduced waist circumference

BY JOHN SCHIESZER HOUSTON—Long-term testosterone treatment in hypogonadal men can lead to significant weight loss and improvements in components of metabolic syndrome, according to two new studies presented at The Endocrine Society’s 94th Annual Meeting. Both studies were conducted in Germany and used a slow-release, injectable form of testosterone (testosterone undecanoate).

“The substantial weight loss found in our study, an average of 36 pounds, was a surprise,” said lead researcher Farid Saad, PhD, who is with Gulf Medical University, Ajman, United Arab Emirates, and Berlin-headquartered Bayer Pharma.

Dr. Saad and his colleagues conducted an open-label, single-center, cumulative, prospective registry study. The trial included 225 men aged 38 to 83 years (mean age 60.6 years). For this investigation, 215 men were studied for at least two years, 182 men were studied for three years, and 148 men were studied for four years. A total of 116 men had at least five years of follow-up.

Testosterone trials Prior studies using testosterone therapy in testosterone-deficient men have consistently showed changes in body composition, such as increased lean mass and decreased fat mass. However, the net effect on weight seemed unchanged in those studies, according to Dr. Saad. This current study had a longer follow-up and used longacting injections of testosterone than the previous studies.

The investigators restored testosterone to normal levels in 255 hypogonadal men and the treatment lasted for up to five years, with injections given at day 1, after 6 weeks, and then every 12 weeks after that. Patients did not follow a controlled diet or standard exercise program but received advice to improve their lifestyle habits.

Significant weight loss On average, the men weighed 236 pounds before beginning testosterone treatment and 200 pounds after treatment (106.2 vs. 90.07 kg). Weight

loss was reportedly continuous, with an average reduction in body weight ranging from about 4% after one year of treatment to more than 13% after five years. Men lost an average of nearly 3.5 inches (8.8 cm) around their waist.

Farid Saad, PhD

The study showed that waist circumference declined from 107.24 to 98.46 cm.

In addition, body mass index (BMI) declined from 33.93 to 29.17 kg/m2.

The mean weight loss after one, two, three, four, and five years was 4.12%, 7.47 %, 9.01%, 11.26%, and 13.21%, respectively.

Overall, 95% of the patients lost weight; 31% lost 20 kg or more, and 77% lost 10% or more of their initial body weight. A total of 97% of the patients experienced a reduction in waist circumference.

“There was no intention to make patients lose weight,” Dr. Saad told Renal & Urology News. “The weight Risk Factors for Male Hypogonadism • Kallmann syndrome • Testicular or pituitary tumors • Undescended testes as an infant • Mumps infection affecting the testicles • HIV/AIDS • Klinefelter syndrome • Hemochromatosis • Prior chemotherapy or radiation treatment Source: Male hypogonadism page. Mayo Clinic website.

Available at http://www.mayoclinic.com/health/malehypogonadism/DS00300/DSECTION=risk%2Dfactors.

Accessed August 1, 2012.

loss was never expected. This was found as a side effect of treatment.

Some of the men came in for erectile dysfunction treatment.”

Metabolic syndrome risks decreased In a separate study also presented at this meeting, testosterone replacement therapy was found to significantly improve symptoms of metabolic syndrome associated with testosterone deficiency. Investigators started collecting data in 2004 from 261 patients with late-onset hypogonadism at three centers in Germany. Patients received 1,000 mg of testosterone undecanoate on the first day of the study, at week 6, and then every three months. At each visit, investigators measured subjects’ hormone, glucose, and lipid levels, as well as blood pressure (BP).

The mean follow-up was 4.25 years.

The prevalence of metabolic syndrome dropped from 56% to 30% after 57 months of treatment. Triglyceride levels decreased in 77% of patients, glucose levels decreased in 67%, and mean arterial pressure decreased in 78%. The average waist circumference decreased by 11 cm.

Therapy for late-onset hypogonadism “When indicated, testosterone treatment is both essential and safe in elderly patients with symptomatic lateonset hypogonadism,” said lead author Aksam Yassin, MD, PhD, Chairman of the Institute of Urology & Andrology in Norderstedt-Hamburg, Germany.

Previous research has linked metabolic syndrome to testosterone deficiency.

In addition, testosterone deficiency is associated with individual components of metabolic syndrome.

“Testosterone investigation in elderly patients with health problems is an essential part of men’s health practice,” Dr. Yassin said.

Testosterone undecanoate is not yet available in the United States, but it is marketed in Europe, Latin America, Australia, and parts of Asia and Africa.

Dr. Saad is an employee of Bayer Pharma, which makes a brand of testosterone undecanoate. Bayer Pharma partially funded Dr. Saad’s study in its final two years. ■

PCa Linked to Central Fat in Blacks

BY JODY CHARNOW GREATER CENTRAL adiposity increases the risk of prostate cancer (PCa) in black men, new research findings suggest.

In a population-based study of black men living in Barbados, West Indies, researchers analyzed data from 963 newly diagnosed cases of histologically confirmed PCa and 94 randomly selected age-matched controls. PCa was twice as likely to develop among men in the highest quartile of waistto-hip ratio as among those in the lowest quartile, after adjusting for age, marital status, occupation, smoking status, family history of prostate cancer, body mass index, and religion. In addition, black men with the largest waist circumferences had an 84% increased risk of PCa compared with black men who had the smallest waists, investigators reported in Cancer Epidemiology, Biomarkers & Prevention (2012;21:851-858).

“These results suggest that measure of central rather than global adiposity may be more predictive of prostate cancer, especially in westernized African populations, where patterns

The relationship between body size and prostate cancer is complex. of visceral fat distribution are different from other groups,” researchers Barbara Nemesure, MD, of Stony Brook University in Stony Brook, N.Y., and colleagues wrote.

They also observed: “The relationship between body size and prostate cancer is complex, perhaps resulting from influences of the insulin and androgen pathways, hormonal factors, and/ or other genetic and environmental contributors.”

Study subjects were participants in the Prostate Cancer in a Black Population (PCBP) study, the largest nationwide sample of incidence PCa cases from an African-derived population to date, according to the researchers.

The study population had a mean age of 67 years. Cases were twice as likely to have a family history of PCa. ■

34 Renal & Urology News

OCTOBER 2012

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Diabetes Prevention Via Telephone

BY JILL STEIN PHILADELPHIA—A program in which primary care staff counsel patients with metabolic syndrome by telephone using the Diabetes Prevention Program (DPP) lifestyle intervention results in significant weight loss, according to results released at the 72nd Scientific Sessions of the American Diabetes Association.

The data, from the Support, Health Information, Nutrition and Exercise (SHINE) study, also show that the benefits are similar whether the counseling is provided in a one-on-one or group conference call. The intervention used in the study was drawn from the landmark DPP study, which found that weight loss following intense counseling about dietary changes and increased physical activity delayed or prevented diabetes in individuals at high-risk because of pre-diabetes.

“What we have shown in a diverse population—many of whom were low-income—is that you can train personnel from primary care offices to deliver the program, you can use the telephone which extends outreach, and it can be effective in helping people lose weight, which can help decrease their risk of developing diabetes and

related complications,” said Ruth S. Weinstock, MD, PhD, Distinguished Service Professor at SUNY Upstate Medical University at Syracuse and Chief of the Division of Endocrinology, Diabetes, and Metabolism.

The study included individuals aged 18 years or older who were in stable health and had metabolic syndrome defined by International Diabetes Federation (IDF) criteria, a body mass index of 30 kg/m2 or greater, and no diabetes. Investigators randomized subjects to receive the DPP lifestyle change program by a one-on-one counseling or by a group conference call.

“The DPP program was conducted in academic centers and was very resourceintensive, and we hoped to be able to translate the program into one that was more widely available and less costly,” Dr. Weinstock explained. “We thought that it made sense to test the program in the primary care setting because we felt that it would be an advantage for people to be able to access the program through their primary care provider.”

The investigators also believed that delivering the program via the telephone might help extend reach.

The 16-session DPP curriculum was delivered over one year at five diverse

© THINKSTOCK

Researchers report success with a telephone-counseling program in the primary care setting

Preventative phone consults prove effective.

primary care practices by trained staff—either medical office assistants or nurses—that had been selected by the primary care physician.

Study participants underwent onceweekly telephone counseling with available staff for the first five weeks and then monthly thereafter. A dietitian

was available for up to 11 telephone counseling sessions.

Results at one year were available for 114 individuals who received the solo intervention and 123 individuals who received the group intervention.

Solo treatment participants had a mean weight loss of 4.6 kg compared with 6.0 kg for group treatment participants.

Both groups had a 2 kg/m2 decrease in body mass index. Waist circumference decreased by 5.1 cm in the solo intervention group compared with 6.0 cm in the group treatment participants. The researchers found no significant differences in any of the clinical measures between the two treatment groups.

Additionally, the analysis demonstrated that 38.7% and 42.5% of solo and group participants, respectively, lost at least 5% of their baseline weight and that greater weight loss, 7.1 kg, was achieved with participation in at least nine of 16 core sessions.

Dr. Weinstock said that study participants will be followed for an additional two years and that future analyses will examine the effect of telephone delivery of the DPP program on fasting glucose, lipids, blood pressure, physical activity, psychosocial outcomes, and cost-effectiveness. ■

Uncontrolled Hypertension in Diabetic CKD Patients

BY JILL STEIN PHILADELPHIA—The proportion of patients with type 2 diabetes who have uncontrolled hypertension is higher in patients with chronic kidney disease (CKD) than those without CKD, investigators announced at the 72nd Scientific Sessions of the American Diabetes Association.

Robert Stellhorn, MS, Janssen Global Services LLC, Raritan, N. J., and associates examined the extent of uncontrolled hypertension in 2,181 type 2 diabetics using data from the National Health and Nutrition Examination Survey (NHANES) study for the years 19992008. The NHANES group of studies assesses the health and nutritional status of adults and children in the United States using a combination of interviews and physical examinations.

As hypertension is causally related to the development of CKD, and patients with diabetes have higher rates of hyper-

tension, BP control is recognized as a cornerstone of diabetes care. A prior study using NHANES data from 1999-2008 showed that the percentage of type 2 patients with uncontrolled hypertension ranged from 44.9% to 56.9%. The analysis, however, did not take into account CKD status.

BP control is recognized as a cornerstone of diabetes care Patients included in the present analysis were at least 25 years old at the time they were diagnosed with type 2 diabetes and had valid serum creatinine test results.

CKD stages were based on the classification system used by the

National Kidney Foundation. Uncontrolled hypertension was defined as having either a systolic or diastolic pressure reading above 130/80 mm Hg, respectively.

Overall, 45.2% of patients were identified as having some form of CKD. Results showed that 62.3% of CKD patients had uncontrolled hypertension versus 48.6% of patients without CKD. Although the current use of antihypertensive medication was higher in type 2 diabetes patients with CKD than those without it, a significantly larger proportion of these patients had uncontrolled hypertension (67.2% vs. 54.4%).

As patients progressed with CKD to a higher stage, the proportion of patients on any antihypertensive increased and antihypertensive monotherapy declined and combination therapy use increased.

The analysis also showed that the proportion of patients with hemoglobin A1c greater than 7 was higher among

patients with CKD regardless of hypertension status.

The results suggest that additional effort is likely warranted in optimizing BP control in patients with type 2 diabetes, particularly in those with comorbid CKD .

Finally, researchers noted two possible study limitations. First, NHANES data are cross-sectional and do not provide repeated measurements of laboratory values for patients over different time periods. Thus, the determination of estimated glomerular filtration rate (eGFR) and CKD status was based on a single laboratory observation for each patient. Secondly, the older version of the Modification of Diet in Renal Diseases study formula was used to calculate eGFR because most of the data were in the study are from a period prior to the change in formula. As a result, the CKD rates may be slightly underestimated. ■

www.renalandurologynews.com

OCTOBER 2012

Renal & Urology News 35

Statins Lower Death Risk in ACS-CKD Patients CHRONIC STATIN therapy alone or in combination with aspirin is associated with improved short- and longterm survival in patients suffering from both chronic kidney disease (CKD) and acute coronary syndromes (ACS), according to an Italian study.

The study, led by Alessandro Sciahbasi, MD, of Unità Operativa Complessa di Cardiologia, Policlinico Casilino-ASL RMB, Rome, included 1,484 patients with both ACS and CKD, defined as a glomerular filtration rate below 60 mL/min/1.73 m2 as estimated using the Modification of Diet in Renal Disease (MDRD) study equation.

The investigators divided subjects into four groups according to chronic aspirin and statin therapy prior to hospitalization for ACS: group 1 (589 patients who received neither aspirin

The study revealed no significant differences in the rate of in-hospital re-infarction, stroke, or major bleeding among the four groups, according to the investigators.

With regard to study limitations, the authors noted that the chronic therapy the patients were receiving was not ran-

domized. Thus, they could not exclude bias in the comparability of patients. In addition, the study included patients with different degrees of impaired renal function. The number of patients on dialysis was small, so they could not extend their findings to these patients, they pointed out.

The study participants were enrolled in the IN-ACS Outcome Study, an observational Italian study involving 38 centers.

The study was designed to assess the epidemiology, management, and outcome of patients with ACS. Groups 1, 2, 3, and 4 had a mean age of 76, 78, 73, and 74 years, respectively. ■

She had normal kidney function.

She became critically ill.

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She was diagnosed with AKI.

The study demonstrates a benefit with statins alone or combined with aspirin.

nor statin treatment); group 2 (477 patients who received aspirin alone); group 3 (89 who received a statin only); and group 4 (329 who received both aspirin and a statin).

Although groups 3 and 4 had a higher baseline risk profile, they had significantly lower in-hospital mortality rates (1% in group 3 and 2% in group 4 compared with 8% in group 1 and 7% in group 2), researchers reported online ahead of print in the European Journal of Preventive Cardiology.

Groups 3 and 4 also exhibited significantly better survival at the 30-day and one-year follow-up points, according to the researchers. At 30 days, the mortality rates were 1% and 4% in groups 3 and 4, respectively, compared with 10% in both groups 1 and 2. At one year, the rates were 11% in group 3 and 13% in group 4 compared with 20% in group 1 and 23% in group 2, the researchers wrote.

She was treated differently.

AKI and ESRD patients are not the same.

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

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

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

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

OCTOBER 2012

www.renalandurologynews.com

Malpractice News Another state Supreme Court has struck down a cap on noneconomic damages in medical malpractice cases. At the end of July, the Missouri Supreme Court ruled that the current $350,000 limit on awards for pain-and-suffering is unconstitutional because it deprives patients of their right to a trial by jury.

The court held that when the Missouri Constitution was enacted in 1820, residents of the state had the right by common law to seek damages for medical malpractice claims. “Any limit on damages that restricts the jury’s fact-finding role violates the constitutional right to trial by jury,” the court noted.

This decision stemmed from a lawsuit filed by a woman whose son was born with catastrophic brain damage after a delay in emergency Cesarean section. In that case, a jury found that a third-year medical student had not conducted appropriate tests or provided treatment after the patient complained of cramping and decreased fetal movement.

Two days later, the baby was found to have fetal hypoxia and acidosis, and was delivered via C-section. The jury awarded $1.45 million in noneconomic damages and $3.371 million for future medical damages.

These damages were later reduced to $350,000, per the 2005 law that set the cap for medical malpractice cases.

The case was appealed and the state Supreme Court overturned the 2005 law by a 4-3 decision.

The Missouri State Medical Association (MSMA) reacted with great disappointment. In a statement, the MSMA President, Stephen Slocum, said that the decision “turns back the clock to a time when a medical lawsuit crisis had pushed Missouri doctors to the breaking point.”

According to the MSMA, since the 2005 law was enacted, lawsuits against doctors have plummeted by almost 58%, which helped the state add nearly 1,000 physicians. Additionally, the association reported that medical liability insurance premiums had fallen $27 million in that same time period.

Those who opposed the cap, such as patient advocates, claimed that it unfairly targeted children, the elderly,

Missouri court overrules caps after a pivotal case involving a delay in C-section.

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Missouri Court Rules for Unlimited Liability Payouts

and disabled people, who tend to be awarded pain-and-suffering damages rather than damages based on lost wages and future earnings. “Everyone who believes in the constitution should be thrilled with this decision,” said Tim Dollar, president of the Missouri Association of Trial Attorneys.

‘Disclosure, Apology, and Offer’ Program in Massachusetts Massachusetts Governor Deval Patrick recently signed into law a healthcare cost-containment bill estimated to save $200 billion. The bill was the result of joint negotiations between the Massachusetts Medical Society, the Massachusetts Bar Association, and Massachusetts Academy of Trial Attorneys. All three groups are optimistic about the success of the program to reduce costs and improve the malpractice liability situation.

Among other provisions, the new law requires physicians who make medical errors while treating patients to disclose the mistakes. Physicians are allowed to apologize to patients without such apologies being used as an admission of liability. This is part of what is known as the “Disclosure, Apology, and Offer” program. The program involves disclosing errors and unanticipated adverse outcomes to patients, investigating what happened, and establishing systems to prevent future occurrences. In addition, physicians would apologize to patients, and, when warranted, offer

BY ANN W. LATNER, JD

fair financial compensation to injured patients so they do not have to resort to legal action. The law also includes a 182-day “cooling off” period, giving patients and providers time to go through the “disclosure, apology, and offer” process—in hopes that cases can be resolved before they go to court.

The new process is thought to be a significant improvement over the current tort system, which “can sometimes lead to a culture of silence and a ‘deny and defend’ attitude in the medical community,” a statement by the Massachusetts Medical Society noted. “This agreement is an extraordinary accomplishment,” said Alan Woodward, MD, Chair of the Massachusetts Medical Society’s Committee on Professional Liability.

“It will encourage transparency and honesty, protect the rights of patients who have been harmed by avoidable events, improve patient safety, reduce litigation, and, ultimately, cut health care costs.”

One of the components in the new bill is a provision to create a task force, charged with studying the potential overuses of medical testing, also known as “defensive medicine,” where clinicians order unnecessary tests to avoid lawsuits.

Most Americans Concerned About Medical Errors A new survey, conducted by Wolters Kluwer Health, revealed that almost a third of Americans reported experiencing—or having a friend Forty-five percent of patients reported receiving an incorrect healthcare bill.

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36 Renal & Urology News

or family member experience—a medical mistake. Medical mistakes include being given the wrong medication, dosage, or treatment. In addition to these types of errors, more than one in five Americans report having been misdiagnosed by their doctor and nearly 45%, report having received an incorrect bill from their healthcare provider.

The survey, completed in July 2012, consisted of telephone interviews with American consumers commenting on their experiences with and concerns about medical errors. Over 70% of respondents reported being very concerned or somewhat concerned about medical mistakes.

The survey revealed that Americans are taking steps to help minimize mistakes. A majority of surveyed consumers have taken actions to reduce errors. For example, 66% of survey respondents had done research to validate a diagnosis or treatment plan. Once diagnosed, over half (56%) sought a second opinion. Other steps taken to prevent medical errors included writing information down for the doctor or nurse, delaying procedures until a day when a physician might be more rested or focused, and, surprisingly, asking a doctor or nurse to wash their hands (18% of respondents admitted having to ask).

Interestingly, women were always more likely than men to do research, get a second option, and all other actions involved with reducing errors.

According to survey results, consumers think the biggest causes of medical mistakes are miscommunication among hospital staff (35%), doctors or nurses working in a hurried environment (26%), clinicians who are fatigued (14%), and staffing shortages in hospitals (12%).

On a positive note, survey respondents expressed confidence in technology being able to reduce medical errors.

Sixty-eight percent of those surveyed agreed that technology has had a positive impact in reducing the chance for medical mistakes. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

www.renalandurologynews.com

OCTOBER 2012

Renal & Urology News 41

Your Money By including a cash-holding fund in your portfolio, you may diversify your assets and limit losses in downturns BY STAN LUXENBERG

Top performers during the crisis While there is a strong case for the buy-and-hold approach supported by many advisors, a growing number of flexible mutual funds follow a different strategy—selling stocks and shifting to cash when conditions look hazardous.

The funds do not have perfect timing. In some cases, managers have been caught holding cash when stocks were rallying. In general, however, the funds have tended to excel in downturns—and they deliver decent returns in good times. That in itself has produced strong long-term returns.

Should you put all your assets in a flexible

technology stocks are rising, the fund takes a position in the sector. When a sector begins falling, the managers sell the stocks and shift to cash. “We want to own securities that are performing well right now,” says portfolio manager Brad Thompson.

During the first week of April this year, the market began slowing, and the fund shifted to cash. At first, the move seemed untimely because stocks continued rising.

Then markets sank sharply as investors worried about the continuing crisis in Europe. During May, the S&P 500 lost 6%, while Stadion about broke even.

Columbia Thermostat Fund Among the strongest performing funds has been Columbia Thermostat, which has returned 3.8% annually during the past five years, while the S&P 500 lost 1.5%. The fund follows a simple formula that aims to buy stocks when they are cheap and sell when prices look rich.

The formula is based on moves in the S&P 500, which was recently around 1400. When the index is below 1000, Thermostat becomes bullish, putting 90%

A growing number of flexible mutual funds advocate a different strategy—selling stocks and shifting to cash when conditions warrant. fund? Probably not—but by including a cash-holding fund, you may help to diversify your portfolio and limit losses in downturns.

Stadion Managed Portfolio One of the top-performing funds during the financial crisis was Stadion Managed Portfolio. While the S&P 500 lost 37.0% in 2008, Stadion only declined 5.8%. The fund avoided much of the damage by holding a big cash stake. The portfolio managers divide the markets into sectors, such as finance and technology. If

of assets in stocks. As the S&P rises, the fund sells stocks and shifts to bonds and cash. When the index rises above 1750, the fund will have only 10% of assets in stocks. The portfolio recently had 50% of assets in stocks.

Thermostat does not win every year.

As stocks climbed in 2006 and 2007, the fund switched to fixed income. For a time, the fund trailed badly. Then in 2008, the bond stake enabled the portfolio to sail through the financial crisis with relatively little damage. Once markets sank, Thermostat began buying. The fund’s

Money market accounts Bonds

Cash

Blue-chip stocks

Gold

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W

hen markets collapsed during the financial crisis, many investors were furious with their financial advisors for not dumping certain stocks. Throughout the turmoil, many advisors counseled clients to stay the course, maintaining portfolios while stocks sank. Citing time-honored views, the advisors said that it is a mistake to bail out of markets during downturns. Instead, they noted, investors should hold on and wait for the inevitable rebound.

Flexible mutual funds allow investors to sell portfolio assets and shift to cash holdings.

stock-heavy portfolio enjoyed big gains when the market started rocketing up in the spring of 2009.

Ralph Wanger, a veteran portfolio manager who ran Acorn Fund, which outdid the markets for more than two decades, launched Columbia Thermostat in 2002.

During his long career, Wanger—who is now retired—observed that markets tended to move in cycles, rising for years and then suffering prolonged periods of poor returns. From 1962 through 1982, stocks moved sideways. Then starting in 1982, stocks recorded a huge rally that only ended when Internet companies collapsed in 2000. Studying financial history, Wanger figured that the market was due for a time of little gains. He created Thermostat for the poor conditions—and his outlook proved to be on target.

The fund has excelled in the past decade because stocks have stayed static, rising periodically and then falling back. In that erratic environment, Thermostat bought stocks on dips and sold on gains. But in a period of steadily rising markets, Thermostat would be left behind, holding cash while stocks climb. If you think that markets are due to rally for the next decade, should you stay away from Thermostat? Not necessarily, because the fund excels in downturns

and it can be a sound holding that can diversify a portfolio.

Leuthold Asset Allocation Another star during the financial crisis was Leuthold Asset Allocation, which has topped the S&P 500 by half a percentage point during the past five years. The fund can put up to 70% of assets in stocks when they appear cheap compared to bonds. When the market looks expensive, the portfolio can have as little as 30% in stocks. Heading into the financial crisis, the fund had 50% in stocks.

The portfolio currently has 65% of assets in stocks. “Right now valuations are not at the high end, and they are not screaming cheap,” says portfolio manager, Matt Paschke.

Mr. Paschke says that the economy is slowly improving. Homebuilding is increasing, and mortgage interest rates remain at record lows. Other positive signs include increases in the number of jobs and record corporate profit margins.

While stocks seem somewhat attractive, bonds hold little appeal because of their skimpy yields, Mr. Paschke adds. These days he has 4% of the portfolio assets in gold. That serves as an insurance policy, an asset that can hold its value when other investments collapse. ■

42 Renal & Urology News

OCTOBER 2012

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CME FEATURE

The Evaluation and Treatment of Resistant Hypertension With increased incidence of obesity—and higher caloric and salt intake—in the general population, resistant hypertension is more prevalent than ever

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

BY RAYMOND V. OLIVA, MD AND GEORGE L. BAKRIS, MD

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

STATEMENT OF NEED: Primary care clinicians and nephrologists who care for patients with resistant hypertension must be able to identify truly resistant hypertension, as distinguished from pseudo resistance. Clinicians also need the tools to manage patients whose blood pressure stubbornly resists control with traditional agents.

TARGET AUDIENCE: This activity has been designed to meet the educational needs of nephrologists and allied healthcare clinicians involved in the treatment of patients with resistant hypertension.

EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Review the clinical predictors of resistant hypertension.

• Distinguish resistant hypertension from pseudo resistance.

• Evaluate current treatment modalities, and discuss experimental techniques to reduce blood pressure in patients with resistant hypertension.

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

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

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

The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty • Raymond V. Oliva, MD • George L. Bakris, MD

Reported Financial Relationship No financial relationships to disclose Grants/Research Support: Takeda; Forest Consultant: Takeda; Abbott; Eli Lilly; Medtronic, Relapsya Speakers’ Bureau: Takeda

The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Medical Education, and Victoria C. Smith, MD, 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 October 2012 through October 2013, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/renalanurologynews, and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.

H

igh blood pressure (HBP) is the phenotypic manifestation of hypertension (HT) and if suboptimally controlled is one of the most attributable risks for cardiovascular (CV) death worldwide.1 The net adjusted prevalence ratios of HT in the United States continue to increase, but due to increased awareness, there is some improvement in the treatment and control of HT.2 Several large HT outcome trials, however, showed failure to achieve BP goals—despite protocoldefined treatment regimens, with 20-35% of the participants not achieving BP control even with more than three antihypertensive medications.3-6 Resistant hypertension (RH) is defined in the 2008 American Heart Association’s scientific statement as BP that remains above goal in spite of the concurrent use of three antihypertensive agents of different classes—one of which is a diuretic—with all drugs prescribed at maximally-tolerated doses.7 Patients who require >4 anti-

hypertensive medications to achieve BP control should also be considered resistant to treatment. This definition does not apply to patients who have recently been diagnosed with HT. RH is a term used to identify patients who are at high risk of having reversible causes of HT, and who may benefit from special diagnostic and therapeutic considerations.7

Prevalence of resistant hypertension Presently, the true prevalence of RH is not known. A major problem is that not all uncontrolled HT is resistant, based on the definition given by the American Heart Association. Uncontrolled HT that is not resistant is defined as follows: patients who lack BP control secondary to poor adherence and/or inadequate treatment regimen.7 To accurately determine the prevalence of RH, a forced titration study of a large, diverse HT cohort is required. However, several HT studies offer an alternative look at the prevalence of this condition. In a recent National Health and Nutrition Examination Survey (NHANES) survey, only 53% of patients have BP control at <140/90.8 Only thirty-seven percent of

Raymond V. Oliva, MD, is Clinical Associate Professor in the Department of Medicine at the University of the Philippines-Philippine General Hospital in Manila.

George L. Bakris, MD, is Professor of Medicine in the Hypertensive Diseases Unit at the University of Chicago Pritzker School of Medicine in Chicago.

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participants with chronic kidney disease (CKD), achieve BP control at 130/80 mm Hg.9 In another study using an unselected population sample, the prevalence of RH was 8.9% among individuals, and 12.8% have their BP controlled to <140/90 mm Hg.10 In a cross-sectional analysis of the Framingham Heart Study participants, only 48% had BP control to <140/90, and less than 40% of the elderly participants were at BP goal.11 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial represented the U.S. general population. After roughly five years of follow-up in ALLHAT, 34% of participants remain uncontrolled while on an average of two BP medications.

Overall, 51% of participants needed three or more BP medications, indicating resistance.

Prognosis of resistant hypertension No epidemiological studies have prospectively evaluated the prognosis of patients with RH in comparison to those with Stage 1 HT. Presumably, prognosis will be poor among patients with RH due to long-standing elevated BP and associated CV risks, such as diabetes mellitus, left ventricular hypertrophy (LVH), obstructive sleep apnea (OSA), and/or CKD.12 The Veterans Administration Cooperative Studies demonstrated a 96% reduction in the CV events over 18 months using a triple antihypertensive regimen compared to placebo, suggesting substantial treatment benefit.13

Predictors of resistant hypertension An analysis of the Framingham study shows that older age was the strongest predictor of poor BP control. Data showed that patients aged >75 years are approximately one fourth as likely as those <60-years-old to have controlled, systolic BP (SBP).14 This may be attributable to the stiffening of the arteries, causing isolated systolic HT in the elderly. Other strong predictors for lack of SBP control are the presence of LVH and obesity. In terms of controlling diastolic BP (DBP), the strongest negative predictor was obesity, as BP was less controlled (by one third) compared to lean patients.15 In the ALLHAT and Framingham studies, older age, higher

OCTOBER 2012

Table 1. Factors That May Improve Medication Adherence with RH Patients Using a selection of agents with low side-effect profiles, such as RAAS blockers Keeping the regimen simple—once-daily dosing with single pill combinations The use of pill boxes Encouraging self-BP monitoring Utilizing family to help patients with memory deficits Improving communication between doctor and patient Implementing a team approach in the management of RH Elevating medication adherence as a critical healthcare issue

baseline SBP, LVH, and obesity all predicted treatment resistance.16 One of the strongest predictors of treatment resistance is presence of CKD, stage 3 or higher, defined by serum creatinine >1.5 mg/dl.7 People with diabetes, African Americans (especially women), and those living in the southeastern U.S. are also at increased risk for RH. Both studies indicate that—in an aging population— the prevalence of obesity, CKD, and diabetes increase the risk for RH.

The dilemma of pseudo resistance Pseudo resistance refers to poorly-controlled HT that appears to be resistant, but in fact its resistance is attributable to factors other than inability to control BP with medication or lifestyle changes.

Such factors include: 1) inaccurate BP measurement; 2) white coat HT; 3) failure to detect a secondary cause, such as primary aldosteronism, or; 3) poor adherence to therapy.7, 17-19 A careful evaluation must exclude these factors before labeling a patient with RH. Although guidelines are available to properly assess office BP readings, several mistakes often produce falsely elevated readings. The three most common mistakes in BP measurement include: a) measuring the BP before letting the patient sit quietly for five minutes; b) taking only a single reading in one arm, and; c) inappropriately using a small arm cuff for a larger arm circumference.7,19 Other BP reading errors can be triggered by a patient’s smoking prior to measurement, and if the clinician does not fully supporting the patient’s arm at heart level.20 In the elderly, presence of highly-calcified or arteriosclerotic arteries results in the overestimation of intra-arterial BP.21 Poor adherence to antihypertensive therapy is another cause of presumed RH. Studies suggest that up to 40% of patients with newly diagnosed HT

will discontinue their medications during the first year of treatment.22,23 In surveillance of over 4,000 patients, a 50% antihypertensive discontinuation rate was seen within the first year of treatment.24 Factors that may improve medication adherence by patients are listed in Table 1.

A notable contributing factor to pseudo resistance is clinical inertia among physicians. Clinical inertia is defined as a conscious decision not to adequately treat a condition despite knowing that the disease is present.25 Lack of training and experience on the proper use of antihypertensive agents, or an overestimation of the care already provided may be factors here.26 Poor adherence to medication is typically seen at all levels of practice, and is less common in referral practices of board certified clinical HT specialists (Garg/ Singer papers). In a retrospective study at a HT specialty clinic, poor medication adherence is seen in only 16% of the evaluated patients.7 Once factors contributing to pseudo resistant HT are identified, the problem is easily correctable. To encourage better adherence, make the patient responsible for his/her disease.

Improved adherence is well documented with home BP determination and having the patient report to a healthcare professional at regular intervals. The use of 24-hour ambulatory measurements to rule out white coat effect or masked HT is also important.

Factors in development Several factors may contribute to the development of RH. Certain classes of pharmacologic agents produce transient or even persistent elevations of BP. Non-steroidal anti-inflammatory drugs (NSAIDs) hinder BP control.27 Meta-analyses of their effects have indicated average increases in mean arterial pressure of approximately

Renal & Urology News 43

5.0 mm Hg. NSAIDs can also blunt the BP-lowering effects of several antihypertensive medications, with the exception of calcium channel blockers (CCB).28 Similar effects have been seen with selective cyclooxygenase-2 inhibitors.29 These effects presumably occur secondary to the inhibition of renal prostaglandin production, particularly prostaglandin E2 and prostacyclin, with subsequent sodium and fluid retention. Sympathomimetics, such as nasal decongestants and anorexic pills, oral contraceptives, glucocorticoids, erythropoietin, and cyclosporine can also interfere with BP control. Black licorice found in oral tobacco products and herbal supplements, such as ma Huang, increase BP by suppressing the metabolism of cortisol, resulting in the increased stimulation of mineralocorticoid receptors. Illicit drugs, such as cocaine and amphetamines, are also common causes of RH.7, 25 Excess dietary salt is a key and, perhaps, the most important factor responsible for many cases of RH by directly increasing BP through volume overload, and blunting the BP-lowering effect of most classes of antihypertensive agents except CCBs and diuretics. The majority of patients with RH have higher salt intake than the general population, exceeding more than 10 grams/day.30-32 The effects of increased dietary salt intake tend to be more pronounced in saltsensitive patients, including the elderly, African Americans, and stage 3 or higher CKD patients.

While modest alcohol consumption does not generally increase BP, heavy alcohol intake (>3 to 4 drinks of “hard liquor”/day) has a dose-related effect on BP, both on normal and hypertensive individuals.33 In an analysis of Chinese adults ingesting >30 drinks per week, the risk of having HT increased from 12% to 14%. Cessation of heavy alcohol ingestion reduced 24-hour ambulatory SBP measurements in such patients by 7.2 mm Hg, and DBP by 6.6 mm Hg.34 Obesity is a very common feature in patients with RH. Most obese patients tend to have an increased need of antihypertensive medications and increased likelihood of never achieving BP control. Mechanisms of obesity-induced HT are complex and not fully understood. Contributing factors in such patients include insulin resistance and hyperinsulinemia, with consequent impairment of sodium excre-

44 Renal & Urology News

OCTOBER 2012

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tion, increased sympathetic nervous system activity, increase in aldosterone production by adipocytes, and presence of OSA and sleep disturbances.35-37

Treatment modalities The goal BP in all hypertensive patients is <140/90 mm Hg. There is evidence supporting a lower BP goal in patients with stage 3 or higher CKD, if >300 mg/day of proteinuria is present.

The 2008 AHA guidelines recommend both nonpharmacologic and pharmacologic therapies for treatment.7,38

Nonpharmacologic interventions Lifestyle changes, including weight loss, regular exercise, ingestion of a high fiber, low fat, and low-salt diet (of primary importance), and moderate alcohol intake should be strongly encouraged. Excessive sodium and excessive weight—along with poor sleep habits— are most commonly associated with RH. A recent weight loss study showed that a 10 kg weight loss is associated with an average of 6.0 mm Hg reduction of SBP. Morbidly obese patients who have failed to lose more than 10-15 pounds should be referred for surgical evaluation.39, 40 The benefit of salt reduction is well documented in general HT patients. Salt restriction to <3 grams/day is associated with modest reductions in BP. Current guidelines suggest that dietary sodium in HT patients should be <100 mmol/ day (2.4 gm of sodium or 6 g sodium chloride).41, 42 Alcohol intake should be limited to no more than one ounce of ethanol/day in most men (~2 drinks) and 0.5 ounce of ethanol/day in women and lighter-weight individuals.43 Ingestion of a diet rich in fruits and vegetables, high in low-fat dairy products, potassium, magnesium, calcium, and low in total saturated fats was found to reduce BP by 11.4/5.5 mm Hg.44-46 Pharmacologic treatment Pharmacologic treatment involves meaningful use of three different antihypertensive medications titrated to the maximally tolerated dose, one of which is a diuretic appropriate for the level of kidney function. Recommendations in the modification and intensification of treatment are based on pharmacologic principles in the context of the underlying pathophysiology of HT, the clinical experience of the physician, and treatment guidelines. The present rationale is

to ensure that all mechanisms for BP elevation are blocked by maximizing treatment.47-49 The patient’s regimen should be simplified using long-acting fixed-dose combination agents when possible, to improve adherence, reduce pill counts, and permit once-daily dosing.

In keeping with the recent NICE BP guidelines, most patients should be on a renin-angiotensin-aldosterone (RAAS) system blocker, along with a calcium antagonist, and an appropriately-dosed diuretic. The physician must ensure that these agents are prescribed at maximally-tolerated doses and may exceed dose limits in morbidly obese patients.

This triple regimen of an angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB), long-acting CCB, and a long-acting diuretic—preferably chlorthalidone or indapamide— is often effective and well tolerated by patients. This triple regimen can be given as two pills with the wide variety of available fixed-dose combinations.25,50 Combining an ACE-I with ARB was less effective in terms of BP reduction than adding a diuretic or a CCB, and did not reduce CV or renal events.51,52 In a separate trial, the combination of the direct renin inhibitor, aliskiren, and an ARB was also associated with a small additional BP drop,53 but no outcome data are available. Thus, dual RAAS blockade is not recommended.

Cornerstones of treatment An appropriate diuretic remains the cornerstone of treatment, as persistent volume expansion contributes to RH. In 279 patients taking thiazide diuretics, researchers saw a significant increase in levels of brain natriuretic peptide and atrial natriuretic peptide among RH patients, suggesting volume expan-

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CME FEATURE

Patients need to understand that aerobic exercise reduces arterial blood pressure.

ference occurring overnight, as compared to a 50 mg daily dose of the HCTZ.55 Switching HCTZ users to chlorthalidone resulted in an additional 8 mm Hg drop, and an increased number of patients reaching BP goal.56 Chlorthalidone is initially recommended at 12.5 mg once a daily, with subsequent titration up to 25 mg daily.

It is necessary to monitor serum electrolytes; however, this is generally given with an ARB or ACE-I so the risk of hypokalemia is very low unless the patient is nonadherent with sodium restriction. Among patients with an estimated glomerular filtration rate <40 mL/min/1.73m2, thiazide diuretics are less effective. Loop diuretics, such as furosemide or torsemide (preferred due to longer action), are necessary for effective volume control.7 The Systolic Hypertension in Europe (Syst-Eur) trial also has a great deal of outcome data on indapamide, demonstrating risk reduction for both heart

Early discontinuation of antihypertensive treatment and suboptimal execution of the prescribed daily regimens are common facets of poor patient adherence. sion. 54 Chlorthalidone is preferred over hydrochlorothiazide (HCTZ) for treatment, the former appearing to have more potency than the latter drug. Greater ambulatory BP reduction was demonstrated with chlorthalidone, 25 mg once daily, with the largest dif-

failure and strokes. Indapamide also has a lower side effect profile compared to chlorthalidone. When given in doses of 2.5 mg daily, it has proven effective.

Adding aldosterone antagonists provides significant benefit to existing drug regimens in patients with RH,

as these patients were found to have higher levels of plasma aldosterone.

In a study of patients on an average of four antihypertensive medications, the addition of spironolactone resulted in an average of 25/12 mm Hg reduction of BP after six months of treatment.57 In the BP lowering arm of the AngloScandinavian Cardiac Outcomes Trial (ASCOT), patients receiving spironolactone as a fourth line antihypertensive medication for uncontrolled BP resulted in a 21.9/9.5 mm Hg drop in BP regardless of age, sex, smoking and presence of diabetes.58,59 The advantage of using spironolactone is that it can lower BP even with normal or low aldosterone levels. The most common adverse effect of spironolactone is breast tenderness, particularly in men—especially in doses above 25 mg/day. This can be avoided by using a more selective mineralocorticoid receptor antagonist, eplerenone, which has demonstrated BP-lowering efficacy and can reduce proteinuria.60-62 Eplerenone must be given twice daily.

Amiloride is another potassiumsparing diuretic associated with BP reduction. In a blinded comparison of amiloride 10 mg taken once daily, spironolactone 25 mg daily, or a combination of both used in African American patients on a two-drug regimen (a diuretic and a CCB), the mean decrease in BP was 12.2/4.8 mm Hg for amiloride, 7.3/3.3 mm Hg for spironolactone, and 14.1/5.1 mm Hg for the combination of both drugs.63 Hyperkalemia may occur when prescribing these agents, especially in combination with an ACE-I or ARB, thus

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necessitating close monitoring if kidney function is not within the normal range.

Physicians should educate patients to avoid food and supplements rich in potassium, and to avoid medications such as NSAIDs.64 If the patient is still hypertensive on maximally tolerated doses of three or four drugs—including spironolactone— he should be referred to a board certified hypertension specialist. A directory of board certified specialists is available online at the American Society of Hypertension website.

Vasodilating beta blockers (carvedilol, nebivolol, bisoprolol) may be used as fifth-line agents especially, if tachycardia i.e. resting heart rate >84 is present.65 Vasodilating beta blockers have fewer side effects compared to traditional beta blockers and are just as efficacious for lowering BP.66 Centrallyacting agents should not be used with beta blockers, as this provides little-tono- additional BP lowering, if the beta blocker is maximally titrated.

Experimental therapies New experimental techniques are being evaluated to reduce BP in RH. A randomized trial of 106 patients on five antihypertensive medications, including a diuretic, underwent catheter-based radiofrequency ablation of the renal sympathetic nerves and was conducted for six months. The technique decreased BP from 178/97 mm Hg to 143/85 mm Hg.67-69 In another cohort study, BP was reduced by 23/11 mm Hg at 12-months and 32/14 mm Hg at 24-months using the same technique.69 Complications related to radiofrequency ablation are rare and include femoral artery pseudoaneurysm.

Another experimental therapy for RH is the use of electrical stimulation of the carotid sinus baroreflex system.

In a study involving 45 patients with a mean BP of 179/105 mm Hg (maintaining on five medications), there was a mean reduction by 21/12 mm Hg at three months after device implantation, and 32/22 mm Hg after two years.70

Summary RH is more prevalent today with increased incidence of obesity, and higher caloric and salt intake in the general populus. Effective management should be based on pathophysi-

ologic principles and outcome data.

This requires careful examination and the exclusion of factors associated with pseudo resistance. The modification of factors related to true resistance is needed to achieve better BP goals. An aggressive treatment should be designed to compensate for all mechanismsof BP elevation in a given patient. The proper combination of antihypertensive medications should be instituted, and, if this fails, the patient should be referred to an HT specialist. Hopefully, experimental therapies will achieve more effective BP control in difficult cases of RH going forward. ■ REFERENCES 1. Mensah GA, Bakris G. The United nations high level meeting addresses noncommunicable diseases, but where is hypertension? J Clin Hypertens (Greenwich) 2011;13:787-790.

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18. Kaplan NM. Resistant hypertension. J Hypertens 2005;23:1441-1444.

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24. Vrijens B, Vincze G, Kristanto P, et al. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ 2008;336:1114-1117.

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27. Johnson AG. NSAIDs and increased blood pressure. What is the clinical significance?

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28. Conlin PR, Moore TJ, Swartz SL. et al. Effect of indomethacin on blood pressure lowering by captopril and losartan in hypertensive patients. Hypertension 2000;36:461-465.

29. Whelton A, White WB, Bello AE, et al. Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or =65 years of age with systemic hypertension and osteoarthritis.

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30. He FJ, MacGregor GA. Effect of longer-term modest salt reduction on blood pressure. Cochrane Database Syst Rev 2004;(3):CD004937.

31. Luft FC, Weinberger MH. Review of salt restriction and the response to antihypertensive drugs. Satellite symposium on calcium antagonists. Hypertension 1988;11:I229-I232.

32. Schafflhuber M, Volpi N, Dahlmann A, et al. Mobilization of osmotically inactive Na+ by growth and by dietary salt restriction in rats. Am J Physiol Renal Physiol 2007;292:F1490-F1500.

33. Aguilera MT, de la Sierra A, Coca A, et al. Effect of alcohol abstinence on blood pressure: assessment by 24-hour ambulatory blood pressure monitoring.

Hypertension 1999;33:653-657.

34. Wildman RP, Gu D, Muntner P, et al. Alcohol intake and hypertension subtypes in Chinese men.

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35. Nishizaka MK, Pratt-Ubunama M, Zaman MA, et al.

Validity of plasma aldosterone-to-renin activity ratio in African American and white subjects with resistant hypertension. Am J Hypertens 2005;18:805-812.

36. Hall JE. The kidney, hypertension, and obesity.

Hypertension 2003;41:625-633.

37. Hall JE, Kuo JJ, da Silva AA, et al. Obesity-associated hypertension and kidney disease. Curr Opin Nephrol Hypertens 2003;12:195-200.

38. Pisoni R, Ahmed MI, Calhoun DA. Characterization and treatment of resistant hypertension. Curr Cardiol Rep 2009;11:407-413.

39. Aucott L, Rothnie H, McIntyre L, et al. Long-term weight loss from lifestyle intervention benefits blood pressure?: a systematic review. Hypertension 2009;54:756-762.

40. Poobalan AS, Aucott LS, Smith WC, et al. Long-term weight loss effects on all cause mortality in overweight/obese populations. Obes Rev 2007;8:503-513.

41. He FJ, Marciniak M, Visagie E, et al. Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives. Hypertension 2009;54:482-488.

42. Nishizaka MK, Pratt-Ubunama M, Zaman MA, et al.

Validity of plasma aldosterone-to-renin activity ratio in African American and white subjects with resistant hypertension. Am J Hypertens 2005;18:805-812.

43. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572.

44. Appel LJ, Miller ER, III, Jee SH, et al. Effect of dietary patterns on serum homocysteine: results of a randomized, controlled feeding study. Circulation 2000;102:852-857.

45. Moore TJ, Vollmer WM, Appel LJ, et al. Effect of dietary patterns on ambulatory blood pressure : results from the Dietary Approaches to Stop Hypertension (DASH) Trial. DASH Collaborative Research Group. Hypertension 1999;34:472-477.

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46. Svetkey LP, Simons-Morton D, Vollmer WM, et al. Effects of dietary patterns on blood pressure: subgroup analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial. Arch Intern Med 1999;159:285-293.

47. Czarina Acelajado M, Calhoun DA. Treatment of resistant hypertension. Minerva Cardioangiol 2009;57:787-812.

48. Graves JW, Bloomfield RL, Buckalew VM, Jr. Plasma volume in resistant hypertension: guide to pathophysiology and therapy. Am J Med Sci 1989;298:361-365.

49. Taler SJ. Treatment of resistant hypertension. Curr Hypertens Rep 2005;7:323-329.

50. Gradman AH, Basile JN, Carter BL, Bakris GL. Combination therapy in hypertension. J Clin Hypertens (Greenwich ) 2011;13:146-154.

51. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-553.

52. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559.

53. Oparil S, Yarows SA, Patel S, et al. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, doubleblind trial. Lancet 2007;370:221-229.

54. Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, et al.

Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med 2008;168:1159-1164.

55. Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 2006;47:352-358.

56. Khosla N, Chua DY, Elliott WJ, Bakris GL. Are chlorthalidone and hydrochlorothiazide equivalent bloodpressure-lowering medications? J Clin Hypertens (Greenwich) 2005;7:354-356.

57. Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens 2003;16:925-930.

58. Oparil S. The ASCOT blood pressure lowering trial.

Curr Hypertens Rep 2006;8:229-231.

59. Chapman JN, Kirby P, Caulfield MC, Poulter NR. Cardiovascular risk factors in a cohort of 30,000 high-risk men and women in the UK: cross-sectional, retrospective and prospective studies of screenees for the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). J Hum Hypertens 2001;15:S23-S26.

60. Gheorghiade M, Khan S, Blair JE, et al. The effects of eplerenone on length of stay and total days of heart failure hospitalization after myocardial infarction in patients with left ventricular systolic dysfunction. Am Heart J 2009;158:437-443.

61. Pitt B, Reichek N, Willenbrock R, et al. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 2003;108:1831-1838.

62. Pitt B, Williams G, Remme W, et al. The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther 2001;15:79-87.

63. Eide IK, Torjesen PA, Drolsum A, et al. Low-renin status in therapy-resistant hypertension: a clue to efficient treatment. J Hypertens 2004;22:2217-2226.

64. Calhoun DA, Zaman MA, Nishizaka MK. Resistant hypertension. Curr Hypertens Rep 2002;4(3):221-228.

65. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 2000;36:646-661.

66. Townsend RR, DiPette DJ, Goodman R, et al. Combined alpha/beta-blockade versus beta 1-selective blockade in essential hypertension in black and white patients. Clin Pharmacol Ther 1990;48:665-675.

67. Mahfoud F, Schlaich M, Kindermann I, et al. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation 2011;123:1940-1946.

68. Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903-1909.

69. Krum H, Schlaich M, Whitbourn R, et al. Catheterbased renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275-1281.

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46 Renal & Urology News

OCTOBER 2012

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1. Which of the following is the best definition of resistant hypertension? a. The patient needs to be on three different medications with BP >140/90 mm Hg. b. The patient needs to be on maximally tolerated doses of three or more antihypertensive medications with BP >140/90 mm Hg. c. The patient needs to be on maximally tolerated doses of four or more antihypertensive medications with BP >140/90 mm Hg. d. The patient needs to be on maximal doses of three or more antihypertensive medications regardless of BP level. e. None of the above 2. A patient presents with a BP of 154/98 mm Hg with normal kidney function. He is currently on hydroclorothiazide 25 mg/d, valsartan 320 mg/day, and lisinopril 10 mg/d. Which of the following needs to occur for him to meet the definition of resistant hypertension? a. His lisinopril needs to be titrated to 40 mg/day. b. He needs to have another class of agent added and titrated. c. He needs to be on a low salt diet including maximal therapy. d. His BP is <160 mm Hg, so he doesn’t have resistant hypertension. e. B and C 3. Which of the following systems play a key role in the genesis of resistant hypertension? a. The renin-angiotensin system b. Volume overload (high sodium intake) c. Bradykinin d. The sympathetic nervous system e. All of the above 4. If someone is receiving maximal doses of a thiazide diuretic and an

ACE inhibitor with normal kidney function, and the patient’s BP is >160/100 mm Hg, which of the following therapy additions, if given and titrated to maximal doses, with BP remaining above 140/90 mm Hg, would qualify the patient as having resistant hypertension? a. Clonidine and a beta blocker b. Spironolactone and beta blocker c. Spironolactone and a calcium antagonist d. Angiotensin II receptor blocker (ARB) and clonidine e. ARB and beta blocker 5. Which of the following statements about renal denervation is true? a. It is an approved an accepted procedure in the United States. b. It is an effective but short-lived treatment of resistant hypertension lasting only two years. c. It is an experimental procedure in the U.S. and accepted in Europe and Australia with efficacy lasting at least 3 years. d. It is highly effective, but only in people receiving more than six medications daily for BP control. e. It is contraindicated in people with pacemakers.

6. Which of the following are true when evaluating a patient with suspected resistant hypertension? a. It is a “rule-out” diagnosis (all secondary causes excluded). b. Patients must be on a low sodium diet along with appropriate mixtures of multiple medications with poor control of BP. c. Combinations of agents affecting the same hemodynamic system do not count as two separate antihypertensive agents. d. Serum potassium must be within the normal range to ensure that all factors affecting BP are managed. e. All of the above

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