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From Medscape = Education=20 Nephrology

Anemia in Patients With End-Stage Renal Disease Undergoing Dialysis: = Efficacy and Safety of Current and Investigational Treatment Options = CME/CE

Jay B. Wish, MD

Authors= and=20 Disclosures

CME/CE Released: 03/30/2011; Valid for credit = through=20 03/30/2012

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Erythropoiesis-stimulating agents (ESAs) have become such an integral = part of=20 the treatment of anemia in patients with end-stage renal disease (ESRD)=20 undergoing dialysis that it is difficult to envision nephrology practice = without=20 them. The use of ESAs has resulted in improved quality of life and = avoidance of=20 transfusions among dialysis patients. Although the total annual Medicare = expenditure for ESAs administered to ESRD patients in the United States = peaked=20 in 2006, it remains close to $2 billion per year^[1] = and in=20 the fourth quarter of 2006, 94% of hemodialysis patients received = ESAs.^[2] =

ESAs Are Not Without Risks

Nonetheless, our romance with ESAs has had its rough patches, going = back to=20 1999 and the publication of the Normal Hematocrit Cardiovascular Trial=20 (NHCT).^[3] = Observational data from the United States Renal Data System = (USRDS)^[4] = suggested=20 that dialysis patients with hematocrit (Hct) > 39%, which is "normal" = in the=20 general population, had better outcomes than dialysis patients in the = Hct target=20 range of 33%-36% recommended by the 1997 National Kidney Foundation = (NKF)=20 Dialysis Outcomes Quality Initiative (DOQI) guidelines^[5] = for the=20 treatment of the anemia of chronic kidney disease (CKD). The NHCT was = designed=20 to test the hypothesis that a normal Hct offers a survival and = cardiovascular=20 event advantage compared with an Hct of 30%. The randomized prospective = study of=20 1233 hemodialysis patients with underlying cardiac disease was = terminated early=20 because of the low likelihood that patients in the normal Hct arm = (target Hct=20 42%) would have better outcomes than those in the control arm (target = Hct 30%).=20 The risk ratio for deaths and nonfatal myocardial infarction in the = normal Hct=20 arm was 1.3 compared with the control arm (confidence interval, = 0.9-1.9). The=20 results of this study did not significantly change clinical practice, = the US=20 Food and Drug Administration (FDA) labeling of recombinant human = erythropoietin=20 (EPO), or Medicare reimbursement policies for EPO because normalization = of the=20 Hct in dialysis patients was never the standard of care.

The 2000 decade was also not kind to ESAs, which came under increased = scrutiny regarding their safety. The publication of the Correction of = Hemoglobin=20 and Outcomes in Renal Insufficiency (CHOIR)^[6] = and=20 Cardiovascular Risk Reduction by Early Anemia Treatment with = Epoetin-beta=20 (CREATE)^[7] = studies=20 attracted the attention of the US Congress and the FDA and resulted in a = new=20 "black box" warning regarding the safety of ESAs (Table 1).

Table 1. Black Box Warning

Erythropoiesis-Stimulating Agents (ESAs)

In patients with chronic kidney disease (dialysis and = nondialysis)=20 ESAs can increase the risk for death and serious cardiovascular = adverse=20 events when targeting higher hemoglobin vs lower hemoglobin=20 concentrations.

Recombinant human erythropoietin products have an FDA black box=20 warning for an increased risk for deep vein thrombosis in = perisurgical=20 patients receiving ESAs who are not receiving deep vein thrombosis = prophylaxis.

From http://www.fda.gov/Drugs/DrugSaf= ety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126481.htm<= /A>.

The CHOIR study randomly assigned 1432 CKD patients not on dialysis = (ND)=20 treated with EPO alfa to target hemoglobin (Hb) of 13.5 vs 11.3 g/dL. = After a=20 3-year follow-up, composite cardiovascular endpoints (including = mortality) were=20 significantly higher in the high Hb arm, and there was no difference in = quality=20 of life (QOL) between the 2 arms.^[6] = The=20 CREATE study, conducted in Europe, randomly assigned 603 CKD-ND patients = to=20 early EPO beta therapy to a target Hb of 13-15 g/dL vs salvage EPO = therapy to a=20 target Hb of 10.5-11.5 g/dL.^[7] = Although=20 there was no difference in the primary cardiovascular and survival = outcomes=20 between the 2 groups, the patients in the high Hb group showed a trend = toward an=20 increased mortality risk of 48%, more rapid progression to dialysis, and = improved QOL scores. Despite the CHOIR^[6] = and=20 CREATE^[7] = studies=20 being performed in CKD-ND patients, their results were extrapolated to = the=20 dialysis population by Medicare and the NKF Kidney Disease Outcomes = Quality=20 Initiative (KDOQI),^[8] = the=20 successor to DOQI. In 2008, Medicare changed its reimbursement policy = for ESAs=20 to exclude 50% of the payment during the third month that a patient has = an Hb=20 level > 13 g/dL for 3 consecutive months. The 2007 revision of the = NKF KDOQI=20 anemia guidelines recommended that the target Hb level should be 11-12 = g/dL and=20 should not exceed 13 g/dL for CKD-ND and dialysis patients receiving = ESAs.

A number of authors have attempted to put into perspective the = association=20 between higher Hb levels and adverse outcomes in the randomized = controlled=20 trials of ESA therapy, which differ from observational data suggesting = that=20 higher Hb levels are associated with improved outcomes in dialysis=20 patients.^[7] = The FDA=20 did its own analysis of the NHCT^[3] = and=20 CHOIR^[6] = studies=20 and found the intention-to-treat association between Hb target and = adverse=20 outcomes to be misleading. There was an inverse relationship between = achieved Hb=20 level and adverse outcomes in both arms of both studies. A secondary = analysis of=20 CHOIR by Szczech and colleagues revealed that when the data are adjusted = for ESA=20 dose and patients not achieving their Hb target, the difference in = outcomes=20 between the high and low Hb target arms becomes insignificant. The use = of a high=20 dose of ESA becomes the major predictor of adverse outcomes in both = target=20 groups. A reasonable conclusion from the secondary analysis by Szczech = and=20 colleagues is that high doses of ESAs have direct vascular toxicity; = however the=20 need for greater ESA doses for the treatment of anemia in sicker = patients=20 potentially and plausibly generates confounding by indication, and newer = statistical methods may be required to sort these issues out.^[9] = There=20 remains a schism within the nephrology community regarding the issue of = whether=20 the focus for the future of patient safety should be on avoiding high Hb = levels=20 with ESA therapy or avoiding high ESA doses in resistant patients. = However,=20 changes in ESA reimbursement for dialysis patients in the United States, = which=20 became effective on January 1, 2011, may make the debate moot.^[10]=

In 2011, ESAs and other previously separately billable medications = for=20 dialysis patients such as intravenous (IV) iron and vitamin D analogs = will be=20 rolled into a bundled payment, shifting them from being profit centers = to being=20 cost centers for dialysis providers. There will be a new economic = imperative to=20 constrain expenses by using as little ESA as possible to achieve the = Medicare=20 target Hb level of 10-12 g/dL. Dialysis providers are expected to = achieve this=20 reduction in ESA use though the more aggressive use of IV iron, = increased=20 subcutaneous (SC) administration of ESAs, decreasing target Hb levels to = the=20 lower end of the FDA/Medicare target range of 10-12 g/dL, the use of = lower-cost=20 ESAs and iron agents when available, and limiting ESA doses in = ESA-resistant=20 patients (previously reimbursed as high as 400,000 units of EPO alfa and = 1200=20 mcg of darbepoetin alfa per month).^{[11,12]=20
Although a number of studies have demonstrated that SC-administered =
short-acting=20
ESAs (eg, EPO) are 20%-25% more effective than when these agents are=20
administered intravenously, the 2007 NKF KDOQI anemia guidelines^[8] =
recommend=20
that ESAs be administered intravenously in hemodialysis patients because =
of the=20
risk for pure red cell aplasia (PRCA) and the discomfort associated with =
SC=20
dosing. PRCA, which is caused by the formation of anti-EPO antibodies, =
has been=20
associated with quality issues in ESA manufacturing and has been =
observed with=20
increasing frequency among patients receiving biosimilar ESAs in those =
countries=20
where such agents are available. No case of antibody-associated PRCA has =
been=20
documented in patients treated with only IV ESA administration.}

The economic imperative to decrease overall costs will make the ESA = market=20 competitive as new agents that stimulate erythropoiesis are approved by = the FDA=20 and released into the marketplace.

New and Emerging Treatment Options

Synthetic PEGylated Peptides

The agent closest to approval by the FDA is peginesatide, which could = enter=20 the market as early as 2012 if approved. Peginesatide is not a = recombinant ESA=20 protein but a novel synthetic PEGylated peptide with strong affinity for = the ESA=20 receptor. Phase 2 and phase 3 studies have demonstrated that = peginesatide is=20 effective when administered once monthly.^{[13,14] Phase=20
3 studies have demonstrated that peginesatide is comparable to EPO with =
regard=20
to efficacy and safety in the treatment of anemia in hemodialysis=20
patients.^[14]=
Unlike=20
recombinant ESAs, peginesatide is stable at room temperature, has lower=20
immunogenicity, and has a much simpler (and less expensive) =
manufacturing=20
process, which avoids the need for cell lines and genetic engineering=20
techniques. Because peginesatide bears no homology to the human =
erythropoietic=20
protein, antibodies against peginesatide do not cross-react with EPO, =
and=20
anti-EPO antibodies do not cross-react with peginesatide. Therefore, if =
a=20
patient develops anti-peginesatide antibodies these will not neutralize =
the=20
patient's endogenous EPO and the patient will not develop PRCA. =
Moreover,=20
patients with antibody-mediated PRCA have been shown to respond to =
peginesatide=20
by an increase in their Hb concentration because peginesatide is not =
neutralized=20
by anti-EPO antibodies.^[15]=}

Protein-Based ESAs

Protein-based ESAs currently used in other parts of the world are = expected to=20 enter the US market after patents on recombinant EPO expire in 2014. = These=20 include the continuous erythropoietin receptor activator (CERA), EPO = omega, and=20 EPO delta (Table 2). CERA is a pegylated EPO molecule that is effective = when=20 administered once monthly. EPO beta, like EPO alfa, has been in clinical = use for=20 over 20 years and differs only in its glycosylation pattern. EPO omega = uses baby=20 hamster kidney cells rather than Chinese hamster ovary cells for the = manufacture=20 of the protein, and EPO delta uses human fibrosarcoma cell cultures. The = latter=20 is also called gene-activated EPO because the expression of the native = human EPO=20 gene is activated by transformation of the cell with the cytomegalovirus = promoter. "Biosimilar" ESAs are analogous to "generic" copies of the = reference=20 agent. A biosimilar agent is "a medicine which is similar to a biologic = medicine=20 that has already been authorized" and whose patent has typically = expired.^[16]= However,=20 unlike the generic version of a chemical agent, there is no guarantee = that a=20 biosimilar agent is identical to the reference agent since the structure = of the=20 large proteins involved cannot be unequivocally determined. The = complexities=20 related to the manufacturing, packaging, storage, and shipping of=20 biopharmaceutical agents make their biosimilar competitors much more = vulnerable=20 to efficacy and safety issues, so greater vigilance is required to = assure that=20 biosimilar agents undergo adequate pre- and postmarketing scrutiny to = assure=20 their therapeutic value. For example, an epidemic of PRCA has been = reported in=20 Thailand associated with the use of biosimilar ESAs, thus emphasizing = the=20 critical need for extensive premarket testing and postmarketing = surveillance=20 with such agents.^[17]=

Table 2. Protein-Based Erythropoiesis-Stimulating Agents

Currently Available in United States
Generic Name	Brand Name	Production	Duration of Action
Epoetin alfa	Epogen=C2=AE/Procrit=C2=AE	Chinese hamster ovary	Short
Darbepoetin alfa	Aranesp=C2=AE	Chinese hamster ovary	Intermediate
Not Currently Available in United States
Generic Name	Brand Name	Production	Duration of Action
Epoetin beta	NeoRecormon=C2=AE	Chinese hamster ovary	Short
Epoetin omega	Epomax	Baby hamster kidney	Short
Epoetin delta	Dynepo	Human fibrosarcoma	Short
CERA	Mircera=C2=AE	Pegylated epoetin	Long

Emerging Directions

A number of other approaches to stimulate red blood cell production = are under=20 development, but they are not likely to be submitted for FDA approval = for=20 several years.^[18]=20Hypoxia-inducible factor (HIF) is the substance within the = cell that=20 supports EPO gene expression. In the absence of decreased oxygen = delivery to the=20 cell due to anemia or hypoxemia, HIF is rapidly degraded by a prolyl = hydroxylase=20 enzyme. A number of agents that inhibit this prolyl hydroxylase enzyme = have been=20 shown to increase red blood cell production, even in patients with ESRD. = These=20 agents have the advantage of being orally active, and they also seem to=20 upregulate other genes involved in the erythropoietic process, notably = those=20 that improve iron utilization.

Efforts are underway to develop inhibitors to hepcidin to improve red = blood=20 cell production in inflamed patients. Hepcidin is a substance produced = by the=20 liver in the setting of inflammation that increases iron sequestration = in the=20 reticuloendothelial system and decreases iron absorption from the=20 gastrointestinal tract, thereby making less iron available for = erythropoiesis.=20 This contributes to the low Hb levels and high ESA resistance observed = in=20 patients with inflammatory conditions.^[19]=

Role of Iron in Anemia Management

Iron is essential for red blood cell production. Iron deficiency, = absolute or=20 functional, is a major cause of low Hb levels and ESA resistance in = hemodialysis=20 patients. It is estimated that a hemodialysis patient loses 2000-3000 mg = of iron=20 yearly due to blood left in the dialysis circuit, oozing from the needle = sites=20 after the procedure, frequent phlebotomies for testing, and vascular = access=20 procedures. This may lead to absolute iron deficiency, which is defined = by the=20 NKF KDOQI anemia guidelines as transferrin saturation < 20% and serum = ferritin < 200 ng/mL in hemodialysis patients.^[20]=

Hemodialysis patients may also have functional iron deficiency, which = is=20 defined as a response to IV iron supplementation with an increase in = rise in Hb=20 level and/or a decrease in ESA requirements to achieve the same Hb level = in a=20 patient with ferritin > 200 ng/mL. Functional iron deficiency is = related to=20 an imbalance between the iron demands of the erythroid marrow and iron = delivery=20 by transferrin, the iron carrier protein in the blood. It can be caused = by=20 accelerated red blood cell production induced by ESA therapy, low = transferrin=20 levels secondary to malnutrition, and/or iron mobilization impairment = from=20 stores in the reticuloendothelial system in the setting of inflammation = or=20 infection. Iron supplementation is required for these patients, but = there are=20 safety concerns with these iron compounds. High-molecular-weight iron = dextran=20 may cause the rare occurrence of an anaphylactic reaction (mediated by = preformed=20 immunoglobulin E [IgE] dextran antibodies) or anaphylactoid reaction = (non-IgE=20 mediated). Although this life-threatening event is less common with=20 low-molecular-weight iron dextran, dextran-free iron-containing agents = (eg, iron=20 sucrose, iron gluconate) are favored because they less commonly cause=20 immunologically mediated reactions, thus serving as safer options. The = major=20 limitation of iron sucrose and iron gluconate is the lower total dose = that can=20 be administered in a single administration compared with iron = dextran.

Nonetheless, even nondextran iron compounds are associated with side = effects,=20 especially hypotension, which is thought to be related to the small = amount of=20 free iron released into the blood. Because of concerns regarding the = safety of=20 IV iron preparations, many nephrologists tended to be conservative = regarding IV=20 iron therapy in the prebundling era, as increased ESA requirements that = may have=20 resulted from iron deficiency were reimbursed by Medicare. In the = postbundling=20 era, dialysis providers will seek the safest and most cost-effective = interplay=20 between IV iron and ESA therapy.

Following the 2006 implementation of a bundled payment policy for = dialysis in=20 Japan, increased IV iron use was associated with a 10%-15% decrease in = EPO use=20 in hemodialysis patients.^[21]= It is=20 expected that IV iron protocols will shift more to a maintenance than to = a=20 repletion approach and that targets for transferrin saturation will = increase, as=20 will the ceiling for serum ferritin level among patients receiving IV = iron=20 therapy, based on a number of studies demonstrating the EPO-sparing = effects of=20 these strategies.^[22-25]

There are currently 3 IV agents in use in dialysis facilities: sodium = ferric=20 gluconate, iron sucrose, and ferumoxytol. The first 2 agents are = covalently=20 bound irons and adverse reactions are primarily due to reactions to free = iron.=20 Ferumoxytol is an encapsulated iron and adverse reactions are primarily = to the=20 polysaccharide coating. The incidence of serious adverse reactions to = all 3=20 agents is comparable in the 0.2%-0.6% range.^{[26-33]=20
Sodium ferric gluconate and iron sucrose must be given by slow injection =
or=20
infusion; ferumoxytol is administered by rapid injection. Patients who =
have an=20
adverse reaction to one of the covalently bound iron preparations may =
tolerate=20
ferumoxytol and vice versa because the mechanism of the adverse reaction =
differs=20
based on the structure of the agent. Ferric carboxymaltose, another =
encapsulated=20
iron that can be administered in a large dose by rapid injection, was =
approved=20
in Europe and is undergoing phase 3 trials in the United States.^[34]=
A=20
generic form of sodium ferric gluconate is awaiting FDA approval in the =
United=20
States and would likely have a cost advantage compared with other =
currently=20
available IV iron agents. Iron dextran, the least expensive of the =
currently=20
available IV iron agents in the United States, has been associated with =
fatal=20
anaphylactic reactions and is not widely used in the dialysis setting =
for that=20
reason. Iron pyrophosphate, an iron additive to the dialysate, is =
currently in=20
phase 3 clinical trials.^[35]=
Earlier=20
studies suggest that dialysate iron pyrophosphate is safe and effective =
in=20
maintaining iron stores among hemodialysis patients who are iron =
replete, but it=20
does not provide adequate iron to repair a significant iron =
deficit.^[36]=}

Summary

In summary, the nephrologist in 2011 is at the intersection of the = most=20 significant change in dialysis reimbursement in 30 years, increased = concerns=20 regarding the safety of currently available ESAs, and the threshold of a = number=20 of new erythropoietic agents and iron supplements that have the = potential to=20 improve patient outcomes while constraining costs. The development and=20 consistent application of standardized anemia management protocols at = the=20 dialysis facility level, based on evidence and local continuous quality=20 improvement activities, holds the potential to achieve improved outcomes = with=20 decreased cost and risk. ^[37]= The=20 nephrologist, as patient advocate and "captain of the ship" that = includes the=20 interdisciplinary team, must seize this opportunity to promote the = adoption of=20 patient care processes that are based on evidence. In the case of anemia = management, evidence may align in many ways with processes that lead to = cost=20 reduction.

Supported by an independent educational grant from Affymax, Inc., = and=20 Takeda Pharmaceuticals North America, Inc.

Earn=20 CME/CE Credit =C2=BB

References=

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References

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Authors and Disclosures

As an organization accredited by the ACCME, Medscape, LLC, requires = everyone=20 who is in a position to control the content of an education activity to = disclose=20 all relevant financial relationships with any commercial interest. The = ACCME=20 defines "relevant financial relationships" as financial relationships in = any=20 amount, occurring within the past 12 months, including financial = relationships=20 of a spouse or life partner, that could create a conflict of = interest.

Medscape, LLC, encourages Authors to identify investigational = products or=20 off-label uses of products regulated by the US Food and Drug = Administration, at=20 first mention and where appropriate in the content.

Author(s)

Jay B. Wish, MD

Professor of Medicine, Case Western Reserve University; Medical = Director,=20 Dialysis Program, University Hospitals Case Medical Center, Cleveland,=20 Ohio

Disclosure: Jay B. Wish, MD, has disclosed the following = relevant=20 financial relationships:
Served as an advisor or consultant for:=20 sanofi-aventis; GlaxoSmithKline; AMAG Pharmaceuticals, Inc.; Affymax,=20 Inc.
Served as a speaker or a member of a speakers bureau for: Amgen = Inc.;=20 AMAG Pharmaceuticals, Inc.

Dr. Wish does not intend to discuss=20 off-label uses of drugs, mechanical devices, biologics, = or=20 diagnostics approved by the US Food and Drug Administration = (FDA) for=20 use in the United States.

Dr. Wish does intend to discuss=20 investigational drugs, mechanical devices, biologics, = or=20 diagnostics not approved by the FDA for use in the United = States.

Editor(s)

Elizabeth Samander, PhD

Scientific Director, Medscape LLC

Disclosure: Elizabeth = Samander, PhD,=20 has disclosed no relevant financial relationships.

Jane Lowers

Senior Scientific Director, Medscape LLC

Disclosure: Jane = Lowers has=20 disclosed no relevant financial relationships.

CME Reviewer

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosure: Nafeez = Zawahir, MD,=20 has disclosed no relevant financial relationships.

Nurse Planner

Laurie E. Scudder, DNP, NP

Nurse Planner, Continuing Professional Education Department, = Medscape, LLC;=20 Clinical Assistant Professor, School of Nursing and Allied Health, = George=20 Washington University, Washington, DC

Disclosure: Laurie E. = Scudder, DNP,=20 NP, has disclosed no relevant financial = relationships.

[ CLOSE = WINDOW=20 ]

CME/CE Information

CME/CE Released: 03/30/2011; Valid for credit through = 03/30/2012

Target Audience

This activity is intended for nephrologists, nephrology nurses, and = nurse=20 practitioners.

Goal

The goal of this activity is to summarize important clinical data and = offer=20 expert commentary on emerging treatment information about novel = approaches to=20 treating anemia in patients with end-stage renal disease (ESRD).

Learning Objectives

Upon completion of this activity, participants will be able to:

Evaluate the benefits and limitations of current treatment options = for=20 patients with anemia due to ESRD=20
Review the mechanisms of action of emerging treatment options for = chronic=20 kidney disease-related anemia in patients with ESRD=20
Describe the economic impact of anemia management for patients on = dialysis=20

Credits Available

Physicians - maximum of 0.50 AMA PRA Category 1 = Credit(s)=E2=84=A2

Nurses - 0.50 ANCC Contact Hour(s) (0.5 contact hours = are in=20 the area of pharmacology)

All other healthcare professionals completing continuing education = credit for=20 this activity will be issued a certificate of = participation.

Physicians=20 should claim only credit commensurate with the extent of their = participation in=20 the activity.

Accreditation Statements

For Physicians

Medscape, LLC is accredited by the Accreditation Council for = Continuing=20 Medical Education (ACCME) to provide continuing medical education for=20 physicians.

Medscape, LLC designates this enduring material for a maximum of 0.50 = AMA PRA Category 1 Credit(s)=E2=84=A2 . = Physicians should=20 claim only credit commensurate with the extent of their participation in = the=20 activity.

Medscape, LLC staff have disclosed that they have no = relevant=20 financial relationships.

Contact This Provider

For Nurses

Medscape, LLC is accredited as a provider of continuing nursing = education by=20 the American Nurses Credentialing Center's Commission on = Accreditation.

Awarded 0.50 contact hour(s) of continuing nursing education for RNs = and=20 APNs; 0.50 contact hours are in the area of = pharmacology.

Accreditation=20 of this program does not imply endorsement by either Medscape, LLC or = ANCC.

Contact This Provider

For questions regarding the content of this activity, contact the = accredited=20 provider for this CME/CE activity noted above. For technical assistance, = contact=20 CME@medscape.net

Instructions for Participation and Credit

There are no fees for participating in or receiving credit for this = online=20 educational activity. For information on applicability and acceptance of = continuing education credit for this activity, please consult your = professional=20 licensing board.

This activity is designed to be completed within = the=20 time designated on the title page; physicians should claim only those = credits=20 that reflect the time actually spent in the activity. To successfully = earn=20 credit, participants must complete the activity online during the valid = credit=20 period that is noted on the title page.

Follow these steps to = earn CME/CE=20 credit*:

Read the target audience, learning objectives, and author = disclosures.=20
Study the educational content online or printed out.=20
Online, choose the best answer to each test question. To receive a = certificate, you must receive a passing score as designated at the top = of the=20 test. Medscape Education encourages you to complete the Activity = Evaluation to=20 provide feedback for future programming.

You may now view or print the certificate from your CME/CE Tracker. = You may=20 print the certificate but you cannot alter it. Credits will be tallied = in your=20 CME/CE Tracker and archived for 6 years; at any point within this time = period=20 you can print out the tally as well as the certificates by accessing = "Edit Your=20 Profile" at the top of your Medscape homepage.

*The credit that = you=20 receive is based on your user profile.

Hardware/Software Requirements

To access Medscape Education users will need

A computer with an Internet connection.=20
Internet Explorer 6.x or higher, Firefox 2.x or higher, Safari 2.x = or=20 higher, or any other W3C standards compliant browser.=20
Adobe Flash = Player and/or=20 an HTML5 capable browser may be required for video or audio playback.=20
Occasionally other additional software may required such as PowerPoint = or Adobe Acrobat Reader.=20

Print This
Email=20 this
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Disclaimer

The material presented here does not necessarily reflect the views of = Medscape, LLC, or companies that support educational programming on=20 www.medscape.org. These materials may discuss therapeutic products that = have not=20 been approved by the US Food and Drug Administration and off-label uses = of=20 approved products. A qualified healthcare professional should be = consulted=20 before using any therapeutic product discussed. Readers should verify = all=20 information and data before treating patients or employing any therapies = described in this educational activity.

Medscape Education =C2=A9 2011 Medscape, = LLC

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Topic Alert

Thank you for = subscribing to Topic=20 Alert.

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"Prostate=20 Cancer" has been added to your Topic Alert list. You will receive = an=20 email when new content is available from Medscape on your selected = topics.

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If you subscribed to this topic in error or wish to = manage=20 your Topic Alert list click here.=20

CME/CE Information=20
Earn=20 CME/CE Credit =C2=BB

Credits Available

Physicians - maximum of 0.50 AMA PRA Category 1 = Credit(s)=E2=84=A2

Nurses - 0.50 ANCC Contact Hour(s) (0.5 contact hours = are in=20 the area of pharmacology)

According to your Medscape profile, you will be issued ANCC = Contact=20 Hour(s) for this activity. If this is incorrect, please edit your profile =

Medscape, LLC is accredited by the Accreditation Council for = Continuing=20 Medical Education (ACCME) to provide continuing medical education for=20 physicians.

Contact This Provider

Medscape, LLC is accredited as a provider of continuing nursing = education by=20 the American Nurses Credentialing Center's Commission on = Accreditation.

Contact This Provider =

All material on this website is protected by = copyright,=20 Copyright =C2=A9 1994-2011 by Medscape, LLC. This website also contains = material=20 copyrighted by 3rd parties.

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If a function is provided it will be invoked = upon successful * completion of the submit and will be passed the response from the = server. * If an options Object is provided, the following attributes are = supported: * * target: Identifies the element(s) in the page to be updated with = the server response. * This value may be specified as a jQuery selection string, = a jQuery object, * or a DOM element. * default value: null * * url: URL to which the form data will be submitted. * default value: value of form's 'action' attribute * * type: The method in which the form data should be submitted, = 'GET' or 'POST'. * default value: value of form's 'method' attribute (or = 'GET' if none found) * * beforeSubmit: Callback method to be invoked before the form is = submitted. * default value: null * * success: Callback method to be invoked after the form has been = successfully submitted * and the response has been returned from the server * default value: null * * dataType: Expected dataType of the response. One of: null, 'xml', = 'script', or 'json' * default value: null * * semantic: Boolean flag indicating whether data must be submitted in = semantic order (slower). * default value: false * * resetForm: Boolean flag indicating whether the form should be reset = if the submit is successful * * clearForm: Boolean flag indicating whether the form should be = cleared if the submit is successful * * * The 'beforeSubmit' callback can be provided as a hook for running = pre-submit logic or for * validating the form data. If the 'beforeSubmit' callback returns = false then the form will * not be submitted. The 'beforeSubmit' callback is invoked with three = arguments: the form data * in array format, the jQuery object, and the options object passed = into ajaxSubmit. * The form data array takes the following form: * * [ { name: 'username', value: 'jresig' }, { name: 'password', = value: 'secret' } ] * * If a 'success' callback method is provided it is invoked after the = response has been returned * from the server. It is passed the responseText or responseXML value = (depending on dataType). * See jQuery.ajax for further details. * * * The dataType option provides a means for specifying how the server = response should be handled. * This maps directly to the jQuery.httpData method. The following = values are supported: * * 'xml': if dataType =3D=3D 'xml' the server response is = treated as XML and the 'after' * callback method, if specified, will be passed the = responseXML value * 'json': if dataType =3D=3D 'json' the server response will be = evaluted and passed to * the 'after' callback, if specified * 'script': if dataType =3D=3D 'script' the server response is = evaluated in the global context * * * Note that it does not make sense to use both the 'target' and = 'dataType' options. If both * are provided the target will be ignored. * * The semantic argument can be used to force form serialization in = semantic order. * This is normally true anyway, unless the form contains input elements = of type=3D'image'. * If your form must be submitted with name/value pairs in semantic = order and your form * contains an input of type=3D'image" then pass true for this arg, = otherwise pass false * (or nothing) to avoid the overhead for this logic. * * * When used on its own, ajaxSubmit() is typically bound to a form's = submit event like this: * * $("#form-id").submit(function() { * $(this).ajaxSubmit(options); * return false; // cancel conventional submit * }); * * When using ajaxForm(), however, this is done for you. * * @example * $('#myForm').ajaxSubmit(function(data) { * alert('Form submit succeeded! Server returned: ' + data); * }); * @desc Submit form and alert server response * * * @example * var options =3D { * target: '#myTargetDiv' * }; * $('#myForm').ajaxSubmit(options); * @desc Submit form and update page element with server response * * * @example * var options =3D { * success: function(responseText) { * alert(responseText); * } * }; * $('#myForm').ajaxSubmit(options); * @desc Submit form and alert the server response * * * @example * var options =3D { * beforeSubmit: function(formArray, jqForm) { * if (formArray.length =3D=3D 0) { * alert('Please enter data.'); * return false; * } * } * }; * $('#myForm').ajaxSubmit(options); * @desc Pre-submit validation which aborts the submit operation if form = data is empty * * * @example * var options =3D { * url: myJsonUrl.php, * dataType: 'json', * success: function(data) { * // 'data' is an object representing the the evaluated json = data * } * }; * $('#myForm').ajaxSubmit(options); * @desc json data returned and evaluated * * * @example * var options =3D { * url: myXmlUrl.php, * dataType: 'xml', * success: function(responseXML) { * // responseXML is XML document object * var data =3D $('myElement', responseXML).text(); * } * }; * $('#myForm').ajaxSubmit(options); * @desc XML data returned from server * * * @example * var options =3D { * resetForm: true * }; * $('#myForm').ajaxSubmit(options); * @desc submit form and reset it if successful * * @example * $('#myForm).submit(function() { * $(this).ajaxSubmit(); * return false; * }); * @desc Bind form's submit event to use ajaxSubmit * * * @name ajaxSubmit * @type jQuery * @param options object literal containing options which control the = form submission process * @cat Plugins/Form * @return jQuery * @see formToArray * @see ajaxForm * @see $.ajax * @author jQuery Community */ jQuery.fn.ajaxSubmit =3D function(options) { if (typeof options =3D=3D 'function') options =3D { success: options }; options =3D jQuery.extend({ url: this.attr('action') || window.location, type: this.attr('method') || 'GET' }, options || {}); var a =3D this.formToArray(options.semantic); // give pre-submit callback an opportunity to abort the submit if (options.beforeSubmit && options.beforeSubmit(a, this, options) = =3D=3D=3D false) return this; // fire vetoable 'validate' event var veto =3D {}; jQuery.event.trigger('form.submit.validate', [a, this, options, = veto]); if (veto.veto) return this; var q =3D jQuery.param(a);//.replace(/%20/g,'+'); if (options.type.toUpperCase() =3D=3D 'GET') { options.url +=3D (options.url.indexOf('?') >=3D 0 ? '&' : '?') + = q; options.data =3D null; // data is null for 'get' } else options.data =3D q; // data is the query string for 'post' var $form =3D this, callbacks =3D []; if (options.resetForm) callbacks.push(function() { = $form.resetForm(); }); if (options.clearForm) callbacks.push(function() { = $form.clearForm(); }); // perform a load on the target only if dataType is not provided if (!options.dataType && options.target) { var oldSuccess =3D options.success || function(){}; callbacks.push(function(data, status) { jQuery(options.target).attr("innerHTML", = data).evalScripts().each(oldSuccess, [data, status]); }); } else if (options.success) callbacks.push(options.success); options.success =3D function(data, status) { for (var i=3D0, max=3Dcallbacks.length; i < max; i++) callbacks[i](data, status); }; // are there files to upload? var files =3D jQuery('input:file', this).fieldValue(); var found =3D false; for (var j=3D0; j < files.length; j++) if (files[j])=20 found =3D true; if (options.iframe || found) // options.iframe allows user to force = iframe mode fileUpload(); else jQuery.ajax(options); // fire 'notify' event jQuery.event.trigger('form.submit.notify', [this, options]); return this; // private function for handling file uploads (hat tip to YAHOO!) function fileUpload() { var form =3D $form[0]; var opts =3D jQuery.extend({}, jQuery.ajaxSettings, options); =20 var id =3D 'jqFormIO' + jQuery.fn.ajaxSubmit.counter++; var $io =3D jQuery('