Journal of Managed Care Medicine Volume 15, Number 2

Vol.15, No.2, 2012

Journal of Managed Care Medicine

Decision Making in Advanced Breast Cancer

Detection, Treatment and Control: The Keys to Managing Osteoporosis in Postmenopausal Women

Fibromyalgia: Improving Diagnostic and Treatment Strategies for Better Patient Outcomes

Hyperlipidemia: The Silent CVD Risk Factor with Enormous Impact

Improving Outcomes and Reducing Costs with ICS Monotherapy in the Management of Asthma

Updates and Controversies in Diabetes Care

Clinical and Cost Consequences of Incorporating a Novel Non-Invasive Prenatal Test into the Diagnostic Pathway for Fetal Trisomies

Estimation of Long-Term Increased Risk of Coronary Heart Disease and Type 2 Diabetes Associated with Metabolic Complications Observed in the CATIE Study:

Relative Risk and the Number Needed to Harm for Second-Generation Antipsychotics

PLUS: Spring Managed Care Forum Program Guide

www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 3

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JMCM Journal of Managed Care MedicineThe Official Journal of the

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a Peer-reviewed Publication Vol. 15, No. 2, 2012

TABLE OF CONTENTS

decision Making in advanced breast cancerMichael Naughton, Md ...................................................................................... 5

detection, treatment and control: the Keys to Managing osteoporosis in postmenopausal Womenellen Miller, Md .................................................................................................. 9

fibromyalgia: improving diagnostic and treatment strategies for better patient outcomesdon l. goldenberg, Md ....................................................................................14

hyperlipidemia: the silent cVd risk factor with enormous impactMichael Miller, Md, faCC, faha ..................................................................... 20

improving outcomes and reducing costs with ics Monotherapy in the Management of asthmadennis spangler, Md ........................................................................................ 24

updates and controversies in diabetes careTom a. elasy, Md, MPh .................................................................................... 31

clinical and cost consequences of incorporating a novel non-invasive prenatal test into the diagnostic pathway for fetal trisomiessusan s. garfield, drPh; shannon O. armstrong, Ba ..................................... 34

estimation of long-term increased risk of coronary heart disease and type 2 diabetes associated With Metabolic complications observed in the catie study: relative risk and the number needed to harm for second-generation antipsychoticssonja V.sorenson, MPh; henry Nasrallah, Md; Kafi N. sanders, MPh .......... 42

plus: spring Managed care forum program guide ..................................53

BPA Worldwide Membership Applied for December 2011

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P.O. Box 71895 • Richmond, VA 23255-1895

4 Journal of Managed Care Medicine | Vol. 15, No. 2 | www.namcp.org

Editorial Review Boardalan adler, Md, MsMedical directorindependence Blue Cross

Madeleine biondolillo, Mddirector, healthcare safety and QualityMassachusetts department of Public health

paul bluestein, MdChief Medical OfficerConnecticare

anthony bonagura, MdMedical directoraetna inc.

philip M. bonaparte, MdChief Medical Officerhorizon NJ health

d. Kete cockrell, MdMedical directorinternational Medical group

pat deverka, Md, Ms, Mbesenior research directorCenter for Medical Technology Policy

stan n. finkelstein, MdCo-director, Program on the Pharma-ceutical industry director, harvard-MiT division of health sciences & TechnologyMassachusetts institute of Technology

howard garber, Md, MphMedical directorJohns hopkins health Care

Mary parish gavinski, MdChief Medical OfficerCommunity Care

annetine gelijns, phdCo-directorinternational Center for health Outcomes and innovation research (inChOir) Columbia university

uwe g. goehlert, Md, Msc, Mph, Mba, faafpstaff PhysicianNorthwestern Medical Centerdepartment of emergency Medicine

steven e. goldberg, Md, MbaVP and Chief of Medical affairsexpress scripts

atul grover, Md, phdassociate directorassociation of american Medical Colleges

humberto guerra-garcia, Md, Mph, facpChief Medical Officerunited healthcare Community Plan-delaware

leo M. hartz, Md, MhMVP Clinical advocacy/Chief Medical OfficerBlue Cross of Northeast Pa

barry K. herman, Md, MMMexecutive Medical directorClinical research and Medical affairssunovion Pharmaceuticals, inc.

Kathy hudson, phddirector, genetics and Public Policy CenterJohns hopkins university

thomas Kaye, rph, Mba, fashpsenior Pharmacy directorPassport health Plan

stephen Keir, drphCo-directorCenter for Quality of life/supportive Care research

robert prestonTisch Brain Tumor Centerduke university Medical Center

fernando c. larach, Md, facr, MbaPresidenta-Bay area Medical Clinics, Pa

catherine Marino, MdChief Medical OfficerMagnaCare

Jeff Martin, pharmdClinical account directorinnoviant inc.

peter W. Mccauley sr., Md, cpeMedical directorgottlieb/West Towns PhO inc.

Wesley Mizutani, MdTalbert Medical group

thomas Morrow, Mddirectorgenentech

lawrence Mullany, Md, MbaMedical directorunited healthcare

ray Mummery, Md, cMceChief Medical Officer, dimension health

denis o’connell, Mdregional Medical directorBlue Cross Blue shield of NC

a. Mark parker, Md, MbaMedical directorQuality assessment systems inc.

gary r. proctor, MdChief Medical Officer, federal divisionValueOptions inc.

John W. richards Jr., Md, MMM, cpePresident/CeOinnovative health strategies

Kevin roache, Md, MMM, cpe, facpeVice President Medical affairsPeoples health, inc.

aran ron, Md, Mba, MphPresident and Chief Operating Officergroup health inc.

Mark r. rosenberg, Md, phdPresident/CeOBhM healthcare solutions

Jay schechtman, Md, Mbasenior VP, Chief Medical Officerhealthfirst

nancy single, phdassistant director for strategic Planning and ProgramThe Ohio state university Comprehensive Cancer Center

robert h. small, MdBehavioral health Medical directorTriWest healthcare alliance

Jacque J. sokolov, MdChairmanssB solutions

scott spradlin, do, facpf, acoiVP Medical affairs/Chief Medical Of-ficergroup health Plan

bruce steffens, MdMarket Medical director iowa–Central illinoisunited healthcare

William d. strampel, do, facoidean, Michigan state universityCollege of Osteopathic Medicine

Jeff taylor, rph, MsPharmacy directoraetna

prentiss taylor Jr., Mdregional Medical Center directoradvocate health Care

pam thomas, Md, Mph, facoeMConsulting Medical directorWellness, health and Productivity Management strategies


ThERE ARE APPROxiMATEly 200,000 nEW cases of breast cancer in the United States annually. Breast cancer is a leading cause of death in women with about 40,000 deaths in the U.S. each year. The mortality from this disease has been gradually de-clining since the mid-1990s. Screening is one of the reasons for this decline. Through effective screen-ing, the majority of patients (63 percent) are diag-nosed with localized disease (Exhibit 1). localized disease is considered curable. Two out of three women treated for localized disease are cured.

Unfortunately, 6 percent of women present with metastatic disease. Many other women will have a relapse of the disease. For patients who have advanced or metastatic disease, the disease is universally fatal with a median survival of 24 to 30 months. There are isolated reports of women with metastatic disease who have long-term survival, but these are rare.

Breast cancer is no longer thought of as one dis-ease. There are distinct clinical subtypes with vary-ing natural history. Some women have very aggres-sive disease with short survival and others have much less aggressive disease. Several factors affect the nature of the disease. These include whether the tumor is hormone sensitive or insensitive (estrogen

or progesterone receptors) or human epidermal growth factor receptor-2 (her-2) positive or nega-tive. her-2 is a cell membrane surface-bound recep-tor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation. Approximately 20 percent of breast cancers have an amplification of the her-2 gene or overexpression of its protein product. Pa-tients can have triple negative disease (estrogen, pro-gesterone, and her-2 negative).

Compared to other cancers, there are many thera-pies available for breast cancer that have a reasonable track record of safety and efficacy. Because it is not curable at this time, the goals in treating advanced breast cancer are to prolong survival and decrease the burden of disease. Most patients will be on ther-apy for the majority of their expected survival.

A major issue with advanced breast cancer treat-ment is deciding which therapy to use. The benefit of a particular palliative treatment amust be weighed against toxicity for the individual patient. Some of the considerations in deciding benefit include the probability of response, probability of symptomatic improvement, anticipated toxicity, and the patient’s goals. For example, alopecia may be a major concern

summaryalthough breast cancer is very treatable, once the disease has become metastatic it is no longer curable. Treatment will depend on several factors, including patient goals, the type of tumor, and the menopausal status of the patient. New treatments and new ways of targeting therapy are on the horizon and will continue to influence the treatment of advanced breast cancer.

Key points• Breast cancer is a very treatable disease. • advanced disease is still not curable. • There are distinct clinical subtypes with varying natural history.• Treatment options depend on the type of tumor and the menopausal status of the patient. • Bevacizumab no longer has an fda approved indication for breast cancer treat-ment.• Better targeting of therapy is on the horizon with genetic profiling of tumors.

Decision Making in Advanced Breast CancerMichael Naughton, Md

for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.


for some women. There are chemotherapy agents that can spare them from having this adverse effect. The bottom line is to seek the least toxic therapy that achieves disease control.

Patients can have many different goals in treat-ment of their cancer, such as to beat the disease or to live until some particular milestone. health care providers need to help patients achieve their goals if possible, but they also need to help them understand what realistic goals are for the extent of their disease.

There are treatment guidelines to assist in the choice of treatment. The national Comprehensive Cancer network (nCCn) guidelines are the most often used, are comprehensive, and are frequently updated. The American Society of Clinical Oncol-ogy (ASCO) does offer guidelines but these are much more conservative.

Exhibit 2 provides an overall scheme of how met-

astatic breast cancer is broken down by different dis-ease type (estrogen receptor positive, her-2 posi-tive, and triple negative) and what the typical treatment options are for each type. There are a va-riety of hormone-based therapies for estrogen re-ceptor positive disease. her-2 positive disease is treated with trastuzumab (herceptin®) or lapatinib (Tykerb®). A patient’s tumor can express both estro-gen and her-2 receptors so combination therapy may be used. Chemotherapy is the only treatment strategy for triple negative disease.

hormone-based therapies are relatively nontoxic therapy, which can often provide extended disease control. As shown in Exhibit 3, tumors with both estrogen and progesterone receptors will respond best to hormone-based therapies which decrease the production or effect of estrogen.1 Premenopausal women can be treated with gonadotropin-releasing

exhibit 1: stage distribution at diagnosis

29%localized

regional

distant

unstaged

63%

2%6%

exhibit 2: Metastatic setting

Metastatic Breast Cancer diagnosed

her2 +

Trastuzumab,lapatinib

er, estrogen receptor; Pr, progesterone receptor; Oa, ovarian ablation; ai,

aromatase inhibitor; her2, human epidermal growth factor receptor 2

er or Pr + er and Pr -

Visceral Crisis ChemotherapyNo Visceral Crisis

Premenopausal Postmenopausal Chemotherapy

Tamoxifen+Oa

al


exhibit 3: response to endocrine therapy based on receptor status1

er-/Pgr- er+/Pgr- er-/Pgr+ er+/Pgr+

80

60

40

20

0

percentresponsetoendocrinetherapy

receptor status

hormone agonists (leuprolide, goserelin) to block production of estrogen from the ovaries or antiestro-gens (tamoxifen) to block estrogen from entering cancer cells or ovarian ablation. in metastatic breast cancer for premenopausal women, the most effective option is to combine tamoxifen and ovarian ablation.

Because their ovaries no longer produce signifi-cant amounts of hormones, postmenopausal women have different options. in these women, the majority of the hormones are produced by the adrenal gland. Testosterone produced by the adrenal glands is con-verted to estrogen by aromatase found in fat tissue. This production can be blocked with aromatase in-hibitors. The available agents [letrozole (Femara®), anastrozole (Arimidex®), exemestane(Aromasin®)] are very similar in terms of efficacy and toxicity. Tamoxifen and fulvestrant (Faslodex®), a pure estro-gen antagonist, are also options.

When fulvestrant was initially approved, it was used at a lower dose, which was not very effective. newer data show that a higher dose (500 mg) with an initial loading dose achieves a better outcome. This agent is a monthly injectable, which is well tol-erated. Fulvestrant appears to be slightly more effec-tive in terms of time to progression than the aroma-tase inhibitors.2

her-2 positive disease is treated with a her-2 tar-geting agent. These agents alter down stream cancer cell signaling and halt growth and division. The two currently available agents are trastuzumab, an in-jectable agent, and lapatinib, an oral agent. Adverse effects leading to dose reduction or discontinuation are more common with lapatinib. Trastuzumab has been shown to increase survival (~5 months in me-dian survival) and lapatinib increases time to pro-gression when added to chemotherapy. Although both target her-2, they have distinct mechanisms so

they can be used sequentially.her-2 positive tumors can also be estrogen positive

or negative. Women who co-express both are candi-dates for hormone therapy and a her-2 targeting agent. Women who are estrogen negative will receive chemotherapy along with a her-2 targeting agent. Data support continuing the her-2 targeting agent throughout the disease course even if progression oc-curs. Thus a woman may be switching chemotherapy or hormone-based therapy because of ineffectiveness, but the her-2 agent would be continued.

There are many new agents in development that target her-2. One agent under study is trastuzumab bound to a chemotherapy agent (T-DM1). This is trying to deliver chemotherapy directly into the cancer cell.

There are numerous scenarios where a woman with breast cancer will end up needing chemother-apy treatment. Chemotherapy is the only option for triple negative disease. Women with estrogen re-sponsive tumors will eventually become resistant and require chemotherapy.

One issue with chemotherapy in advanced breast cancer is whether to give agents sequentially or as combination therapy. This is the trade-off between toxicity and benefit. With combination therapy, ad-verse effects increase but time to progression is lon-ger. Unfortunately, at one year, the survival is no better with combination therapy versus sequential single agent. Combination therapy does increase re-sponse rates so if the woman has a high volume of disease, combination therapy would be indicated.

First-line chemotherapy response rates will be in the 40 percent range. Response rates decline with each subsequent chemotherapy choice - 20 percent for second line, 10 to 15 percent for third line, etc.

Many times women will be treated with anthra-


cycline-based chemotherapy, which has many ther-apy limiting adverse effects. A newer agent, pegylat-ed liposomal doxorubicin (Doxil®), is as effective as doxorubicin and epirubicin but results in lower rates of adverse effects. it does not cause alopecia and nausea, which are almost universal with the other two agents. Additionally, it does not have a lifetime dose limit like the other two agents.

Capecitabine (xeloda®), an oral agent, can be a less toxic option than anthracyclines for a woman with a hormone response tumor that has progressed. Getting managed care approval for use can be a problem because it is only FDA approved for use in women who have already been treated with an an-thracycline.

Eribulin (halaven®) is the newest chemotherapy agent for breast cancer. it is a synthetic analog of halichondrin B, a natural marine sponge product. it has been studied in women who have previously been treated with multiple chemotherapy agents and showed a higher median progression-free survival (2.6 months).3

Bevacizumab (Avastin®) previously was FDA ap-proved for use in combination with the paclitaxel for those patients who have not been treated with che-motherapy for her-2 negative metastatic breast can-cer. The FDA revoked approval of this agent for the breast cancer indication on november 18, 2011 be-cause “Avastin used for metastatic breast cancer has not been shown to provide a benefit, in terms of delay in the growth of tumors, that would justify its serious and potentially life-threatening risks. nor is there evidence that use of Avastin will either help women with breast cancer live longer or improve their quality of life.”4

With chemotherapy for metastatic breast cancer, there are no good predictors of efficacy, other than her-2 status. The current division of disease based on receptors is determined by the immunohisto-chemistry of the tumor. More is being learned about the molecular composition of tumors. The next wave of classification of breast cancer is molecular profiling looking at the gene patterns and signa-tures.

conclusionBreast cancer is a very treatable disease. Unfortu-nately, advanced or metastatic disease is still not cur-able. Depending on the type of tumor, there are many treatment options available. in addition, bet-ter targeting of therapy is on the horizon with ge-netic profiling of tumors.

Michael Naughton, Md is an assistant Professor of Medicine at the

Washington university school of Medicine in st. louis, MO.

references1. Bryan RM, Mercer RJ, Bennett RC, et al. Androgen receptors in breast

cancer. Cancer. 1984 ;54:2436-40.

2. Robertson JF, llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500

mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer:

results from the FiRST study. J Clin Oncol. 2009;27:4530-5.

3. Vahdat lT, Pruitt B, Fabian CJ, et al. Phase ii study of eribulin mesylate, a

halichondrin B analog, in patients with metastatic breast cancer previously

treated with an anthracycline and a taxane. J Clin Oncol. 2009;27:2954-61.

4. FDA Press Release. FDA Commissioner Removes Breast Cancer indication

from Avastin label. november 18, 2011, Available at http://www.fda.gov/

newsEvents/newsroom/PressAnnouncements/ucm279485.htm. Accessed

1/13/2012.


OSTEOPOROSiS iS DEFinED AS A SySTEMiC skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone is a dynamic tissue that is constantly being remodeled. Osteoclasts remove old bone and osteoblasts replace the tissue with new fresh bone. in the normal state, before menopause, these two states are totally balanced – the amount of bone re-moved is replaced on a constant basis. With the loss of estrogen at menopause, there is an increased rate of bone turnover and the osteoblasts cannot keep up which results in a net loss of bone and increased risk of fracture.

Osteoporosis is a major national health problem. Approximately 10 million Americans have osteopo-rosis, and another 34 million have osteopenia, a de-creased bone mass. Forty to fifty percent of women aged 50 and older will suffer an osteoporosis-related fracture in their lifetimes.1 Osteoporosis results in 700,000 vertebral fractures and 300,000 hip frac-

tures annually. The prevalence of osteoporosis is ex-pected to increase with the growth of the elderly population.

Fractures secondary to osteoporosis result in sig-nificant health impact. Patients who experience a vertebral fracture are at greater risk of any subse-quent fracture. These patients may become unable to walk unassisted, lose height, develop spinal defor-mities, experience significant pain, and are at greater risk of death.2 Unfortunately, vertebral fractures are often unrecognized.3 hip fractures are the most costly complication of osteoporosis. Exhibit 1 illus-trates the increased morbidity and mortality after a hip fracture.4

Additionally, osteoporosis has significant eco-nomic impact. Each year in the United States, os-teoporotic fractures are responsible for more than 500,000 hospitalizations, 800,000 emergency room visits, and 2.6 million physician office visits. The consequences of osteoporotic fractures include

summaryOsteoporosis is often a silent disease until it results in a fracture. Because of this silent nature, it is underdiagnosed. Certain patients should be screened for this disease by bone density measurement. There are several effective treatments, but patients have to adhere to therapy for many years to maximize the benefit. enhanc-ing adherence is an area for managed care intervention.

Key points• The important consequence of osteoporosis is fractures.• fractures are costly to both the patient and the health care system.• Osteoporosis is preventable and treatable, but it is underdiagnosed and under-treated.• Women meeting certain criteria need to be screened for osteoporosis.• diagnosis of osteoporosis is based on BMd testing.• Patients with low BMd can be assessed for fracture risk to determine need for treatment.• Patients with osteoporosis require treatment to prevent further bone loss and reduce risk of fracture.• There are numerous therapeutic options for treating osteoporosis.• adherence to therapy is important for maximizing fracture risk reduction.

Detection, Treatment and Control: The Keys to Managing Osteoporosis in

Postmenopausal Womenellen Miller, Md



placement of approximately 180,000 individuals in nursing homes yearly. in 2005, osteoporosis-related fractures were responsible for an estimated $19 bil-lion in costs.5 By 2025, experts predict that these costs will rise to approximately $25.3 billion.

Osteoporosis is preventable and, once it develops, treatable. Screening for and treatment of osteopo-rosis in postmenopausal women is cost effective. it results in improved quality of life, which outweighs the treatment costs.6 There are fewer fractures and associated morbidity and a reduction in hospitaliza-tions. Earlier detection and treatment can reduce the economic burden of this disease even further. Addi-tional bone density screening for one million at-risk women could lead to a $77.86 million net savings for Medicare, due to a decrease in fractures.7 This

additional screening might lead to the treatment of 440,000 new patients, preventing more than 35,000 fractures.8

in 2004, the Surgeon General’s report on osteo-porosis highlighted the predictive value of bone mineral density (BMD) testing, noting that BMD testing remains the ‘gold standard’ test for those at risk of osteoporosis and that BMD is a strong inde-pendent predictor of fracture risk.9 This report fur-ther notes that the relationship between BMD and fracture is stronger than the relationship between cholesterol and heart attack.

The international Society for Clinical Densitom-etry recommends a central dual-emission x-ray ab-sorptiometry (DxA) of the spine, proximal femur, and femoral neck for diagnosis of osteoporosis.10

exhibit 1: increased Morbidity and Mortality4

death Within Permanent unable to Walk unable to Carry Out 1 year disability independently >1 independent adl

1 year after hip fracture

% o

f P

atie

nts

adl = activity of daily living

20

30

40

80

exhibit 2: indications for bMd testing: risk factor profiles11

• Perimenopausal women with a specific risk factor associated with increased fracture risk (e.g., smoking, family history, thinness)

• low impact fracture after age 50

• adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids) associated with bone loss

• individuals with primary hyperparathyroidism

• anyone being considered for pharmacologic therapy for osteoporosis

• anyone being treated for osteoporosis, to monitor treatment effect

• Postmenopausal women discontinuing estrogen


This will accurately give a BMD in grams/centime-ter2. The diagnosis is based on the patient’s lowest bone density score at any of the three sites screened using their T-score. The T-score is the number of standard deviations above or below the mean for a healthy 30-year-old adult of the same sex and eth-nicity as the patient. A T-score between -1.0 and -2.5 is considered osteopenia. A T-score of -2.5 is considered osteoporotic. Peripheral ultrasound mea-surements of the heel are useful for screening low-risk patients but should not be used for diagnosis or follow-up. The indications for BMD testing are listed in Exhibit 2.11

All patients with osteoporosis will get treatment but clinicians have to determine what type of treat-ment to offer people with osteopenia. Because the majority of patients identified with low bone mass will fall in the osteopenia category, the majority of fractures occur in this group. The use of clini-cal factors can improve identification of people with osteopenia at higher fracture risk so they can be treated. The WhO Frax™ Risk Assessment Tool determines an individual’s 10-year risk of hip and major osteoporotic fracture based on BMD and oth-er important risk factors.12 The risk factors included in this tool are listed in Exhibit 3.12 Patients with a 20 percent or greater risk of a major osteoporotic fracture or a 3 percent or greater risk of hip fracture should be treated with pharmacologic therapy.11 Ex-hibit 4 includes the other indications for pharmaco-logic therapy in postmenopausal women.

Osteoporosis is underdiagnosed and un-dertreated. The disease is often silent un-til it results in a fracture. Although osteoporo-sis can be prevented through appropriate diet and exercise, adherence to preventive measures is poor. Additionally, adherence to oral pharmacologic treatment is poor. in one study, 20 percent of patients taking daily bisphosphonates abandoned therapy within seven months.13 The development of weekly bisphosphonate therapy improved persistence, but it is still not optimal with these agents because of the strict way they must be taken (i.e., with eight ounces of water, no lying down for two hours afterwards, and 30 minutes before eating any food). Poor adher-ence leads to compromised fracture risk reduction (Exhibit 5).14 Even small improvements in adherence (i.e., 10 percent) can translate into fewer fractures per patient, resulting in a net reduction in medical costs.15

There are many reasons for adhearence issues in osteoporosis treatment. A major issue is that the treatment of concomitant diseases may take priority over an issue of treatment that has the goal of try-ing to prevent a fracture from occurring many years into the future.

The standard interventions for improving adher-ence for a silent disease should be applied here. Pa-tients need to be educated about the risk of fracture and the reasons for maintaining treatment for many years. health care providers need to assess patient preferences, medication-taking behaviors, and cur-rent polypharmacy burden. Patients can be enrolled in support and adherence programs or given access to case management services for continual care. im-proving adherence with osteoporosis therapy is an area for managed care to intervene.

nonpharmacologic interventions that prevent bone loss include calcium 1200-1500 mg/day through diet or supplementation, vitamin D 800-1000 iU/day through supplementation, regular weight-bearing exercise, and avoidance of tobacco and excessive alcohol. These interventions are ap-propriate for all postmenopausal women. Women who have low bone mass should also be instructed in fall prevention strategies.

There are multiple pharmacologic agents, which can build bone. Teriparatide (Forteo®), calcitonin (Fortical®, Miacalcin®), raloxifene (Evista®), deno-sumab (Prolia®), and bisphosphonates are all FDA approved for treating osteoporosis. The bisphos-phonates include alendronate (Fosamax®, generic), ibandronate (Boniva®), risedronate (Actonel®), and zoledronate (Zometa®). Calcitonin is the easiest to take because it is a daily nasal spray. Raloxifene is also approved to reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis or at high risk for developing breast cancer. The bisphosphonates are the most commonly prescribed agents with daily oral, weekly oral, monthly oral, intravenous push every three months (ibandronate),

exhibit 3: risk factors included in

the Who fracture risk assessment Model12.

• Current age

• use of oral glucocorticoid therapy

• gender

• secondary osteoporosis (e.g., rheumatoid arthritis)

• Personal history of a fracture

• Personal history of a hip fracture

• femoral neck BMd

• Current smoking

• low body mass index (kg/m2)

• alcohol intake of 3 or more drinks/day


and intravenous infusion yearly (zoledronic acid) formulations. The yearly infusion is done at an in-fusion center after the patient is hydrated. For pre-vention, zoledronic acid is given every other year. There are 10-year or greater data on safety and ef-ficacy with bisphosphonates.

Bisphosphonates are associated with some rare adverse effects. These include osteonecrosis of the jaw and atypical femoral shaft fractures. Osteone-crosis is an area of exposed bone in the maxillofacial region that does not heal within eight weeks. The majority of cases have occurred in patients receiving high-dose intravenous bisphosphonates for cancer. The mechanism why this occurs is unknown. Some cases have occurred after oral surgery. Many pro-viders question whether these agents should be dis-continued before oral surgery. There is no published evidence to support or oppose discontinuation. Be-cause bisphosphonates have very long half-lives in bone, recovery of normal bone turnover and osteo-clastic function may be too gradual to have clinical significance. Patients should have any dental issues which might require surgery addressed before start-ing on a bisphosphonate.

Atypical fractures of the femoral shaft have also recently been reported with bisphosphonate use. These are transverse fractures of the femoral shaft that have occurred bilaterally in two-thirds of the reports. Delayed healing or nonhealing is common. These fractures have been associated with prolonged use (> 5 years) of alendronate with or without an-other anti-resorptive medication. Patients treated with bisphosphonates should be cautioned to report any new hip or thigh pain. These atypical fractures have been rarely reported.

Denosumab, the newest agent, was approved in 2010 for treatment of postmenopausal women with osteoporosis at high risk for fracture. Denosumab is a monoclonal antibody that targets receptor activator of nuclear factor kappa-B ligand (RAnK ligand), a protein that acts as the primary signal to promote bone removal. it inhibits osteoclast formation, sur-vival, and function. Denosumab reduces vertebral fractures by 68 percent, hip fracture by 40 percent, and nonvertebral fractures by 20 percent.16 it is giv-en as a subcutaneous injection every six months.

To assess therapeutic response to pharmacothera-py, BMD testing should be repeated after two years of therapy. A satisfactory response is when BMD is maintained or increased. if BMD declines, reasons such as technical issues (e.g., validity of DxA com-parison), nonadherence, and inadequate vitamin D or calcium should be considered before stopping therapy.

conclusionOsteoporosis-related fractures can dramatically af-fect the functional status of women who sustain them. These fractures represent a significant clini-cal burden; yet they often go unevaluated and un-treated. There are effective methods for evaluating individual fracture risk. Management strategies for patients with osteoporosis include ensuring basic bone health needs are met, screening for secondary causes of osteoporosis, and initiating pharmacologic therapy when appropriate.

ellen Miller, Md is an associate Professor of Medicine at hofstra North

shore-liJ school Of Medicine.

exhibit 4: nof guidelines for initiating pharmacologic therapy in postmenopausal Women11

initiation of Pharmacologic Therapy recommendedin the Presence of any of the following:

fracture • a vertebral or hip fracture

T-score • T-score = -2.5 at femoral neck or spine

fraX® • WhO 10-year probability of any major fracture = 20% assesment • WhO 10-year probability of a hip fracture = 3%


references1. Chrischilles EA, Butler CD, Davis CS, Wallace RB. A model of lifetime os-

teoporosis impact. Arch Intern Med. 1991;151:2026-32.

2. lips P. invest in your Bones: Quality of life. Why Prevent the First Fracture?

international Osteoporosis Foundation. 2003. Available at http://www.iof-

bonehealth.org

3. US Department of health and human Services. Bone health and Osteopo-

rosis: A Report of the Surgeon General. Rockville, MD: US Department of

health and human Services, Office of the Surgeon General; 2004.

4. Cooper C. The crippling consequences of fractures and their impact on qual-

ity of life. Am J Med. 1997;103:12S-17S.

5. national Osteoporosis Foundation. Fast Facts. Available at http://www.nof.

org/node/40. Accessed January 12, 2012.

6. Tosteson An, Melton lJ 3rd, Dawson-hughes B, et al. Cost-effective osteo-

porosis treatment thresholds: the United States perspective. Osteoporos Int.

2008;19:437-47.

7. King AB, Saag KG, Burge RT, et al. Fracture Reduction Affects Medicare

Economics (FRAME): impact of increased osteoporosis diagnosis and treat-

ment. Osteoporos Int. 2005;16:1545-57.

8. Schousboe JT, Ensrud KE, nyman JA, et al. Universal bone densitometry

screening combined with alendronate therapy for those diagnosed with osteo-

porosis is highly cost-effective for elderly women. J of Am Geriatr Soc.

2005;53:1697-1704.

9. US Department of health and human Services. Bone health and Osteopo-

rosis: A Report of the Surgeon General. Rockville, MD: US Department of

health and human Services, Office of the Surgeon General; 2004.

10. international Society for Clinical Densitometry. Official Positions 2007.

Available at http://www.iscd.org/Visitors/pdfs/iSCD2007OfficialPositions-

Adult.pdf. Accessed 1/12/12

11. national Osteoporosis Foundation. Clinician’s Guide to Prevention and

Treatment of Osteoporosis. 2008.

12. FRAx™ WhO Fracture Risk Assessment Tool. http://www.shef.ac.uk/

FRAx/tool.jsp. Accessed 1/12/12.

13. Tosteson An, Grove MR, hammond CS, et al. Early discontinuation of

treatment for osteoporosis. Am J Med. 2003;115:209-16.

14. Siris ES, harris ST, Rosen CJ, et al Adherence to bisphosphonate therapy

and fracture rates in osteoporotic women: relationship to vertebral and nonver-

tebral fractures from 2 US claims databases. Mayo Clin Proc. 2006;81:1013-22.

15. Gold DT, Alexander iM, Ettinger MP. how can osteoporosis patients ben-

efit more from their therapy? Adherence issues with bisphosphonate therapy.

Ann Pharmacother. 2006; 40:1143-50.

16. Cummings SR, San Martin J, McClung MR, et al. Denosumab for preven-

tion of fractures in postmenopausal women with osteoporosis. N Engl J Med.

2009;361:756-65.

exhibit 5: poor compliance and persistence leads to compromised fracture risk reduction14

N=35,537

24-M

ont

h fr

actu

re r

isk,

%

12

10

8

6

4

2

0

Nonpersistent Persistent

10

P=0.001 7.7

29% riskreduction


ChROniC WiDESPREAD PAin AFFECTS UP to 15 percent of the population, generally with no identifiable structural basis. There are many differ-ent “labels” that one can legitimately use for an in-dividual with this type of pain, if one decides to use any label. Fibromyalgia is an arbitrary label for a syndrome of chronic widespread pain. Many func-tional somatic syndromes overlap, including FM, chronic fatigue syndrome, irritable bowel syndrome, chronic headaches, irritable bladder syndrome, jaw or facial pain disorders, pelvic pain, and vulvodynia. Depending on the specialist seen, the patient may receive a different diagnosis. Additionally, no medi-cal specialty has accepted “ownership” of these pa-tients with chronic widespread pain. Rheumatolo-gists have led the way in research, but many do not care to treat these patients.

FM is the most common chronic widespread pain condition worldwide and affects 3 to 5 percent of the population.1 Currently, many fibromyalgia patients

are not diagnosed or require years to get a diagnosis. Patients will have symptoms for an average of a year before seeking care. On average, a patient with FM will require 2.3 years and see 3.7 doctors before re-ceiving a diagnosis.2 The duration of time without a diagnosis adversely affects outcome. Peak age for diagnosis is between the ages of 35 and 60 years, but it affects all ages. Women are affected more com-monly than men. Twenty-five to 35 percent of FM patients are unable to work because of symptoms.

in addition to widespread pain, the most common symptoms are fatigue, morning stiffness, and sleep disturbances.3 Symptom severity varies over time. Pain and fatigue are the symptoms patients want to see improved the most.4 At the time of FM diagno-sis, mood disorders are present in 30 to 50 percent of patients, primarily depression.5

Sleep disruption is prominent and problematic in this disease. FM patients report insomnia, ear-ly morning awakenings, and poor quality of sleep.

summaryfibromyalgia (fM) is a chronic pain disorder that requires accurate diagnosis and management. Many of the medications currently used for this condition are inef-fective. There are fda approved medications and behavioral and physical interven-tions that are effective, especially when used in combination. improving diagnosis and management utilizing appropriate specialty referral for difficult to manage pa-tients will help managed care achieve better patient outcomes.

Key points• Chronic widespread pain is a real disease and is common. • fM is a syndrome of altered pain perception. • diagnosis of fM is good for patients and health care. • fM should be managed by primary care with rheumatology, physical medicine, and mental health specialists as consultants. • selected patients require multi-component therapy and should be managed by a multidisciplinary team. • Managed care can have an impact with these patients by helping limit use of opi-oids and other ineffective agents and costly testing and procedures.

Fibromyalgia: Improving Diagnostic and Treatment Strategies for Better Patient Outcomes

don l. goldenberg, Mdfor a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.


Objective polysomnographic recording shows dis-ordered sleep. Some will also have co-existing sleep apnea or restless leg syndrome which needs to be treated. Disturbance of deep sleep magnifies the af-fective component of pain.6, 7

FM can be difficult to diagnose. it is the prototype for a fundamentally different type of pain syndrome where pain is not due to damage or inflammation of peripheral tissues. it is frequently accompanied by a variety of other somatic symptoms and syndromes.

Because of issues with using the American Col-lege of Rheumatology (ACR) diagnostic criteria and accurately completing a tender point count, new criteria have been proposed which use two scores – widespread pain index and symptom severity score (Exhibit 1).8 A patient examination is needed in ad-dition to the criteria to confirm the diagnosis and exclude other chronic pain conditions such as ar-thritis. The proposed criteria no longer include a tender point count.

The diagnostic workup of FM should be inexpen-sive, but it is sometimes hard to convince primary care doctors not to do additional testing. in addition to a patient history and careful musculoskeletal ex-amination, selected laboratory tests should be used to rule out other diagnoses. The commonly ordered tests include complete blood count, erythrocyte sedimentation rate, and thyroid function tests. Sero-logic tests for rheumatoid arthritis and other condi-tions should only be conducted if history or physi-cal exam suggests a rheumatologic diagnosis. x-rays and imaging studies are typically not helpful unless there is strong evidence for a structural disorder.9 An

early referral from primary care to a FM specialist may lead to an earlier diagnosis.

The pathophysiology of FM is unknown, but re-cent data suggest that alterations of the central ner-vous system (CnS) may contribute to the chronic widespread pain of FM. Central sensitization is emerging as a leading theory of FM pathophysiol-ogy.10 Functional MRi data provide supporting ev-idence that FM is a central pain processing disorder. There is an imbalance between pain augmentation and pain perception. Therapeutic agents that reduce neuronal hyperactivity by reducing the release of neurotransmitters are one way to relieve the chronic pain of FM.

Although FM is a central nervous system disorder and not a musculoskeletal disorder, rheumatologists have been taking care of the majority of patients. A neurologist probably should be the specialist caring for these patients, but most do not want to deal with this condition.

Exhibit 2 presents an algorithm for managing pa-tients with FM.11,12 Many patients with FM will re-quire a referral to a mental health professional to manage psychosocial and mood issues.

Only a few agents have strong evidence for effi-cacy in managing FM (Exhibit 3).12 Unfortunately, many agents, such as anti-inflammatories and opi-oids that show no evidence for efficacy, are com-monly used.

Tricyclic (TCA) and serotonin and norepineph-rine reuptake inhibitors (SnRi) antidepressants al-ter brain levels of neurotransmitters to restore bal-ance in pain perception. They are also effective in

exhibit 1: new proposed diagnostic criteria8

symptom severity (ss) scorescore ranges from 0 (no problem) to3 (severe) for each group of symptoms: fatigue Waking unrefreshed from sleep Cognitive symptoms Plus a score of 0 (no symptoms) to 3 (great deal of symptoms) for all somatic symptoms combined

Total ss score = 0-12

Widespread Pain index (WPi): in how many areas has the patient had pain (over the last week)?

score 1 point for each area shoulder girdle* upper arm, lower arm* hip (buttock, trochanter)* upper leg, lower leg* Jaw* Chest abdomen upper back, lower back Neck (*score left & right side separately)

Total WPi score = 0-19

fM can be diagnosed based on a questionnaire that includes:


treating the depression that commonly accompanies chronic pain conditions. The TCAs are effective for all clinical outcomes (pain, quality of sleep, fatigue, and sense of well-being) but have safety and toler-ability issues due to nonselective binding to antihis-taminergic and α-adrenergic receptors. The SnRis, duloxetine and milnacipran, are both FDA approved for treating FM and significantly improve clinical outcomes.13,14 Pregabalin, an anticonvulsant, is also FDA approved for managing FM.15 Gabapentin, another anticonvulsant approved for other types of chronic pain, has data to show it is effective but does not have FDA approval.16 none of these agents is dramatically effective. About 50 percent of patients will get a 25 percent reduction in pain relief. Only 25 percent will get a truly meaningful response of a 50 percent reduction in pain. More effective options are needed and patients need education on realistic expectations for pain reduction.

For patients who predominately have exhaustion and mood symptoms, an SnRi is suggested as initial therapy. For patients with predominately pain and sleep issues, an anticonvulsant should be the initial

choice. if the initial pharmacotherapy choice does not adequately improve symptoms, it may be bet-ter to add a second medication rather than switch, however,combination therapy trials have not yet been published.

nonpharamacologic therapy is as important as medications. The nonpharmacologic strategies with strong evidence for efficacy in this condition are listed in Exhibit 4.12,17,18 improved outcomes can be obtained by combining pharmacologic and non-pharmacologic treatments.

Exercise should be recommended for all FM pa-tients. Patient comorbidities may determine the ac-ceptable types of exercise. Many of these patients have been sedentary for a long time and are difficult to get moving again. Obesity is also common in this patient population. Water-based exercise programs are particularly helpful because they are easiest for patients. Continued exercise is necessary to main-tain positive effects on pain. Patient self-efficacy – the belief that he or she can achieve and maintain a program - is essential for sustained participation.19 home-based ‘lifestyle physical activity’ may be

exhibit 2: core treatment of fibromyalgia11, 12

confirm diagnosis

identify important symptom domains, their severity,and level of patient function

evaluate for comorbid medical andpsychiatric disorders

assess psychosocial stressors, levelof fitness, and barriers to treatment

May require referral to a specialistfor full evaluation

Provide education about fibromyalgia

review treatment options

initiate monotherapy based onpatient’s presentation and evidence-

based guidelines


more beneficial than a formal program in some FM patients.20

Cognitive behavioral therapy (CBT) can help to improve coping with pain and to reduce depressed mood and health care-seeking behavior in FM. in one study comparing CBT to standard care, the patients who received CBT had improved physical functioning and decreased pain.21

Patient education is another important aspect of nonpharmacologic therapy. Most patients have chronic, persistent symptoms and need to be educat-ed about what is a realistic outcome for symptoms.

The best approach is to combine pharmacologic, physical, and behavioral therapies, such as medica-tion, exercise, and CBT. The problem for providers is getting insurance reimbursement for interventions outside of pharmacologic therapy. Unfortunately, few patients get all these appropriate therapies. Only 3 percent of FM patients in one study were getting the three types of therapy.22

Diagnosing and treating FM is good for the cli-nician, patient, and health care system. it reduces health care and societal costs.23 A diagnosis is good for the patient only if it is coupled with accurate

exhibit 3: fM pharmacological therapies12

“antidepressants” Tricyclic compounds (amitriptyline, cyclobenzaprine)sNris and Nsris (milnacipran, duloxetine)Pregabalin

Tramadolgabapentinselective serotonin reuptake inhibitors (ssris)gamma hydroxybutyratedopamine agonists (Pramipexole)

growth hormone, 5-hydroxytryptamine, s-adenosyl-l-methionine (saMe)

Opioids, corticosteroids, nonsteroidal anti-inflammatory drugs, benzodiazepine and nonbenzodiazepine hypnotics, guanifenesin, thyroid hormone

strongevidence

Modestevidence

Weakevidence

Noevidence

exhibit 4: nonpharmacologic strategies: evidence of efficacy12,17,18

Modest eVidence

• strength training• acupuncture• hypnotherapy• eMg biofeedback• Balneotherapy (medicinal bathing)• Transcranial electrical stimulation

WeaK eVidence• Chiropractic• Manual and massage therapy• ultrasound

eVolVing eVidence• Tender-point injections• Tai-chi, yoga

strong eVidence

• exercise – Physical and psychological benefits – May increase aerobic performance and tender point pain pressure threshold, and improve pain – efficacy not maintained if exercise stops

• Cognitive-behavioral therapy – improvements in pain, fatigue, mood, and physical function – improvement often sustained for months

• Patient education/self-management – improves pain, sleep, fatigue, and quality of life

• Combination (multidisciplinary therapy)


information and education.More than 50 percent of visits for FM symptoms

are to primary care physicians. Currently, 16 percent of FM visits are to rheumatologists. The ACR sug-gests that rheumatologists serve as consultants (ter-tiary care). Other specialists should include physiat-rists, pain management experts, and mental health providers. For a subset of the most difficult patients to treat, a multidisciplinary team needs to be in-volved (Exhibit 5).

conclusionChronic widespread pain is real and common. FM is not a distinct entity but rather is at the extreme end of a spectrum of altered pain perception. Diag-nosis of FM is good for patients and for health care. it is hoped that earlier diagnosis and treatment will lead to better outcomes. FM should be managed by primary care with rheumatology, physical medicine, and mental health as consultants. Selected patients require multi-component therapy and should be managed by a multidisciplinary team. Managed care can have an impact with these patients by helping limit the use of opioids and other ineffective agents and costly testing and procedures.

don l. goldenberg, Md is Chief of rheumatology at Newton-Wellesley

hospital in Newton, Massachusetts and a Professor of Medicine at Tufts

university school of Medicine.

references1. Weir PT, harlan GA, nkoy Fl, et al. The incidence of fibromyalgia and its

associated comorbidities: a population-based retrospective cohort study based

on international Classification of Diseases, 9th Revision codes. J Clin Rheuma-

tol. 2006;12:124-8.

2. Choy E, Perrot S, leon T, et al. A patient survey of the impact of fibromyal-

gia and the journey to diagnosis. BMC Health Serv Res. 2010;10:102.

3. Wolfe F, Smythe hA, yunus MB, et al. The American College of Rheuma-

tology 1990 Criteria for the Classification of Fibromyalgia. Report of the Mul-

ticenter Criteria Committee. Arthritis Rheum. 1990;33:160-72.

4. Bennett RM, Russell J, Cappelleri JC, et al. identification of symptom and

functional domains that fibromyalgia patients would like to see improved: a

cluster analysis. BMC Musculoskelet Disord. 2010;11:134.

5. McBeth J, Silman AJ. The role of psychiatric disorders in fibromyalgia. Curr

Rheumatol Rep. 2001;3:157-64.

6. Vierck CJ Jr. Mechanisms underlying development of spatially distributed

chronic pain (fibromyalgia). Pain. 2006;124:242-63.

7. Moldofsky h. The significance of the sleeping-waking brain for the under-

standing of widespread musculoskeletal pain and fatigue in fibromyalgia syn-

drome and allied syndromes. Joint Bone Spine. 2008;75:397-402.

8. Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheu-

matology preliminary diagnostic criteria for fibromyalgia and measurement of

symptom severity. Arthritis Care Res. 2010;62:600-10.

9. Goldenberg Dl. Diagnosis and differential diagnosis of fibromyalgia. Am J

Med. 2009;122(12suppl):S14-S21.

10. Clauw DJ, Crofford lJ. Chronic widespread pain and fibromyalgia: what we

know, and what we need to know. Best Prac Res Clin Rheumatol. 2003;17:685-

701.

11. Arnold lM. Biology and therapy of fibromyalgia. new therapies in fibromy-

algia. Arthritis Res Ther. 2006;8:212.

12. Goldenberg Dl, Burckhardt C, Crofford l. Management of fibromyalgia

syndrome. JAMA. 2004;292:2388-95.

13. Arnold lM, Rosen A, Pritchett yl, et al. A randomized, double-blind,

placebo-controlled trial of duloxetine in the treatment of women with fibromy-

algia with or without major depressive disorder. Pain. 2005;119:5-15.

14. Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacipran in

patients with fibromyalgia. J Rheumatol. 2005;32:1975-85.

15. Arnold lM, Russell iJ, Diri EW, et al. A 14-week, randomized, double-

blinded, placebo-controlled monotherapy trial of pregabalin in patients with

fibromyalgia. J Pain. 2008;9:792-805.

exhibit 5: interdisciplinary pain Management

PrimaryClinician and

Patient

Pain specialist

Psychiatrist

Neurologist

Physiatrist

Psychologist

Occupational TherapistPhysical Therapist

integrated coordinated

rheumatologist

spine surgeon

Pharmacist

social Worker

anesthesiologist

Physician assistant


16. Arnold lM, Goldenberg Dl, Stanford SB, et al. Gabapentin in the treatment

of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter

trial. Arthritis Rheum. 2007;56:1336-44.

17. Williams DA, Cary MA, Groner Kh, et al. improving physical functional

status in patients with fibromyalgia: a brief cognitive behavioral intervention. J

Rheumatol. 2002;29:1280-6.

18. Busch AJ, Barber KA, Overend TJ, et al. Exercise for treating fibromyalgia

syndrome. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003786.

19. Sarzi-Puttini P, Buskila D, Carrabba M, et al. Treatment strategy in fibro-

myalgia syndrome: where are we now? Semin Arth Rheum. 2008;37:353-65.

20. Staud R, Robinson ME, Weyl EE, Price DD. Pain variability in fibromyal-

gia is related to activity and rest: role of peripheral tissue impulse input. J Pain.

2010;11:1376-83.

21. Williams DA, Cary MA, Groner Kh, et al. improving physical functional

status in patients with fibromyalgia: a brief cognitive behavioral intervention. J

Rheumatol. 2002;29:1280-6.

22. Sauer K, Kemper C, Glaeske G. Fibromyalgia syndrome: prevalence, phar-

macological and non-pharmacological interventions in outpatient health care.

An analysis of statutory health insurance data. Joint Bone Spine. 2011;78:80-4.

23. Annemans l, Wessely S, Spaepen E, et al. health economic consequences

related to the diagnosis of fibromyalgia syndrome. Arthritis Rheum. 2008;58:895-

902.


hyPERliPiDEMiAS ARE A MAJOR PUBliC health concern in the U.S. More than 100 million U.S. adults have a dyslipidemia. in addition, an es-timated 6 percent of adolescents have elevated lipid values.1

hyperlipidemia leads to atherosclerosis and car-diovascular disease (CVD). The aplolipoprotein (ApoB) containing lipoproteins are atherogenic. These include low-density lipoprotein cholesterol (lDl-C), intermediate density lipoprotein (iDl), very low- density lipoprotein (VlDl), VlDl rem-nants, chylomicron remnants, and lipoprotein a [lp(a)]. Most of these particles are not routinely measured. ApoB recognizes sites on tissues such as macrophages that allows for its unadulterated incorporation into macrophages leading to foam cell formation – the first step in the formation of atherosclerotic plaque. high-density lipoprotein cholesterol (hDl-C) is anti-atherogenic because it is involved in the efflux of lipids for hepatobiliary excretion.

lDl-C is the primary target of therapy. lDl-C

levels vary with genetic variations in cholesterol me-tabolism and diet. Some patients with genetic vari-ants that lead to low lDl-C have long life spans because they don’t develop extensive atherosclero-sis. Patients with familial combined hyperlipidemia (FCh, both elevated lDl-C and triglycerides) have about double the risk of heart disease compared to someone without mild elevations of lDl-C alone. Patients with familial hypercholesterolemia (Fh) have high and very high lDl-C levels depending on whether they are heterozygous or homozygous.

it is critical to understand the role lDl-C plays in the development of disease. lDl-C must be modified to be atherogenic. Three conditions lead to modified lDl-C – diabetes, cigarette smoking, and hypertriglyceride states. in diabetes, lDl-C is glycosylated so it can then be taken up by mac-rophages in an unregulated manner. Smoking is atherogenic because cigarette smoke contains sug-ars that can glycosylate proteins including lDl-C. When high triglycerides (TG) are also present, small dense lDl-C particles are formed which are more

summaryhyperlipidemia is a silent but deadly risk factor for developing cardiovascular dis-ease (CVd). The combination of hyperlipidemia with other CVd risk factors signifi-cantly increases a patient’s chance for developing CVd. Managed care can have an impact on outcomes related to hyperlipidemia by developing programs to improve screening and treatment to reach appropriate goals.

Key points• although ldl-C is the primary target of therapy, more emphasis is being placed on non-hdl-C which encompasses all the atherogenic lipoproteins.• lifetime risk for developing CVd increases with increasing numbers of risk factors.• Pharmacologic therapy for primary prevention is cost effective if a patient’s esti-mated five-year risk is greater than 8 percent.• despite national guidelines and quality measures, a large number of patients are not achieving appropriate goals.• Managed care can improve outcomes by implementing interventions to help pa-tients identify and reduce their risk factors and achieve appropriate goals.

Hyperlipidemia: The Silent CVD Risk Factor with Enormous Impact

Michael Miller, Md, faCC, fahafor a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.


susceptible to modification. Even at “normal” levels, patients with these three conditions have very ath-erogenic lDl-C.

The combination of high lDl-C and TGs leads to significant risk of CVD.2 The combination is worse than either being elevated alone. This appears to be a result of activated proinflammatory pathways.3 This combined dyslipidemia commonly occurs in patients with type 2 diabetes.

Metabolic syndrome is another risk factor for developing cardiovascular disease. Metabolic syn-drome raises risk of developing type 2 diabetes fivefold and CVD twofold. lifestyle interventions, started early in the metabolic syndrome process, can reverse the elevated risk of disease. A significant number of adolescents in the U.S. have metabolic syndrome. if these young people continue on this path, there is a good chance that they will develop CVD very early in life.

lifetime risk for developing CVD increases with increasing numbers of risk factors. if a patient has optimal risk factors, they will have an estimated 8 percent risk of developing CVD in their lifetime if they are female and 5 percent for male.(Exhibit 1).4 Optimal risk factors are defined as total choles-terol less than 180 mg/dl, blood pressure less than 120/80 mmhg, nonsmoker, and nondiabetic.

All adults should be screened for lipid disorders every five years. There are published screening guidelines for children and adolescents.5 Those with a family history of premature coronary heart disease (<55 in men; < 65 in women) or a cardiovascular risk factor (body mass index > 85th percentile, hyper-

tension, diabetes, or smoking) should be screened. Pharmacologic therapy is recommended in children at least 10 years old when lDl-C is greater than 190 mg/dl or 160 mg/dl with positive family history or two other risk factors after a six-to 12-month trial of dietary management.6 The goal lDl-C is at least less than 130 mg/dl,and optimally it should be re-duced to less than 110 mg/dl. Statins are considered first-line therapy in children and adolescents.

The currently recommended lDl-C goals for adults are shown in Exhibit 2.7 Although we fo-cus on lDl-C, many other lipoproteins are ath-erogenic. These other particles are accounted for in non-hDl-C levels – calculated as total cholesterol minus hDl-C. non–hDl-C is actually superior to lDl-C in predicting ChD risk.8 non-hDl-C values will likely be given greater importance in the next update of the national Cholesterol Education Program (nCEP) guidelines. Under the current guidelines, non–hDl-C is a secondary target for lipid lowering in patients with elevated triglycerides (200 mg/dl or greater) after reaching their lDl-C goal. A patient’s non-hDl-C goal is their lDl-C goal plus 30 mg/dl.

lifestyle factors play an important role in CVD risk. Dietary changes and physical activity are im-portant in reducing risk. Most clinicians do not rec-ommend a diet that has an induction (i.e., starving) stage. Slow gradual weight loss of one to one and a half pounds per week is more likely to result in long-term weight management. The simplest way to lose weight is to reduce caloric intake or increase energy expenditure to add up to a 500 calories per

exhibit 1: lifetime risk for cVd increases with greater risk factor burden4

Optimal risk factors defined as total cholesterol <180 mg/dl, BP <120/<80 mmhg, nonsmoker, and nondiabetic.

Major risk factors are defined as total cholesterol >240 mg/dl, systolic BP >160 mmhg, diastolic BP >100 mmhg, smoker, and diabetic.

CVd = cardiovascular disease; BP = blood pressure.

risk factor Burden at age 50 (estimated risk by age 95)

life

tim

e r

isk

for

CV

d, % 80

70

60

50

40

30

20

10

0 all Optimal >1 Not >1 1 Major >2 Major Optimal elevated

Women

Men

69

8 5

27

36 39

4639

50 50


day reduction.For primary prevention, there is data to suggest

that pharmacologic therapy with statins is cost effec-tive. At generic prices of $1 per day, the initiation of lifetime 40 mg simvastatin daily in the U.S. is cost effective for people aged 40 to 80 years, who have five-year risk of major vascular events of eight or greater.9 When assessing the overall benefit of pri-mary prevention therapies like lipid lowering, there is a move to assess lifetime risk rather than shorter horizons such as 10- and 20-year risk.

A significant number of patients with dyslipidemia are not treated or if treated are not at optimal goals. in the 2011 national Center for Quality Assurance (nCQA) State of health Care Quality report, 40 to 57.2 percent of patients with known cardiovascular disease (secondary prevention) are not at an lDl goal of 100 mg/dl.10 The rate varies by type of plan with commercial hMOs achieving the best control rate.

Managed care can improve outcomes by develop-ing programs which help patients reduce their risk factors, adhere to therapy, and achieve appropriate goals. nurse case managers can be used to help pa-tients reduce their cardiovascular risk and achieve their lipid goals.11 They can facilitate instituting and maintaining lifestyle changes and help patients be adherent with pharmacotherapy.

conclusionhyperlipidemia is a silent disease until the patient

develops cardiovascular disease. it remains prevalent with greater risk in association with co-morbidities such as metabolic syndrome and diabetes. lDl-C reduction remains the primary goal of therapy, but non-hDl-C is getting more attention. Statin ther-apy is cost effective in people with a five-year risk of CVD greater than 8 percent. Managed care can facilitate risk factor modification.

Michael Miller, Md, faCC, faha is a Professor of Medicine in epidemi-

ology and Preventive Medicine at the university of Maryland Medical

Center in Baltimore, Md.

references1. Ford ES, li C, Zhao G, Mokdad Ah. Concentrations of low-density lipopro-

tein cholesterol and total cholesterol among children and adolescents in the

United States. Circulation. 2009;119;1108-15.

2. Barter PJ, Rye KA. is there a role for fibrates in the management of dyslipid-

emia in the metabolic syndrome? Arterioscler Thromb Vasc Biol. 2008;28:39-46.

3. libby P. Fat fuels the flame: triglyceride-rich lipoproteins and arterial inflam-

mation. Circ Res. 2007;100:299-301.

4. lloyd-Jones DM, leip EP, larson MG, et al. Prediction of lifetime risk for

cardiovascular disease by risk factor burden at 50 years of age. Circulation.

2006;113:791–8.

5. Daniels SR, Greer FR; Committee on nutrition. lipid screening and cardio-

vascular health in childhood. Pediatrics. 2008;122:198-208.

6. McCrindle BW, Urbina EM, Dennison BA, et al. Drug therapy of high-risk

lipid abnormalities in children and adolescents: a scientific statement from the

American heart Association Atherosclerosis, hypertension, and Obesity in

youth Committee, Council of Cardiovascular Disease in the young, with the

exhibit 2: adult ldl-c goals7

risk category

Very highChd plus: diabetes, aCs, metabolic

syndrome, or poorly controlledrisk factors

highChd, Chd risk equivalenta

Moderately highfrs of 10%-20%; =2 risk factors

Moderatefrs<10%; =2 risk factors

low0-1 risk factor

ldl-c goalmg/dl

<100<70 (optional)

<100

<130<100 (optional)

<130

<160

a Chd risk equivalent = diabetes, other atherosclerotic disease (e.g., peripheral arterial disease, >50% carotid artery stenosis), 10-year framingham risk

for hard Chd events (nonfatal Mi, Chd death) >20%.

aTP = adult Treatment Panel; NCeP = National Cholesterol education Program; aCs = acute coronary syndromes; frs = framingham risk score (10-

year risk for Mi or Chd death).


Council on Cardiovascular nursing. Circulation. 2007;115:1948-67.

7. Grundy SM, Cleeman Ji, Merz Cn, et al. implications of recent clinical trials

for the national Cholesterol Education Program Adult Treatment Panel iii

guidelines. Circulation. 2004;110:227–39.

8. liu J, Sempos CT, Donahue RP, et al. non-high-density lipoprotein and

very-low-density lipoprotein cholesterol and their risk predictive values in cor-

onary heart disease. Am J Cardiol. 2006;98:1363-8.

9. heart Protection Study Collaborative Group. Statin cost-effectiveness in the

United States for people at different vascular risk levels. Circ Cardiovasc Qual

Outcomes 2009;2:65-72.

10. nCQA. The State of health Care Quality 2011. Available at http://www.

ncqa.org/tabid/1402/Default.aspx?q=State+of+health+Care+Quality. Ac-

cessed 2/19/2012.

11. Ma J, Berra K, haskell Wl, et al. Case management to reduce risk of cardiovas-

cular disease in a county health care system. Arch Intern Med. 2009;169:1988-95.


An ESTiMATED 20 MilliOn AMERiCAnS currently have asthma. The prevalence of asthma has been increasing across all gender, age, and racial groups since the 1980s. The reasons for the increased prevalence are many, including the rise in obesity. Asthma is more common among children, adult women, and African Americans.1

The annual cost of asthma in the U.S. is estimated at $18 billion.1 Of these costs, $10 billion is for direct medical costs, and $8 billion is for lost earnings due to illness or death. Each year, asthma results in two million emergency department visits, 10 million outpatient visits, 500,000 hospitalizations, 15 mil-lion lost workdays due to absenteeism, and 14 mil-lion missed school days. Studies have shown that asthma costs are more than two times higher in those with uncontrolled disease and that these costs rise with increasing asthma severity.2,3

Asthma is responsible for more than 4,000 deaths annually. Although the death rate from asthma has declined slightly over the years, it is still significant.

Current asthma control and morbidity is no better than a decade ago (Exhibit 1).4 Thus, something needs to change about the way we manage asthma.

Over the past 40 years, the treatment of asthma has transitioned from bronchoconstriction as the major problem to inflammation. Asthma is a chronic in-flammatory disease of both the large and small air-ways. inflammation occurs in asthma of all severity levels. The inflammation leads to airway hyper-re-sponsiveness which sets the patient up for acute flares when exposed to triggers such as smoke. nocturnal symptoms are associated with small airway inflam-mation. Over 33 percent of adults and adolescents with asthma experience nocturnal asthma symp-toms. Controlling inflammation is the key to con-trolling the disease and the related costs. Control of inflammation reduces or eliminates bronchospasm.

There are various ways of diagnosing asthma, but pulmonary function testing (PFT) by spirometry is the best method. Unfortunately, most physicians are not doing PFT. Peak flow is the more common

summaryasthma is a chronic inflammatory lung disease for which there are many treatment options. despite good therapies and practice guidelines, morbidity and mortality are still an issue. Much of this could be reduced along with the related costs by improving care through use of pulmonary function tests and managed care medica-tion controls. improved care will require changes in provider and patient behavior.

Key points• asthma is an inflammatory and chronic disease of the entire lung, which can vary over time.• anti-inflammatory medication is essential for long-term control.• disease control also requires management of environmental triggers, lifestyle problems, and concomitant conditions.• Pulmonary function tests should be performed for diagnosis and at follow-up visits to assess control.• small airway inflammation should be considered in all asthmatic patients.• Only small particle inhaled corticosteroids will reach the smallest airways and should be preferred first-line agents.• all moderate and severe asthmatics should have a consultation with a board certi-fied specialist.

Improving Outcomes and Reducing Costs with ICS Monotherapy in the Management of Asthma

dennis spangler, Md for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.


method used, and it is inadequate because it only measures large airway function. it does not give a good measure of total lung function. Peak flow will misdiagnose the control of asthma. One-third of pa-tients will be given a higher asthma severity designa-tion when PFT results are used rather than peak flow.

According to the national Asthma Education and Prevention Program (nAEPP), patients can be di-vided into several disease severity categories on which treatment is based (Exhibit 2).5 Fifty percent of patients with asthma have persistent asthma; of these, 70 percent have mild to moderate disease. Those with mild persistent or worse disease require chronic controller medication. The preferred treat-ment for mild to moderate persistent asthma is in-haled corticosteroid (iCS) monotherapy. The ma-jority of patients can be controlled on iCS monotherapy.

A misconception among physicians is that it is ap-propriate for patients to need to use a short-acting beta agonist (SABA) inhaler on a regular basis. if a patient is using a rescue inhaler for symptoms more than twice weekly or having nightly symptoms more than twice monthly, they are under poor con-trol. Other indicators of poor control include use of greater than two SABA canisters per year, two un-scheduled office visits per year, and two rescue doses of steroids per year. The use of SABA for exercise-induced bronchospasm does not apply when deter-mining if a patient is well controlled. Allowing

chronic poor control leads to deterioration in lung function over time and exacerbations (Exhibit 3). Everyone’s lung function declines with aging, but people with uncontrolled asthma decline at a faster rate. Studies show that patients who have had poor control as children have lung function 20 percent below normal by their 20s.

not only are asthmatics not being adequately con-trolled but many times inappropriate medications are being used for mild disease. Combination thera-py of an iCS and a long-acting beta agonist (lABA) is overused in mild persistent asthma.6,7 in addition to overusing combination therapy, excessive doses of iCS tend to be used. Although there is a place for combination therapy, the extensive use of these agents has not changed asthma-related morbidity or mortality. The formulary process can be used by managed care to reduce this inappropriate use.

in fact, iCS/lABA combinations are no longer indicated for long-term asthma maintenance thera-py. lABAs now have an FDA black box warning because alone they can precipitate severe rapid onset of respiratory failure. lABAs must always be com-bined with an iCS. There are subsets of patients who may actually have worsening of their asthma with use of lABAs even when combined with iCS.

in mild persistent asthma, leukotriene modifiers do not work as well as iCSs to prevent exacerbations.7 They only work about 30 percent of the time and are typically more expensive than iCS monotherapy.

aia=asthma in america survey aiM=asthma insight and Management survey

exhibit 1: asthma Morbidity is no better than a decade ago4

acute care for asthma in the past 12 months (1998–2009)

aia 1998 (n=1788) aiM 2009 (n=2294)

pe

rce

nta

ge

of

pat

ien

ts 4035302520151050

36 34

19 16

7 7

25 26

ho

spit

aliz

ed

ove

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ht

em

erg

ency

roo

m

Oth

erun

sche

dul

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erg

ency

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t

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thes

e


in trying to reduce morbidity, mortality, and costs related to asthma, it is important to understand the cause of recurrent exacerbations in asthma. Recur-rent exacerbations may be related to infections, in-adequate environmental and allergen trigger con-trol, and uncontrolled inflammation.

Air trapping in the small airways after expiration is associated with recurrent asthma exacerbations. Air trapping in the distal small airways leads to greater obstruction. The people with recurrent ex-acerbations – those with many hospital admissions and emergency room visits - have small airway in-flammation that is not being treated.8 This small airway inflammation is not detected by peak flow. On PFT, these patients have increased closing vol-umes and closing capacities compared with patients with similar FEV1 values.

As shown in Exhibit 4, some allergen particles are small enough to reach the smallest airways which can be a cause of small airway inflammation. There are steroid receptors all the way into the smallest airways. Studies have shown that particle size of the iCS does make a difference in lung deposition.9-11 The smaller particles stay aerosolized longer and de-posit less in the mouth and upper airways, even when used without a spacer. Use of small particle iCS has also been shown to reduce markers of in-

flammation greater than larger particles.12 Treating the smallest airways may require use of the iCS with the smallest particle size (ciclesonide [Alvesco®] and beclomethasone hFA [Qvar®]).

There is a misperception in the medical commu-nity that fluticasone (Flovent®) is a more potent in-haler which as a result is the most commonly pre-scribed iCS. A comparison of a small particle iCS (beclomethasone hFA) and fluticasone, which has a larger particle size in moderate to severe asthma, found that PFT parameters and albuterol use signifi-cantly improved with small particle iCS use.13 A lower dose of a small particle iCS can be used. in a real-world trial of fluticasone versus beclometha-sone, the rate of exacerbations was not different, but the beclomethasone patients achieved the same re-sults with a 40 percent lower dose and used less SABA.14 Small particle iCSs have also been shown to reduce air trapping in severe asthma compared with fluticasone.15

Follow-up visits are essential to assess symptom control, adjust medications, and repeat PFTs. Pa-tients are poor judges of how they are doing. PFT need to be done to support what the patient is saying and to assess disease control. Follow-up visits are also a good time to evaluate proper inhaler use, eval-uate treatment adherence, reinforce education, re-

exhibit 2: naepp asthma guidelines for initiation of therapy in adults5

persistent asthma: daily Medication

intermittent Mild Persistent

Moderate Persistent

severe Persistent

sTeP 1

Preferred:saBa PrNa

sTeP 2

Preferred:low-dose iCs

alternative:

Cromolyn, lTra,

Nedocromil,

or Theophylline

sTeP 3

Preferred:Medium-dose

iCs,Or

low-dose iCs+ laBa

alternative:low-dose iCs +

either lTra,Theophylline,

or Zileuton

sTeP 4

Preferred:Medium-dose

iCs + laBa

alternative:

Medium-dose iCs

+ either lTra,

Theophylline,

or Zileuton

sTeP 5

Preferred:high-dose

iCs + laBa

aNd

Consider

Omalizumab

for patients

who have

allergies

sTeP 6

Preferred:high-dose

iCs + laBa +

oral

corticosteroids

aNd

Consider

Omalizumab

for patients

who have

allergies

saBa as needed for symptoms

Clinicians are advised “for patients who have asthma not sufficiently controlledwith a low-dose iCs alone, the step-up option to increase the iCs dose should be

given equal weight to that of the addition of a laBa to iCs”


view environmental controls, and review treatment goals. The importance of weight loss, smoking dis-continuation, and treatment of reflux should be re-inforced. Patient adherence with medications and environmental controls, and management of com-plicating conditions is essential. Complicating con-ditions include reflux, sinusitis, and rhinitis. These can all worsen asthma symptoms. Adherence can be enhanced with oral and written educational materi-als, action plans, and open communication. Patients should be demonstrating their inhaler technique to providers periodically.

All patients with moderate persistent or severe persistent asthma should be seen by a board certified asthma specialist at least for consultation. Once asth-ma control is established, they could return to pri-mary care for continued care but may still need pe-riodic specialist visits. Patients need written plans, and they require step-up therapy if they are not con-trolled. Patients should be seen in two to six weeks after starting therapy. Once control is established, therapy should be stepped down. A step down should take place once asthma is well controlled for three months.5

The costs of asthma depend on the severity of dis-ease, the extent of exacerbations, and the extent of avoidance/control measures.16 Patients with uncon-trolled asthma use a disproportionate share of re-sources, however, even mild persistent asthma is costly.17 Of the medical cost for treating asthma, 50 percent is for rescue or emergency treatment and 33 percent is for medications and regular treatments.18

The iCSs are the least costly of the three major con-troller medications for mild persistent asthma.19

There are several steps that need to be taken to improve asthma care. We need better ways to dis-seminate and get “buy-in” for the nAEPP guide-lines. Patients must be educated on what is “good asthma care”. Additionally, we need to change phy-sician behavior toward asthma. it is not acceptable for a patient to be using a SABA a couple of times a week or to require steroids a couple of times a year. Managed care needs to develop better asthma dis-ease management programs which encourage physi-cians to do pulmonary function testing. The health care system needs to move from disease control to disease modification to disease prevention (more al-lergy care, environment controls, weight loss, etc.). From a scientific standpoint, there needs to be better understanding of the phenotypes of asthma. Addi-tionally, there need to be better tools available for evaluating small airways more effectively.

conclusionAsthma must be treated as an inflammatory disease. iCS monotherapy is the least costly and most effec-tive of the three major controller medications for mild persistent asthma. Although not specified in the current treatment guidelines, based on the evidence a small particle iCS should be the treatment of choice. Managed care could reduce the costs of asth-ma care by reducing overtreatment with combina-tion therapy, encouraging the use of PFTs and small particle iCSs, and educating practitioners on indica-tors of control.

dennis spangler, Md is an assistant Professor at the Medical College

of georgia and is section Co-chair of allergy at Children’s health Care

exhibit 3: asthma and airway remodeling

4.5

4

3.5

3

2.5

2

1.5

1

0.5

0

airway inflammation

remodeling

Chronic Persistentairway Obstruction

and hyperresponsiveness

feV1(l)

age (years)

Normal

asthma

asthma

Normal

20 40 60 80


of atlanta in atlanta, ga.

references1. Asthma and Allergy Foundation of America. Asthma facts and figures. http://

www.aafa.org/display.cfm?id=8&sub=42. Accessed 1/24/2012.

2. Sullivan SD, Rasouliyan l, Russo PA, et al. Extent, patterns, and burden of

uncontrolled disease in severe or difficult-to-treat asthma. Allergy.

2007;62:126-33.

3. Colice G, Wu EQ, Birnbaum h, et al. healthcare and workloss costs associ-

ated with patients with persistent asthma in a privately insured population. J

Occup Environ Med. 2006;48:794-802.

4. 2009 Asthma insight and Management (AiM) Survey. Available at: http://

takingaimatasthma.com/pdf/executive-summary.pdf. Accessed 1/24/2012.

5. national heart, lung, and Blood institute. national Asthma Education and

Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and

Management of Asthma—Full Report 2007. national institutes of health; Au-

gust 28, 2007.

6. Friedman h, Wilcox T, Reardon G, et al. A retrospective study of the use of

fluticasone propionate/salmeterol combination as initial asthma controller ther-

apy in a commercially insured population. Clin Ther. 2008;30:1908-17.

7. American lung Association Asthma Clinical Research Centers, Peters SP,

Anthonisen n, et al. Randomized comparison of strategies for reducing treat-

ment in mild persistent asthma. N Engl J Med. 2007;356:2027-39.

8. in ‘t Veen JC, Beekman AJ, Bel Eh, Sterk PJ. Recurrent exacerbations in

severe asthma are associated with enhanced airway closure during stable epi-

sodes. Am J Respir Crit Care Med. 2000;161:1902-6.

9. Martin RJ. Therapeutic significance of distal airway inflammation in asthma.

J Allergy Clin Immunology. 2002; 109:S447-S460.

10. leach Cl, Davidson PJ, hasselquist BE, Boudreau RJ. lung deposition of

hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocar-

bon fluticasone and chlorofluorocarbon beclomethasone: a cross-over study in

healthy volunteers. Chest. 2002;122:510-16.

11.leach Cl, Bethke TD, Boudreau RJ, et al. Two-dimensional and three-di-

mensional imaging show ciclesonide has high lung deposition and peripheral

distribution: a nonrandomized study in healthy volunteers. J Aerosol Med.

2006;19:117-26.

12. Ohbayashi h. One-year evaluation of the preventative effect of hydrofluo-

roalkane-beclomethasone dipropionate on eosinophilic inflammation of asth-

matic peripheral airways. Respiration. 2007;74:146-53.

13. Aubier M, Wettenger R, Gans SJ. Efficacy of hFA-beclomethasone dipro-

pionate extra-fine aerosol (800 microg day(-1)) versus hFA-fluticasone propio-

nate (1000 microg day(-1)) in patients with asthma. Respir Med. 2001;95:212-20.

14. Price D, Martin RJ, Barnes n, et al. Prescribing practices and asthma con-

trol with hydrofluoroalkane-beclomethasone and fluticasone: a real-world ob-

servational study. J Allergy Clin Immunol. 2010;126:511-8.

15. Thongngarm T, Silkoff PE, Kossack WS, nelson hS. hydrofluoroalkane-

134A beclomethasone or chlorofluorocarbon fluticasone: effect on small air-

ways in poorly controlled asthma. J Asthma. 2005;42:257-63.

16. Colice G, Wu EQ, Birnbaum h, et al. healthcare and workloss costs associ-

ated with patients with persistent asthma in a privately insured population. J

Occup Environ Med. 2006;48(8):794-802.

17. Bootman Jl, Crown Wh, luskin AT. Clinical and economic effects of

suboptimally controlled asthma. Manag Care Interface. 2004;17:31-6.

18. Weiss KB, Sullivan SD. The health economics of asthma and rhinitis. i. As-

sessing the economic impact. J Allergy Clin Immunol. 2001;107:3-8.

19. Colice Gl, yu AP, ivanova Ji, et al. Costs and resource use of mild persistent

asthma patients initiated on controller therapy. J Asthma. 2008;45:293-9.

exhibit 4: small particle allergens and ics reach the smallest airways

Cockroach, dust mite, mold

5.0 µm

rodent, 1.0 µm pet

indoor aeroallergens

Mas

s M

ed

ian

ae

rod

ynam

ic d

iam

ete

r (M

Ma

d)

inhaled corticosteroids

5 µm

4 µm

3 µm

2 µm

1 µm

fluticasone dPi ~4.0 µmBudesonide 4.0 µm

Beclomethasone CfC 3.5 µm

Mometasone dPi 2.6-3.3 µmfluticasone CfC 2.6 µmfluticasone hfa 2.4-2.6 µm

Beclomethasone hfa 1.1 µmCiclesonide 1.0 µm

IMPORTANT SAFETY INFORMATION ContraindicationsDALIRESP is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C).

Warnings and Precautions• DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm.• Prescribers should advise patients, their caregivers, and families to be alert for the emergence or worsening of insomnia, anxiety, depression,

suicidal thoughts or other mood changes, and if such changes occur, to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment if such events occur. Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with DALIRESP. – Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In controlled clinical trials 5.9% of patients

treated with DALIRESP reported psychiatric adverse reactions vs 3.3% treated with placebo. The most common psychiatric adverse reactions were insomnia (2.4% vs 1.0%), anxiety (1.4% vs 0.9%), and depression (1.2% vs 0.9%). Three patients treated with DALIRESP experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) compared to one patient (suicidal ideation) treated with placebo.

• Patients should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated and treatment discontinuation considered. – In addition to weight loss being reported as a common adverse reaction (7.5% of patients treated with DALIRESP vs 2.1% placebo), weight

was prospectively assessed in two 1-year clinical trials. In these studies that compared DALIRESP to placebo, 20% vs 7% experienced moderate weight loss (5-10% of body weight) and 7% vs 2% experienced severe weight loss (>10% body weight). During the follow-up period after discontinuing DALIRESP, the majority of patients regained some of the weight they had lost.

• Use with strong cytochrome P450 enzyme inducers (eg, rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended, as they decrease the exposure and may reduce the therapeutic effectiveness of DALIRESP.

Adverse ReactionsIn clinical trials the most common adverse reactions (≥2% and greater than placebo) were diarrhea (9.5% vs 2.7%), weight loss (7.5% vs 2.1%), nausea (4.7% vs 1.4%), headache (4.4% vs 2.1%), back pain (3.2% vs 2.2%), influenza (2.8% vs 2.7%), insomnia (2.4% vs 1.0%), dizziness (2.1% vs 1.1%), and decreased appetite (2.1% vs 0.4%).

Please also see Brief Summary of full Prescribing Information on reverse side.COPD=chronic obstructive pulmonary disease.

References: 1. DALIRESP (roflumilast) Prescribing Information. Forest Pharmaceuticals, Inc. St. Louis, MO. 2. US Food and Drug Administration. FDA news release. March 1, 2011. http://www.fda.gov/NewsEvents/newsroom/PressAnnouncements/ucm244989.htm. Accessed November 16, 2011. 3. Data on file. Forest Laboratories, Inc. 4. Calverley PMA, Rabe KF, Goehring U-M, Kristiansen S, Fabbri LM, Martinez FJ; for the M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685-694. 5. US Food and Drug Administration. Atrovent approval history (NDA 019085, 1986). Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed November 16, 2011.

For patients with severe COPD associated with chronic bronchitis and a history of exacerbations

DALIRESP is a registered trademark of Nycomed GmbH.© 2012 Forest Laboratories, Inc. 84-12000159 03/12

DALIRESP® is the first and only selective PDE4 inhibitor to reduce the risk of COPD exacerbations1,2

• Reduces moderate or severe exacerbations by 17% vs placebo1,3,4

• Effective alone or in combination with a bronchodilator1,3

�• Effective in older and younger patients (>65 and 40-65 years)1,3

• Statistically significant increase in lung function (pre-bronchodilator FEV1) of 48 mL vs placebo1,4

– DALIRESP is not a bronchodilator; this increase was not clinically significant1,3

• The first class of drugs approved for COPD in 25 years2,5

INDICATIONS AND USAGEDALIRESP is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.

Learn more at Booth #125

This file has been prepared by

Pub: Various Trim: VariousColor: 4/C Bleed: 8.75’’ x 11.25’’

LPI: Live: 7” x 10”Material Due Date: Job: FLDX11171D

DALIRESP® (roflumilast) tablets Rx OnlyBrief Summary of Full Prescribing InformationInitial U.S. Approval: 2011

INDICATIONS AND USAGEDALIRESP® is indicated as a treatment to reduce the risk of COPDexacerbations in patients with severe COPD associated with chronicbronchitis and a history of exacerbations.Limitations of UseDALIRESP is not a bronchodilator and is not indicated for the reliefof acute bronchospasm.

CONTRAINDICATIONSThe use of DALIRESP is contraindicated in the following conditions:Moderate to severe liver impairment (Child-Pugh B or C) [seeClinical Pharmacology (12.3)and Use in Special Populations (8.6)].

WARNINGS AND PRECAUTIONSTreatment of Acute BronchospasmDALIRESP is not a bronchodilator and should not be used for therelief of acute bronchospasm.Psychiatric Events including SuicidalityTreatment with DALIRESP is associated with an increase in psychi-atric adverse reactions. In 8 controlled clinical trials 5.9% (263) ofpatients treated with DALIRESP 500 mcg daily reported psychiatricadverse reactions compared to 3.3% (137) treated with placebo.The most commonly reported psychiatric adverse reactions wereinsomnia, anxiety, and depression which were reported at higherrates in those treated with DALIRESP 500 mcg daily (2.4%, 1.4%,and 1.2% for DALIRESP versus 1.0%, 0.9%, and 0.9% for placebo,respectively) [see Adverse Reactions (6.1)]. Instances of suicidalideation and behavior, including completed suicide, have beenobserved in clinical trials. Three patients experienced suicide-relatedadverse reactions (one completed suicide and two suicide attempts)while receiving DALIRESP compared to one patient (suicidalideation) who received placebo.Before using DALIRESP in patients with a history of depressionand/or suicidal thoughts or behavior, prescribers should carefullyweigh the risks and benefits of treatment with DALIRESP in suchpatients. Patients, their caregivers, and families should be advisedof the need to be alert for the emergence or worsening of insomnia,anxiety, depression, suicidal thoughts or other mood changes,and if such changes occur to contact their healthcare provider.Prescribers should carefully evaluate the risks and benefits of con-tinuing treatment with DALIRESP if such events occur.Weight DecreaseWeight loss was a common adverse reaction in DALIRESP clinicaltrials and was reported in 7.5% (331) of patients treated withDALIRESP 500 mcg once daily compared to 2.1% (89) treated withplacebo [see Adverse Reactions (6.1)]. In addition to being reportedas adverse reactions, weight was prospectively assessed in twoplacebo-controlled clinical trials of one year duration. In these stud-ies, 20% of patients receiving roflumilast experienced moderateweight loss (defined as between 5-10% of body weight) comparedto 7% of patients who received placebo. In addition, 7% of patientswho received roflumilast compared to 2% of patients receivingplacebo experienced severe (>10% body weight) weight loss.During follow-up after treatment discontinuation, the majority ofpatients with weight loss regained some of the weight they had lostwhile receiving DALIRESP. Patients treated with DALIRESP shouldhave their weight monitored regularly. If unexplained or clinicallysignificant weight loss occurs, weight loss should be evaluated, anddiscontinuation of DALIRESP should be considered.Drug InteractionsA major step in roflumilast metabolism is the N-oxidation ofroflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. Theadministration of the cytochrome P450 enzyme inducer rifampicinresulted in a reduction in exposure, which may result in a decreasein the therapeutic effectiveness of DALIRESP. Therefore, the useof strong cytochrome P450 enzyme inducers (e.g. rifampicin,phenobarbital, carbamazepine, phenytoin) with DALIRESP is notrecommended. [see Drugs That Induce Cytochrome P450 (CYP)Enzymes (7.1) and Clinical Pharmacology (12.3)].

ADVERSE REACTIONSThe following adverse reactions are described in greater detail inother sections:

• Psychiatric Events Including Suicidality [see Warnings andPrecautions (5.2)]

• Weight Decrease [see Warnings and Precautions (5.3)]Adverse Reactions in Clinical StudiesBecause clinical trials are conducted under widely varying condi-tions, adverse reaction rates observed in the clinical trials of a drugcannot be directly compared to rates in the clinical trials of anotherdrug and may not reflect the rates observed in practice.The safety data described below reflect exposure of 4438 patients toDALIRESP 500 mcg once daily in four 1-year placebo-controlled tri-als, two 6-month placebo-controlled trials, and two 6-month drugadd-on trials [see Clinical Studies (14.1)]. In these trials, 3136 and1232 COPD patients were exposed to DALIRESP 500 mcg once dailyfor 6 months and 1-year, respectively.

The population had a median age of 64 years (range 40-91), 73%were male, 92.9% were Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) of8.9 to 89.1% predicted. In these trials, 68.5% of the patients treatedwith DALIRESP reported an adverse reaction compared with 65.3%treated with placebo.The proportion of patients who discontinued treatment due toadverse reaction was 14.8% for DALIRESP-treated patients and9.9% for placebo-treated patients. The most common adversereactions that led to discontinuation of DALIRESP were diarrhea(2.4%) and nausea (1.6%).Serious adverse reactions, whether considered drug-related or notby the investigators, which occurred more frequently in DALIRESP-treated patients include diarrhea, atrial fibrillation, lung cancer,prostate cancer, acute pancreatitis, and acute renal failure.Table 1 summarizes the adverse reactions reported by ≥ 2% ofpatients in the DALIRESP group in 8 controlled COPD clinical trials.

Table 1: Adverse Reactions Reported by ≥ 2% of PatientsTreated with DALIRESP 500 mcg daily and Greater Than Placebo

TreatmentAdverse Reactions DALIRESP Placebo(Preferred Term) (N=4438) (N=4192)

n (%) n (%)Diarrhea 420 (9.5) 113 (2.7)Weight decreased 331 (7.5) 89 (2.1)Nausea 209 (4.7) 60 (1.4)Headache 195 (4.4) 87 (2.1)Back pain 142 (3.2) 92 (2.2)Influenza 124 (2.8) 112 (2.7)Insomnia 105 (2.4) 41 (1.0)Dizziness 92 (2.1) 45 (1.1)Decreased appetite 91 (2.1) 15 (0.4)Adverse reactions that occurred in the DALIRESP group at afrequency of 1 to 2% where rates exceeded that in the placebo groupinclude:Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis,vomitingInfections and infestations - rhinitis, sinusitis, urinary tract infection,Musculoskeletal and connective tissue disorders - muscle spasmsNervous system disorders - tremorPsychiatric disorders - anxiety, depression

DRUG INTERACTIONSA major step in roflumilast metabolism is the N-oxidation ofroflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 [seeClinical Pharmacology (12.3)].Drugs That Induce Cytochrome P450 (CYP) EnzymesStrong cytochrome P450 enzyme inducers decrease systemicexposure to roflumilast and may reduce the therapeutic effective-ness of DALIRESP. Therefore the use of strong cytochrome P450inducers (e.g., rifampicin, phenobarbital, carbamazepine, and pheny-toin) with DALIRESP is not recommended [see Drug Interactions(5.4) and Clinical Pharmacology (12.3)].Drugs That Inhibit Cytochrome P450 (CYP) EnzymesThe co-administration of DALIRESP (500 mcg) with CYP3A4inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine,enoxacin, cimetidine) may increase roflumilast systemic exposureand may result in increased adverse reactions. The risk of suchconcurrent use should be weighed carefully against benefit. [seeClinical Pharmacology (12.3)].Oral Contraceptives Containing Gestodene and Ethinyl EstradiolThe co-administration of DALIRESP (500 mcg) with oral contracep-tives containing gestodene and ethinyl estradiol may increaseroflumilast systemic exposure and may result in increased sideeffects. The risk of such concurrent use should be weighedcarefully against benefit [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONSPregnancyTeratogenic effects: Pregnancy Category C: There are no adequateand well controlled studies of DALIRESP in pregnant women.DALIRESP was not teratogenic in mice, rats, or rabbits. DALIRESPshould be used during pregnancy only if the potential benefitjustifies the potential risk to the fetus.DALIRESP induced stillbirth and decreased pup viability in miceat doses corresponding to approximately 16 and 49 times, respec-tively, the maximum recommended human dose (MRHD) (ona mg/m2 basis at maternal doses > 2 mg/kg/day and 6 mg/kg/day,respectively). DALIRESP induced post-implantation loss in rats atdoses greater than or equal to approximately 10 times the MRHD(on a mg/m2 basis at maternal doses ≥ 0.6 mg/kg/day). No treat-ment-related effects on embryo-fetal development were observedin mice, rats, and rabbits at approximately 12, 3, and 26 times theMRHD, respectively (on a mg/m2 basis at maternal doses of 1.5,0.2, and 0.8 mg/kg/day, respectively).Nonteratogenic effects: DALIRESP has been shown to adverselyaffect pup post-natal development when dams were treated with thedrug during pregnancy and lactation periods in mice. These studies

found that DALIRESP decreased pup rearing frequencies at approx-imately 49 times the MRHD (on a mg/mg2 basis at a maternal doseof 6 mg/kg/day) during pregnancy and lactation. DALIRESP alsodecreased survival and forelimb grip reflex and delayed pinnadetachment in mouse pups at approximately 97 times the MRHD(on a mg/m2 basis at a maternal dose of 12 mg/kg/day) duringpregnancy and lactation.Labor and DeliveryDALIRESP should not be used during labor and delivery. There areno human studies that have investigated effects of DALIRESP onpreterm labor or labor at term; however, animal studies showed thatDALIRESP disrupted the labor and delivery process in mice.DALIRESP induced delivery retardation in pregnant mice at dosesgreater than or equal to approximately 16 times the MRHD (on amg/m2 basis at a maternal dose of > 2 mg/kg/day).Nursing MothersRoflumilast and/or its metabolites are excreted into the milk oflactating rats. Excretion of roflumilast and/or its metabolites intohuman milk is probable. There are no human studies that haveinvestigated effects of DALIRESP on breast-fed infants. DALIRESPshould not be used by women who are nursing.Pediatric UseCOPD does not normally occur in children. The safety and effective-ness of DALIRESP in pediatric patients have not been established.Geriatric UseOf the 4438 COPD subjects exposed to DALIRESP for up to 12months in 8 controlled clinical trials, 2022 were > 65 years of ageand 471 were > 75 years of age. No overall differences in safety oreffectiveness were observed between these subjects and youngersubjects and other reported clinical experience has not identifieddifferences in responses between the elderly and younger patients,but greater sensitivity of some older individuals cannot be ruled out.Based on available data for roflumilast, no adjustment of dosage ingeriatric patients is warranted [see Clinical Pharmacology (12.3)].Hepatic ImpairmentRoflumilast 250 mcg once daily for 14 days was studied in subjectswith mild-to-moderate hepatic impairment classified as Child-PughA and B (8 subjects in each group). The AUCs of roflumilast androflumilast N-oxide were increased by 51% and 24%, respectivelyin Child-Pugh A subjects and by 92% and 41%, respectively in Child-Pugh B subjects, as compared to age-, weight- and gender-matchedhealthy subjects. The Cmax of roflumilast and roflumilast N-oxidewere increased by 3% and 26%, respectively in Child-Pugh Asubjects and by 26% and 40%, respectively in Child-Pugh Bsubjects, as compared to healthy subjects. DALIRESP 500 mcg hasnot been studied in hepatically impaired patients. Clinicians shouldconsider the risk-benefit of administering DALIRESP to patients whohave mild liver impairment (Child-Pugh A). DALIRESP is notrecommended for use in patients with moderate or severe liverimpairment (Child-Pugh B or C) [see Contraindications (4) andClinical Pharmacology (12.3)].Renal ImpairmentIn twelve subjects with severe renal impairment administered asingle dose of 500 mcg roflumilast, the AUCs of roflumilast androflumilast N-oxide were decreased by 21% and 7%, respectivelyand Cmax were reduced by 16% and 12%, respectively. No dosageadjustment is necessary for patients with renal impairment [seeClinical Pharmacology (12.3)].

OVERDOSAGEHuman ExperienceNo case of overdose has been reported in clinical studies withDALIRESP. During the Phase I studies of DALIRESP, the followingsymptoms were observed at an increased rate after a single oraldose of 2500 mcg and a single dose of 5000 mcg: headache,gastrointestinal disorders, dizziness, palpitations, lightheadedness,clamminess and arterial hypotension.Management of OverdoseIn case of overdose, patients should seek immediate medical help.Appropriate supportive medical care should be provided. Sinceroflumilast is highly protein bound, hemodialysis is not likely to bean efficient method of drug removal. It is not known whetherroflumilast is dialyzable by peritoneal dialysis.Manufactured by:Nycomed GmbH.Production Site OranienburgLehnitzstrasse 70 – 9816515 OranienburgGermanyManufactured for:Forest Pharmaceuticals, Inc.Subsidiary of Forest Laboratories, Inc.St. Louis, MO 63045, USADaliresp® is a registered trademark of Nycomed GmbH.© 2010, 2011 Forest Laboratories, Inc.084-12000414-BS-RMC17137-SEP11Please also see full Prescribing Information at www.daliresp.com.


GiVEn OUR POPUlATiOn’S inCREASinG weight and age, diabetes is a growing problem in the U.S. The prevalence of diabetes increases with age, with the highest rates in those over 65 (Exhibit 1).1 The highest number of new cases are in the 45 to 65 age group. Some of the current controversies in the manage-ment of diabetes include appropriate goals and med-ications. As new studies are published, managed care and providers must make decisions on whether prac-tice needs to change. ACCORD is an example of a newer study which had a significant impact on care.2 This study in type 2 diabetes found that the use of intensive therapy to target normal glycated hemoglobin (A1C) levels for 3.5 years increased mortality and did not signifi-cantly reduce major cardiovascular events. The au-thors concluded that these findings identify a previ-

ously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. The important thing to understand about this study is the subjects were older patients with pre-existing heart disease. The study attempted to achieve near normal glycemic control (A1C of 6%) compared to standard (A1C < 7%). in older patients with pre-existing heart disease, an A1C of less than 7 is an appropriate goal but the A1C should not be reduced to near normal based on the results of the ACCORD study.

Several controversies related to diabetes medica-tions have occurred in the past few years. Data on rosiglitazone (Avandia) increasing risk of heart at-tacks and heart failure is just one example. This has led to significantly reduced use of rosiglitazone.

Several studies have linked insulin use to increased risk for developing cancer.3-5 Other studies have not

summaryalthough there are many aspects of diabetes management, glucose control has been the most controversial in recent years. as new studies are published, managed care, clinicians and patients have questions on how management of diabetes should change.

Key points• in older patients with pre-existing heart disease, an a1C of less than 7 is an ap-propriate goal, but a1C should not be reduced to near normal based on the results of the action to Control Cardiovascular risk in diabetes (aCCOrd) study.• Metformin is initiated at the time of diagnosis unless a contraindication is present.• all the available oral agents have similar efficacy when used as second-line medi-cations. • The choice of a second-line agent will depend on patient factors, adverse effects, convenience, and costs.

Updates and Controversies in Diabetes CareTom a. elasy, Md, MPh



shown a link.6 The publication of these studies re-sulted in a flood of emails and calls to many man-aged care medical directors. At this time, it is un-known whether this is a true effect of the medication or the underlying disease is the reason for possible increased risk.

in addition to ongoing controversies about medi-cations, there are many challenges to managing pa-tients with type 2 diabetes. The one challenge that gets the least press is time. Primary care providers do not have enough time to implement the current U.S. preventive service guidelines much less to manage acute problems.7 The health care system needs to get out of the mode of the doctor being responsible for everything during a visit. We need to determine a way to utilize other health care provid-ers to provide the needed services.

The other aspects of diabetes management are im-portant but are not as hard or controversial as glu-cose management. Because the major killer of pa-tients with diabetes is heart disease, other cardiovascular risk factors including hypertension and lipids need to be tightly controlled.

To manage glucose, the majority of patients are being treated with oral agents (Exhibit 2).1 The American Diabetes Association (ADA) guidelines recommend metformin as the initial therapy at the time of diagnosis unless a contraindication is pres-ent. The recommendations were changed a few years ago to immediately initiate medication rather than giving the patient three to six months to lose weight and exercise.

The efficacy of oral agents as monotherapy depends on the baseline A1C – the higher the baseline A1C, the greater the reduction. On average, oral agents re-sult in a 1 to 2 percent reduction in A1C. Mono-therapy fails in the majority of patients either initially because the A1C was excessively high or in the long term given the progressive nature of the disease.

When monotherapy fails, addition of a second agent generally has an additive effect with a net ad-ditional decline in A1C of 1 to 2 percent. Most pa-tients will require at least two medications to achieve control.

The data are uncertain as to what is the most ap-propriate second-line agent. As of now, there are no known clear efficacy differences for second-line agents. Because the efficacy of all the oral agents as second-line agents is similar, the distinguishing fac-tors between agents are patient factors, adverse ef-fects, convenience, and cost. The two main issues for adverse effects are weight gain and hypoglycemia.

incretin agents are a relatively new area of thera-py. incretins are gut hormones that enhance insulin secretion in response to food (i.e., glucose-depen-dent insulin secretion). Glucagon like peptide (GlP-1) is the most well-characterized incretin that is secreted from l cells of the intestines. GlP-1 se-cretion is diminished in type 2 diabetes. The incre-tin agents are secretogogues which only work in the presence of food so they result in a lower incidence of hypoglycemia compared with the sulfonylureas. Typically, hypoglycemia does not occur at all if they are used as monotherapy. These agents also lead to

20-44 45-64 >65

age group

exhibit 1: estimated percentage of people aged 20 years or older with diagnosed and undiagnosed

diabetes, by age group, united states, 2005-20081

3.7%

13.7%

26.9%


modest weight loss by increasing satiety. This lower rate of the two adverse effects of most concern has lead to wide use of these agents. Exenatide (Byetta®) was first to market, followed by liraglutide (Victo-za®). These are widely prescribed injectables that are indicated as adjuncts to other medications. Many more of these are under study and likely to make it to market.

The other incretin agents are the dipeptidyl pepti-dase inhibitors (DPP-iV) inhibitors, which work by inhibiting the enzyme that degrades naturally oc-curring GlP-1. Sitagliptin ( Januvia®) was first to market with saxagliptin (Onglyza®) being the sec-ond agent. These agents have few adverse effects and are weight neutral. These are oral agents with once daily dosing. Many more DPP-iV agents are also likely to come to market.

Many patients with type 2 diabetes will require insulin therapy. An important point with insulin therapy is it is a two-step process. Therapy should be initiated and then intensified. Addition of insulin, as a second agent or third agent, is often achieved by adding bedtime nPh, glargine, or detemir. All of these forms of long-acting insulin are effective in reducing A1C by at least an additional 2 percent.

conclusionSeveral new options for therapy of type 2 diabetes have become available in recent years. More of these are to come. First-line therapy for patients with type 2 diabetes is metformin. in developing guidelines for second-line medications, all the available oral

agents have similar efficacy. The choice of agent will depend on patient factors, adverse effects, conve-nience, and costs. Because new studies are consis-tently being published, managed care management guidelines will require frequent updating.

tom a. elasy, Md, MPh is the Medical director of the Vanderbilt

eskind diabetes Clinic at Vanderbilt university Medical Center in

Nashville, TN.

references1. national Center for health Statistics. 2005–2008 national health and nutri-

tion Examination Survey. Available at http://www.cdc.gov/nchs/nhanes.htm.

Accessed 1/26/2012.

2. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein

hC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes.

N Engl J Med. 2008;358:2545-59.

3. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies

on cancer risk in type 2 diabetes. Diabetologia. 2009;52:1766-77.

4. hemkens lG, Grouven U, Bender R, et al. Risk of malignancies in patients

with diabetes treated with human insulin or insulin analogues: a cohort study.

Diabetologia. 2009;52:1732-44.

5. Colhoun hM; SDRn Epidemiology Group. Use of insulin glargine and

cancer incidence in Scotland: a study from the Scottish Diabetes Research net-

work Epidemiology Group. Diabetologia. 2009;52:1755-65.

6. Ruiter R, Visser lE, van herk-Sukel MP, et al. Risk of cancer in patients on

insulin glargine and other insulin analogues in comparison with those on hu-

man insulin: results from a large population-based follow-up study. Diabetologia.

2012;55:51-62.

7. yarnall KS, Pollak Ki, Østbye T, , et al. Primary care: is there enough time

for prevention? Am J Public Health. 2003;93:635-41.

exhibit 2: percentage of adults with diagnosed diabetes receiving treatment with insulin or oral medication,

united states, 2007-20091

58% 14%

12%16%

insulin only

insulin and oral medication

Oral medication only

No medication


backgroundTRiSOMiES 21 (DOWn SynDROME, T21), 18 (Edwards syndrome, T18), and 13 (Patau syndrome, T13) are the most common live born aneuploidies (serious conditions caused by extra chromosomes).1 Trisomy 21 is the most frequently occurring of the three, occurring in, on average, one of every 740 live births, though incidence increases with mater-nal age.2 The average life expectancy for T21 indi-viduals is 50 years. it is the leading cause of cogni-

tive impairment and affected persons also have a higher incidence of other health conditions includ-ing congenital heart disease, hearing, intestinal, and eye problems, celiac disease, leukemia, and thyroid dysfunction.3

Trisomy 18 occurs in about one in 5,000 live births,4 though, like T21, incidence increase with maternal age. Due to the presence of several life-threatening medical problems, many infants with trisomy 18 die within their first month and as few as

summarybackground: since 2007, the american College of Obstetricians and gynecologists (aCOg) has recommended that all pregnant women be offered prenatal screening for fetal aneuploidy (i.e., trisomies 21, 18, 13). Current screening options include tests with sub-optimal sensitivity and specificity rates, while diagnostic procedures are invasive and create risk of procedure related miscarriage. The verifi™ test, a non-invasive test using circulating cell-free dNa (cfdNa), extracted from a mater-nal blood sample as early as 10 weeks gestation has demonstrated comparable sen-sitivity and superior specificity to invasive diagnostics in detecting fetal aneuploidy in chromosomes 21, 18, and 13. Methods: a cost-model was developed to evaluate the impact of incorporating this prenatal test into routine high-risk maternal screening practice. The multi-stage transition probability model leveraged published cost estimates from Medicare as well as practice patterns and disease rates from published literature. results: The model demonstrates that inclusion of the verifi™ prenatal test pro-vides clear clinical benefits. These include a 66 percent reduction in invasive diag-nostic induced miscarriages and 38 percent more women receiving a T21 diagnosis. Total costs for prenatal screening and diagnosis for fetal aneuploidies are reduced by 1 percent annually. conclusion: significant clinical and cost advantages are likely to occur when novel non-invasive prenatal screening tests with high sensitivity and specificity are incor-porated into routine high-risk screening practice.

Key points• high sensitivity and specificity non-invasive prenatal testing has the potential to reshape the prenatal testing paradigm.• When offered to women following a positive result from a screening test, these tests reduce the need for invasive testing.• The reduction in use of invasive prenatal testing reduces number of procedure induced miscarriages and may reduce total costs of prenatal care.

Clinical and Cost Consequences of Incorporating a Novel Non-Invasive

Prenatal Test into the Diagnostic Pathway for Fetal Trisomies

susan s. garfield, drPh; shannon O. armstrong, Ba


5 percent survive until their first birthday.4 The con-dition is associated with severe physical and cogni-tive disabilities including severe intellectual disabil-ity, heart defects and other major organ abnormalities, and low birth weight.4

less common, trisomy 13 occurs in approximately one in 7,000 to 10,000 live births, likewise increas-ing with maternal age.5,6 Similar to trisomy 18, most infants with trisomy 13 die within the first seven days of life due to severe anatomic abnormalities, and 91 percent of trisomy 13-affected infants die be-fore their first birthday.7 This condition is associated with severe physical and cognitive disabilities in-cluding cleft lip or palate, clenched hands and poly-dactyl, decreased muscle tone, hernias, severe cog-nitive defects, seizures, and microcephaly.6 in addition to the above characteristics, infants with trisomy 13 may have a single umbilical artery at birth which can be a sign of congenital heart defects such as abnormal heart placement, atrial or ventric-ular septal defect, and patent ductus arteriosus.6

Though rare, each of these trisomies creates dif-ferent degrees of complications for the infant, in-cluding high infant mortality with T18 and T13. Due to a host of health concerns associated with an-euploidies, knowledge of fetal status can help clini-cians and parents plan for appropriate care.

Since 2007, the American College of Obstetricians and Gynecologists (ACOG) has recommended all pregnant women be offered prenatal screening for fetal aneuploidy (i.e., trisomies 21,18,13). Technolo-

gies currently used for routine screening include ma-ternal serum screening (first and/or second trimester) and measurement of nuchal translucency by ultra-sound (nT testing, first trimester). Second trimester ultrasound exam of the fetus is also used to detect anatomic abnormalities associated with these condi-tions and adds information to overall fetal assessment.

While these screening modalities are useful in identifying pregnancies at elevated risk for fetal an-euploidy, they are not diagnostic and their sensitiv-ity and specificity along with high screen positive rates lead to a significant number of false positives and, consequently, the possibility of unnecessary in-vasive diagnostic procedures.8,9,10 The trisomy 21 detection rate for first trimester combined screening is approximately 77 to 86 percent and is associated with a false positive rate of 3.2 to 5.6 percent.8 Sec-

exhibit 2: t21 incidence at birth23

Maternal age

under 30 years old

30-34 years old

35-39 years old

40-44 years old

45-49 years old

incidence at birth

0.0753%

0.1532%

0.5441%

1.8226%

3.2794%

exhibit 1: Model inputs and outputs

Model inputs

Test specific reimbursement rates

Test specific acceptance rates differentiated bynormal and high risk patients

age breakdown of pregnant cohort

Test specific performance characteristics(sensitivity and specificity)

Miscarriage rates, by aneuploidy

aneuploidy prevalence by age

invasive diagnostic induced miscarriage rates

invasive diagnostic testing practice following initialpositive screening result

Model outputs

Total costs for prenatal screening and diagnosis ofaneuploidies

Total costs by testing modality (trip/quad screen,ultrasound, amnio, CVs, verifi™ test)

invasive procedures (amnio and CVs) rates

Miscarriage rates and costs

early identification of fetal aneuploidy rates

Total number of each testing modality (firsttrimester screening tests, trip/quad screen,ultrasound, amnio, CVs, verifi™ test)Total diagnosed aneuploidies (T21, T18, T13)

amnio rate per diagnosed aneuploidy

Cost per diagnosed aneuploidy


ond trimester serum screening and sequential screenings are associated with a higher detection rate (85 percent and 94 percent, respectively), but also an increased rate of false positive results (8.5 percent and 11 percent).8

invasive diagnostic testing, such as chorionic villus sampling (CVS) in first trimester or amniocentesis in second trimester, often follows a positive screening test in order to confirm the results. however, these tests carry increased risk to both the pregnant wom-an and fetus, including an increased risk of miscar-riage. While point estimates vary, data from several systematic reviews, randomized controlled trials, and national registry studies suggest a procedure-re-lated miscarriage rate of approximately 0.5 to 1 per-cent following amniocentesis or CVS.11,12,13,14

While 95 percent of obstetricians report routinely offering screening to all pregnant patients,15 not all women with a positive screening result elect to pur-sue invasive testing; and some with negative screen-ing results still seek invasive testing. Uptake esti-mates of invasive diagnostic testing following a positive serum screen vary, with most studies re-porting rates of approximately 60 percent.16,17,18,19 The reasons for not having an invasive diagnostic procedure vary, but a high percentage of women re-port that fear of complications impact their deci-

sions. in contrast, a small proportion of women whose pregnancies are determined to be low risk for fetal aneuploidies elect to undergo additional test-ing, despite the associated increased risk of miscar-riage. Most of these women are found to have fe-tuses with normal chromosomes (or karyotypes).

There is a clear unmet need for accurate, safe, non-invasive prenatal diagnostic technologies that allow for early diagnosis of fetal aneuploidies to pro-vide more accurate information to pregnant women and their clinicians. Recent technological advances have spawned the development of novel prenatal di-agnostic tests which are now poised to change the clinical and economic landscape of prenatal testing.

Specifically, technologies incorporating the analy-sis of circulating cell-free DnA (cfDnA) extracted from a maternal blood sample as early as 10 weeks gestation have received widespread interest from the medical community and from women.20,21 These di-agnostics have the potential to revolutionize prenatal testing by providing substantially more accurate re-sults and reducing or eliminating the need for inva-sive procedures and their associated risk of fetal loss.

One recently commercialized non-invasive prena-tal test that uses maternal whole blood from a single blood draw to detect aneuploidy in chromosomes 21, 18, and 13 by massively parallel DnA sequencing

exhibit 3: test performance rates

test

1st Trimester combined screenfor T21 (serum plus NT)

1st trimester combined (serumplus NT) screen for T18

2nd Trimester serum screen forT21 in women <35 years old

2nd Trimester serum screen forT21 in women <35 years old

2nd Trimester serum screen forT18 in women < 35 years old

2nd Trimester serum screen forT18 in women >35 years old

2nd Trimester ultrasound T21



CVs

amniocentesis

sensitivity

81%24

89%24

76.64%24

91.14%24

55%24

55%24

79.9%26

83%27

91%28

99.25%29

99.4%30

specificity

94.1%10

99%25

95.15%24

88.9%24

99%24

99%24

93.3%26

99%27

99%28

98.65%29

99.5%30


maternal plasma DnA22 is the verifiTM prenatal test (Verinata health inc., Redwood City, CA). The blood sample is obtained by routine peripheral veni-puncture, and the plasma is then separated from the blood cells. Total DnA in the plasma is then extract-ed, with the resulting mixture containing cfDnA of both maternal and fetal origin. Massively parallel se-quencing (MPS) of DnA is then performed to gen-erate millions of DnA sequence tags which are then aligned with a reference genome DnA sequence and undergo analysis with a proprietary algorithm to yield an aneuploidy classification for the sample for the chromosomes of interest (e.g., 21, 18, and 13). The result, provided within eight to 10 business days of obtaining a blood sample, is reported. The test can be done as early as ten weeks gestation.

The MatErnal Blood iS Source to Accurately Di-agnose Fetal Aneuploidy (MEliSSA) study was de-signed to demonstrate the performance of the veri-fiTM test (clinicaltrials.gov identifier nCT01122524). The MEliSSA study enrolled patients with pregnan-cies at high risk for fetal aneuploidy due to at least one of the following factors: advanced maternal age (38 years of age or older in this study), a positive re-sult from a serum screening test, soft or hard markers from ultrasound associated with fetal aneuploidy (e.g., increased nT thickness, cystic hygroma, con-genital anomaly or amniotic fluid anomaly), or pre-vious aneuploidy pregnancy. Blood samples were ob-tained from 2,882 women prior to their undergoing invasive prenatal diagnostic procedures at 60 sites in the United States. All singleton pregnancies with any abnormal karyotype and a random complement of subjects with euploid (normal chromosome number) karyotypes were selected by an independent biostat-istician for analysis in a prospective, blinded fashion. independent classifications of aneuploidy status were made for each sample, namely: chromosome 21,

chromosome 18, and chromosome 13 as affected or unaffected. These classifications were then compared to the corresponding fetal karyotype by the indepen-dent biostatistician to determine performance of the verifiTM test. Within the analysis cohort of 532 sam-ples, the test correctly identified 89 of 89 (100 per-cent; 95 percent Ci 95.9-100.0) cases of trisomy 21, 35 of 36 (97.2 percent; 95 percent Ci 85.5-99.9) cas-es of trisomy 18, and 11 of 14 (78.6 percent; 95 per-cent Ci 49.2-99.9) cases of trisomy 13. There were no false positives (specificity = 100 percent).21

Based on the clinical results obtained from the MEliSSA study, an economic model was developed to evaluate the cost consequences of practice change given the results found in the study, if the test were incorporated into standard of care. The model de-tails the expected clinical and economic impact of incorporating this test into routine clinical practice for high-risk pregnancies. The impact of test adop-tion was modeled using cost and assigned test per-formance variables from the MEliSSA trial as well as accepted medical evidence in the field of prenatal screening and diagnosis. The model followed prac-tice patterns of having positive test results followed by an invasive procedure to verify the results.

MethodologyBridgehead developed a detailed transition state probability model in Microsoft Excel that captures the complex screening and diagnostic paradigm from both a cost and clinical practice perspective. The model takes theoretical cohort of 100,000 preg-nant women at high risk for fetal aneuploidy based on either first or second trimester screening and as-sesses expected cost and clinical impact the intro-duction of the verifiTM test for Trisomy 21, 18, and 13 will have as compared to current practice. The model inputs and outputs are detailed in Exhibit 1.

exhibit 4: cost inputs

test estimated cost

1st Trimester combined screen $378.50

2nd Trimester serum screen $117.96

2nd Trimester ultrasound exam of fetus $330.18

Chorionic Villus sampling $1,669.98

amniocentesis $1,386.76

verifi™ prenatal test cost $1,200


The model divides the cohort into two groups by inherent risk, and each group proceeds through a theoretical pregnancy chronologically. Women may begin prenatal care in either the first or second tri-mester. it was assumed that 81 percent of women begin their prenatal care in the first trimester. The first testing point offered is the first trimester screen. Under the standard of care, women with a positive from the first trimester screen may be offered either an immediate CVS or a second trimester amniocen-tesis. With verifiTM testing, women may receive ei-ther an immediate verifiTM test or CVS or a second trimester amniocentesis. Positives from the verifiTM test in the first trimester were eligible to receive ei-ther CVS or amniocentesis. it was assumed, using published miscarriage rates for each trisomy, that some true positive from the first trimester would miscarry before the second trimester amniocentesis.

At the conclusion of the first trimester, all women who had not previously received first trimester screening are offered the second trimester serum screen. Positives from the second trimester serum screen are offered either amniocentesis or verifiTM test followed by amniocentesis. Women are offered second trimester ultrasound independent of any pre-vious testing, with positives from the ultrasound be-ing offered either amniocentesis or verifiTM test fol-lowed by amniocentesis.

The model utilizes a combination of published in-cidence and miscarriage rates for T21, T18 and T13, sensitivity and specificity of current prenatal screens and invasive diagnostic procedures, and expected re-imbursement rates to estimate the clinical and eco-nomic impact of incorporating the test into routine prenatal screening paradigms. Weighted average in-cidence rates were calculated using clinically accept-able risk formula cited in Cuckle et al (Exhibit 2).23

Test performance characteristics from the literature

were used within the model (Exhibit 3). Because performance of the second trimester serum screen for T21 is dependent on maternal age, performance characteristics used within the model are weighted averages based on maternal age.24 The verifi™ test was modeled at sensitivity/specificity characteristics of 100 percent/100 percent, 97.2 percent/100 per-cent, and 78.6 percent/100 percent respectively for Trisomy 21, 18, and 13 (as compared to invasive di-agnostic procedures).

Costs were estimated using January 2012 Medi-care reimbursement rates based on applicable CPT codes plus 20 percent, in order to estimate the ac-tual reimbursement provided by private U.S. health insurance organizations. Costs were considered in their totality, including physician’s fees, facility fees and laboratory fees for each test, with the exception of serum testing. These blood tests are provided as part of routine prenatal care. They do not require a separate or additional physician visit. Costs for se-rum testing were considered as the laboratory costs only. Prenatal testing costs used within the model are shown in Exhibit 4.

Finally, the adoption rate of current prenatal test-ing was considered, as not all pregnancies receive prenatal screening or invasive testing. The use of prenatal testing is dependent upon geography, ma-ternal age, and maternal socioeconomic status. The uptake of prenatal testing was stratified based on in-herent maternal risk (advanced maternal age or pre-vious aneuploidy pregnancy) and was estimated us-ing a combination of published literature and quantitative primary research with clinicians and patients (Exhibit 5). Rates of amniocentesis uptake following a positive screening test were taken from Mueller et al 2005.17

it was assumed that women receiving a first tri-mester combined screen would not also receive a

exhibit 5: adoption rates of prenatal testing

test normal risk high risk

1st Trimester Combined screening 50% 65% Triple or Quad serum screening 70% 80%

2nd Trimester ultrasound 90% 95%

CVs (without a prior screen) 1% 3%

amnio (without a prior screen) 1% 5%

CVs (following a positive screen) 22% 20%

amnio (following a positive screen) 70% 60%


second trimester screen, though they may receive a second trimester ultrasound. Therefore, the rates of acceptance for second trimester screening (70 per-cent or 80 percent, depending on baseline risk) were applied to only the women who had not elected a first trimester screen. Similarly, women who had re-ceived a first trimester CVS were not eligible to re-ceive a second trimester amniocentesis. The lower uptake of CVS is based on a single study of the im-pact of first trimester combined screening on inva-sive diagnostic procedure uptake, showing a prefer-ence for amniocentesis over CVS (71 percent versus 29 percent).31 While some women receive a “fully integrated” screen, which uses both the first trimes-ter combined screen and second trimester maternal serum screen, that screening modality was not con-sidered within this model.

Women in the model were eligible to receive the verifiTM test in the first trimester following a positive first trimester screen. Additionally, women were eligible to receive the test in the second trimester following a positive result from the second trimester serum screen or second trimester ultrasound. it was not assumed that the test would increase uptake of prenatal testing generally. Within the model, the uptake of the test in either the first or second trimes-ter was confined to the maximum uptake of existing prenatal screening and diagnostics. Further, it was assumed that 80 percent of women at baseline high risk and 71 percent of women at baseline normal risk would choose the test following a positive screening result. This adoption rate assumes a small increase in demand over invasive diagnostic testing for non-in-vasive follow-up diagnostic testing after a positive screening result due to elimination of miscarriage anxieties.

Miscarriage rates of 0.5 percent for amniocentesis and 1 percent for CVS were used to estimate ex-

pected miscarriages in the two scenarios. The mod-el explored the use of the verifiTM test both with and without a confirmatory invasive procedure follow-ing a positive test result from the test.

A sensitivity analysis was conducted to understand the impact to overall results of each component variable. The sensitivity result findings were used to identify areas of high impact as well as to determine where future work should be focused.

resultsThe model demonstrates that inclusion of the verifiTM test into the prenatal testing paradigm for high-risk women will provide clear clinical benefits. The big-gest benefit to women comes from a reduction in miscarriages due to invasive testing. in the modeled population of five million covered lives with 100,000 pregnancies annually, invasive diagnostic induced miscarriages are reduced from 60 to 20, a 66 percent reduction. When an invasive procedure is never used following a positive test result, miscarriages are fur-ther reduced to 18.

Another clinical benefit of the verifiTM test is an ear-lier and accurate diagnosis of fetal aneuploidy. Testing with this novel blood test is possible as early as the tenth gestational week. The high performance of this test, regardless of gestational age, allows more women to receive an earlier definitive diagnosis. The adoption of the novel test results in 15 percent more women receiving a T21 diagnosis (148 with the standard of care versus 170 with verifi™ testing) and 2 percent more women receiving a T18 diagnosis (44 with the standard of care versus 45 with verifiTM testing), in the modeled population of 100,000 pregnancies.

Finally, the cost impact of the verifiTM test is an important consideration for health plans. in addition to being clinically beneficial compared to the cur-rent prenatal testing paradigm, use of the test prom-

exhibit 6: Modeled prenatal diagnostic pathway which incorporates non-invasive prenatal testing

*Non-invasive prenatal test model is based on data from the Melissa study, evaluating the performance of the verifi™ test

positive screeningtest result

non-invasiveprenatal diagnostic*

amniocentesis or cVs

no further testing

+

–


ises to moderately reduce overall costs. Total costs for prenatal screening and diagnosis for fetal aneu-ploidies is expected to be $59,748,721 for 100,000 pregnancies under the current standard of care. The total cost for prenatal testing which incorporates the verifi™ test is expected to be $59,228,142 for 100,000 pregnancies, a savings of $520,578 or nearly 1 percent annually. The inclusion of verifiTM testing is driven by an important assumption within the model. A higher acceptance rate for verifiTM testing has been assumed as compared to acceptance rates for either CVS or amniocentesis. it has been antici-pated that more women will accept a non-invasive blood test with no miscarriage risk. While the use of CVS and amniocentesis has been reduced by 72 per-cent in this model through the introduction of veri-fiTM testing, 927 more women receive some form of follow-up diagnostic after a positive screen in the verifiTM scenario than in the standard of care.

While seemingly moderate, the 1 percent savings is accompanied by an improved clinical experience by ruling out the need for clinically unnecessary in-vasive testing for many women. The model shows that with this test, the number of invasive proce-dures necessary in order to diagnosis a single aneu-ploidy is reduced by 81 percent from 43 to eight.

Sensitivity analysis reveals several important drivers of overall costs within the model. The cost of the ver-ifiTM test had a large impact on the overall cost benefit of testing. With pricing of up to $1,200 per test, adop-tion of the verifiTM test yields cost savings when pro-vided to women with a positive screening test. The cost of amniocentesis is also an important determinant of total costs. As the cost of amniocentesis increases, total cost benefit of the verifiTM test also increases.

Because uptake of screening tests ultimately de-termines eligibility for testing, the use of screening tests is an important driver of costs. Most significant to cost outcomes is the rate of second trimester ul-trasound as many fetal trisomies are first identified during ultrasound. As use of the second trimester ultrasound drops, fewer women are indicated for in-vasive testing, resulting in fewer diagnoses, but low-er costs. Testing with verifiTM remains cost effective at ultrasound adoption rates below 40 percent.

Similar to adoption rates, the specificity of prenatal screening is an important driver of costs and outcomes as specificity determines the total number of clinically unnecessary invasive tests. Specificity of ultrasound, second trimester serum screening, and first trimester screen were impactful to overall cost benefit.

conclusionsThe availability of a highly sensitive test that identi-fies risk for major aneuploidy disorders (i.e., Down

syndrome, Edwards syndrome, Patau syndrome) is a major change in prenatal screening. With sensitivity and specificity approaching or equaling 100 percent, the significantly improved accuracy will almost cer-tainly lead to rapid practice change among obstetri-cians and maternal and fetal medicine specialists and uptake by pregnant women. Payers will be chal-lenged to consider how to cover the verifiTM test and other novel non-invasive prenatal diagnostics, either enabling broad-based access or limiting coverage to a pre-defined population of women determined to be high risk.

The findings of the model suggest a highly sensitive and specific test that identifies trisomy 21,18, and 13 would be cost saving by offsetting costs associated with clinically unnecessary invasive tests and resulting miscarriages. The high economic and emotional costs of amniocentesis and CVS could be significantly cur-tailed by use of non-invasive prenatal diagnostics, leading to more rational use of health care resources.

While several non-invasive prenatal diagnostics are currently in development, tests with the highest sensitivity and specificity will have the most positive economic impact to payers by decreasing false posi-tive rates and associated unnecessary follow-up costs for invasive tests by 71 percent. These economic savings can be considered alongside the significant decrease in anxiety and reassurance women will have with safer, earlier, and improved availability of results. These types of advancements in care are rare.

Today, the clinical evidence for most non-invasive prenatal tests recently launched or soon to enter the market focuses on high-risk pregnancies (i.e., > age 35, previous aneuploidy birth, etc.). however, as data emerge about the utility of these tests as true screeners in the general population more economic analysis will be required to fully quantify the likely impact. Preliminary assessment using the perfor-mance variables from current studies on the theo-retical cohort of 100,000 pregnancies suggest that screening all pregnancies would reduce unnecessary invasive tests by 88 percent and prevent 53 pregnan-cies from falling victim to diagnostic induced mis-carriage. This significant clinical benefit comes at some cost when broadly applied. As such, ongoing modeling efforts can be used to detail the implica-tions of different price, utilization, and performance variables to ongoing cost-effectiveness.

Ultimately, payers and other policy makers need to work with manufacturers, clinicians, and wom-en’s health organizations to facilitate patient educa-tion about the availability of these novel diagnostics. Additionally, given the cost-effectiveness and clini-cally superior performance non-invasive prenatal tests provide compared to current practice, coverage


policies should be developed that enable access for all indicated women. Further study is warranted to assess patient acceptance, clinician adoption, and real-world impact on practice patterns and behavior.

susan garfield, drph a Vice President at Bridgehead international, is

a health economist with expertise in market access, reimbursement

and novel technologies. Prior to joining Bridgehead, she was the

director,global reimbursement, Policy and economic strategy at Qia-

geN Corporation. she received her doctorate of Public health from

Boston university.

shannon armstrong, ba is a Consultant at Bridgehead internation-

al. she has developed economic models highlighting the clinical and

economic benefits of a range of technologies. Before joining Bridge-

head, she spent six years as the director of research and Marketing at

infoedge. she received a B.a. from the university of Pennsylvania.

funding

funding for this research was provided by Verinata health inc. (red-

wood City, Ca)

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trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency, fetal heart

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lence of trisomies 13 and 18 compared to trisomy 21 -(Down syndrome). Pre-

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7. Rasmussen SA, Wong lyC, yang Q, May KM, Friedman JM. Population-based

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8. Malone FD, Canick JA, Ball Rh, nyberg DA, Comstock Ch et al. First-

trimester or second-trimester screening, or both, for Down’s syndrome. new

England Journal of Medicine. 2005; 353: 2001–2011.

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screening in the United States in 2001: a survey of maternal-fetal medicine

specialists. American Journal of Obstetrics and Gynecology. 2002;187:1230-4

10. Wald nJ, Rodeck C, hackshaw AK, et al. First and second trimester antena-

tal screening for Down’s syndrome: the results of the Serum, Urine and Ultra-

sound Screening Study (SURUSS). health Technology Assessment. 2003;7:1-77.

11. Mujezinovic F, Alfirevic Z: Procedure-related complications of amniocen-

tesis and chorionic villus sampling. Obstet Gynecol. 2007; 110: 687–694

12. Tabor A, Vestergaard ChF, lidegaard Ø. Fetal loss rate after chorionic villus

sampling and amniocentesis: an 11-year national registry study. Ultrasound Ob-

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ing practice of obstetricians. Am J Obstet Gynecol. 2009;200: 459.e1-459.e9

16. Beekhuis JR, de Wolf BThM, Mantingh A, heringa MP. The influence of

serum screening on the amniocentesis rate in women of advanced maternal age.

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20. Sehnert AJ, Rhees B, Comstock D et al. Optimal Detection of Fetal Chro-

mosomal Abnormalities by Massively Parallel DnA Sequencing of Cell-Free

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22. Verinata health inc. MatErnal Blood iS Source to Accurately Diagnose Fetal

Aneuploidy (MEliSSA). in: ClinicalTrials.gov [internet]. Bethesda (MD): na-

tional library of Medicine (US). 2011- [cited 2012 Jan 30]. Available from: http://

clinicaltrials.gov/ct2/show/nCT01122524 nlM identifier: nCT01122524.

23. Cuckle hS, Wald nJ, Thompson SG. Estimating a woman’s risk of having a

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protein level. Br J Obstet Gynaecol. 1987; 94:387–402.

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ond trimester of pregnancy. J Ultrasound Med. 2001; 20(10):1053-63.

28. lehman CD, nyberg D, Winter TC iii, Kapur RP, Resta RG, luthy DA.

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introductionGlOBAl MORTAliTy STATiSTiCS inDiCATE that cardiovascular disease is the leading cause of death in patients with schizophrenia and other ma-jor mental illnesses, and contributes to a 3-fold in-crease in age-adjusted mortality.1-3 Additional evi-

dence documents that cardiovascular risks including overweight status and obesity, diabetes, dyslipid-emia, and smoking have a higher prevalence in pa-tients with schizophrenia and other major mental illnesses compared with the general population.6

however, existing data do not provide clarity about

summary second-generation antipsychotic agents have variable liability to cause weight gain, dyslipidemia, hyperglycemia, and associated cardiovascular complications. We sought to model change in 10-year risk for coronary heart disease (Chd) and type 2 diabetes mellitus as a function of change in the fasting metabolic parameters of patients with schizophrenia enrolled in phase 1 of the Clinical antipsychotic Trials of intervention effectiveness (CaTie) study. This model incorporated risk equations from the framingham heart study (fhs) for Chd and from national epidemiologic surveys for diabetes. annual incidence rates were estimated for primary and sec-ondary Chd, stroke events, and new-onset diabetes. risks for each second-gener-ation antipsychotic included in the CaTie study were quantified using relative risk (rr) vs ziprasidone.The model estimated that over a 10-year time period treatment with olanzapine, and to a lesser extent quetiapine and risperidone, would increase the risk for Chd and diabetes in both men and women. in contrast, the model indicated that zipra-sidone would not increase the risk for Chd or diabetes relative to no treatment (no change from patients’ baseline metabolic status).

Key points• global mortality statistics indicate that cardiovascular disease is the leading cause of death in patients with schizophrenia and other major mental illnesses.1-3

• We estimated medication-attributable risk for Chd and diabetes in a simulation model by applying validated prediction algorithms to the changes in weight and other metabolic parameters observed in phase 1 of the CaTie study for patients treated with second-generation antipsychotics.4,5 • second-generation antipsychotic treatment selection, as well as adherence to metabolic testing guidelines (as recommended by the american diabetes associa-tion/american Psychiatric association), should be carefully considered in patients with schizophrenia.

Estimation of Long-Term Increased Risk of Coronary Heart Disease and Type 2 Diabetes

with Metabolic Complications Observed in the Catie Study: Relative Risk and the Number

Needed to Harm for Second-Generation Antipsychotics

sonja V.sorenson, MPh; henry Nasrallah, Md; Kafi N. sanders, MPh


the differential impact of individual second-genera-tion antipsychotic medications on the long-term risk of developing type 2 diabetes mellitus or cardio-vascular complications (e.g., angina, myocardial in-farction [Mi], and stroke).7,8

Current antipsychotic consensus guidelines and second-generation antipsychotic class warnings de-scribing cardio-metabolic risk among antipsychotic users were derived from the findings in retrospec-tive-cohort and case-report studies.9,10 Completion of the CATiE study (funded by the national insti-tute of Mental health) provided further supporting evidence from a randomized, double-blind, prag-matic clinical trial indicating medication-related

changes in weight, lipid, and glucose parameters as-sessed in a fasting state.4 The results of the CATiE study (n = 1460) describe increases in bodyweight of >7 percent in 7 to 30 percent of second-genera-tion antipsychotic users who were prescribed olan-zapine, quetiapine, risperidone, or ziprasidone. Overall mean weight change from baseline to end-point ranged from -0.3 lb/month to 2.0 lb/month.4 Worsening of other metabolic parameters over time, including glycosylated hemoglobin, total cholester-ol, and triglyceride concentration, is also described in the study results.4 in descending order, the agents that caused the greatest adverse changes were olan-zapine, quetiapine, and risperidone; ziprasidone was

exhibit 2: 9-month estimated change from baseline in Weight- and exposure-adjusted

Mean lipid concentrations based on the catie population*

Weight (lb)TC (mg/dl)Tg (mg/dl)ldl-C (mg/dl)a

olanzapine18.09.440.51.3

Quetiapine4.56.621.22.4

risperidone3.6–1.3–2.4–0.8

Ziprasidone–2.7–8.2–16.5–4.9

TC = total cholesterol; Tg = triglycerides; ldl-C = low-density lipoprotein cholesterol.

* for weight, monthly rate of change from CaTie data multiplied by nine; for lipids, exposure-adjusted mean is the least-squares mean from an analysis of

covariance adjusting for whether the patient had had an exacerbation in the preceding 3 months and for duration of exposure to study drug during phase 1. aldl-C derived as follows: ldl-C = TC – hdl-C – (1/5*Tg), assuming no change in hdl-C.

source: lieberman 2005.7

adult Patientswith Chronic/recurrent schizophrenia

Ziprasidone

Other atypical antipsychotic agent:(1) Olanzapine(2) risperidone(3) Quetiapine

No Treatment switch

discontinue Treatment

same as above

Continue Treatment(no additional switch)

discontinue Treatment(remain off treatment)

remain off treatment

Psychiatric relapse

No Psychiatric relapse

same as above

same as above

Metabolic effects/Weight gain

No Metabolic effects/Weight gain

Metabolic effects/Weight gain

No Metabolic effects/Weight gain

Other adverse eventsNo Other adverse events

Other adverse eventsNo Other adverse events

Other adverse eventsNo Other adverse eventsOther adverse eventsNo Other adverse events

ePs

sexual dysfunction

insomnia

Patient Characteristics

Time invariant:sex

smoking statusage at disease onset

update annually:age

hypertension statuslipid levelsChd history

Treatment-related adverse events (Metabolic)elevated lipid levels, Weight gain

risk of Type 2 diabetes and Complicationsfunction of weight gain, Baseline risk factors

assess risk of Chd events usingframingham risk equationselevated lipid levels, diabetes and hypertension status

exhibit 1: Model structure


not associated with weight gain or worsening of metabolic parameters. The complete results of the CATiE study have been previously published.11

notwithstanding the importance of the CATiE trial in clarifying the metabolic effects of the sec-ond-generation antipsychotic agents, the duration of medication exposure (median = six months) and post-treatment metabolic assessments were insuffi-cient to examine directly the subsequent diabetes and cardiovascular disease events. To obtain long-term disease estimates, CATiE investigators applied the 10-year prediction algorithms from the FhS to the phase 1 baseline metabolic assessments to esti-mate the risk for a primary ChD event at enroll-ment. Results indicated a 34 percent higher risk in men and a 50 percent higher risk in women for ChD than in age- and gender-matched controls in the general population. Elevations in ChD risk were attributable to substantially higher rates of smoking (68 percent vs 35 percent); diabetes, de-fined as fasting blood sugar ≥126 mg/dl, or treat-

ment with oral hypoglycemic agents or insulin (13 percent vs 3 percent); hypertension, defined as sys-tolic blood pressure (SBP) ≥140, diastolic blood pressure ≥90 mmhg, or treatment with antihyper-tensive medication (27 percent vs 17 percent); and lower serum concentrations of high-density lipo-protein cholesterol (hDl-C) (43.7 mg/dl vs 49.3 mg/dl).7

The CATiE study is also ideal for assessing medi-cation-attributable risk because of the study’s ran-domized, double-blind, pragmatic design and fast-ing laboratory assessments, which allow potential confounders such as lifestyle, behavior, access to medical care, and medication history to be con-trolled more effectively than in previous research. As a result, estimates of ChD and diabetes risk de-rived from the CATiE study may complement ex-isting retrospective studies and case reports12,13 about the long-term disease consequences of treatment with second-generation antipsychotics. These stud-ies largely support the hypothesis that olanzapine

exhibit 3: 10-year event rate per 10,000 population and number needed to harm (nnh) event type

Males diabetes

Chd events angina

Mi (nonfatal)

stroke (nonfatal)

all Chd death

Total Chd

Psychiatric hospitalizations

females diabetes

Chd events angina

Mi (nonfatal)

stroke (nonfatal)

all Chd death

Total Chd


Ziprasidone

rate(2.5% - 97.5% percentiles)

1,294.5 (944.8 – 2,557.7)

270.7 (247.8 – 305.1)

295.2 (272.4 – 324.5)

118.6 (115.8 – 122.9)

94.6 (88.5 – 106.1)

779.0 (726.0 – 856.8)

15,029.1 (10,551.6 –19,594.9)

2,064.7 (1,304.1 – 2,806.0)

782.2 (309.4 – 873.3)

361.2 (172.0 – 391.3)

58.8 (52.2 – 64.8)

62.1 (44.1 – 70.6)

1,264.3 (580.8 – 1,391.6)

15,062.9 (10,332.6 – 20,267.7)

NNha

458,991

–710

–693

–24,747

–4,051

–319

–0.398

309,937

–188

–424

–19,695

–4,001

–125

–0.397

olanzapine


1,521.3 (963.3 – 2,619.4)

317.2 (280.4 – 338.3)

344.4 (308.8 – 361.6)

120.8 (117 – 124.3)

104.7 (95.7 – 115.2)

887.1 (803.2 – 937.9)

10,676.3(7,648.7 – 14,171.3)

2,391.9(1,388.2 – 2,875.2)

944.8 (384.4 – 1032.4)

424.7 (210.3 – 458.2)

60.9 (53.4 – 66.8)

71.6 (50.7 – 80.0)

1,502.0(702.9 – 1,627.2)

10,701.0(7,299.2 – 14,196.7)

NNha

44

308

287

5,588

1,305

130

–0.339

31

91

251

6,172

1,435

63

–0.338

Quetiapine


1,351.1(945.7 – 2,563.0)

296.7 (275.1 – 330.8)

322.4 (301.2 – 350.1)

119.4 (116.7 – 124.2)

99.7 (93.5 – 111.2)

838.1 (787.6 – 914.6)

17,508.3(13,785.0 – 21,500.4)

2,202.6(1,320.8 – 2,827.6)

896.9 (364.1 – 988.7)

408.0 (198.3 – 439.1)

60.1 (53.0 – 66.1)

68.0 (48.0 – 76.9)

1,433.1 (665.3 – 1,560.3)

17,547.9 (13,832.9 – 21,276.4)

NNha

177

836

782

28,882

3,790

361

–0.441

73

162

430

11,842

2,936

112

–0.440

risperidone


1,351.1 (939.3 – 2,558.1)

283.0 (260.4 – 315.0)

307.9 (286.2 – 334.7)

119.0 (116 – 123.6)

97.1 (90.9 – 108.0)

807.0 (754.8 – 878.6)

13,470.6(10,088.7 – 16,750.1)

2,202.6(1,324.6 – 2,827.4)

833.7 (334.6 – 918.3)

380.3 (184.1 – 408.8)

59.6 (52.7 – 65.4)

65.1 (46.2 – 73.5)

1,338.7 (619.6 – 1,456.0)

13,500.9 (10,082.9 – 16,986.8)

NNha

177

–5,736

–6,074

–180,185

266,785

–2,934

–0.374

72

–6,183

–2,214

29,923

21,435

–1,875

–0.37

no antipsychotic


1,294.5(957.3 – 2,617.7)

284.7 (264.5 – 316.2)

309.6 (290.1 – 334.6)

119.0 (116.2 – 123.4)

97.1 (91.1 – 108.8)

810.4 (762.5 – 881.7)

40,174.6(40,161.6 – 40,182.6)

2,064.6 (1,276.8 – 2,878.0)

835.3 (336.4 – 924.1)

384.8 (185.5 – 409.6)

59.3 (52.4 – 66.0)

64.6 (46.2 – 74.0)

1,344.0 (622.3 – 1,463.0)

40,265.7(40,252.0 – 40,285.9)

NNh

--

--

--

--

--

--

--

--

--

--

--

--

--

--


increases the risk of diabetes compared with no treatment or treatment with other antipsychotics (except clozapine), but are inconclusive with regard to other second-generation antipsychotics.8,13

The primary objective of the present study was to estimate 10-year risk for ChD and diabetes in a simulation model by applying validated prediction algorithms to the changes in weight and other meta-bolic parameters observed in phase 1 of the CATiE study for patients treated with second-generation antipsychotics.4,5 Medication-attributable risk for each antipsychotic was quantified as relative risk (RR) and number needed to harm (nnh).

MethodsA Markov model was developed to estimate ChD and diabetes risk over a 10-year time period in 10,000 U.S. adult patients (≥18 years) with chronic schizophrenia treated with second-generation anti-psychotics. A risk-prediction algorithm derived from the FhS14 that included factors relevant to second-generation antipsychotic agents, such as triglyceride (TG) concentrations and predictors of primary as well as secondary cardiovascular events, was incor-porated into the model (Exhibit 1). At baseline, the simulated patients with chronic schizophrenia were assigned a specific treatment and baseline risk profile

(e.g., age, sex, smoking status, body-mass index [BMi], lipid levels, and alcohol use).

At each one-year cycle, patients’ risk profiles were updated and patients were assigned a treatment-spe-cific risk of: (1) acute psychiatric relapse/hospitaliza-tion, (2) nonmetabolic adverse events (i.e., extrapy-ramidal symptoms, insomnia, and sexual dysfunction) based on the CATiE study data, (3) diabetes (ac-counting for BMi and age), (4) hypertension, and (5) primary or secondary ChD and stroke events. Each treatment-specific risk was based on the mag-nitude of changes in BMi and lipid levels resulting from the treatment to which they were assigned, as well as other risk factors (e.g., age, sex, diabetes, and smoking status). Exhibit 2 shows the changes in weight and lipid levels used in the model; it was as-sumed that these changes occur within the first year of treatment and remain stable thereafter. Patients were also assigned a risk of noncardiovascular death.

To derive 10-year risk estimates, the annual inci-dence of ChD and diabetes was multiplied by the number of patients expected to survive in the prior year. The values, calculated for each year, were then summed to provide 10-year risk estimates. The model simulated risk in hypothetical patients with characteristics derived from patients enrolled in phase i of the CATiE study.4

table 4. relative risk of events

event type

Males

diabetes (95% Ci)

Chd events

angina

Mi (nonfatal)

stroke (nonfatal)

all Chd death

Total Chd (95% Ci)


females

diabetes (95% Ci)

Chd events

angina

Mi (nonfatal)

stroke (nonfatal)

all Chd death

Total Chd (95% Ci)


olanzapine vs

Ziprasidone

1.18 (1.00 – 1.54)

1.17

1.17

1.02

1.11

1.14 (1.06 to 1.16)

0.71

1.16 (1.00 to 1.29)

1.21

1.18

1.04

1.15

1.19 (1.12 to 1.83)

0.71

Quetiapine vs

Ziprasidone

1.04 (1.00 – 1.30)

1.10

1.09

1.01

1.05

1.08 (1.04 to 1.13)

1.16

1.07 (1.00 to 1.13)

1.15

1.13

1.02

1.10

1.13 (1.07 to 1.70)

1.16

risperidone vs

Ziprasidone

1.04 (0.65 – 1.38)

1.05

1.04

1.00

1.03

1.04 (0.97 to 1.11)

0.90

1.07 (1.00 to 1.14)

1.07

1.05

1.01

1.05

1.06 (0.99 to 1.59)

0.90

Ziprasidone vs

no treatment

1.00

0.95

0.95

1.00

0.97

0.96

0.37

1.00

0.94

0.94

0.99

0.96

0.94

0.37


chd riskThe annual probability of primary and secondary ChD events (e.g., angina, Mi, and ChD death) was estimated using previously published FhS equa-tions.14 Separate risk equations for initial and subse-quent ChD events were employed to account for the increased likelihood of subsequent cardiovascular events after an initial episode. An additional FhS risk equation was used to estimate the annual prob-ability of stroke and has been previously published.15 Risk equations based on the U.K. Prospective Dia-betes Study (UKPDS) were used to predict annual ChD and stroke events in patients with diabetes be-cause the FhS was not powered to evaluate ChD in this population.16 The D’Agostino equation indepen-dently predicted primary and subsequent ChD events, including angina, coronary insufficiency, Mi, and ChD death (sudden and nonsudden). To differentiate between events, the Markov model ap-plied the relative frequency of each event reported by D’Agostino then stratified cohorts by sex and pri-mary vs subsequent events to determine the relative proportion of different ChD events. Only Framing-ham equations were used in the sensitivity analyses.

diabetes riskThe probability of developing diabetes, given an in-dividual’s BMi and age, was estimated using data from two large national surveys: for men, the health Professionals’ Follow-up Study17-a study of 51,529 male health professionals followed over five years and for women, the nurses’ health Study,18 which followed a cohort of 113,861 women aged 30-55 years for over eight years (no participant had diabe-tes at study entry). Each study found a strong asso-ciation between BMi and risk of onset of diabetes. For the model, we fitted exponential curves, one for men and one for women, based on the RRs report-ed for BMi categories, 9 for women (<19 – >28.9 kg/m2) and 8 for men (<23 – >34.9 kg/m2). The resultant curves fit the original data well (R2=0.98 for men; R2=0.96 for women).

Equation 1, Malesy = 0.0016 exp 0.2748*BMI

Equation 2, Femalesy = 0.0008 exp 0.2797*BMINote: exp denotes the exponential function ex, where e is the number (approximately 2.718281828) for which the function ex is its own derivative; x is the product of the terms to the right of exp; y is expressed as incidence of diabetes per 1000 per year.

For BMi values above the upper limit of the high-

est BMi category, linear curves were fitted (For men: y = 16.9590 + 0.2362* BMi; for women: y = 7.6054 + 0.0956 *BMi). These represent a conser-vative assumption because risk was increasing expo-nentially, rather than linearly, prior to that point.

The annual incidence of diabetes was then further adjusted for age, so the transition probability for dia-betes in a given year was:

Equation 3P(Diabietes

year)=P(Diabete|BMI)*RR (Diabetes|Age

year)

equation assumptionsBased on data from a study by McEvoy et al., ChD and diabetes risk was estimated for a 39-year-old male or a 44-year-old female patient with schizophrenia having similar demographic and cardiovascular risk factors of patients in the CATiE study.4,19 height, which was not published for CATiE subjects, was set at 69.2 inches for men and 63.7 inches for women, based on data from the Third national health and nutrition Examination Survey.20 The proportion of smokers (men, 73 percent; women, 56 percent), indi-viduals with diabetes (men, 11 percent; women, 16 percent) and hypertension (20 percent), and the levels of total cholesterol (TC) (men, 203.7 mg/dl; wom-en, 208.3 mg/dl) and hDl-C (men, 42.3 mg/dl; women, 47.7 mg/dl) were derived from CATiE baseline values.7,19,21 low-density lipoprotein choles-terol (lDl-C) levels were calculated with the empir-ically-derived Friedewald equation (equation 4), which assumes that TG concentrations are <400 mg/dl. Baseline lDl-C levels were 122.5 mg/dl and 125.8 mg/dl for men and women, respectively.

Equation 4LDL-C = TC – (HDL-C + 0.2 * triglycerides)SBP (men, 123.9 mm Hg; women, 122.3 mm Hg), baseline BMI (men, 28.8; women, 32.8), and TG concentrations (men, 194.7 mg/dL; women, 173.8 mg/dL) were derived from a study by McEvoy et al.19 Change from baseline in weight and laboratory values of TC and TG concentrations (exposure-adjusted means) were obtained from the CATIE study,4 and change in LDL-C was computed from these values. The changes in weight and lipid concentrations used in the model are listed in Exhibit 2.Changes in HDL-C and SBP were not reported by Lieberman et al.,4 therefore these values were set to zero in all analyses. Sensitivity analyses explored the effect of allowing HDL-C to decline as a result of treatment with olanzapine, quetiapine, risperidone, and ziprasidone.

Measures The primary measures were the rate of primary


exhibit 5: sensitivity analysis

event type Ziprasidone olanzapine risperidone Quetiapine

base case

diabetes 1679.6 1956.6 1776.9 1776.8

CVda 1021.6 1194.6 1072.8 1135.6

scenario: 20% increase in baseline weight

diabetes 2408.5 2436.7 2416.8 2419.9

CVda 1055.1 1207.4 1104.2 1168.5

scenario: including treatment-specific hdl-c changes

diabetes 1679.6 1956.6 1776.9 1776.8

CVda 1021.6 1195.6 1073.8 1137.1

scenario: all framingham equations

diabetes 1679.6 1956.6 1776.9 1776.8

CVda 1055.0 1241.0 1111.0 1177.7

scenario: 5-year time period

diabetes 1493.4 1602.2 1533.4 1533.4

CVda 322.5 370.2 337.1 355.3


diabetes 1864.4 2303.1 2016.5 2016.4

CVda 2347.7 2749.5 2466.3 2606.3


diabetes 2036.1 2617.3 2237.1 2236.8

CVda 4508.4 5169.0 4704.6 4922.0

scenario: starting age of 35 years

diabetes 1516.5 1657.9 1563.7 1563.7

CVda 595.4 691.0 622.7 656.7


diabetes 1745.3 2072.6 1855.2 1855.2

CVda 1189.9 1389.3 1248.2 1318.2


diabetes 1739.6 2060.5 1847.6 1847.5

CVda 1628.9 1885.9 1704.0 1789.2

scenario: all males (starting age of 39 years)

diabetes 1294.5 1521.3 1351.1 1351.1

CVda 779.0 887.1 807.0 838.1

scenario: all females (starting age of 44 years)

diabetes 2064.7 2391.9 2202.6 2202.6

CVda 1264.3 1502.0 1338.7 1433.1

scenario: starting bMi 10 percent lower

diabetes 1495.0 1670.3 1538.5 1538.5

CVda 808.6 1167.1 1062.8 1125.1

scenario: starting bMi 10 percent higher

diabetes 1972.1 2384.6 2037.6 2037.6

CVda 1045.9 1205.2 1095.7 1159.6

scenario: switching/discontinuation

diabetes 2144.9 2059.8 2357.5 1697.9

CVda 1118.1 1105.1 1124.0 1074.2

aincludes Chd (angina and myocardial infarction) and stroke.

CVd = cardiovascular disease; hdl-C = high-density lipoprotein cholesterol; BMi = body mass index.


ChD events (acute Mi, coronary insufficiency, an-gina pectoris, sudden ChD death, nonsudden ChD death) and the rate of type 2 diabetes per 10,000 treated patients. Secondary measures included the rate of angina events, acute Mi, ischemic or hemor-rhagic stroke, ChD-related deaths, total primary and secondary ChD events excluding ChD-related deaths, and total primary and secondary ChD events including death per 10,000 treated patients.

one-way sensitivity analysesOne-way sensitivity analyses varied the following parameters and scenarios: age of population at start of the model (35 and 55 years), hDl-C levels (2-mg/dl decline for olanzapine and risperidone and a 3-mg/dl decline for quetiapine consistent with published research22), use of only FhS risk equa-tions14,15 to predict ChD events, baseline BMi, and allowing for switching/discontinuation.

statistical analysesThe risk equations and model analyses were pro-gramed in Excel.23 Statistical analyses used RR ra-tios and nnh. The RR ratio was calculated as the ratio of events for a given antipsychotic relative to ziprasidone and relative to baseline. (Confidence in-tervals [Cis] for RR ratios were derived from the model’s probabilistic sensitivity analysis and are dif-ferent from calculations of Cis based on empirical data.) nnh quantifies the tendency of a treatment to produce negative effects, using the absolute dif-ference in rates of adverse events between treated and control groups. nnh is interpreted as the num-ber of patients who need to be treated to cause harm to one patient. it is calculated as the inverse of the absolute difference in the rate of harm in treated vs control patients.

resultsThe predicted number (and simulated 2.5 percent and 97.5 percent confidence limits) of diabetes, an-gina, Mi, stroke, and ChD death events for each antipsychotic agent per 10,000 patients over the 10-year period for men (starting age 39 years) and wom-en (starting age 44 years) are presented in Exhibit 3. Of patients treated with antipsychotics, ziprasidone had the lowest predicted number of ChD events per 10,000 patients over 10 years in men (270 angina events and 295 Mis) and women (782 angina events, 361 Mis). Olanzapine had the greatest predicted in-cidence of angina (n = 317 for men; n = 945 for women) relative to the other agents. Olanzapine and quetiapine had the highest number of predicted Mis (olanzapine, 344 for men and 425 for women; que-tiapine, 322 for men and 408 for women). Metabolic

changes had little effect on the predicted number of strokes or ChD-related mortality, which were simi-lar across all antipsychotics.

The predicted number of psychiatric relapses/hos-pitalizations per 10,000 patients treated with each antipsychotic agent over a 10-year time period was lowest for olanzapine (n = 10,676 for men and n = 10,701 for women), intermediate for risperidone (n = 13,471 for men and n = 13,501 for women) and ziprasidone (n = 15,029 for men and n = 15,063 for women), and highest for quetiapine (n = 17,508 for men and n = 17,548 for women) (Exhibit 3).

Comparing nnh to a reference case of no anti-psychotic exposure, olanzapine resulted in lower nnhs for angina and Mi events for both men and women compared with the other antipsychotic agents, showing that fewer patients needed to be treated with olanzapine to cause harm to one patient (Exhibit 3). For men, relative to no antipsychotic exposure, the nnh to result in one case of diabetes was 44 for olanzapine compared with 177 for que-tiapine and risperidone; similar results were predict-ed for women. Given the similar diabetes incidence for ziprasidone-treated patients vs those with no an-tipsychotic exposure, the nnh for ziprasidone was over 400,000. Among ziprasidone-treated patients, the nnh for ChD events was lower than the base-line rate because ziprasidone lowered weight and other metabolic risk factors, on average, during the course of the CATiE study.

The RR ratios were calculated for each antipsy-chotic compared with ziprasidone (Exhibit 4). Olanzapine increased the RR of ChD by elevating the RR of Mi to 1.17 in men and 1.18 in women. Quetiapine showed similar elevations in the RR of Mi and other ChD events. Relative to ziprasidone, olanzapine also increased the risk for diabetes, by 1.18 in men (95 percent Ci, 1.00 to 1.54) and 1.16 in women (95 percent Ci, 1.00 to 1.29).

sensitivity analysesnone of the scenarios tested in our sensitivity analy-ses produced results that were materially different from the base-case scenario (Exhibit 5). ChD and diabetes events correlated positively with age, such that a younger starting age produced lower rates of diabetes. in another scenario, we incorporated some worsening of hDl-C in to the model (consistent with prior studies of olanzapine, risperidone, and quetiapine),22 which also slightly increased the ex-pected number of ChD events for these second-generation antipsychotics. Using only the FhS risk equations to predict ChD risk resulted in a higher number of cases in each treatment arm.


discussionThe present study models data from a randomized, controlled trial to evaluate the long-term medica-tion-attributable risk of ChD and diabetes in pa-tients with schizophrenia. Whether it was due to the intrinsic nature of schizophrenia and/or the effects of previously administered antipsychotics, patients in the CATiE study entered with an elevated risk of type 2 diabetes mellitus and ChD at baseline. These findings suggest that the magnitude of metabolic changes observed during the course of the CATiE study may have important implications for under-standing the health consequences of second-genera-tion antipsychotic treatment and for the long-term management of patients with schizophrenia.24

Given the differential impact of specific second-generation antipsychotics on these metabolic param-eters, the model predicted that treatment with olan-zapine, and to a lesser extent quetiapine and risperidone, further elevates the risk of ChD and diabetes compared with baseline or treatment with ziprasidone, assuming that the metabolic parameters remain constant over the 10-year time period. in particular, the relatively low nnh values for olan-zapine suggest that this treatment may pose the greatest increased risk for ChD and diabetes with long-term use. For example, olanzapine has an esti-mated nnh for diabetes of 44 and 31 in men and women, respectively. longer medication exposure may place patients at a greater risk than is estimated in this study. in contrast, there was no evidence of medication-attributable risk of ChD and diabetes in ziprasidone-treated patients relative to baseline.

The present findings are consistent with previous analyses. A recent analysis estimating the 10-year ChD risk for the CATiE population also deter-mined that olanzapine was associated with an in-creased risk of ChD (0.5 percent [standard error (SE) 0.3]) as was quetiapine (0.3 percent [SE 0.3]). Ziprasidone was predicted to have a decrease in ChD risk (−0.6 percent [SE 0.4]). The difference in estimated 10-year ChD risk between olanzapine and ziprasidone patients 40 years of age was statisti-cally significant (p=0.004).25 A retrospective analy-sis of data from more than 100,000 Medicaid pa-tients revealed that in patients screened for pre-existing diabetes, who were on antipsychotic monotherapy, and in whom diabetes was identified with prescription claims only, patients treated with olanzapine had an increased risk for diabetes relative to patients who did not receive treatment (odds ratio [OR] = 1.149).26 A study of more than 19,000 pa-tients in the U.K.-based General Practice Research Database demonstrated that patients treated with olanzapine had significantly increased odds of devel-

oping diabetes compared with nonusers of antipsy-chotics (OR = 5.8, 95 percent Ci: 2.0 to 16.7) and patients treated with conventional antipsychotics (OR = 4.2, 95 percent Ci: 1.5 to 12.2).27

The results of this model suggest that clinicians need to be aware of the possibility that long-term treatment with olanzapine and quetiapine and, to a lesser extent, risperidone, may increase patients’ risk for ChD events and type 2 diabetes mellitus. it is tempting to think that attentive clinicians would routinely provide interventions for modifi-able metabolic risk factors as necessary during the management of patients with schizophrenia. how-ever, in the total CATiE population, high percent-ages of patients had metabolic disorders at baseline and, moreover, a high percentage of patients with these disorders were untreated at baseline.28 Spe-cifically, dyslipidemia, when defined by elevated TG levels (in fasting patients, n = 690) and low hDl-C levels (in all subjects, n = 1445), was found in 47 percent and 48 percent of CATiE pa-tients, respectively. The overall prevalence of dia-betes was 10 percent; 11 percent when applied only to patients whose fasting glucose results were ob-tained ≥8 hours after the last meal. The overall prevalence of hypertension was 33 percent. The rates of nontreatment for these conditions were 88 percent for dyslipidemia, 62 percent for hyperten-sion, and 30 percent for diabetes.28

limitationsThe current model has limitations that must be con-sidered when evaluating these results. First, due to the inaccessibility of patient-level CATiE data, the model was populated with data from published summary statistics on patient characteristics and metabolic changes attributable to each second-gen-eration antipsychotic. however, there is no clear evidence to suggest that this methodology is the most reasonable substitute for patient-level data. Secondly, this is not a prospective study; 10-year risk estimates were model-derived by applying 10 one-year risk estimates using risk equations devel-oped by D’Agostino et al., Wolf et al., and the UK-PDS14,15,16 and accumulating the results over 10-year-ly cycles. Thirdly, despite its rigor and suitability for assessing medication-attributable risks, the CATiE study involved relatively short periods of medication exposure. longer medication exposures may lead to higher event rates and, conversely, patients stopping medication altogether or switching to medications without weight gain or other metabolic disturbanc-es, which may in fact lower their subsequent risk for disease. Finally, the equations used are somewhat dated; newer risk equations (e.g., Wilson)29 may


have altered the assumptions and yielded different results.

One strength of the model is that whereas Goff et al. estimated only the risk for primary ChD events using a single, 10-year prediction equation derived from Wilson et al.,7, 29 the current model includes both primary and secondary ChD events.7 Despite these differences in the application of risk-predic-tion methods, a comparison of the methods reveals that treatment groups are affected in similar ways: while the overall number of events predicted for each treatment is subject to change based on the method of risk prediction, the marginal difference between treatments is not significantly changed over the 10-year time period used by the model.

conclusionOur results underscore the conclusions of the American Diabetes Association/American Psychi-atric Association Consensus Statement (2004) that olanzapine-treated patients are at an elevated risk for weight gain, diabetes, and dyslipidemia com-pared with patients receiving other second-genera-tion antipsychotics or no treatment; the risk for pa-tients treated with quetiapine and risperidone, while still elevated in this model, was of a lesser magnitude.9 Consistent with clinical trial data and other evidence, comprehensively reviewed by new-comer, ziprasidone-attributable risk for diabetes and ChD in our model was zero (RR = 0.96 for total ChD and 1.00 for diabetes).13 An important con-tributor to this finding was the reduction in weight and associated reduction in diabetes risk in phase 1 of the CATiE study.4 Other important determi-nants of the effects of ziprasidone were the mean reductions from baseline in lDl-C and TGs in ziprasidone-treated patients.

in view of the Food and Drug Association’s warn-ings and consensus guidelines regarding metabolic complications associated with some second-genera-tion antipsychotics, and in view of the apparent inat-tention by some clinicians to the problem,30 this re-mains an important issue in patient care. While the primary goal of treatment is to control the symp-toms of schizophrenia and avoid acute exacerbations (especially those resulting in hospitalization), it is important to balance the risk-benefit profile of these treatments. Per treatment guidelines, optimal care would involve routine testing for metabolic chang-es, documentation of medical interventions, and, possibly, adjustments to the patient’s antipsychotic drug regimen.

sonja V. sorensen, Mph is a senior research scientist with united

Biosource Corporation in Bethesda, Md. she has extensive experience

in decision-analytic modeling across numerous therapeutic areas, in-

cluding schizophrenia and dyslipidemia. her probabilistic and deter-

ministic models have included budget impact models for formulary

decision-making and cost-effectiveness models for global and u.s.

settings.

henry nasrallah, Md is an internationally recognized psychiatrist, ed-

ucator, and researcher. he is the associate dean for faculty develop-

ment, Professor of Psychiatry and Neuroscience, and director of the

schizophrenia Program at the university of Cincinnati College of Med-

icine, Oh. his research focuses on the neurobiology and psychophar-

macology of psychosis and bipolar disorder.

Kafi n. sanders, Mph is associate director of Outcomes research at

Pfizer and has held positions in the Cardiovascular/Metabolic, Neuro-

science, and Pulmonary Vascular disease groups for the last five years.

she supports in-line projects and in-licensing opportunities at the

united states, country, and regional levels. she is currently a doctoral

candidate in Public health.

disclosures

This research was funded by Pfizer inc. dr. sonja V. sorensen, dennis

revicki, and lael s. Cragin are currently employed by the united Bio-

source Corporation (uBC), which provides consulting and other re-

search services to pharmaceutical, device, government, and nongov-

ernment organizations. Timothy Baker was employed by uBC during

the conduct of the research and development of the manuscript. uBC

was a paid consultant to Pfizer to develop the model that constitutes

the basis for this manuscript. No financial payment was made for the

development of the manuscript. henry Nasrallah is Professor of Psy-

chiatry, Neurology, and Neuroscience, and director of the schizophre-

nia Program at the university of Cincinnati College of Medicine, Oh.

dr. Nasrallah has received research grants from the following industry

sources: forest, gsK, Janssen, Otsuka, Pfizer inc, roche, sanofi-aven-

tis, and shire. he is on the advisory boards and speakers’ bureaus of

astraZeneca, Janssen, Pfizer inc, Novartis, and Merck. he does not

own stocks of any pharmaceutical company. James harnett and Kafi N.

sanders are employees of Pfizer inc.

funding

This study was sponsored by Pfizer inc. editorial support was provided

by frances Brentson, Ms, annie Nield, Phd, and Bill Kadish, Md at

PareXel and was funded by Pfizer inc.

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ic-related risk of diabetes mellitus in a Medicaid psychosis population: sensitiv-

ity to study design. Am J Health Syst Pharm. 2006;63(5):431-441.

27. Koro CE, Fedder DO, l’italien GJ, et al. Assessment of independent effect

of olanzapine and risperidone on risk of diabetes among patients with schizo-

phrenia: population based nested case-control study. BMJ. 2002;325(7358):243.

28. nasrallah hA, Meyer JM, Goff DC, et al. low rates of treatment for hyper-

tension, dyslipidemia and diabetes in schizophrenia: data from the CATiE

schizophrenia trial sample at baseline. Schizophr Res. 2006;86(1-3):15-22.

29. Wilson PW, D’Agostino RB, levy D, et al. Prediction of coronary heart

disease using risk factor categories. Circulation. 1998;97(18):1837-1847.

30. Morrato Eh, newcomer JW, Kamat S, et al. Metabolic screening after the

American Diabetes Association’s consensus statement on antipsychotic drugs

and diabetes. Diabetes Care. 2009;32(6):1037-1042.


spring Managed Care forum: guide TO CONfereNCe suPPOrTers

actelion pharmaceuticals, Sponsor

actelion Pharmaceuticals is a biopharmaceutical

company focusing on the discovery, development

and commercialization of innovative treatments to

serve unmet medical needs. actelion is commit-

ted to research in cardiopulmonary disease, sleep

disorders, and immunology.

aereocrinebooth 230

aerocrine is a breakthrough medical technology

company focused on improved management and

care of patients with inflammatory airway diseases.

NiOX MiNO® enables fast, reliable measurements

of airway inflammation and may therefore play a

critical role in more effective diagnosis, treatment

and follow-up of patients.

altegra healthbooth 117

altegra health™ is the result of the combina-

tion of five highly recognized healthcare industry

leaders. Our suite of technology-enabled services

includes proven solutions for risk adjustment, data

analytics, encounter reporting, medical chart audit

and coding, member engagement, eligibility and

enrollment, and quality performance improvement.

These solutions, combined with our reimbursement

and advisory services professionals’ knowledge of

the payer and provider markets, enable us to de-

liver enhanced revenue, strengthened compliance,

and improved overall performance to our health

plan and provider clients. for additional informa-

tion, please find us at www.altegrahealth.com.

american regent, inc.booth 211

american regent, inc. is the manufacturer and

distributor of Venofer®, (iron sucrose injection,

usP), the #1 selling iV iron in the u.s.1 Venofer®

is available in 50mg/ 2.5ml, 100mg/5ml and

200mg/10ml single use vials. Venofer® is

preservative-free and latex-free.

¹Based on iMs National sales Perspective (Jan-

uary 2012) – fourth Quarter 2012 results – dollar

Volume ($) and units (100mg equivalents).

amylin pharmaceuticals booth 100

amylin Pharmaceuticals is a biopharmaceutical

company dedicated to improving lives of patients

through the discovery, development and commer-

cialization of innovative medicines. amylin is com-

mitted to delivering novel therapies that transform

the way diabetes, obesity and related metabolic

disorders are treated. amylin is headquartered in

san diego, Calif. More information about amylin

Pharmaceuticals is available at www.amylin.com.

authentidate

booth 228

authentidate is a provider of telehealth, hospi-

tal discharge, referral, and order management

software and products for the healthcare industry.

Our hospital discharge software automates and

simplifies the discharge process. inscrybe health-

care enables healthcare providers, suppliers,

and insurers to exchange, update and electroni-

cally sign healthcare quickly and accurately. Our

telehealth solutions include vital signs monitoring

devices and applications that help reduce hospital

readmissions, increase care plan compliance

and improve overall outcomes for chronically ill

patients.

auxilium pharmaceuticals booth 131

auxilium Pharmaceuticals, inc. is a specialty

biopharmaceutical company committed to provid-

ing innovative solutions for unmet medical needs

which are often undiagnosed or under-treated.

april 26-27, 2012gaylor palms resort & convention center

Kissimmee, florida




bayer healthcare pharmaceutical booth 115

Bayer healthCare Pharmaceuticals inc. is the

u.s.-based pharmaceuticals unit of Bayer health-

Care llC, a division of Bayer ag. The company

markets products for diagnostic imaging, general

medicine, hematology, neurology, oncology and

women’s healthcare. its aim is to discover and

manufacture products that will improve human

health worldwide by diagnosing, preventing and

treating diseases.

biogen idecbooth 204

Through cutting-edge science and medicine,

Biogen idec discovers, develops and delivers

to patients worldwide innovative therapies for

the treatment of neurodegenerative diseases,

hemophilia and autoimmune disorders. founded in

1978, Biogen idec is the world’s oldest indepen-

dent biotechnology company. Patients worldwide

benefit from its leading multiple sclerosis thera-

pies, and the company generates more than $5

billion in annual revenues.

coram specialty infusion services booth 212

Coram is a leading national provider of specialty

home infusion and specialty pharmacy services

with more than 30 years of experience servicing

the needs of complex patients. With more than 85

branches and over 65 infusion suites throughout

the country, Coram offers both national pres-

ence and comprehensive local coverage. Coram’s

nurses, pharmacists, dietitians and other clinical

staff are known in the industry for providing an ex-

ceptional level of personalized care to thousands

of home and infusion suite iV patients every day.

for more information, please visit our website at

www.coramhc.com.

dendreon

booth 106

dendreon Corporation is a biotechnology

company whose mission is to target cancer and

transform lives through the discovery, develop-

ment and commercialization of novel therapeutics.

The company applies its expertise in antigen

identification, engineering and cell processing to

produce active cellular immunotherapy product

candidates designed to stimulate an immune

response. dendreon’s first product, PrOVeNge®

(sipuleucel-T), was approved by the fda in april

2010 for the treatment of asymptomatic or mini-

mally symptomatic metastatic, castrate-resistant

(hormone-refractory) prostate cancer.

dorland health booth 226

dorland health, an access intelligence, llC Com-

pany, is a leading publisher and media company

providing education, training, tools, information

resources, guidance and practical advice for

practitioners and specialists in the healthcare field.

dorland health services include the Case in Point

learning Network, Case in Point, Case in Point

Weekly, Professional Patient advocate institute,

Patient advocate report , Or Manager, industry-

specific resource directories and reports, confer-

ences and events, webinars, award programs,

special reports, and offers continuing education.

eisai

booth 103

eisai inc. is the u.s. pharmaceutical operation of

eisai Co. ltd., a research-based human healthcare

(hhc) company that discovers, develops and mar-

kets products throughout the world. eisai’s areas

of commercial focus include neurology, gastroin-

testinal disorders and oncology/critical care.

first call pharmacybooth 113

first Call iV Pharmacy is an aChC accredited

national provider of home infusion and high-tech

specialty pharmacy services throughout america.

Our professional customer service team will

respond to your referral request, coordinate all

services and have your patient at home (where

they want to be) within 24 hours or less. We are

contracted with most major managed care and

insurance companies and accept all workers

compensation cases. We specialize in antibiotics,

TPN, chemotherapy, pain management, iVig, and

all specialty pharmacy products. Our pharmacists,

nurses, pharmacy technicians and home care staff

have over 100 years of homecare experience to

service you and your patients’ needs.

No matter how challenging the case or rural the

area, call us, and your next iV case we be the easi-

est referral you will ever make. regardless of loca-

tion or time, first Call iV Pharmacy is everywhere

you need us to be. We are truly your “first Call”

for all home infusion services.

forest laboratories booth 125

forest Pharmaceuticals, inc. is a wholly-owned

subsidiary of New york City- based forest labo-

ratories, inc. forest’s longstanding global partner-

ships and track record developing and marketing

pharmaceutical products in the usa have yielded

its well-established central nervous system and

cardiovascular franchises and an emerging portfo-

lio in anti-infective and respiratory medicine.

genomic health, inc booth 121

genomic health, inc., a life science company located in

redwood City, California, conducts genomic research

to develop clinically-validated oncology molecular

diagnostics, which provide individualized information

on the likelihood of disease recurrence and response

to chemotherapy. These diagnostic technologies

generate information that payers, physicians and

members can use in assessing treatment decisions.

gilead, Sponsor

booth 101

gilead sciences is a biopharmaceutical company

that discovers, develops and commercializes in-

novative therapeutics in areas of unmet medical

need. The company’s mission is to advance the

care of patients suffering from life-threatening

diseases worldwide. headquartered in foster City,

California, gilead has operations in North america,

europe and asia Pacific.

glaukos corporation booth 108

glaukos® Corporation is a privately-held, ophthal-

mic company located in laguna hills, California,

that is dedicated to researching and developing

micro-technologies to improve glaucoma therapy

and has developed the istent® Trabecular Micro-

Bypass stent. The istent is intended to reduce

iOP in patients with mild-to-moderate open-angle

glaucoma undergoing concurrent cataract surgery.

hra healthcare research & analytics booth 112

Our team of experienced interviewers will be

distributing carefully developed questionnaires.

We’ll be gathering the answers to vital marketing

and clinical questions- answers that can affect the

introduction of new products or the continuation of

existing healthcare products and services.


Get connected to the perspectives of 100 stakeholders who manage 143 million covered livesConnecting you with relevant information is part of our commitment to you. That’s why Lilly commissioned the publication of a report based on the Managed Care Oncology Index.* This study surveyed managed care executives, practicing oncologists, and oncology practice managers who shared their views on interesting oncology topics such as:• Coverage and reimbursement of oncolytics • Oncology management strategies • Clinical pathways

The publication, Trend Report on Oncology Management, is just one example of how Lilly Oncology can connect you with important information to assist your organization in managing members with cancer. To get your copy of the trend report, simply call 1-800-247-7832 and a Lilly Account Manager–Oncology Payer Services will contact you to arrange delivery of your copy and answer any questions you might have about other available services.

ON77402 03/2012 PRINTED IN USA © 2012, Lilly USA, LLC. ALL RIGHTS RESERVED.

* The index is an independent study undertaken by The Zitter Group, a managed care consulting fi rm specializing in market research.

Visit www.lillyoncology.com. | Creating better connections.

618865_M04 Connections_ad_REV.indd 1 3/16/12 2:50 PM



hologic

booth 133

hologic is a leading developer, manufacturer and

supplier of premium diagnostic and medical imag-

ing systems and surgical products dedicated to

the healthcare needs of women.

We are committed to enhancing women’s lives

through earlier detection, improved diagnosis and

less invasive treatments. Our core business areas

focus on mammography, breast Mri and breast

biopsy, radiation treatment for early-stage breast

cancer, cervical cancer screening, treatment for

menorrhagia, osteoporosis assessment, and pre-

term birth screening.

learn more at www.hologic.com.

impediMed

booth 232

Pre-emptive management of breast cancer-

related lymphedema lower cost while improving

outcomes. Bioimpedance spectroscopy (Bis)

quantitates extracellular fluid differences between

the arms. Compliments new Nih paradigm of

pre-emptively managing lymphedema and iOM

recommendations for monitoring late effects of

cancer treatment. aids physician in assessment

of lymphedema prior to irreversible changes.

earlier detection allows earlier, more cost-effective

intervention minimizing intensive OT/PT treatment

and expensive compression pumps. standardized,

objective, and validated. Point of care device.

ipsen

booth 213

ipsen is a global specialty-driven pharmaceutical

company who’s ambition is to become a leader

in specialty healthcare solutions for targeted

debilitating diseases. its development strategy is

supported by two us franchises: Neurology with

dysport® for Cervical dystonia and endocrinol-

ogy with somatuline® depot for acromegaly &

increlex® for short stature. r&d is focused on

innovative and differentiated technological patient

driven platforms with r&d expenditure totaling

more than 21% of group sales. The group has total

worldwide staff of close to 4,500 employees.

lifescan & animas corporation booth 104

part of the Johnson & Johnson family of Companies

lifescan & animas Corporation, part of the John-

son & Johnson family of Companies – Our vision

is to create a world without limits for people with

diabetes. We provide innovation in solutions that

include episodic and continuous glucose monitor-

ing, insulin delivery, software, and education.

Millennium laboratories booth 201

Millennium laboratories is the leading research-

based clinical diagnostic company dedicated to

improving the lives of people suffering from pain.

The company provides healthcare professionals

with scientific data, clinical tools and services that

help personalize treatment plans to improve clini-

cal outcomes and patient safety.

The company utilizes leading technology and

proprietary methodologies to provide some of the

fastest and most reliable medication monitoring

and drug detection results backed by expert toxi-

cologists and dedicated customer service.

neuroMetrix booth 110

NeuroMetrix - fast, accurate, and quantitative

evaluation of diabetic peripheral neuropathy

(dPN). NeuroMetrix markets the NC-stat®

dPNCheck™ a low cost, point of care device for

quantitative assessment of sural nerve conduction

for early and accurate identification of dPN. early

detection and intervention can reduce costly and

debilitating complications of diabetic peripheral

neuropathy.

nexus healthcare llc booth 218

Nexus healthcare is an executive search firm

dedicated to placing medical directors, chief

medical officers and exceptional healthcare execu-

tives in the heathcare industry nationwide. Our

extraordinary client base consists of managed care

organizations, health systems, hospitals and physi-

cian group practices. Our innovative approach to

executive search allows us to identify key individu-

als for our clients’ organizational challenges that

can best support their strategic objectives. We

have access to the highest caliber of managed care

talent. if you have an available position of have

an interest in our placement service, please give

us a call.

novartis pharmaceuticals booth 102

www.us.novartis.com

located in east hanover, N.J., Novartis Pharma-

ceuticals Corporation is an affiliate of Novartis ag,

which provides healthcare solutions that address

the evolving needs of patients and societies.

focused solely on healthcare, the Novartis group

offers a diversified portfolio to best meet these

needs: innovative medicines, preventive vaccines,

diagnostic tools, cost-saving generic pharmaceuti-

cals and consumer health products. The Novartis

group is the only company with leading positions

in each of these areas. headquartered in Basel,

switzerland, Novartis group companies employ

approximately 99,000 full-time-equivalent as-

sociations and operate in more than 140 countries

around the world.

novasys Medical booth 119

Novasys Medical, inc. is dedicated to the develop-

ment of innovative therapies in women’s health.

The company’s renessa® system is an in-office

treatment for female stress urinary incontinence.

The renessa treatment utilizes radiofrequency

energy to remodel collagen in the bladder neck

and urethra, firming the tissue and reducing incon-

tinence episodes without the downtime, risks and

recovery associated with surgery.

novo nordisk booth 105

Novo Nordisk is a focused healthcare company

and a world leader in diabetes care.

oncoMed, the oncology company booth 205

OncoMed, The Oncology Pharmacy, provides

comprehensive, proven oncology pharmacy solu-

tions to more than 1,600 oncologists and 35 payers

through a growing national network of certified

and JCahO-accredited pharmacies. in addition to

providing robust clinical management, compound-

ing, and dispensing services that meet the highest

professional standards for quality, safety, and

timely and accurate treatment delivery, OncoMed

provides critical financial, administrative, and

compliance support for oncology and hematology

physicians, cancer centers of excellence, cancer

patients, pharmaceutical manufacturers, and

health plans.

otsuka america pharmaceutical booth 214 and 216

Otsuka america Pharmaceutical, inc. (OaPi) is a

successful, innovative, fast-growing healthcare

company that commercializes Otsuka-discovered



and other product opportunities in North america,

with a strong focus on, and commitment, to neuro-

science, cardiovascular, oncologic, and gastroin-

testinal therapeutic treatments.

for additional information, please visit www.

otsuka-us.com.

perkinelmer booth 208

Perkinelmer Managed Markets offers the following

service providers which leverage leading-edge

technology and proprietary capabilities: signa-

ture genomics. The innovator in microarray as a

diagnostic tool. We’ve processed over 50,000

cases, more than all other providers combined.

NTd labs. a leader in prenatal screening and

the exclusive provider of the free beta hCg first

trimester down syndrome screening. Perkinelmer

genetics. The nation’s largest provider of newborn

screening services. We‘ve screened over 4 million

babies since 1994.

resMed booth 220

resMed is a global leader in medical equipment

for the screening, treatment, and management of

sleep-disordered breathing and other respiratory

disorders. Our product line includes automatic

positive airway pressure devices, bilevel devices,

continuous positive airway pressure devices, nasal

pillows systems, nasal mask systems, full face

mask systems, humidifiers, and software/clinical

systems.

si-bone booth 127

si-BONe, inc. is the leading sacroiliac (si) joint

medical device company dedicated to the de-

velopment of tools for diagnosing and treating

patients with low back issues related to si joint

pathology. The company is manufacturing and

marketing a minimally invasive surgical (Mis) tech-

nique for the treatment of si joint disorders.

salix pharmaceuticals booth 107 and 109

salix Pharmaceuticals is a specialty pharmaceuti-

cal company dedicated to acquiring, developing

and commercializing brand name, prescription

pharmaceutical products used in the treatment of

a variety of gastrointestinal diseases. salix’s strat-

egy is to identify and acquire late-stage propri-

etary pharmaceutical products having an existing

base of safety and efficacy data in humans for the

treatment of gastrointestinal disease, and to apply

the Company’s regulatory, product development,

and sales and marketing expertise to commercial-

ize these products.

seniorbridge booth 129

seniorBridge is a national health management

company with an 11-year heritage of managing the

care of people with complex chronic conditions

and functional limitations in their homes. The com-

pany’s interdisciplinary approach, developed by

experts in the field of aging, utilizes an integrated

care management team of nurse practitioners,

nurses and social workers who coordinate and

provide personalized care resulting in decreased

hospital admissions, readmissions, emergency

room visits and medical expenses.

smith & nephew booth 207

smith & Nephew has eXOgeN 4000+, only fda-

approved orthobiologic bone healing device

for non-invasive treatment of indicated fresh

fractures and reduce the incidences of non-unions.

smith & Nephew has helped millions of patients

reduce pain from osteoarthritis of the knee with

suParTZ® Joint fluid Therapy, with over 230

million injections worldwide and over 20 years of

experience. Visit www.smith-nephew.com for more

information on these and other products that help

alleviate pain in joints and promote healing.

tandem diabetes care booth 224

after years of research, and thousands of in-depth

conversations with people with diabetes and their

health care providers, Tandem diabetes Care™

has developed t:slim™, the first touch screen

insulin delivery system. t:slim’s vivid color touch

screen is your window to an easy-to-use interface

that provides quick access to all features. With the

footprint of a credit card and the design of a smart

phone, t:slim is the modern way to deliver insulin.

terumo bct booth 209

Terumo BCT is the world leader in blood compo-

nent technologies and an innovator in the field of

cell culture and cell therapy. TerumoBCT.com

Valeritas

booth 206

Valeritas is launching the V-go, the first simple,

fully disposable device for the delivery of basal-

bolus insulin therapy for adults with diabetes. The

V-go provides a continuous preset basal rate of

insulin and allows for on-demand bolus dosing

around mealtimes thereby providing an alternative

to taking multiple daily insulin injections.

Verinata health, Sponsor

booth 200, 202

Verinata is driven by a sole, extraordinary purpose

– maternal and fetal health. Our initial focus is to

develop and offer non-invasive tests for early iden-

tification of fetal chromosomal abnormalities using

our proprietary technologies. We aim to reduce

the anxiety associated with today’s multi-step

process, the unacceptable false-positive rates, the

non-specific and sometimes confusing results of

current prenatal screening methods, as well as the

risk of current invasive procedures. in support of

national guidelines recommending first trimester

aneuploidy risk assessment, we believe women

who desire such an assessment should be offered

a single blood draw test with a definitive result.

Verinata has completed its blinded pivotal study

to clinically validate the sensitivity and specificity

of its first prenatal test. The verifi™ prenatal test

is a non-invasive assay for the determination of the

three primary chromosomal aneuploidies for tri-

somies 21, 18 and 13. for more information about

Verinata, please go to www.verinata.com.

www.verinata.com

1Data on file. Verinata Health, Inc.

We are months ahead of the curve.

Testing for fetal chromosomal abnormalitiescan be safer, simpler and more definitive.1

To learn more about the verifi™ prenatal test, contact us:

1• 855 • BMOMKND (1• 855 • 266 • 6563)

M01

Client: Verinata Job#: VTA101/13C Approval Signatures:

File: VTA101_13C_PRODUCT_P4C_JMCM_M01.inddAE: Date:

AD: Date:

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PF: Date:

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Vendor: JMCM pub, Journal of Managed Care Medicine

Notes: no bleed

VTA101_13C_PRODUCT_P4CB_JMCM_M01.indd 1 3/14/12 3:34 PM

www.ethiconendosurgery.com

EthiconEndo-Surgery

Reimbursement and Healthcare Economics

Real Issues Real Solutions Real Savings

The EES Reimbursement & Healthcare Economics team delivers solutions for today’s healthcare environment.

With over 20 years of experience in the surgical field, we offer innovative approaches and proven strategies that:

To learn more, contact us at [email protected]

• Decrease surgical spend• Improve quality and outcomes• Address obesity prevalence and costs• Enhance member education & engagement• Create provider partnerships• Assist in developing Healthcare Reform solutions

DSL#10-1156

Documents

Journal of Managed Care Medicine Volume 15, Number 2