FINAL REPORT TO THE FLORIDA AGENCY FOR HEALTH CARE ADMINISTRATION (AHCA) Project 19

Transcription

1 1 FINAL REPORT TO THE FLORIDA AGENCY FOR HEALTH CARE ADMINISTRATION (AHCA) Project 19 Prescription Utilization Patterns and Hospitalizations in Epilepsy Patients on Anti Epileptic Drugs Abraham G. Hartzema, PharmD, MSPH, PhD, FISPE Professor and Eminent Scholar, Perry A. Foote Chair in Health Outcomes and Pharmacoeconomics, University of Florida, College of Pharmacy, Gainesville, Florida Richard Segal, PhD Professor and Chair, Department of Pharmaceutical Outcomes and Policy, University of Florida, College of Pharmacy, Gainesville, Florida Jane Ritho, Pharm. D., Ph. D candidate Department of Pharmaceutical Outcomes and Policy, University of Florida, College of Pharmacy Gainesville, Florida The Florida Center for Medicaid and the Uninsured June 30, 2011

2 2 TABLE OF CONTENTS page EXECUTIVE SUMMARY...3 Project Narrative...5 Specific Aim and Objectives...5 Background...6 Cost and Economic Data...9 RESEARCH DESIGN AND METHODS...10 Data Source...10 Study Measures...10 Data Analysis...12 FINDINGS...13 PART 1: Descriptive Analysis of Epilepsy Population...13 PART II: Use of Antiepileptic Drugs as Initial Treatment in Florida Medicaid Beneficiaries Diagnosed with Epilepsy...22 PART III: Determinants of Antiepileptic Drugs as Initial Treatment in Florida Medicaid Beneficiaries Diagnosed with Epilepsy...28 PART IV: Determinants of Medication Switching involving Antiepileptic Drugs in Florida Medicaid Beneficiaries Diagnosed with Epilepsy...35 PART V: To estimate the effect of Initial Treatment Choice involving Second- Generation AEDs on Epilepsy-Related Hospitalizations DISCUSSION...43 APPENDIX A...46 ICD-9-CM Codes Used for Disease Diagnosis...46 APPENDIX B...47 National Drug Codes (NDCs) for First-Generation AEDs...47 APPENDIX C...52 Study Flow Diagram for Identification of Cohort...52 APPENDIX D...53 Coding Algorithm for Health Care Resource Utilization and Cost Identification...53 APPENDIX E...55 Definition of Study Measures and Levels of Measurement...55 APPENDIX F...56 Data Cleaning...56

3 3 EXECUTIVE SUMMARY Antiepileptic drugs (AEDs) are efficacious in pharmacotherapeutic management of epilepsy, however, more information on the effectiveness of second-generation drugs in new epilepsy patients in clinical practice is needed. This is a retrospective study to describe prescription patterns involving SAEDs and to evaluate the effectiveness of traditional (FAEDs) drugs versus SAEDs on epilepsy-related emergency room visits and hospitalizations using Florida Medicaid claims data for a period of five (5) years from July 2004 through June 2009 with beneficiaries age <65 years old and not dual eligible. Patients with epilepsy and prescribed AEDs during the study period were identified for inclusion in the study population using ICD-9- CM codes from medical claims and NDC codes from pharmacy claim files, respectively. We described the epilepsy patient population, including their clinical and demographic characteristics, prescription utilization patterns and medical resource use attributed to epilepsy patients prescription drug and medical resource utilization patterns, and identified factors predicting hospitalizations (inpatient and emergency room) related to epilepsy. Multivariate regression analysis was performed to compare estimates of the effect of treatment choices involving second-generation AEDs on epilepsy-related hospitalization rates, adjusting for patient clinical (seizure type, co-morbidities, co-medications), sociodemographics (age, gender, and race), geographic location, and initiating provider specialty as covariates. A total of 15,376 Florida Medicaid beneficiaries were identified with a new epilepsy diagnosis during the 5-year study period at an estimated average monthly total cost of $3,982 per member per month (PMPM). Prescription drug costs were estimated at $146.4 million; although the majority of prescriptions were first-generation drugs (0.88PMPM) compared to secondgeneration drugs (0.67 PMPM), three-quarters of total pharmacy costs were associated with second-generation drugs ($108.5 million, $172 PMPM). One quarter of total pharmacy costs were from first-generation drugs ($37.9 million, $60 PMPM). However, the cost associated with second-generation drugs are will decrease as more drugs go off-patent and become available as generic drugs. Only 5,234 patients identified had a new epilepsy diagnosis and receiving pharmacological treatment with first or second-generation drugs. New patients were equally distributed by gender, and predominantly pediatric patients below age 21 years old when their

4 4 epilepsy was first diagnosed. A very small proportion of these patients had comorbid diseases or were on other prescription drugs at baseline, and over half of these patients were diagnosed with either generalized or partial seizures initially. Finally, fewer patients on monotherapy failed initial treatment; only 10% of Florida Medicaid beneficiaries with a new epilepsy diagnosis switched initial AED therapy, which was lower than the average (30%) reported in epilepsy literature. Overall, we found that the over 55% of new patients prescribed second-generation drugs were adults average 21 years old, and lamotrigene, topiramate, oxcarbazepine and levetiracetam were the most frequently prescribed second-generation antiepileptic drugs prescribed as monotherapy. Seizure type, referral to neurology physician and prior medical resource use patterns were crucial determinants of initial treatment with second-generation antiepileptic drugs compared to first-generation drugs. The likelihood of switching initial medication was higher for patients treated initially with second-generation drugs and lower for patients initiated on dual or polytherapy ( 2 drugs), compared to patients on first-generation drugs. Finally, compared to first-generation users, patients on second-generation drugs had a higher risk of utilizing healthcare resources, potentially due to seizure misdiagnosis, inappropriate therapy selection or suboptimal therapeutic doses and delayed referral to neurology physicians. Patient referrals to neurology physicians was significantly associated with use of second-generation drugs as initial therapy, and were likely involved in therapy decisions to switch patient medication in clinical practice. However, further examination of the individual drugs showed gabapentin, oxcarbazepine and levetiracetam users were less likely to use emergency room or inpatient hospital services compared to patients who did not receive these drugs as first-line treatment. On the other hand, patients on topiramate were more likely to use inpatient and emergency room, but the difference in resource utilization was not significantly different from non-topiramate users. Therefore it is our recommendation that new patient referrals to neurology physicians be done in a timely manner to ensure patients receive optimal treatment involving secondgeneration drugs. Also, patients and their primary care physicians involved in patient follow-up need to be educated to recognize adverse side-effects and to seek medical attention in and reduce the cost associated with emergency-room and inpatient hospital visits.

5 5 Project Narrative Epilepsy is a leading cause of neurologic disease in the United States. The clinical, economic, and psychological consequences of poor seizure control to patients, their families and society are substantial and major public health concerns. Decision-makers, who face rising healthcare expenditures and prescription drug costs in the presence of limited healthcare resources and growing budget constraints, are interested in identifying treatment strategies that improve health outcomes and minimize costs related to epilepsy. Randomized clinical trials have shown the comparative efficacy of first versus secondgeneration antiepileptic drugs (FAEDs vs. SAEDs) in reducing epilepsy seizure frequency, with compelling evidence showing SAEDs are better tolerated and have a lower incidence of adverse side-effects. Although antiepileptic drugs are posited to reduce epilepsy-related morbidity and premature mortality, major limiting factors to prescribing SAEDs as first-line therapy in new epilepsy patients are (1) the paucity of information on the their comparative effectiveness as monotherapy, and (2) their cost. Moreover, some patients (30%) fail initial drug treatment in medical practice and medication switching is sometimes necessary to optimize patient outcomes in chronic epilepsy treatment. Inappropriate therapy selection in epilepsy management with SAEDs will also increase hospitalizations related to breakthrough seizures and epilepsy-related complications. Hence, more information is needed on reasons for and effectiveness of SAEDs and medication switching patterns specific to Florida Medicaid beneficiaries. Specific Aim and Objectives Concern about limited healthcare resources and rising prescription drug expenditures to Florida Medicaid has underscored the need to increase current knowledge on SAEDs with respect to (1) the comparative effectiveness of alternative drug treatment options, (2) factors associated with likelihood of switching medication and the effect on medical resource use in routine medical practice. The overall aim of this study is to increase current knowledge of the comparative effectiveness of prescription utilization patterns involving SAEDs, and how therapy switching decisions impact longitudinal health outcomes in ambulatory epilepsy patients in Florida Medicaid. Healthcare providers and patients could also make informed decisions when initiating or switching therapy which optimize patient healthcare outcomes and minimize medical resource use. Amidst concerns about limited healthcare resources, the long-term goal is

6 6 to improve understanding of how delivery and utilization of SAEDs could be optimized from a healthcare cost and public health perspective. Background Epilepsy is a prevalent neurological disease affecting 3 million Americans of all ages (1% of the U.S. population); the clinical, economic, and psychological burden to patients and society is substantial and a public health concern. [1] It is characterized by recurrent seizures that occur in absence of (reversible) precipitating factors; lack of seizure control (1) increases patient risk for accidental injuries (fractures, head injuries, motor-vehicle accidents), disability, and psychological morbidity (anxiety, depression) which impact patient productivity, [2] (2) increases healthcare resource use and medical expenditures. [3] Most patients will require lifelong treatment; the annual cost of epilepsy is estimated at $15.5 billion, of which 85% are indirect costs to society (e.g. loss of workdays, employment restrictions). [4] Health care providers, policy-makers and decision-makers facing growing budget constraints are interested in effective disease management strategies that optimize health outcomes and minimize medical resource utilization. The clinical goals of pharmacotherapy in epilepsy are to eliminate seizures, reduce adverse drug side-effects and improve patient quality-of-life. Effective disease management involving antiepileptic drugs as first line treatment could optimize patient outcomes and reduce physical, psychosocial and economic consequences associated with poor seizure control. Secondgeneration antiepileptic drugs (SAEDs) marketed after 1990 provide multiple treatment options with different clinical and pharmacological effects for effectively reducing epilepsy-related morbidity. [5] Examples of first-generation drugs (gold standard) include phenytoin, phenobarbital, primidone, valproic acid, carbamazepine, and ethosuximide, and secondgeneration drugs include gabapentin, lamotrigine, topiramate, tiagabine, zonisamide, oxcarbazepine, levetiracetam, and pregabalin (see Table 1). [6,7,8,9] The clinical and pharmacological benefits associated with SAEDs, and evidence-based treatment guidelines identifying pharmacotherapy as the preferred standard of care in epilepsy management changed prescription drug utilization patterns in medical practice.[ 5,10] Prescription drug utilization patterns and associated prescription drug costs are projected to increase as more patients are diagnosed and living longer with epilepsy, and as treatment guidelines recommend early

7 7 Table 1: Summary of Antiepileptic Drugs and FDA-Approved Indications Antiepileptic Drug** Phenytoin a (PHT) Ethosuximide b,c (ESM) Primidone c (PRM) Phenobarbital b,c (PB) Divalproate (DS) or Valproic Acid c (VPA) Carbamazepine a (CBZ) Felbamate a,b,c (FBM) Gabapentin a,b,c (GBP) Lamotrigene a (LTM) Oxcarbazepine a (OXC) Tiagabine c (TGB) Levetiracetem e (LEV) Topiramate a,c,d (TPM) Main Side-Effects Lethargy, peripheral neuropathy, gingival hyperplasia, osteoporosis Blood dyscrasias, anorexia, depression Macrocytic anemia, sedation, depression, erectile dysfunction Learning difficulties, erectile dysfunction, sedation, paradoxical hyperactivity, depression, osteoporosis Weight gain, hepatotoxicity, pancreatitis, thrombocytopenia, osteoporosis, hair loss FDA Approved (Year); age in years (yo) Cause Drug-Drug Interaction First Generation Antiepileptic Drugs (FAEDs) Monotherapy (1939) ; >0 yo Monotherapy (1960) ; >3 yo Monotherapy (1954) ; >8 yo Monotherapy (1912); >0 yo Add-on therapy (1978-VPA;1983- DS); >10 yo Target Adult Daily Dose (mg/day) Brand Names Yes Dilantin, Phenytek Generic Available Yes Yes 250 Zarontin Yes Yes Mysoline Yes Yes Luminal Yes Yes Depakote Depakote ER Depakene Bone Marrow suppression, Add-on therapy Yes Tegretol Yes hyponatremia, dizziness, diplopia, sexual dysfunction, osteoporosis (1968); >0 yo Tegretol XR, Carbatrol, Equetro No Second Generation Antiepileptic Drugs (SAEDs) Aplastic Anemia, Monotherapy Yes Felbatol No hepatotoxicity (1993); >2 yo Weight gain, peripheral edema. Add-on therapy No Neurontin Yes (1993); >3 yo Stevens Johnson Syndrome, Monotherapy Yes Lamictal Yes rash, increased risk of renal or (1994); >2 yo hepatic failure, tics, insomnia. Hyponatremia, rash Monotherapy (2000); >4 yo Add-on therapy (1997); 12 yo Add-on therapy (1999); > 4 yo Monotherapy (1996); > 2 yo No Yes Yes Trileptal No Psychosis, weakness, encephalopathy Yes Gabitril No Irritability/behavior changes, No Keppra No somnolence Kidney stones, open-angle No Topamax No glaucoma, metabolic acidosis, weight loss. Zonisamide a,b,d Rash, kidney stones, Add-on therapy No Zonegran Yes (ZNS) photosensitivity, weight loss (2000); > 16 yo Pregabalin c Drowsiness, dizziness, fatigue, Add-on therapy No Lyrica No (PGB) myoclonic jerks, peripheral (2005); edema, weight gain. Vigabatrin c permanent peripheral visual Add-on therapy Yes Sabril No (VGB) field defect (25-33%), mood or (2009); >4 yo behavior changes, drowsiness Lacosamide a Nausea, vomiting, depression, Add-on therapy No Vimpat No (LCM) sedation, diplopia, muscle (2008) weakness Rufinamide a Fatigue, drowsiness, nausea, Add-on therapy No Banzel No (RFN) vomiting, hypersensitivity, rash *** Narrow therapeutic index and serious adverse side-effects which require frequent laboratory monitoring ** Mechanism of action of AEDs: a=sodium channel blocking drugs; b=calcium channel blocking drugs; c=gabaergic drugs or GABAmimetic drugs; d=carbonic anhydrase inhibitors; and e=unknown Common drug-drug interactions: Anticoagulatnts, Digoxin, Neuroleptics, Antacids, Antibiotics, Contraceptives, Muscle Relaxants; CCB= Calcium Channel Blockers

8 8 intervention with SAEDs in new patients; therefore, evaluating longitudinal drug utilization patterns in patient subpopulations using real-world data is important to patients, healthcare providers, and policy-makers. Physicians in clinical practice face a challenge in selecting SAEDs for epilepsy patients without any prior history of antiepileptic drug use. Crucial for choosing initial therapy is not only knowledge of the drug efficacy (mechanism of action, tolerability, adverse side-effects) and patient risk factors (seizure type, disease severity, sociodemographics), but also knowledge about concurrent comorbid diseases and concurrent medications. Furthermore, treatment guidelines and consensus statements by the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) since 2004 have recommended several SAEDs (gabapentin, lamotrigine, topiramate, and oxcarbazepine) as initial treatment in new onset epilepsy in adults; 11 these recommendations are not as well-defined in pediatric populations and treatment in pediatric patients is at the discretion of the prescribing physicians. Individual patients also respond differently to AED therapy, often in unpredictable ways; approximately 30% of new patients may fail initial monotherapy because it is challenging to initially select a specific AED and dose that will work for a particular patient. [5] Consequences of treatment failure or inappropriate treatment selection may include a relapse of epilepsy symptoms or breakthrough seizures that result in increased medical resource use (emergency department or inpatient hospitalizations). Medication switching is sometimes necessary to optimize patient outcomes in chronic epilepsy treatment. Medication switching in new patients may indicate intolerability to specific drugs. In other instances, patients with chronic disease become tolerant to treatment resulting in an increase in epilepsy-related hospitalizations related to breakthrough seizures and epilepsy-related complications. However, insufficient information is available on effectiveness of medication switching patterns specific to Florida Medicaid beneficiaries. Other studies have also shown poor adherence and early discontinuation of therapy increased patient risk of seizure recurrence, accidental injury, poor patient productivity, increased hospitalizations and medical costs in Medicaid patients as in other populations. [17,18,19,20,21]

9 9 Furthermore, significant differences in drug utilization patterns, [12] epilepsy-related hospitalizations, [20] and death [21] have been associated with variation in patient clinical factors (seizure diagnosis, comorbid conditions), sociodemographic characteristics (age, race, gender), and physician characteristics (specialty). However, information on the risks and benefits of initial treatment with SAEDs or therapy switching patterns using real-world data, and specific to Florida Medicaid patients, is scarce to help inform therapy decisions by healthcare providers, patients and policy makers about which drugs work best for specific patient subgroups (by age, race, gender) during a crucial treatment transition period. Cost and Economic Data In 2006, Medicaid accounted for approximately 9% of an estimated $217 billion in prescription drug costs in the United States (U.S.), which in turn comprises approximately 12.3% of the total U.S. national health expenditure ($1,762 billion). [13] Prescription drug costs are growing at a disproportionate rate compared to the Consumer Price Index (CPI). Florida Medicaid is managed by Florida s Agency for Healthcare Administration (AHCA), and Florida has the fourth-largest Medicaid population in the U.S. with an estimated 2.4 million eligible beneficiaries monthly; [14] their estimated total healthcare expenditure for fiscal year was $15.7 billion. [15] Annual total pharmacy reimbursement costs for AEDs (anticonvulsants) were approximately $95 million in 2003 (157,000 AED users or 7% of all Florida beneficiaries) and $102 million in 2004 (160,000 AED users or 7.5% of all Florida beneficiaries). [16] Prescription drug costs are projected to increase as the number of Florida Medicaid beneficiaries on antiepileptic drugs (anticonvulsants) increases. The clinical, economic, and psychological consequences of poor seizure control in epilepsy patients is substantial, with compelling evidence of continuing increases in epilepsyrelated hospitalizations and medical costs. Epilepsy-related patient hospitalizations from 2000 to 2005 in Healthcare Cost and Utilization Project (HCUP) data increased by 51 percent, at an estimated cost of $1.8 billion in 2005; about 65% of hospital admissions were through the emergency department and Medicaid was the primary payer for approximately 30% of hospital stays. [17] Medication non-adherence is also associated with increased seizure risk, [18] low patient productivity and accidental injury, [19] increased epilepsy-related hospitalizations, [20] medical costs, [19] and death [21] in Medicaid patients as in other populations. Understanding the

10 10 relationship between patient characteristics and health care resource utilization is of growing importance as (1) more patients are diagnosed and living longer with epilepsy who require lifelong-therapy, (2) treatment failure and switching medications in chronic patients increases patient risk of breakthrough seizures and subsequent healthcare resources during the transition period, and (3) costly new prescription medications are approved by the Food and Drug Administration for epilepsy (lacosamide or Vimpat and rufinamide or Banzel in 2008). [22] RESEARCH DESIGN AND METHODS Data Source Florida Medicaid fee-for-service claims database provides comprehensive data on monthly eligibility, healthcare resource utilization and associated costs for beneficiaries. This study utilized a retrospective cohort design to identify all Florida Medicaid beneficiaries between 0 and 64 years of age enrolled between July1, 2004 and June 30, 2009 (5-fiscal years) who had 1 inpatient or 2 outpatient medical claims for epilepsy, defined as International Classification of Disease Clinical Modification Version 9 (ICD-9-CM) code 345.xx during the study period. For each patient, the date of the first medical claim with an epilepsy diagnosis was identified as the index date. Pharmacy claims were used to identify epilepsy patients with 1 pharmacy claim for any first or second-generation antiepileptic drug using National Drug Codes (NDC) (Appendix B). A minimum of 6 months of continuous Medicaid eligibility before and 3 months after the index date was required to distinguish new epilepsy episodes (incident) from previously diagnosed epilepsy patients (prevalent). However, medical claims for Florida Medicaid beneficiaries age 65 years or dual-eligible patients were excluded from the analysis because complete medical and prescription drug records are not available. Also excluded were medical records for epilepsy patients residing in long-term care facilities or nursing homes because information on prescription drug use is not distinguishable from medical claims records. Study Measures Data elements available from Florida Medicaid claims (Medical, Inpatient and Pharmacy) included demographics, Medicaid eligibility status, date of service, primary and secondary diagnosis codes, drug codes, day supply, drug quantity, procedure codes, provider specialty,

11 11 geographic location, and payment amounts were used to describe the epilepsy patient population and healthcare resource utilization patterns as follows: Healthcare Utilization and Cost Measures Florida Medicaid fee-for-service claims (medical, pharmacy, and eligibility) data was used to identify epilepsy-related utilization and cost categories. hospital inpatient (hospital admission and length of hospitalization) emergency room visit hospital outpatient visit physician office visit Pharmacy claims related to FAEDs or SAEDs Other population characteristics were categorized as follows: Baseline Sociodemographic Factors: Patient age (years), race (Caucasian, Black, Hispanic, Other/unknown), gender (male, female, geographic area (county), Medicaid eligibility categories (Aid to families with dependent children-afdc, Supplemental Security Income-SSI, Other programs within Medicaid) were obtained from the enrollment files at the index date. Baseline Clinical Factors: Seizure disorder (generalized, partial, other), disease intractability (intractable, non-intractable), pre-existing mental health disorders, Charlson Comorbidity Index. Physician Factors: Diagnosing physician specialty (Neurology). Treatment: Antiepileptic drug treatment (first, second, dual) therapy, medication switching (yes/no). See Appendix A for ICD-9-CM codes for diagnosis codes related to epilepsy and comorbid diseases. See Appendix B for NDC codes used to identify FAEDs and SAEDs. See Appendix C for algorithm used to identify study sample of Florida Medicaid beneficiaries meeting inclusion and exclusion criteria for identifying epilepsy patients.

12 12 See Appendix D for coding algorithms for identifying healthcare resource utilization in epilepsy patients. See Appendix E for the description of other descriptive measures of patterns of healthcare resource use, measures of study variables, data sources, and level of measurement. Data Analysis A description of the study sample of Florida Medicaid beneficiaries with an epilepsy diagnosis was completed. Summary statistics were used (means & medians for continuous variables and proportions for categorical data). Descriptive summary of epilepsy-related patterns of prescription drug use (medication persistence, medication adherence) and hospitalizations (incidence of emergency room, inpatient hospitalizations, and inpatient hospitalizations related to status epilepticus, which is considered a neurological emergency related to epilepsy) were described for the sample of Florida Medicaid beneficiaries diagnosed with epilepsy. To examine the association between patient clinical and sociodemographic characteristics, prior resource use, geographic location, treating physician specialty and (i) initial treatment choice involving antiepileptic drugs and (ii) medication switching, multivariate logistic and multinomial regression analysis were conducted. To examine the effectiveness of SAEDs on incidence of epilepsy-related inpatient hospitalizations (emergency room visits and inpatient hospitalizations), multivariate cox proportional hazards were used. The cohort was restricted to new-users and exposure-month was used as the time-scale since eligibility to Florida Medicaid is determined on a monthly basis prescription drug refills are also on a monthly basis.

13 13 FINDINGS PART 1: Descriptive Analysis of Epilepsy Population This section provides a descriptive analysis of Florida Medicaid beneficiaries enrolled for at least one month between July 1, 2004 and June 30, 2009 with an epilepsy diagnosis, in terms of their demographic characteristics, healthcare and cost. Demographic Characteristics The baseline demographic characteristics of epilepsy patients in the study population are summarized in Table 2. A total of 15,376 Florida Medicaid beneficiaries were identified during the 5-year period with an epilepsy diagnosis (using ICD9-CM code 345.xx) with at least one pharmacy claim for an antiepileptic drug: 5,234 (34%) were incident patients with 6 months of continuous eligibility prior to the initial epilepsy diagnosis date, and 10,142 (66%) were prevalent patients with an epilepsy diagnosis. They contributed a total of 630,674 member months of Florida Medicaid eligibility during the 5-year period. Gender: o Overall, over half of the epilepsy population was female (52%). Incident patients were relatively equally distributed by gender (51% women vs. 49% male); however, the majority of prevalent patients were male (70%). Age: o The average age of the entire population was 24 years old (SD±18) at the time of initial diagnosis; slightly more than half (51%) were pediatric patients (age 19 years old or younger). The majority of incident patients (61%) were pediatric patients while the majority of prevalent patients (57%) were adult patients age 20 years and older. The median age was 28 years (IQR=26) for incident patients and 13 years (IQR= 28) for prevalent patients. Race: o Overall, the majority of the population was Caucasians (35%). African-Americans were 19%, Hispanics were 14% and Other (American-Indian, Asian, Other or Unknown) were 32% of the population. The race distributions were similar for both incident and prevalent patients.

14 14 Table 2. Baseline Demographics of Florida Medicaid Epilepsy Population Incident Prevalent Total %* N %* N %* N Total Beneficiaries 100 5, , ,376 Member Month (Average per Member) , , ,674 Gender Age at Index Epilepsy Claim (years) Race/ Ethnicity Medicaid Eligibility Disease Type Geographic Area Year of Index Diagnosis Female (vs. Male) 51 2, , ,998 Average (±SD) (±15) 30.9 (±18) 20.4 (±18) Median (Interquartile Range) (16-28 (5-13 ( ) 33) 37) < , , , Oct 20 1, , , , , , , , , , ,779 Caucasian 32 1, , ,350 Black , ,893 Hispanic , ,191 Other/unknown 35 1, , ,942 AFDC 38 1, , ,759 SSI 52 2, , ,265 Other Eligibility ,352 Generalized Seizures 33 1, , Partial Seizures 21 1, , Other Seizures 46 2, , Intractable Seizure 18 1, , Non-Intractable Seizure 82 4, , History (Hx) of Mental Disorders Hx of Other Comorbid Diseases 89 4, , ,905 Urban Rural *Proportions were rounded to the nearest whole number , , , , , , , , , , ,

15 15 Medicaid Eligibility: o In the entire population, the majority of beneficiaries diagnosed with epilepsy (67%) qualified for Supplemental Security Income (SSI), which is specifically for lowincome beneficiaries who meet federal qualifications for assistance through disability for the State of Florida. Over half (52%) of incident patients and three-quarters (75%) of prevalent patients were in this category. Disease Type: o Overall, 39% of the epilepsy population had generalized seizures (electrical disruptions from seizures occur throughout the brain; ICD-9-CM=345.0x-345.3x). Almost a quarter (22%) had partial seizures (electrical disruptions from seizures occur in only part of the brain; ICD-9-CM=345.4x, 345.5x, 345.7x). Almost half (48%) of the population with epilepsy had other seizure disorders (ICD-9- CM=345.8x-345.9x). o The trend was similar for incident patients; however generalized seizures were more common in prevalent patients (43%), followed by other seizures (35%) and partial seizures (22%). Only 20% of seizures at baseline were characterized as intractable seizures or seizures which were difficult to control; this trend was consistent for incident and prevalent patients. Geographic Area: o Thirty-three of Florida s 67 counties were classified as rural on the basis of the 2000 census data. We found the majority of patients in the epilepsy population (91%) resided in an urban county at baseline. This study found that the clinical and sociodemographic distribution of patients in Florida Medicaid beneficiaries with a new epilepsy diagnosis were comparable to other epilepsy patient populations with a disproportionately high incidence of epilepsy in children and adults, and an equal distribution of patients by gender. 23 Other studies reported partial seizures were the most prevalent epilepsy diagnosis in adolescents and adults, while generalized seizures were common in children younger than 10 years old. 24 By race, epilepsy was prevalent in racial-ethnic minorities and children with disabilities due to mental retardation or cerebral palsy. 25 In addition, epilepsy-related mortality rates are reported to be disproportionately high in high in non-caucasians. 26 Hence, Florida Medicaid beneficiaries

16 16 diagnosed with epilepsy were comparable to other epilepsy patient populations identified in medical practice. Healthcare Resource Utilization Healthcare resource utilization was examined for all Florida Medicaid beneficiaries during the 5-year study period from July 1, 2004 to June 30, The descriptive analysis was performed for all patients with an epilepsy diagnosis, who were categorized by whether the patient was grouped as incident (new patient with 6 months of continuous Florida Medicaid eligibility prior to initial epilepsy diagnosis) or prevalent (existing patient without 6 months of continuous Florida Medicaid eligibility prior to the initial epilepsy diagnosis). Pharmacy claims for FAEDs or SAEDs were also examined. All costs were inflated to 2009 US dollars using the medical care component of the Consumer Price Index. These costs excluded resource use and costs associated with long-term care facilities (buckets 05, 06, 07, 08, 09). As expected, the inpatient, outpatient, pharmacy, physician and other PMPM (per member per month) healthcare resource use and PMPM costs was higher for prevalent patients than incident patients. For epilepsy-related healthcare resource use and costs, all medical and pharmacy claims for patients with a primary diagnosis of epilepsy were examined and the descriptive findings for resource utilization and cost are summarized in Table 3. Epilepsy-related costs accounted for $2.5 billion with an estimatedoverall monthly cost of $3,981 PMPM over 5 fiscal years. All-cause healthcare resource utilization (inpatient, outpatient, pharmacy, physician and other resources, excluding long-term care facilities) for 15,376 Florida Medicaid epilepsy patients over 5 fiscal years accounted for a total of $ 5 billion dollars ($5,040,930,881) with an overall monthly cost of $15,849 PMPM. Inpatient Hospitalization: o Incident: Of 351,302 total epilepsy-related hospital admissions, new patients contributed to 113,725 (32%) of hospital admissions (0.49 visits PMPM) and 468,864 hospitalization days ( 2 days PMPM) with an estimated average monthly cost of $121 PMPM.

17 17 o Prevalent: These patients contributed to 237,577 (67%) of hospital admissions (0.59 visits PMPM) and 851,300 hospitalization days (2.12 days PMPM) with an estimated average monthly cost of $160 PMPM. o Incident patients accounted for 30% ($27.8 million) of the total inpatient costs while inpatient costs for prevalent patients accounted for 70% ($64.4 million) of the total inpatient costs related to epilepsy. Emergency Room Visits: o Incident: Of 7,937 total epilepsy-related emergency room visits, incident patients contributed to 2,864 (36%) emergency room visits (0.1 visits PMPM) with an estimated average monthly cost of $1.3 PMPM. o Prevalent: These patients contributed to 5,073 (64%) emergency room visits with an estimated average monthly cost of $ 1.3 PMPM. o Emergency room costs for incident patients accounted for 36% ($297 thousand) of the total emergency room costs while emergency-room costs for prevalent patients accounted for 64% ($520 thousand) of the total emergency room costs related to epilepsy. Outpatient (Hospital) Visits: o Incident: Of 369,602 total epilepsy-related outpatient hospital visits, incident patients contributed to 118,854 (32%) of outpatient visits with an estimated average monthly cost of $71 PMPM. o Prevalent: These patients contributed to 250,748 (67%) of outpatient visits with an estimated average monthly cost of $82 PMPM. o Outpatient hospital visits for incident patients accounted for 33% ($16.4 million) of the total outpatient hospital costs while prevalent patients accounted for 66% ($32.9 million) of the total outpatient hospital visits related to epilepsy. Pharmacy: o Incident: Of 988,373 total pharmacy claims, 22 % (224,268) were first-generation AEDs and 16% (152,851) were second-generation AEDs. Pharmacy claims accounted for $55,447,653, of which first-generation drugs and second-generation drugs had an estimated average monthly cost of $ $64 PMPM and $177 PMPM, respectively.

18 18 o Prevalent: Pharmacy claims for first-generation and second-generation AEDs accounted for 34% (335,411) and 28% (275,843), respectively, of the total pharmacy claims for antiepileptic drugs, an estimated pharmacy cost of $ 90,983,793; firstgeneration drugs and second-generation drugs had an estimated average monthly cost of $57 PMPM and $169 PMPM, respectively. o Of $146.4 million in total epilepsy-related pharmacy costs, prevalent patients contributed to the majority (62%) of these total pharmacy costs. o Although a smaller proportion of prescription claims dispensed were for secondgeneration drugs, these drugs accounted for a higher proportion of the pharmacy costs than first-generation drugs. Physician Visits: o Incident: Of 957,772 total physician office visits during the 5-year period, new patients had 302,324 (32%) physician office visits with an estimated average monthly cost of $146 PMPM. Only 18,470 (6%) of these office visits were neurology physician office visits at an estimated average monthly cost of $9.3 PMPM. o Prevalent: These patients contributed to 655,448 (68%) physician office visits with an estimated average monthly cost of $206 PMPM. Only 43,744 (7%) of these office visits were neurology physician office visits at an estimated average monthly cost of $15.4 PMPM. o Epilepsy-related physician office costs for incident patients were 29% ($33.6 million) of total physician office visit costs, of which neurology physician office visits accounted for only 7% ($2.1 million) of these physician office visit costs. Conversely, epilepsy-related physician office costs were 71% ($82.5 million) of total physician office visit costs, of which neurology physician office visits accounted for only 7% ($6.1 million) of these physician office visit costs.

19 19 Table 3 Epilepsy-Related Healthcare Resource Utilization & Expenditure in Florida Medicaid Epilepsy Population in 5 year period (July 1, 2004-June 30, 2009) Incident 1 Prevalent 2 Total 3 Resource Utilization Total Expenditure Resource Utilization Total PMPM Total ($) % PMPM Total PMPM Total ($) % PMPM Cost Cost Total Expenditure Resource Utilization Total Expenditure Total PMPM Total ($) PMPM Cost Inpatient Hospital 113, ,867,283 3% , ,472,071 4% , ,339, Admission Hospital 468, , ,320, Days Emergency 2, , % 1.3 5, ,145 0% 1.3 7, , Department Visit Hospital Outpatient 118, ,437,655 2% , ,932,741 2% , ,370, Visit Physician Office Visit 302, ,656,012 4% , ,570,440 5% , ,226, , ,130, % , ,185, % , ,315, Neurology Visit Pharmacy 1st Gen 224, ,683,315 6% , ,227,980 5% , ,431, Claims 2nd Gen 152, ,764, , ,755, ,613,927 85% ,369,309,722 84% ,108,923, Other Services Total ,233, % ,638,909, % ,511,142, Based on 5,234 patients and 229,969 member month 2 Based on 10,142 patients and 400,705 member-months PMPM= per member per month 3 Based on 15,376 patients and 630,674 member-month Descriptive of Epilepsy-Related Prescription Drug Patterns for Patients on Monotherapy Table 4a provides a summary of prescription drug use patterns by type of antiepileptic drug used for the top 15 drugs prescribed as monotherapy to Florida Medicaid beneficiaries with an epilepsy diagnosis. A descriptive summary of the trends observed for patients who did not switch medication compared to those patients whose medication changed during the study period (switched to another single drug or augmented to two or more drugs). The three most common drugs prescribed as monotherapy in pediatric patients under age 21 years were oxcarbazepine, valproic acid and carbamazepine, of which only oxcarbazepine has a pediatric indication for monotherapy; valproic acid, carbamazepine, and gabapentin have pediatric indications as add-on therapy. The average patient age at baseline, average duration (days) on treatment (persistence) on each drug and the total duration of exposure in person-days for each drug regimen was provided.

20 20 Table 4 Baseline Characteristics of Pharmacy and Healthcare Resource Use Patterns by Type of Antiepileptic Drug Prescribed as Monotherapy for Pediatric Epilepsy Patients (age < 21 years old) by Switch Group (No Medication Switch versus at least 1 Medication Switch) Mean Persistence (days) Baseline Mean Age (years) Mean Adherence (MPR) Total Exposure (person days) Mean Hospital Days Hospital Incidence per 1000 days Emergency Room Incidence per 1000 days Status Epilepticus Incidence per 1000 days Drugs Prescribed to Epilepsy Patients as Monotherapy Drug Category Mechanis m of Action No Switch Group (NO) versus Switch Group (YES) (characteristics before switch) No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes OXCARBAZEPINE 2 Na ,288 61, VALPROIC_ACID 1 GABA ,690 59, CARBAMAZEPINE 1 Na ,832 69, PHENOBARBITAL 1 Ca, GABA ,775 58, LEVETIRACETAM 2 Unknown ,888 18, LAMOTRIGINE 2 Na ,403 22, TOPIRAMATE 2 Na, Ca, GABA ,303 25, PHENYTOIN 1 Na ,963 10, ETHOSUXIMIDE 1 Ca, GABA ,592 2, ZONISAMIDE 2 Na, Ca, Carbonic ,521 7, CLONAZEPAM 1 GABA ,688 4, DIAZEPAM 1 GABA ,634 2, GABAPENTIN 2 Na, Ca, GABA ,640 3, LORAZEPAM 1 GABA ,020 2, PRIMIDONE 1 GABA Mechanism of action of AEDs: Na=sodium channel blocking drugs; Ca=calcium channel blocking drugs; GABA=GABAergic drugs or GABAmimetic drugs; Carbonic=carbonic anhydrase inhibitors; and unknown=unknown mechanism

21 21 The three most common drugs prescribed as monotherapy in pediatric patients under age 21 years were oxcarbazepine, valproic acid and carbamazepine, of which only oxcarbazepine has a pediatric indication for monotherapy; valproic acid, carbamazepine, and gabapentin have pediatric indications as add-on therapy. Most of these SAEDs have a narrow mechanism of action. Although Zonidamide is indicated as add-on therapy for children age over 16 years old, it is prescribed as initial therapy to children age 11 years. Medication persistence varied for patients on monotherapy; the majority of no switch patient group were on monotherapy for at least 365 days, except for gabapentin, diazepam, lorazepam,,and primidone. On the other hand, persistence was less than 365 days for most drugs on the switch group, except for phenobarbital, gabapentin Medication adherence was very high (>90%) in the no therapy switch just prior to switching medication compared to the therapy switch group (>80%), with the exception of diazepam (<50%). This could indicate that non-adherence to medication was not the main reason for medication switching. Overall resource utilization patterns, measured using hospital incidence per 1000 days, emergency room incidence per 1000 days and hospitalizations related to status epilepticus per 1000days was higher in the patients who switched medication compared to the patients who maintained the same drug without switching medication. The average age of patients at the time treatment was initiated was similar in the no switch and switch groups. Also, switching patient medication is a complex process that places patients at increased risk for breakthrough seizures, as seen by the high incidence of epilepsy-related emergency room use and inpatient hospitalizations in the medication switch group compared to the non-switch patient group.

22 22 PART II: Use of Antiepileptic Drugs as Initial Treatment in Florida Medicaid Beneficiaries Diagnosed with Epilepsy A total of 5,234 Florida Medicaid beneficiaries were identified with a new epilepsy episode. Table 5 shows the distribution of antiepileptic drug use in this sample of new users. The majority of the patients (61%, n=3194) were children and adolescents 19 years old and the mean age of the study cohort was 19 years old (±18 SD). When initial treatment was compared, we found on average that SAED users were slightly younger (18.2 years old ±18 SD) compared to FAED users (19.7 years old ±18 SD) and compared to the study sample average (19 years old). A summary of the baseline characteristics of these patients is as follows: Of the 5,234 patients in the study cohort treated with antiepileptic drugs, 45% (n=2375) received a first-generation antiepileptic drug (FAED), 21% (n=1092) received a second-generation antiepileptic drug (SAED) as monotherapy, and 24% (n=1249) received 2 antiepileptic drugs concurrently (dual therapy) as initial therapy. By gender, the distribution of males (n=2538) versus females (n=2688) was relatively equal (49% vs. 51%). o Within each category by gender, a higher proportion of patients were consistently prescribed FAEDs (45%) compared to SAEDs (21%) as initial therapy. By race/ethnicity, the majority of patients were Caucasian (32%, n=1662) or Other (Asian, American Indian or unknown) race patients (35% n=1813). o A higher proportion of patients within each of the race categories were consistently prescribed FAEDs (45%) compared to SAEDs (21%). Over half (51%) of the Florida Medicaid beneficiaries with a new epilepsy obtained Medicaid Eligibility through Supplemental Social Security (SSI) i.e. met the federal qualifications for assistance through disability. o Within each Medicaid eligibility category, the majority of patients with eligible for SSI (48%), Aid to Families with Dependent Children (AFDC) (44%) and other eligibility categories were consistently prescribed FAEDs compared to SAEDs. Almost one-third of these patients were diagnosed initially with epilepsy in 2006 (30%) and 2007 (32%).

23 Age at Index Diagnosis, % (n) Gender, % (n) Race/ Ethnicity, % (n) Medicaid Eligibility, % (n) Area, % (n) Index Diagnosis Year, % (n) Baseline Clinical Factors, % (n) Prior 6- Month Health Service Use, % (n) Prescribing Physician % (n) Table 5. Baseline Patient Characteristics of New AED Users Age 0-64 Years Total Dual Poly Tx FAED SAED (%=10 0n=5,234) (%=23. n=1,249 86) (%=9.90 n=518) (%=45.38 n=2,375) (%=20.86 n=1,092) Average mean±sd (±18.01) (±17.65) (±17.89) (±18.15) (±18.14) 0-9 years old 2, (513) (216) (950) (482) years old 1, (235) (108) (483) (207) years old (164) 9.56 (57) (255) (120) years old (122) 7.81 (40) (250) (100) years old (111) (49) (219) (89) years old (104) (48) (218) (94) Male 2, (578) (269) (1,152) (539) Female 2, (667) 9.23 (248) (1,220) (553) Caucasian 1, (393) (170) (761) (338) Black (242) 8.79 (84) (430) (200) Hispanic (173) (92) (358) (173) Other/unknown 1, (437) 9.43 (171) (824) (381) AFDC 1,, (484) (210) (869) (425) SSI 2, (617) 8.93 (241) (1,288) (554) Other Eligibility (144) (66) (216) (113) Urban 4, (1,093) 9.99 (464) (2,102) (981) Rural (152) 9.20 (54) (270) (111) (27) (14) (57) (22) , (356) (144) (601) (271) , (356) (169) (709) (317) , (383) 8.77 (147) (781) (365) (127) 8.53 (44) (228) (117) Generalized Seizures 1, (408) 11 (190) (807) (334) Partial Seizures 1, (269) (118) (498) (217) Other Seizures 2, (572) 8.78 (210) (1,070) (541) Intractable Seizures 1, (291) (171) (365) (235) Non-Intractable Seizures 4, (958) 8.32 (347) (2009) (857) Hx of Mental Disorders (28) 7.97 (11) (65) (34) Hx of Other Comorbid Diseases (4) 3.33 (1) (15) (10) Other Prescription Drugs 3, (937) 9.95 (386) (1,761) (797) Physician Office Visits (19) 1.33 (2) (80) (49) Inpatient Hospital Visits (16) 2.26 (3) (66) (48) Emergency Room Visits (118) 5.64 (43) (426) (176) Neurology (57) (32) (98) (77) General Practice (189) 9.05 (83) (441) (204) Dual (2 Antiepileptic drugs) Poly ( 3 Antiepilepic Drugs) SAED (Second Generation Antiepileptic Drugs) FAED (First Generation Antiepileptic Drug 23

24 24 o Although the proportion of patients prescribed FAEDs as initial treatment remained relatively high (44-47%) compared to SAEDs (18-23%) from 2004 to , the trend showed a relatively small but steady increase in the proportion of patients using SAED from 2004 to as initial treatment in this population. Of the 5,234 patients, one-third (33% n=1739) had generalized seizures, 21% (1102) had partial seizures and 46% (n=2393) had other seizure disorders, as determined by the first medical claim identified with an epilepsy-related seizure diagnosis. Over three-quarters had non-intractable seizures (85%), while the proportion of epilepsy patients with a previous history of mental disorders (3%) or other comorbid (non-mental) diseases (1%) was very small. o Almost half of these patients with non-intractable disease, mental disorders, and other comorbid diseases were initially treated with FAEDs compared to SAEDs Three quarters of the patients (75%) used at least one other prescription drug prior to initial diagnosis; 14% used emergency room services and 3% used inpatient hospital services. Only 5% of patients were seen by a neurology physician at baseline. Of the 5,234 patients in the study cohort, the initial treatment of at least 690 (13%) patients underwent medication switching or augmentation; 28% (192) were on SAEDs, 50% (347) were on FAEDs, and 22% were on 2 or more AEDs as initial treatment. Table 6 shows the characteristics of Florida Medicaid beneficiaries on second generation antiepileptic drugs (SAEDs) as initial therapy and the distribution of SAEDs prescribed to this new user population (n=1092). The SAEDs included in the table were gabapentin (GBP), lamotrigene (LTM), levetiracetam (LEV), oxcarbazepine (OXC), topiramate (TPM), zonisamide (ZNS) and other SAED (felbamate, tiagabine, pregabalin). The most commonly prescribed SAEDs were oxcarbazepine (23%), topiramate (20%), lamotrigene (19%) and levetiracetam (19%). The majority of these drugs are indicated for epilepsy treatment in children and adults (see Table 1): Lamotrigene and topiramate are indicated for children (>2 years old) as monotherapy. While gabapentin, levetiracetam and oxcarbazepine are indicated for children and adults as add-on therapy, zonisamide and pregabalin are indicated for adolescents and adults as add-on therapy. In the Florida Medicaid population we found the following trends: