Disease Modification in Parkinson Disease: Are We There Yet? CME

Transcription

1 Disease Modification in Parkinson Disease: Are We There Yet? CME Lawrence W. Elmer, MD, PhD Supported by an independent educational grant from View this activity online at: medscape.org/column/parkinson

2 Disease Modification in Parkinson Disease: Are We There Yet? CME This article is a CME-certified activity. To earn credit for this activity visit: medscape.org/column/parkinson CME Released: 06/24/2011 Valid for credit through 06/24/2012 Target Audience This activity is intended for general neurologists and primary care providers who are involved in the care of patients with Parkinson disease (PD). Goal The goal of this activity is to improve the understanding of disease modification in PD, update clinicians on the most recent studies in this area, and thereby improve the care of patients with PD. Learning Objectives Upon completion of this activity, participants will be able to: 1. Compare data from recent clinical trials on disease-modifying therapies for PD 2. Discuss how emerging theories of PD disease modification may affect care of patients with PD Credits Available Physicians - maximum of 0.5 AMA PRA Category 1 Credit(s) All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Accreditation Statement Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Medscape, LLC designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. Medscape, LLC staff have disclosed that they have no relevant financial relationships. Contact This Provider For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact CME@medscape.net Pg.2

3 medscape.org/column/parkinson Instructions for Participation and Credit There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. Follow these steps to earn CME/CE credit*: 1. Read the target audience, learning objectives, and author disclosures. 2. Study the educational content online or printed out. 3. 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 test. Medscape Education encourages you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates by accessing Edit Your Profile at the top of your Medscape homepage. *The credit that you receive is based on your user profile. Hardware/Software Requirements To access Medscape Education users will need A computer with an Internet connection. Internet Explorer 6.x or higher, Firefox 2.x or higher, Safari 2.x or higher, or any other W3C standards compliant browser. Adobe Flash Player and/or an HTML5 capable browser may be required for video or audio playback. Occasionally other additional software may required such as PowerPoint or Adobe Acrobat Reader. Authors and Disclosures As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines relevant financial relationships as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest. Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content. Author Lawrence W. Elmer, MD, PhD Professor, Department of Neurology, The University of Toledo; Director, Center for Neurological Health, University of Toledo Medical Center, Toledo, Ohio Disclosure: Lawrence W. Elmer, MD, PhD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: GlaxoSmithKline; Novartis Pharmaceuticals Corporation; Teva Neuroscience, Inc.; UCB Pharma, Inc. Served as a speaker or a member of a speakers bureau for: GlaxoSmithKline; Novartis Pharmaceuticals Corporation; Teva Neuroscience, Inc.; UCB Pharma, Inc. Received grants for clinical research from: GlaxoSmithKline; Teva Neuroscience, Inc. Dr. Elmer does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the US Food and Drug Administration (FDA) for use in the United States. Dr. Elmer does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Pg.3

4 Disease Modification in Parkinson Disease: Are We There Yet? CME Editor Priscilla Scherer, RN Scientific Director, Medscape, LLC Disclosure: Priscilla Scherer, RN, has disclosed no relevant financial relationships. CME Reviewer Nafeez Zawahir, MD CME Clinical Director, Medscape, LLC Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships. Peer Reviewer Disclosure: This activity has been peer reviewed and the reviewer has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Acorda Therapeutics; St. Jude Medical; Teva Neuroscience, Inc. Disease Modification in Parkinson Disease: Are We There Yet? CME Lawrence W. Elmer, MD, PhD CME Released: 06/24/2011; Valid for credit through 06/24/2012 Parkinson disease (PD) is the second most common neurodegenerative illness in the United States. Originally described by James Parkinson in his seminal monograph of 1817, he anticipated a day when this progressive disorder would be modified by treatments aimed at arresting the pathologic process: On the contrary, there appears to be sufficient reason for hoping that some remedial process may ere long be discovered, by which, at least, the progress of the disease may be stopped. [1] It is remarkable that in his original description, Dr. Parkinson had the foresight to recognize the need for some intervention that would slow or stop the progression of this illness. In the last 2 decades enormous efforts have been made that are aimed at bringing Dr. Parkinson s hopes to reality. The issue of delaying, slowing, or stopping progression in PD continues to grow in importance, given that the number of individuals afflicted with PD worldwide is expected to more than double in the next 25 years. [2] This will place a tremendous burden on international healthcare systems. In the 1960s and 70s, neurologists began measuring PD progression using a variety of clinical scales. The Unified Parkinson s Disease Rating Scale (UPDRS) is the instrument most commonly used in studies performed throughout North America. Using data from a number of large placebo-controlled clinical trials, it is recognized that the average rate of progression of PD in the untreated state is roughly 8-10 points on the UPDRS per year. However, measurement using the UPDRS demonstrates significant individual variations in the rate of disease progression as well as significant variance in response to symptomatic therapy. [3] These factors, among others, have made it difficult to determine clinical efficacy of a disease-modifying treatment without long periods of study observation and large numbers of study participants. The Quest to Define Disease Modification in Clinical Trials The first large, prospective, multicenter, placebo-controlled trial of disease modification in patients with early PD was performed by the Parkinson Study Group. [4,5] The DATATOP study compared the effect of vitamin E and selegiline, individually or in combination, on disease progression vs that of placebo. The individuals were followed over time with the endpoint defined as the time they required symptomatic intervention with levodopa. While still considered controversial, the initial apparent disease-modifying effects of selegiline were confounded by a symptomatic benefit of that treatment, which contributed to a statistically significant delay in the need for levodopa compared with vitamin E and placebo. Indeed, more controversy ensued when long-term studies were performed with the DATATOP cohort and other study populations treated with selegiline. These long-term analyses suggest that despite the confounding symptomatic effects of selegiline in the early clinical trials studying disease modification, this compound clearly slows the rate of motor decline in PD as measured by either UPDRS motor scores or transition in Hoehn and Yahr scales, although the mechanism of this effect is unclear. [6,7] Multiple other agents have been examined in the past 2 decades testing the hypothesis that they may alter the progression of PD, with or without a concomitant symptomatic benefit. Separation of this symptomatic effect from a disease-modifying effect has been attempted through the use of different clinical study designs as well as through the inclusion of surrogate markers of disease progression. Pg.4

5 medscape.org/column/parkinson Table. Select Studies Investigating the Effects of Various Treatments on PD Progression Agent Mechanism Study Summary Reference Lazabemide MAO-B inhibitor ROADS Lz vs pbo delayed need for LD therapy [8] Pramipexole vs levodopa Dopamine agonist CALM-PD Initial treatment with ppx delayed complications but LD more clinically effective neuroimaging showed slower DAT loss with ppx [9,10] Riluzole Glutamate antagonist Riluzole vs pbo demonstrated no difference in PD progression [11] Ropinirole vs levodopa Dopamine agonist REAL-PET Initial treatment with rop delayed motor complications but LD more clinically effective neuroimaging showed slower DAT loss with rop [12] Rasagiline MAO-B inhibitor TEMPO Early vs delayed start of rasagiline suggested disease modification [13] Levodopa Dopamine precursor ELLDOPA LD vs placebo suggested disease modification on clinical scales but disease worsening on neuroimaging [14] TCH346 Propargylamine TCH346 vs pbo demonstrated no difference in PD progression [15] CEP-1347 Mixed lineage kinase inhibitor PRECEPT CEP-1347 vs pbo demonstrated no difference in PD progression [16] Rasagiline MAO-B inhibitor ADAGIO Early vs delayed start of rasagiline suggested disease modification in 1-mg/day dose but not in 2-mg/day [17] Lz = lazabemide; MAO-B = monoamine oxidase-b; Pbo = placebo; LD = levodopa; Ppx = pramipexole; Rop = ropinirole; DAT = dopamine transporter Pg.5

6 Disease Modification in Parkinson Disease: Are We There Yet? CME More Confounding Factors In most of these studies, the agents under investigation demonstrated strong neuroprotective effects in animal models of PD. Unfortunately, success in treating human disease in animal models does not always translate into similar clinical benefits in humans. In addition, as mentioned, the scale most commonly used in these studies to quantify clinical progression, the UPDRS, is less than optimal as a precise measure of progression. As a result, surrogate markers of disease progression that are purportedly more objective and quantitative with regard to loss of dopaminergic neurons in the nigrostriatal pathway have been developed. Measured over time using these surrogate markers, the ongoing loss of dopaminergic projections during disease progression correlates well with clinical severity in advancing PD. [18] Functional neuroimaging, typically using either PET or SPECT techniques, has emerged as the most commonly used surrogate measure of disease progression in PD. Unfortunately, these techniques are expensive, not widely available (PET scans in particular), and technologically challenging with respect to interpretation of the results. Moreover, the results of PET and SPECT scans in PD have sometimes demonstrated opposite results when compared with UPDRS scores. For example, in clinical trials that compare dopamine agonists with levodopa for the treatment of early PD, [9,10,12] functional neuroimaging demonstrates that the dopamine agonists are associated with slower disease progression based on quantitative assessment of dopamine terminals, suggesting less clinical progression. However, with clinical measures, participants randomized to receive levodopa had better motor scores on the UPDRS compared with those on dopamine agonists. This confusing result was further obfuscated by the ELLDOPA study, in which clinical progression in patients with early PD was studied after randomizing the participants to receive either placebo or 3 different doses of a levodopa preparation. [14] This study found a clear dose-related response curve in subjects receiving levodopa, with higher doses correlating with greater improvements in UPDRS scores. In fact, at the end of the study, subjects randomized to the levodopa arms did not return to the same level of disability as the patients in the placebo group, suggesting some form of disease modification associated with levodopa treatment. However, the results of the functional neuroimaging substudy demonstrated the opposite result, with dopamine terminals showing the greatest decline in the levodopa-treated groups compared with placebo. There also appeared to be a possible doseresponse effect with higher doses of levodopa, but now in the wrong direction! [14] Although multiple attempts have been made to explain these disparate results, it is still concerning, at the least, whether or not levodopa may have a deleterious long-term effect on nigral projections, complicating its clear and dramatic clinical benefits. As mentioned, multiple approaches to study design have been used in an attempt to separate symptomatic benefits from disease-modifying effects, particularly in situations where the treatments themselves may have more than one mechanism of action or evidence of both clinical and disease-modifying effects in preclinical models. In the original DATATOP study, [4,5] in order to separate symptomatic effects from potential disease-modifying activity, subjects underwent a washout period for 1-2 months before one of their clinical evaluations. This approach, however, may also be confounded by long-term effects of treatment, seen in both the DATATOP and ELLDOPA studies. [4,5,14] In addition, attempting prolonged washout periods involving patients with significant disease progression raises important ethical concerns, considering that the patients are taken off symptomatically effective medications. The Delayed-Start Trial Design A novel clinical study model attempts to dissect symptomatic from disease-modifying effects. In this model, patients are randomized initially to receive the investigational treatment or placebo. Following a predefined period, the patients initially placed on placebo are given the same treatment regimen as the early-start group. Theoretically, one can then discriminate the symptomatic from the disease-modifying treatment effects. This delayed-start design was originally proposed by Paul Leber for the study of agents to treat dementia. [19] This design will lead to at least 4 potential results (Figure). [20] One result would be that the delayed-start group achieves the same degree of clinical improvement as the group that received the treatment for the entire time. This suggests that the treatment in question is only symptomatic in its effects and does not affect the long-term course of the illness. A second result would be that the patients who started the treatment later would only experience partial improvement in their symptoms and fail to receive the same degree of clinical improvement as the early-start group. If the 2 groups then progressed at the same rate after the symptomatic effects in both groups are accounted for, the difference between these 2 groups theoretically represents a disease-modifying effect superimposed on a symptomatic effect. A third result would demonstrate no symptomatic effect of the treatment arm but a lower rate of disease progression in the treatment group than in the placebo arm. Theoretically, once the delayed-start group is given the treatment, their rate of progression would equal that of the early-start group, but they would never catch up to that group. This would support an effect that is purely disease-modifying without a symptomatic effect. Finally, if the delayed-start group had clinical improvement but the long-term effects of this treatment modality cause the 2 groups to converge after some period of time, the argument is that this treatment may have given the patients who started early an advantage but that this advantage was not long-lasting (ie, without enduring disease-modifying effects). (Not represented in figure) Pg.6

7 medscape.org/column/parkinson 15 Change From Baseline UPDRS Time, Weeks Natural Disease Progression Symptomatic Disease-Modifying Symptomatic Disease-Modifying Figure. Mean change from baseline total UPDRS in a parallel-design, fixed-dose trial comparing placebo with drug that has purely symptomatic effects, purely disease-modifying effects, and both symptomatic and disease-modifying effects. From Bhattaram VA, et al. AAPS J. 2009;11: [20] Reprinted with permission. Pg.7

8 Disease Modification in Parkinson Disease: Are We There Yet? CME Delayed-Start Trials in Practice Using a delayed-start design, the ADAGIO study was conceived and completed under US Food and Drug Administration (FDA) supervision. [17] More than 1100 participants were randomly assigned to receive rasagiline at a dose of either 1 mg/day or 2 mg/day for 9 months and compared with matching placebo groups. For the second 9-month period, the patients in the placebo groups received rasagiline 1 mg/day or 2 mg/day while the early-start patients continued on their previous doses. The 3 endpoints were based on the UPDRS scores and all had to be met to be considered a positive result: superiority to placebo in the rate of change in UPDRS score during weeks 12-36; superiority to delayed-start treatment in change in UPDRS score from baseline to week 72; and noninferiority to delayed-start treatment in rate of change in UPDRS score from weeks 48 to 72. The 1-mg/day early-start treatment group met all of the FDA s prespecified endpoints compared with the delayed-start group. However, the 2-mg/day earlystart group failed to meet the second of the 3 prespecified endpoints compared with the delayed-start arm. A post-hoc analysis of the ADAGIO study results, [17] published with an addendum, examined the treatment effects in the upper quartile of patients -- those whose UPDRS scores were above 25.5 at the time they enrolled in the study -- and demonstrated robust and statistically significant results from both doses, meeting all the FDA prespecified criteria for disease modification. In this analysis of individuals with more advanced PD at the time of recruitment, rasagiline delayed the rate of PD progression by 5 UPDRS points annually in the 1-mg/day group and by 10 UPDRS points annually in the 2-mg/day group relative to placebo. These results, if replicated in a follow-up prospective study, would strongly suggest disease-modifying effects. A different study that used the delayed-start design was completed late in 2009 comparing early vs delayed treatment with pramipexole. [21] In this study, more than 500 patients were randomly assigned to receive pramipexole 0.5 mg 3 times a day for a total of 9 months or placebo. At the end of 9 months the individuals randomly assigned to receive placebo were then placed on pramipexole 0.5 mg 3 times a day for 6 months. At the end of the study, the degree of symptom worsening as measured by the UPDRS was essentially identical for both early-start and delayed-start groups. In addition, functional neuroimaging demonstrated no significant difference in the percent of dopamine terminals remaining in either group despite the 9-month period during which the delayed-start group was exposed to placebo only. In May 2011, a prospective study of coenzyme Q or 2400 mg/day vs placebo in patients with early PD was terminated. Interim futility analysis of the 16-month study failed to demonstrate any significant difference between treatment groups compared with placebo. The full results of this study are pending publication. [22] Practical Implications for Patients With PD These studies leave many of us, generalists and specialists alike, scratching our heads and asking, So, what does all this mean for my patients? When a person with newly diagnosed PD is at risk of losing his job or faces impending, significant disability, most PD specialists would recommend initiating a levodopa preparation as soon as possible. The reasons for this are several. We recognize that levodopa is the most efficacious agent available for the treatment of most parkinsonian symptoms, an effective dose of levodopa can be titrated rapidly, and patients demonstrating significant motor disability frequently require levodopa regardless of what other medications they may be taking concomitantly. Depending on the patient s age, subsequent medications (specifically dopamine agonists or MAO-B inhibitors) should be considered for persons initially started on carbidopa/levodopa, especially if they are younger and have a long treatment horizon. Unfortunately, the risk for motor fluctuations and dyskinesias appear to be more closely linked to the initiation of levodopa rather than the other medications used in combination with levodopa. Nevertheless, clinical experience and some clinical trials strongly support efforts to keep total levodopa dosages low if adequate clinical efficacy can be achieved with the use of adjunctive therapies in order to avoid the extreme motor fluctuations seen in decades past. In the case of an individual who presents with mild, nondisabling symptoms, the use of the MAO-B inhibitors selegiline or rasagiline as initial therapy is considered controversial by some specialists. Of note, despite the fact that the DATATOP study [4,5] administered selegiline as monotherapy to people with early PD, selegiline has only been approved by the FDA for adjunctive therapy with levodopa. Rasagiline has been approved for the treatment of PD symptoms as monotherapy or adjunctive therapy along with levodopa. In addition, both the TEMPO [13] and the ADAGIO [17] studies have suggested a disease-modifying effect of rasagiline at a dose of 1 mg daily. Unlike many of our PD medications, however, typically a 10- to 12-week trial of rasagiline may be required to determine maximum symptomatic benefit. Dopamine agonists remain another viable option for management of early and advanced symptoms of PD. The primary advantage of these agents over levodopa as initial therapy involves delaying the development of motor fluctuations and/or dyskinesias. With recent releases of once-daily dopamine formulations, these compounds have demonstrated enhanced tolerability and effectiveness in reducing motor fluctuations. However, other potential adverse effects emerge with these agents that, at the very least, must be monitored and addressed whenever appropriate. As physicians, we recognize that one size does not fit all and this statement could not be more true than in the world of PD treatment. However, just as our colleagues in epilepsy would do their patients a disservice to treat them only with phenytoin, we also deny our patients a wealth of opportunity when we restrict them to 1 or 2 pharmacologic regimens. Although levodopa remains the most common agent prescribed for PD, a wealth of knowledge and advances have accrued in the last 20 years of PD pharmacotherapeutic development. When given a choice -- taking carbidopa/levodopa until severe fluctuations and/or dyskinesias emerge followed by surgical intervention with deep brain stimulation vs working with the clinician to find a combination of agents that may delay and/or prevent the need to consider surgical intervention -- most people would err on the side of trying more than one option and avoiding surgery if possible. Pg.8

9 medscape.org/column/parkinson Conclusion In conclusion, extensive effort and numerous attempts to slow the course of PD progression have produced limited success in this area. The only study to date that remains suggestive of significant disease modification is the ADAGIO study, which used the delayed-start design. The delayed-start design has garnered many critics, however. This should not be surprising, given that studies using functional neuroimaging as a measure of PD progression have also come under intense scrutiny, preventing that method of assessing disease progression from being widely accepted as a definitive gauge. Even with these ongoing discussions, it appears that early rather than later treatment of PD helps to avoid progressive deterioration in quality of life. [23] Therefore, despite these setbacks and controversies, clinicians, scientists, patients, and their families remain optimistic that the dream of Dr. James Parkinson -- delaying or halting PD progression -- will one day become reality. In the meantime, we will continue to help those struggling with PD through the use of our modern day therapies. Supported by an independent educational grant from Teva Pharmaceuticals USA. This article is a CME certified activity. To earn credit for this activity visit: References 1. Parkinson J. An Essay on the Shaking Palsy. London: Sherwood, Neely, and Jones; Dorsey ER, Constantinescu JP, Thompson KM, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through Neurology. 2007;68: Hauser RA, Auinger P, Oakes D. Levodopa response in early Parkinson s disease. Mov Disord. 2009;24: Parkinson Study Group. DATATOP: a multicenter controlled clinical trial in early Parkinson s disease. Parkinson Study Group. Arch Neurol. 1989;46: Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson s disease. The Parkinson Study Group. N Engl J Med. 1993;328: Shoulson I, Oakes D, Fahn S, et al. Impact of sustained deprenyl (selegiline) in levodopa treated Parkinson s disease: a randomized placebo controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol. 2002;51: Zhao YJ, Wee HL, Au WL, et al. Selegiline use is associated with a slower progression in early Parkinson s disease as evaluated by Hoehn and Yahr Stage transition times. Parkinsonism Relat Disord. 2011;17: Parkinson Study Group. Effect of lazabemide on the progression of disability in early Parkinson s disease. The Parkinson Study Group. Ann Neurol. 1996;40: Parkinson Study Group. A randomized controlled trial comparing pramipexole with levodopa in early Parkinson s disease: design and methods of the CALM PD study. Clin Neuropharmacol. 2000;23: Parkinson Study Group. Long term effect of initiating pramipexole vs levodopa in early Parkinson disease. Arch Neurol. 2009;66: Rascol O, Olanow W, Brooks D, et al. A 2 year, multicenter, placebo controlled, double blind, parallel group study of the effect of riluzole on Parkinson s disease progression. Mov Disord. 2002;17 (Suppl 5): Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson s disease with ropinirole versus levodopa: the REAL PET study. Ann Neurol. 2003;54: Parkinson Study Group. A controlled, randomized, delayed start study of rasagiline in early Parkinson disease. Arch Neurol. 2004;61: Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson s disease. N Engl J Med. 2004;351: Olanow CW, Schapira AH, LeWitt PA, et al. TCH346 as a neuroprotective drug in Parkinson s disease: a double blind, randomised, controlled trial. Lancet Neurol. 2006;5: Parkinson Study Group. Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease. Neurology. 2007;69: Olanow CW, Rascol O, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson s disease. N Engl J Med. 2009;361: Stoessl AJ. Neuroimaging in Parkinson s disease. Neurotherapeutics. 2011;8: Leber P. Observations and suggestions on antidementia drug development. Alzheimer Dis Assoc Disord. 1996;10(Suppl 1): Bhattaram VA, Siddiqui O, Kapcala LP, Gobburu JV. Endpoints and analyses to discern disease-modifying drug effects in early Parkinson s disease. AAPS J. 2009;11: Schapira A, Barone P, Comella C, et al; PROUD Study Group. Immediate vs. delayed-start pramipexole in early Parkinson s disease: the PROUD study. Parkinsonism Relat Disord. 2009;15(Suppl 2):S Parkinson Study Group. Statement re Termination of QE3 Study. May 27, Available at: clinical_trials/coq10-trial-update.htm Accessed June 6, Grosset D, Taurah L, Burn DJ, et al. A multicentre longitudinal observational study of changes in self reported health status in people with Parkinson s disease left untreated at diagnosis. J Neurol Neurosurg Psychiatry. 2007;78: Disclaimer The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Medscape Education 2011 Medscape, LLC Pg.9