Appendix B



Comparative Effectiveness Studies Inventory Project

A commissioned activity for the IOM
Roundtable on Evidence-Based Medicine

In 2008, a working group was formed at the request of the IOM Roundtable on Evidence-Based Medicine to identify and consider compelling comparisons of clinical interventions in order to inform and advance discussions of criteria important to determining priorities for assessment, to identify a list of possible interventions to be considered, and to offer observations on the kinds of studies needed. Material was presented in draft form at the July 2008 IOM workshop on infrastructure needs for comparative effectiveness research and delivered in final form in March 2009. An abridged version of the text follows, drawn from material produced by Douglas B. Kamerow, M.D., M.P.H., consultant and working group convener, and is based in part on meetings and conversations with working group members. This portion and the complete paper have not been reviewed and should not be considered a product of the Institute of Medicine, the roundtable, or the individual members of the working group.



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Appendix B Comparative Effectiveness Studies Inventory Project A commissioned activity for the IOM Roundtable on Evidence-Based Medicine In 2008, a working group was formed at the request of the IOM Roundtable on Evidence-Based Medicine to identify and consider compelling comparisons of clinical interventions in order to inform and advance discussions of criteria important to determining priorities for assessment, to identify a list of possible interventions to be considered, and to offer observations on the kinds of studies needed. Material was presented in draft form at the July 2008 IOM workshop on infrastructure needs for comparative effectiveness research and delivered in final form in March 2009. An abridged version of the text follows, drawn from material produced by Douglas B. Kamerow, M.D., M.P.H., consultant and working group convener, and is based in part on meetings and conversations with working group members. This portion and the complete paper have not been reviewed and should not be considered a product of the Institute of Medicine, the roundtable, or the individual members of the working group. 9

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0 LEARNING WHAT WORKS STUDY TOPIC SUMMARIES Diagnosis and prognosis of breast cancer using genetic tests: HER2 and others Drug treatment of depression in primary care Drug treatment of epilepsy in children Gamma knife surgery for multiple types of intracranial lesions: comparison with surgery and/or whole brain radiation Inguinal hernia repair: open vs. minimally invasive Outcomes of percutaneous coronary interventions in hospitals with and without onsite surgical backup Over-the-counter drug treatment of upper respiratory tract infections in children Prevention and treatment of pressure ulcers Screening hospital inpatients for methicillin-resistant Staphylococcus aureus infection Tobacco cessation: nicotine replacement agents, oral medications, combinations Treatment of acute thrombotic/embolic stroke: clot removal, reperfusion drugs Treatment of ADHD in children: drugs, behavioral interventions, no Rx Treatment of chronic atrial fibrillation: drugs, catheter ablation, surgery Treatment of chronic low back pain Treatment of localized prostate cancer: watchful waiting, surgery, radiation, or cryotherapy Use of erythropoiesis-stimulating agents in the treatment of hematologic cancers

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 APPENDIX B Diagnosis and Prognosis of Breast Cancer Using Genetic Tests: HER2 and Others Brief description of the condition or problem In 2008, there were an estimated 185,000 new cases of breast cancer in the United States, and more than 40,000 women died from breast cancer. Breast cancer has long been known to be a heterogeneous disease, vary- ing by estrogen receptor expression, tumor grade, and patient age. These characteristics affect diagnosis, prognosis, and treatment. More recently, gene expression status has been added to the list of variations. Multiple studies have proposed many ways to organize gene expression differences in breast cancer. Most genomic-based studies have reported that breast cancer constitutes at least four different entities, with differing gene expression profiles, molecular markers, prognosis, and treatment sensitivities. What are the clinical and treatment implications of these profiles and the result- ing tumor markers? Available treatments or interventions Many treatments for breast cancer exist, such as chemotherapeutics and surgery. Some breast cancers express tumor markers that provide spe- cific targets for treatment. For example, human epidermal growth factor receptor 2 (HER2), a protein involved in normal cell growth, is found in high levels on some breast cancer cells. This so-called HER2 overexpression is seen in 15 to 20 percent of breast cancers and is a good predictor of ben- efit from treatment with trastuzumab (Herceptin), a monoclonal antibody against HER2. It may also correlate with the response to other treatments and to the overall prognosis. Another tumor marker, Oncotype DX, is a multi-gene assay that was developed as a prognostic tool for women with estrogen receptor-positive, lymph node-negative breast cancer. Current evidence Prospective studies have shown that women with HER2-positive breast cancer can decrease their risk of recurrence and death by between one-third and one-half by using trastuzumab. Many clinical practice guidelines and health system guidance documents now routinely approve HER2 testing and trastuzumab treatment for women with recurrent breast cancer. Pro- spective studies of Oncotype DX are less common. It is less widely used as a prognostic tool, although it is approved by some health systems and has been shown to affect the management of patients with early-stage breast cancer.

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2 LEARNING WHAT WORKS Issues needing research, and conclusions Three important characteristics of all tumor markers are their utility (when and how they are used: risk determination, malignancy, prognosis, response to therapy, etc.); the proven magnitude of their effect (the differ- ences in outcome seen in marker-positive and marker-negative patients); and their reliability (measurement standardization, accuracy, and repeat- ability). Generally, the strongest evidence is gathered from prospective studies in which markers are used to determine treatment or other alloca- tion groups, although retrospective analysis can also produce valid results. Depending on the marker being evaluated, either prospective studies or retrospective analyses will be needed to assess whether the marker should be used in clinical care. Such comparative research is needed for all new genetic markers that are introduced. References Andre, F., J. Domont, and S. Delaloge. 2007. What can breast cancer molecular sub-classifica- tion add to conventional diagnostic tools? Annals of Oncology 18(Suppl 9):ix33-36. Carney, W. P., R. Neumann, A. Lipton, et al. 2003. Potential clinical utility of serum HER-2/neu oncoprotein concentrations in patients with breast cancer. Clinical Chemistry 49:1579-1598. Chiuri, V. E., G. Leo, and V. Lorusso. 2007. Clinical and therapeutic perspectives of gene expression profiling for breast cancer. Annals of Oncology 18(Suppl 6):vi5856-5862. Dendukuri, N., K. Khetani, M. McIsaac M, et al. 2007. Testing for HER2-positive breast cancer: A systematic review and cost-effectiveness analysis. Canadian Medical Associa- tion Journal 176:1429-1434. Dhesy-Thind, B., K. I. Pritchard, H. Messersmith, et al. 2008. HER2/neu in systemic therapy for women with breast cancer: A systematic review. Breast Cancer Research and Treat- ment 109:209-229. Hayes, D. F., A. D. Thor, L. G. Dressler, et al. 2007. HER2 and response to paclitaxel in node- positive breast cancer. New England Journal of Medicine 357:1496-1506. Henry, N. L., and D. F. Hayes. 2006. Uses and abuses of tumor markers in the diagnosis, monitoring, and treatment of primary and metastatic breast cancer. The Oncologist 11:541-552. Ross, J. S., J. A. Fletcher, K. J. Bloom, et al. 2004. Targeted therapy in breast cancer. Molecular and Cellular Proteomics 3:379-398. Seidenfeld, J., D. J. Samson, B. M. Rothenberg, et al. 2008. HER2 Testing to Manage Patients with Breast Cancer or Other Solid Tumors. Evidence Report/Technology Assessment No. 172. AHRQ Publ No. 09-E001. Rockville, MD: Agency for Healthcare Research and Quality. Valabrega, G., F. Montemurro, and M. Aglietta. 2007. Trastuzumab: Mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Annals of Oncology 18:977-984. Wolff, A. C., M. E. H. Hammond, J. N. Schwartz, et al. 2007. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for Human Epi- dermal Growth Factor Receptor 2 testing in breast cancer. Journal of Clinical Oncology 25:118-145.

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 APPENDIX B Drug Treatment of Depression in Primary Care Brief description of the condition or problem Lifetime prevalence of depression is up to 17 percent in community sur- veys; the prevalence of major depression in primary care settings is between 6 and 8 percent. Depression leads to much disability and high utilization of health care, and depression is ranked by the World Health Organization as the fourth leading cause of worldwide disease burden. Suicide occurs in 3.5 percent of depressed patients, an increase of up to 20 times the general population rates. Depression also contributes to increased morbidity and mortality from other medical disorders, such as cardiovascular disease and diabetes. Depression is a chronic and recurring disease in most patients, which contributes greatly to its heavy disease burden. Available treatments or interventions Depression is treated most commonly with psychotherapy and drugs. Because of the lack of availability and the cost of psychotherapy in primary care, most primary care patients with depression are treated with drugs. Two major classes of drugs are used: older (and less costly) tricyclic anti- depressants (TCAs); and newer (and more costly) agents, including selec- tive serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Current evidence While most patients with clinical depression are seen in primary care settings, most research on depression treatment has been conducted in patients referred from psychiatrists and psychiatric emergency depart- ments—that is, specialty care settings. Research in primary care has found that both TCAs and SSRIs are more effective than placebos in treating depression. Research assessing the newer agents in primary care has found no consistent benefit of one drug over others in terms of efficacy or adverse effects. It is difficult to draw clinically meaningful guidelines for drug choice from the current studies. In addition, many studies are of demographi- cally homogeneous populations and thus do not allow conclusions about depressed patients who are members of minority groups or in the adolescent or elderly age groups. Issues needing research, and conclusions Large, head-to-head randomized trials with heterogeneous primary care populations of depressed patients are needed to better understand the benefits and harms of the various antidepressant agents. Observational studies using large databases may provide some of the needed evidence, but without randomization, conclusions may be difficult to obtain.

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 LEARNING WHAT WORKS References Arroll, B., S. Macgillivray, S. Ogston, et al. 2005. Efficacy and tolerability of tricyclic antide- pressants and SSRIs compared with placebo for treatment of depression in primary care: A meta-analysis. Annals of Family Medicine 3:449-456. Cipriani, A., P. Brambilla, T. A. Furukawa, et al. 2005. Fluoxetine versus other types of phar- macotherapy for depression. Cochrane Database of Systematic Reviews, Issue 4. DOI: 10.1002/14651858.CD004185.pub2. Culpepper, L. 2006. Chronic depression: Treatment in primary care. Primary Care Companion to the Journal of Clinical Psychiatry 8:104-105. Culpepper, L. 2006. Managing depression in primary care. Primary Care Companion to the Juornal of Clinical Psychiatry 8:88-92. Kroenke, K., S. L. West, R. Swindle, et al. 2001. Similar effects of paroxetine, fluoxetine, and sertraline in primary care: A randomized trial. JAMA 286:2947-2955. Pignone, M., B. N. Gaynes, J. L. Rushton, et al. 2002. Screening for Depression. Systematic Evidence Review No. 6. AHRQ Publication No. 02-S002. Rockville, MD: Agency for Healthcare Research and Quality. Simon, G. 2001. Choosing a first-line antidepressant. JAMA 286:3003-3004. Williams, J. W., C. D. Mulrow, E. Chiquette, et al. 2000. A systematic review of newer phar- macotherapies for depression in adults: Evidence review summary. Annals of Internal Medicine 132:743-756. Drug Treatment of Epilepsy in Children Brief description of the condition or problem Although individual seizures are relatively common in children, epi- lepsy as an ongoing challenge is less so. A heterogeneous group of dis- orders characterized by spontaneous, recurrent seizures, epilepsy affects somewhere between 4 and 8 per 1,000 children. Epileptic conditions in childhood vary in diagnostic criteria, management, and clinical outcomes, and many of them are distinct from adult epilepsies as well. Also, drug treatment in children is different from that in adults because their pharma- cokinetics vary with age. Available treatments or interventions Until the 1990s, six major anticonvulsant drugs were available for children: phenobarbital, phenytoin, carbamazepine, valproic acid, ethosuxi- mide, and the benzodiazepines. These traditional drugs were not optimal because many children with epilepsy did not have their seizures controlled by them or had significant side effects. In the last decade, 10 or more new anticonvulsant drugs have been approved for use in the United States, including felbamate, fosphenytoin, gabapentin, lamotrigine, levetirace - tam, oxcarbazepine, pregabalin, tiagabine, topiramate, and zonisamide. Their indications vary by seizure type or epileptic syndrome and mode of delivery.

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 APPENDIX B Current evidence Considerations when selecting anticonvulsant drugs in children include seizure type, side effects, mechanism of action, potential drug interactions, pharmacokinetic profile, ease of initiation, need for laboratory monitoring, and cost. In general, there is no evidence that any of the newer anticon- vulsant drugs are more efficacious than the traditional drugs in preventing seizures. They often do, however, offer improved pharmacokinetic profiles, fewer drug-drug interactions, and/or better tolerability than the older treat- ments, albeit at a much higher price. Guidelines from authorities have var- ied in their recommendations for use of the newer drugs. Some recommend consideration of some of the newer drugs for initial treatment of new onset partial epilepsy, for instance, while other guidelines state that they should be used only when older drugs are ineffective, result in intolerable adverse affects, or are contraindicated. Issues needing research, and conclusions Prospective head-to-head trials among the newer anticonvulsant drugs and with traditional drugs among children with similar epileptic disorders are needed, along with careful assessment of side effects and drug-drug interactions. It is unlikely these data can be obtained from case series or analysis of existing treatment data. References Connock, M., E. Frew, B.-W. Evans, et al. 2006. The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. Health Technology Assessment 10:1-118. Donner, E. J., and C. Snead. 2005. New drugs in the treatment of epilepsy in children. Current Problems in Pediatric and Adolescent Health Care 35:398-419. Marson, A. G., R. Appleton, G. A. Baker, et al. 2007. A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. Health Technology Assessment 11:1-102. NICE (National Institute for Health and Clinical Excellence). 2004. Newer Drugs for Epilepsy in Children. Technology Appraisal 79. Online. Available at www.nice.org.uk/TA079gu- idance. Accessed December 2006. Wheless, J. W., D. F. Clarke, A. Arzimanoglou, et al. 2007. Treatment of pediatric epilepsy: European expert opinion, 2007. Epileptic Disorders 9:353-412. Gamma Knife Surgery for Multiple Types of Intracranial Lesions: Comparison with Surgery and/or Whole Brain Radiation Brief description of the condition or problem Gamma knife surgery (GKS) is a type of stereotactic radiation treat- ment developed in the 1960s. It delivers a high dose of radiation to a lesion in a single session (hence “surgery”) by converging multiple beams of ioniz- ing radiation on a carefully targeted area, with minimal radiation exposure

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 LEARNING WHAT WORKS to surrounding areas. The resulting radiation injury to targeted cells’ DNA results in the desired effect, e.g., cell death or decreased growth. Available treatments or interventions Traditionally, GKS has been used for small (<4 cm), isolated intra- cranial lesions or tumors. For example it is used as primary treatment for trigeminal neuralgia, arteriovenous malformations (AVMs), and acoustic neuromas. More recently it has been employed to treat brain metastases and as adjunctive treatment (to surgery and whole-brain radiation) for malignant tumors such as glioblastoma multiforme. GKS has been used to treat movement disorders such as Parkinson’s disease. Current evidence GKS is intuitively appealing, given that it is noninvasive (does not require craniotomy) and is generally less costly than brain surgery for the equivalent procedure. That said, very few randomized trials have been per- formed comparing GKS to conventional surgical, microsurgical, or radia- tion treatments. For example, a systematic review of GKS in the treatment of trigeminal neuralgia found 23 case series but no randomized trials. Whereas GKS has become an accepted treatment for certain types of small intracranial lesions, the need for randomized evidence is made clear by the experience with GKS as adjunctive treatment for malignant, infiltrative tumors such as glioblastoma multiforme. While a retrospective case series presented significant benefits of adding GKS to surgery and conventional radiation therapy, when a randomized trial was performed comparing the two strategies no differences in survival outcomes were found. Issues needing research, and conclusions The experience with GKS is an example of the general point that tech- nologies require comparative evidence before they are adopted for new indications. A successful track record in treating one condition combined with case series of use for new indications does not add up to compelling evidence for the new use. Comparative research is necessary to insure that simple “technology creep” is not occurring. Thus, head-to-head trials— with whatever treatment is currently the standard—are necessary before new indications for GKS are routinely approved. References Borcsek, B., I. Boncz, C. Dozsa, et al. 2005. Systematic literature review of the gamma knife. Italian Journal of Public Health 2:178. Chamberlain, M. C. 2006. Treatment options for glioblastoma. Neurosurgical Focus 20(4): E2. Crowley, R. W., N. Poutatian, and J. P. Sheehan. 2006. Gamma knife surgery for glioblastoma multiforme. Neurosurgical Focus 20(4):E17.

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 APPENDIX B Gilbert, M. R. 2006. New treatments for malignant gliomas: Careful evaluation and cautious optimism required. Annals of Internal Medicine 144:371-373. Lim, J. N. W., and L. Ayiku. 2004 (January). The clinical efficacy and safety of stereotactic radiosurgery (gamma knife) in the treatment of trigeminal neuralgia. Medicare Services Advisory Committee. 2007. Gamma knife radiosurgery. Medicare Services Advisory Committee:117. NICE (National Institute for Health and Clinical Excellence). 2004. Stereotactic Radiosurgery for Trigeminal Neuralgia Using the Gamma Knife. Interventional Procedure Guidance . Online. Available at http://www.nice.org.uk/nicemedia/pdf/ip/IPG085guidance.pdf. Nwokedi, E. C., S. J. DiBiase, S. Jabbour, et al. 2002. Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme. Neurosurgery 50:41-47. Souhami, L., W. Seiferheld, D. Brachman, et al. 2004. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme. International Journal of Radiation Oncology Biology Physics 60:853-860. Yamakami, I., Y. Uchino, E. Kobayashi, et al. 2003. Conservative management, gamma-knife radiosurgery, and microsurgery for acoustic neurinomas: A systematic review of outcome and risk of three therapeutic options. Neurological Research 25:682-690. Inguinal Hernia Repair: Open vs. Minimally Invasive Brief description of the condition or problem Inguinal hernias, protrusions of the peritoneum (with or without abdominal contents) through a defect or weakness in the abdominal wall, are very common in men, with about a 25 percent lifetime risk. Thus, surgical hernia repair is one of the most common operations in general surgery. Available treatments or interventions For more than 100 years, inguinal hernia surgery was an open proce- dure with general or (more recently) regional or local anesthesia, although the surgical approach has varied over time. Traditional methods of hernia repair used sutures to close the defect. Newer open techniques involve inserting synthetic mesh in an attempt to decrease recurrent hernias. More recently, minimally invasive surgery techniques, using laparoscopic instru- ments, have been introduced. The two major laparoscopic approaches are transabdominal pre-peritoneal (TAPP) surgery, in which mesh is inserted through the peritoneum to prevent herniation, and totally extraperitoneal repair (TEP), in which the peritoneum is not entered, and the mesh is used to seal the hernia from the outside. Current evidence Evidence and practice clearly favor the use of mesh for open and lapa- roscopic repairs, mainly for reduced recurrence rates. Randomized trials have found that laparoscopic repairs take longer and are more expensive to

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 LEARNING WHAT WORKS perform than open repairs and require general rather than local or regional anesthesia. Recovery is quicker with laparoscopic surgery, and there is less persisting pain and numbness at the surgical site. There is a question of whether laparoscopic surgery has a higher serious complication rate than open surgery, and the recurrence rate may be higher with laparoscopic sur- gery. Few randomized trials have compared TAPP vs. TEP techniques, but the newer TEP is technically more difficult to perform than TAPP and takes longer. Both types of laparoscopic surgery are performed more rapidly as surgeons gain experience with the technique used. Because the peritoneum is not entered, the TEP technique may reduce the risk of damage to intra- abdominal organs. Issues needing research, and conclusions Because of the necessity for a learning curve for laparoscopic tech- niques, combining results from earlier trials may not reflect current out- comes. Large-scale data analysis may answer the question of whether laparoscopic hernia repair is more effective and more cost-effective than open repair. If it does not, then a large randomized trial needs to be under- taken. Also, large trials with long-term follow-up are needed comparing the two major laparoscopic approaches, TAPP and TEP. References Gokalp, A., M. Inal, G. Maralcan, et al. 2003. A prospective randomized study of Lichtenstein open tension-free versus laparoscopic totally extraperitoneal techniques for inguinal hernia repair. Acta Chirurgica Belgica 103:502-506. Gould, J. 2008. Laporoscopic versus open inguinal hernia repair. Surgical Clinics of North America 88:1073-1081. Den Hartog, D., A. H. M. Dur, W. E. Tuinebreijer, et al. 2008. Open surgical procedures for incisional hernias. Cochrane Database of Systematic Reviews, Issue 3. DOI: 10.1002/14651858.CD006438.pub2. McCormack, K., B. L. Wake, C. Fraser, et al. 2005. Transabdominal pre-peritoneal (TAPP) versus totally extraperitoneal (TEP) laparoscopic techniques for inguinal hernia repair: A systematic review. Hernia 9:109-114. McCormack, K, N. Scott, P. M. Go, et al. 2003. Laparoscopic techniques versus open tech- niques for inguinal hernia repair. Cochrane Database of Systematic Reviews, Issue 1. DOI: 10.1002/14651858.CD001785. NICE (National Institute for Health and Clinical Excellence). 2004. Laparoscopic Surgery for Inguinal Hernia Repair. Technology Appraisal Guidance 83. Online. Available at www. nice.org.uk/TA083guidance. Accessed September 2007. Scott, N., P. M. Go, P. Graham, et al. 2001. Open mesh versus non-mesh for groin hernia repair. Cochrane Database of Systematic Reviews, Issue 3. DOI: 10.1002/14651858. CD002197. Wake, B. I., K. McCormack, and C. Fraser. 2005. Transabdominal pre-peritoneal (TAPP) vs to- tally extraperitoneal (TEP) laparoscopic techniques for inguinal hernia repair. Cochrane Database of Systematic Reviews, Issue 1. DOI: 10.1002/14651858.CD004703.

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9 APPENDIX B Outcomes of Percutaneous Coronary Interventions Performed in Hospitals with and without Onsite Surgical Backup Brief description of the condition or problem More than 1 million Americans have a myocardial infarction—heart attack—each year, with about a 40 percent mortality rate. Urgent or pri- mary percutaneous coronary intervention (PCI) by cardiac catheterization is recommended in the setting of an ST-segment elevation myocardial infarc- tion [STEMI]), in order to dilate occluded coronary arteries and improve blood flow. More than 1 million PCIs are performed annually in the United States, both in the treatment of STEMI and on an elective basis. Available treatments or interventions In the setting of an acute myocardial infarction, establishing cardiac reperfusion as soon as possible is critically important. With a STEMI, PCI has been shown to be superior to pharmacologic reperfusion (fibrinolytic therapy) if undertaken within 90 minutes of first medical contact. Over 90 percent of primary PCIs are successful. In a small number of unsuccessful cases, however, urgent cardiac surgery is required. PCI can be performed in hospitals with and without cardiac surgery capabilities, and many hospitals (especially in suburban and rural areas) have cardiac catheterization facili- ties but do not have cardiac surgery onsite. Patients prefer care in their local hospitals, and in many cases hospitals with cardiac surgery capabilities are too distant for immediate access. The question is thus whether it is neces- sary to have cardiac surgery immediately available onsite for primary PCI and/or for elective PCI. Current evidence Numerous case series and case-control studies have shown that PCI can be done safely in selected individual hospitals without onsite cardiac surgery. In these studies, PCI success rates and mortality rates are similar to those at hospitals with onsite surgery. An analysis of national Medicare data for patients aged 65 and older, however, found greater mortality for elective PCIs at hospitals without onsite surgery, and elective PCIs are much more common than primary PCIs. As with many procedures, outcomes are usually better in centers with higher volume, once corrected for case mix. Evidence-based guidelines currently recommend that primary PCI may be allowed in hospitals without onsite cardiac surgery if there is a proven pro- cess for emergency transport and if the operator and facility meet standards of performance and volume. These guidelines recommend against perfor- mance of elective PCI at hospitals without cardiac surgery onsite.

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 LEARNING WHAT WORKS Current evidence Intravenous thrombolytic therapy has been shown to significantly improve acute ischemic stroke outcomes. As a result, all major guidelines recommend that tPA be used in patients with ischemic strokes within 3 hours of the onset of symptoms, assuming lack of contraindications and appropriate facility and clinician experience and capabilities. Despite these guidelines, however, it is estimated that less than 10 percent of stroke patients receive thrombolytic therapy. Reasons include lack of clinical appropriateness, inadequate facilities or inexperienced clinicians, clinician attitudes about the medico-legal consequences of thrombolytic therapy, and delayed presentation or evaluation. Most of the large number of clot-removal technologies have not been tested in randomized trials. They offer the potential to increase the number of patients with acute stroke who can receive early (but not necessarily restricted to the first three hours) interventions to improve their clinical outcomes. Issues needing research, and conclusions Head-to-head trials are needed to compare various thrombolytic agents and percutaneous clot-removal technologies, both individually and com- bined. The goal is to determine the best strategies for patients, depending on type of stroke, time of presentation, medical comorbidities, and avail- able resources. References Adams, H. P. Jr, G. del Zoppo, M. J. Alberts, et al. 2007. Guidelines for the early management of adults with ischemic stroke. Stroke 38:1655-1711. Albers, G. W., P. Amarenco, J. D. Easton, et al. 2008. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 133(6 Suppl):630S-669S. American Heart Association. 2009. Heart Disease and Stroke Statistics—2009 update. Dallas, TX: American Heart Association. Gupta, R., N. A. Vora, and M. B. Horowitz. 2006. Multimodal reperfusion therapy for acute ischemic stroke. Stroke 37:986-990. Liang, B. A., R. Lew, and J. A. Zivin. 2008. Review of tissue plasminogen activator, ischemic stroke, and potential legal issues. Archives of Neurology 65:1429-1433. Mielke, O., J. M. Wardlaw, and M. Liu. 2004. Thrombolysis (different doses, routes of ad- ministration and agents) for acute ischaemic stroke. Cochrane Database of Systematic Reviews, Issue 4. DOI:10.1002/14651858.CD000514.pub2. Molina, C. A., and J. L. Saver. 2005. Extending reperfusion therapy for acute ischemic stroke. Stroke 36:2311-2320. NICE (National Institute for Health and Clinical Excellence). 2008. Stroke: Diagnosis and Initial Management of Acute Stroke and Transient Ischaemic Attack. NICE Clinical Guideline 68. Online. Available at www.nice.org.uk/CG068. Stead, L. G., R. M. Gilmore, F. Bellolio, et al. 2008. Percutaneous clot removal devices in acute ischemic stroke. Archives of Neurology 65:1024-1030. Wardlaw, J. M., G. J. del Zoppo, T. Yamaguchi, et al. 2003. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews, Issue 2. DOI:10.1002/14651858. CD000213.

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9 APPENDIX B Treatment of ADHD in Children: Drugs, Behavioral Interventions, no Rx Brief description of the condition or problem Attention deficit/hyperactivity disorder (ADHD) is a heterogeneous behavioral disorder characterized by hyperactivity, impulsivity, and inatten- tion. It is the most common behavioral disorder in school-age children, with a prevalence of 8 to 12 percent in the United States. The disorder varies in severity, resulting in mild to severe impairment of daily activities. Available treatments or interventions Non-pharmacologic treatments include parental interventions, behav- ioral interventions, and school interventions. Drug used to treat ADHD include stimulants (both immediate- and modified-release), atomoxetine, and other medications. No treatment is an option as well, especially with milder cases. Current evidence Drug therapy is widely regarded as the mainstay of treatment for mod- erate to severe ADHD, with clear evidence of superiority of all drug types over placebo. Behavioral therapy and other non-pharmacologic treatments have also been shown to be more effective than placebo but have generally not been found to be as good as drug therapy. The combination of drug and non-drug therapy is widely recommended but has rarely been proven to be superior to drug therapy alone. Newer, more expensive extended- release preparations of stimulants and other classes of drugs have been proven effective vs. placebo, but they have not consistently been shown to be better than less expensive immediate-release stimulant formulations. The threshold for the need for drug and/or behavioral treatment is not clearly defined. Issues needing research, and conclusions Further research is needed to better define the effectiveness of various behavioral and educational therapies in the overall management of ADHD, in combination with drug therapy. Is behavioral therapy necessary or suf- ficient treatment for children with mile ADHD? Also, head-to-head trials of immediate- and modified-release stimulants and other medications could better define the relative benefits of these medications in different popula- tions of children and adolescents, especially with respect to costs.

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0 LEARNING WHAT WORKS References American Academy of Child and Adolescent Psychiatry. 2007. Practice parameter for the assessment of and treatment of children and adolescents with attention-deficit/ hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psy- chiatry 46:894-921. King, S., S. Griffin, Z. Hodges, et al. 2006. A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents. Health Technology Assessment 10:1-162. Klassen, A., A. Miller, P. Raina, et al. 1999. Attention-deficit hyperactivity disorder in children and youth. Canadian Journal of Psychiatry 44:1007-1016. McLennan, J. D. 2006. Deciding on stimulant use for childhood ADHD. Canadian Family Physician 52:940-942. NICE (National Institute for Health and Clinical Excellence). 2008. Attention Deficit Hy- peractivity Disorder, NICE Clinical Guideline 72. Online. Available at www.nice.org. uk/CG072. Smoot, L. C., L. A. Boothby, and R. C. Gillett. 2007. Clinical assessment and treatment of ADHD in children. International Journal of Clinical Practice 61:1730-1738. Treatment of Chronic Atrial Fibrillation: Drugs, Catheter Ablation, Surgery Brief description of the condition or problem Atrial fibrillation (AF), in which the upper chambers of the heart beat in a chaotic unorganized fashion, is the most common heart rhythm abnormality seen in clinical practice, affecting about 2 million Americans. It can lead to blood clots, stroke, heart failure, and increased mortality. Many patients feel fluttering in their chest from AF and are symptomatic from decreased pumping of blood to the body, leading to weakness, dizzi- ness, and/or shortness of breath. Some patients have asymptomatic AF, but they still may be at increased risk of stroke. AF may be paroxysmal, which comes and goes, or chronic, which is persistent. Available treatments or interventions Drug treatment includes three types of agents. Anticoagulants such as warfarin and antiplatelet drugs such as aspirin are used to prevent blood clots and strokes. Arrhythmia drugs, including propafenone, flecainide, sotalol, and amiodarone, are intended to prevent the fibrillation rhythm. Drugs in a third group are used to control the fast heart rate that often comes with AF. They include digoxin, various beta-blocker drugs, and some calcium channel blockers. Electrical cardioversion, in which an electric shock is administered to an anesthetized patient, can also convert AF to a regular heart rhythm. Catheter ablation techniques can be used to treat AF without surgery by passing a catheter into the left atrium of the heart and using radiofrequency energy to disrupt the electrical impulses that

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 APPENDIX B lead to AF. Finally, open heart surgery can be used to disrupt the electrical impulses, but this is rarely used unless there is another reason (e.g., heart valve repair) for open heart surgery. Current evidence Many patients with AF are elderly and have other heart disease prob- lems that complicate their treatment. Others are younger with so-called “lone” AF. Traditionally, the treatment goal was to keep all patients out of AF by using arrhythmia drugs with or without cardioversion. Arrhythmia drugs do not always successfully control heart rhythms, however, and they have major side effects, up to and including mortality. Recent studies have found that many patients, especially elderly, relatively sedentary patients, have similar overall clinical and quality of life-related outcomes with drugs that control heart rate rather than rhythm. Many of these drugs also have fewer side effects than arrhythmia drugs. Some experts recommend rhythm control as an initial strategy for younger, symptomatic patients presenting with AF for the first time and rate control for patients over age 65 with heart disease and who may be unsuitable for electric cardioversion. Traditionally, catheter ablation was considered only when drug and cardioversion therapy failed. Some recent research, however, mainly in younger patients, has reported high rates of conversion to regular rhythms with catheter ablation, obviating the necessity of years of medications. Long-term follow-up is not yet available for these patients and the studies were done in a small number of highly selected medical centers. Issues needing research, and conclusions The costs and effectiveness of catheter ablation in large groups of dif- ferent populations of patients with AF needs to be determined. As more centers become skilled in catheter ablation techniques, large effectiveness rather than efficacy studies will be useful to determine the best clinical guid- ance for patients with diverse risk factors and comorbidities. Most likely new, randomized trials will have to be undertaken to answer these ques- tions, as current data are probably unsuitable for systematic review. References Andrikopoulos, G., S. Tzeis, N. Maniadakis, et al. 2009. Cost-effectiveness of atrial fibrillation catheter ablation. Europace 11:147-151. Cox, J. L. 2005. The central controversy surrounding the interventional-surgical treatment of atrial fibrillation. Journal of Thoracic and Cardiovascular Surgery 129:1-4. Khargi, K., B. A. Hutten, B. Lemke, et al. 2005. Surgical treatment of atrial fibrillation: A systematic review. European Journal of Cardiothoracic Surgery 27:258-265. Mead, G. E., A. Elder, A. D. Flapan, et al. 2005. Electrical cardioversion for atrial fibrillation and flutter. Cochrane Database of Systematic Reviews, Issue 3. DOI:10.1002/14651858. CD002903.pub2.

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2 LEARNING WHAT WORKS Morady, F., H. Oral, F. Pelosi, et al. 2007. The Treatment of Atrial Fibrillation. University of Michigan Electrophysiology Service. Online. Available at http://www.med.umich. edu/1libr/aha/Pt_ed_A1204.pdf. NICE (National Institute for Health and Clinical Excellence). 2006. Atrial Fibrillation. NICE Clinical Guideline 36. Online. Available at www.nice.org.uk/CG036. Oral, H., C. Pappone, A. Chugh, et al. 2006. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. New England Journal of Medicine 354:934-941. Wanzi, O. M., N. F. Marrouche, D. O. Martin, et al. 2005. Radiofrequency ablation vs. antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation. JAMA 293(21):2634-2640. Wood, M. A., and K. A. Ellenbogen. 2006. Catheter ablation of chronic atrial fibrillation— The gap between promise and performance. New England Journal of Medicine 354:967-969. Treatment of Chronic Low Back Pain Brief description of the condition or problem Acute low back pain serious enough to disrupt daily routines affects about 70 percent of adults sometime during their lives, and it is the second most frequent symptomatic cause for visiting a doctor in the United States. In the vast majority of patients, low back pain resolves within a few weeks with conservative medical management. But about 5 percent of patients go on to have nonspecific chronic low back pain, defined as pain lasting longer than 12 weeks without a specific treatable cause (such as tumor or fracture). These patients experience significant pain and functional impair- ment and consume 90 percent of all the healthcare costs associated with low back pain. Available treatments or interventions The main choice in managing chronic low back pain is whether to continue medical management or undergo spinal surgery. Medical management can include the following interventions individu- ally or in combination: pain, anti-inflammatory, and other medications; physical and rehabilitation therapy and other types of exercise programs: acupuncture and acupressure: cognitive-behavioral therapy: spinal manipu- lation: massage: and other treatments. The mainstay of surgical treatment for nonspecific low back pain is spinal fusion surgery, which can be performed several ways. The intent of the surgery is to stabilize the spine and remove the cause of the chronic low back pain. Between 150,000 and 300,000 spinal fusion surgeries are attempted each year, costing over $16 billion in annual hospital charges.

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 APPENDIX B Current evidence Most evidence on pharmaceutical treatment of chronic low back pain comes from placebo-controlled trials. Short-term trials have found small to moderate levels of effectiveness for decreasing pain and increasing function for acetaminophen, antidepressants, antiepileptic drugs, benzodiazepines, non-steroidal anti-inflammatory drugs, and opioids. Few head-to-head tri- als have been conducted. Few trials have included multiple medications, which are commonly prescribed by doctors. Several non-pharmaceutical therapies show similar effectiveness ver- sus placebo in the treatment of chronic low back pain. These treatments include acupuncture, acupressure, psychological counseling, interdisciplin- ary rehabilitation, exercise, massage, spinal manipulation, and yoga. Again, few head-to-head trials have been conducted, and trials including multiple interventions are also uncommon. At least six randomized trials have compared lumbar fusion surgery with some type of intensive nonsurgical management for chronic low back pain, with conflicting results. Questions have been raised about the vary- ing exclusion criteria and generalizability of these studies. Although some patients were clearly helped by the surgery, it is difficult to define the char- acteristics of patients most likely to benefit. Issues needing research, and conclusions For the treatment of chronic low back pain, most published research of drug and non-invasive nondrug therapy is composed of placebo-controlled trials of single treatments. There is a paucity of research of dual-agent treatment, although most patients are treated this way. Also, head-to-head trials are needed to evaluate the relative effectiveness of drug and non-drug treatments for this condition. But the key need in this area is research on the comparative effective- ness of spinal fusion surgery and nonsurgical approaches. Which types of patients are most likely to benefit from surgery, and when should it be undertaken in the course of the illness? Because of the significant disability associated with chronic low back pain, cost-effectiveness studies are also crucial in helping to decide which approaches return patient function to normal most quickly. Comparative studies are also needed of different surgical approaches and techniques, as well as the appropriate use of pro- cedures such as intradiscal electrothermal therapy and the appropriate role for newer artificial spinal disks. References Andersson, G. B. J., N. A. Mekhail, and J. E. Block. 2006. Treatment of intractable disco- genic low back pain: A systematic review of spinal fusion and intradiscal electrothermal therapy. Pain Physician 9:237-248.

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 LEARNING WHAT WORKS Chou, R. and L. H. Huffman. 2007. Medications for acute and chronic low back pain: A review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Annals of Internal Medicine 147:505-514. Chou, R. and L. H. Huffman. 2007. Nonpharmacologic therapies for acute and chronic low back pain: A review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Annals of Internal Medicine 147:492-504. Deyo, R. A. 2007. Back surgery: Who needs it? New England Journal of Medicine 356:2239-2243. Fairbank, J., H. Frost, J. Wilson-MacDonald, et al. 2005. Randomised controlled trial to compare surgical stabilization of the lumbar spine with an intensive rehabilitation pro- gramme for patients with chronic low back pain: The MRC spine stabilisation trial. BMJ 330:1233-1238. Henschke, N., C. G. Maher, K. M. Refshauge, et al. 2007. Low back pain research priorities: A survey of primary care practitioners. BMC Family Practice 8:40. Hsieh, L. L., C. Kuo, L. H. Lee, et al. 2006. Treatment of low back pain by acupressure and physical therapy: Randomised controlled trial. BMJ 332:696-698. Ibrahim, T., I. M. Tleyjeh, and O. Gabbar. 2008. Surgical versus non-surgical treatment of chronic low back pain: A meta-analysis of randomised trials. International Orthopaedics 32:107-113. Koes, B. 2005. Surgery versus intensive rehabilitation programmes for chronic low back pain. BMJ 330:1220-1221. Melloh, M., C. Roder, A. Elfering, et al. 2008. Differences across health care systems in out- come and cost-utility of surgical and conservative treatment of chronic low back pain: A study protocol. BMJ Musculoskeletal Disorders 9:81. Sherman, K. J., D. C. Cherkin, J. Erro, et al. 2005. Comparing yoga, exercise, and a self-care book for chronic low back pain. Annals of Internal Medicine 143:849-856. Soegaard, R., F. B. Christensen, T. Christiansen, et al. 2007. Costs and effects in lumbar spi- nal fusion: A follow-up study in 136 consecutive patients with chronic low back pain. European Spine Journal 16:657-668. Zeller, J. I. 2006. Artificial spinal disk superior to fusion for treating degenerative disk disease. JAMA 296:2665-2667. Treatment of Localized Prostate Cancer: Watchful Waiting, Surgery, Radiation, Hormone Therapy, or Cryotherapy Brief description of the condition or problem In the United States in 2008, there were an estimated 186,000 new cases of prostate cancer and more than 28,000 deaths from this disease. Prostate cancer is, aside from skin cancers, the leading cause of new cancers and is the second leading cause of cancer deaths in men. However, up to 70 percent of men are found to have cancer in their prostate gland at the time of death, most often in low-grade microscopic amounts that posed no threat to the man during life. Thus, prostate cancer is common, diagnosed in one of six men, but it is fatal in only 3 percent of men. This leads to the perplexing problem of trying to decide which prostate cancers to treat and what treatment to use. Most prostate cancers are now diagnosed by elevated prostate-specific antigen (PSA) levels in routine testing, although

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 APPENDIX B some are still detected on clinical examination of the prostate or from patient symptoms. Available treatments or interventions Major options for localized prostate cancer include watchful waiting, in which the PSA level is followed and no treatment is given initially; radi- cal prostatectomy, which is usually an option only if the cancer is confined within the capsule of the prostate; radiation therapy, with external-beam radiation or implanted radioisotopes (brachytherapy); hormonal therapy with various anti-androgen hormones; and cryotherapy, in which probes are introduced into the tumor to freeze and kill malignant cells. Current evidence No randomized trial data favor one treatment or combination of treat- ments for prostate cancer over another. Patients and their doctors need to balance limited evidence of treatment efficacy with important known side effects as well as patient preferences and the availability and quality of local services. If the cancer is confined to the prostate, then surgery offers the chance for a cure and is often offered to younger men, especially if the biopsies show an aggressive tumor. Prostatectomy has significant side effects, how- ever, such as impotence and incontinence. It is not usually done in patients who have cancer that has spread beyond the prostate capsule. External radiation can be effective in extending survival in men with cancer that has spread locally and is often preceded by hormonal therapy to shrink the tumor mass. It does not require a hospital stay or recupera- tion from surgery, although it has significant side effects as well, including impotence and rectal irritation and injury. Brachytherapy has fewer side effects because the radiation dose is lower than external beam radiation, but the clinical effectiveness is not as well demonstrated as other types of radiation. Cryotherapy has not been tested in many randomized trials comparing it to more conventional treatments, and its effectiveness has mainly been documented in case series. Watchful waiting is often employed in older men and those with concomitant serious diseases, or in younger men with relatively low PSA levels and lower-grade tumors. The literature describing its long-term effectiveness is mainly from the pre-PSA era, when cancers were detected by symptoms at a more advanced stage. It, of course, has no side effects and active monitoring allows later treatment when and if it is deemed appropriate.

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 LEARNING WHAT WORKS Issues needing research, and conclusions Better understanding is needed of the choice, sequencing, and combi- nation of therapies that are most effective for localized and early prostate cancer, including trials comparing radical prostatectomy and radiation in its various forms, including drug therapy. The role of watchful waiting both in the extremely elderly and in young men with low PSA levels and low-grade tumors needs to be established with clinical trials. References Kumar, S., M. Shelley, C. Harrison, et al. 2006. Neo-adjuvant and adjuvant hormone therapy for localized and locally advanced prostate cancer. Cochrane Database of Systematic Reviews, Issue 4. DOI:10.1002/14651858.CD006019.pub2. NCI (National Cancer Institute). 2008. National Cancer Institute Prostate Cancer Treat- ment (PDQ), Health Professional Version. Online. Available at http://www.cancer. gov/cancertopics/pdq/treatment/prostate/healthprofessional. Postma, R.. 2006. Treatment of prostate cancer. Annals of Oncology 17(suppl 10), x207-210. DOI: 10.1093/annonc/mdl261. Shelley, M., T. Wild, B. Coles, et al. 2007. Cryotherapy for localised prostate cancer. Cochrane Database of Systematic Reviews, Issue 3. DOI:10.1002/14651858.CD005010.pub2. Taichman, R. S., R. D. Loberg, R. Mehra, et al. 2007. The evolving biology and treatment of prostate cancer. Journal of Clinical Investigations 117:2351-2361. Zeliadt, S. B., S. D. Ramsey, D. F. Penson, et al. 2006. Why do men choose one treatment over another? Cancer 106:1865-1874. Use of Erythropoiesis-stimulating Agents in the Treatment of Hematologic Cancers Brief description of the condition or problem Anemia, a decreased red blood cell count, is common in cancer, occur- ring in up to two-thirds of patients. It can be caused by the disease itself (due to bone marrow infiltration or hemolysis), by nutritional deficiencies, by the myelosuppressive effects of chemotherapy, or by a combination of these factors. Anemia causes well-documented adverse effects in cancer patients, including weakness, impaired concentration, and, most commonly, fatigue. All of these lead to a decreased quality of life, which has been amply demonstrated in research studies. Anemia may also contribute to decreased responsiveness to radiotherapy or chemotherapy. Available treatments or interventions Before the development of erythropoiesis-stimulating agents, transfu- sions were the treatment of choice for cancer-associated anemia. Although transfusions immediately reverse anemia-related symptoms, the effects are short-lived and do not affect the cause of the anemia. Further, frequent transfusions increase the likelihood of adverse effects such as alloimmu-

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 APPENDIX B nization, allergic reactions, iron overload, and transmission of infectious diseases. Recombinant human erythropoietin was developed to stimulate red cell formation and has been used in a wide range of disorders to treat chronic anemia. It does not increase hemoglobin levels immediately but its effects last longer than transfusions. It is available in two forms, alpha and beta, which are very similar in molecular characteristics and pharmacokinetics. A third erythropoiesis-stimulating agent, darbepoetin alfa, is also available. It is longer acting than erythropoietin and only needs to be given every three weeks. Current evidence Numerous randomized and non-randomized trials have established that erythropoiesis-stimulating agents increase hemoglobin levels and reduce transfusion requirements in cancer patients with anemia. They also decrease fatigue and increase quality of life. U.S. clinical practice guidelines recom- mend that an erythropoiesis-stimulating agent be started as hemoglobin levels reach or fall below 10 g/dL. Many doctors start erythropoiesis-stimulating agents at higher levels, believing the quality of life is dramatically improved if the hemoglobin lev- els are kept from going lower than 11 or 12 g/dL. Although there is some research showing that the quality of life is improved when these agents are started earlier, it is controversial. Recent studies have raised the possibility that erythropoiesis-stimulat- ing agent use may increase the risk for thromboembolism. Thus, patients with standard risk factors for thromboembolic events—history of previous thrombosis, surgery, or prolonged immobilization—may be at increased risk of having a throbolembolic event while taking epoetin or darbepoetin. Questions have also been raised about the effects of erythropoiesis-stimu- lating agents on mortality rates, with some studies showing positive effects and others (particularly in the treatment of solid tumors, not hematologic malignancies) finding increased mortality. Issues needing research, and conclusions Comparative effectiveness research would be helpful in defining the exact benefits, costs, and harms of starting erythropoiesis-stimulating agents at different hemoglobin levels in patients with hematologic malignancies. Head-to-head trials could address the advantages and disadvantages of erythropoietin alpha and beta versus the newer preparation, darbepoetin alfa. Finally, large-scale data collection/registers might be helpful to better understand the risks as well as benefits to cancer outcomes associated with these agents.

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 LEARNING WHAT WORKS References Aapro, M., A. Scherhag, and H. U. Burger. 2008. Effect of treatment with epoetin-β on survival, tumor progression, and thromboembolic events in patients with cancer: An updated meta-analysis of 12 randomised controlled studies including 2301 patients. British Journal of Cancer 99:14-22. Bohlius, J., S. Langensiepen, G. Schwarzer, et al. 2005. Recombinant human erythropoietin and overall survival in cancer patients: Results of a comprehensive meta-analysis. Journal of the National Cancer Institute 97:489-498. Hardee, M. E., M. O. Arcasoy, K. L. Blackwell, et al. 2006. Erythropoietin biology in cancer. Clinical Cancer Research 12:332-339. Jones, M., B. Schenkel, J. Just, et al. 2004. Epoetin Alfa improves quality of life in patients with cancer: Results of a meta-analysis. Cancer 101:1720-1732. Oster, H. S., M. Hoffman, S. Pruchti-Sagiv, et al. 2006. Erythropoietin in clinical practice: Current use, effect on survival, and future directions. Israel Medical Association Journal 8:703-706. Pronzato, P. 2006. Cancer-related anaemia management in the 21st century. Cancer Treat- ments Reviews 32:S1-S3. Rizzo, J. D., M. R. Somerfield, K. L. Hagerty, et al. 2008. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American So- ciety of Hematology clinical practice guideline update. Journal of Clinical Oncology 26:132-149. Straus, D. J. 2005. Treatment of anemia with erythropoietic agents in patients with hemato- logic malignancies. Supportive Cancer Therapies 2:215-224. Straus, D. J., M. A. Testa, B. J. Sarokhan, et al. 2006. Quality-of-life and health benefits of early treatment of mild anemia: A randomized trial of epoetin alfa in patients receiving chemotherapy for hematologic malignancies. Cancer 107:1909-1917.