Improving Men’s Health,Quality of Life, and Cost Outcomes:

Evolving Treatment Strategies for Benign Prostatic Hyperplasia

Faculty

William J. Cardarelli, PharmDDirector of Pharmacy Revenue and Supply

Atrius HealthHarvard Vanguard Medical Associates

Watertown, Massachusetts

Claus G. Roehrborn, MD Professor and Chair

Department of UrologyUT Southwestern Medical Center

Dallas, Texas

Learning Objectives

• Discuss the impact of underdiagnosed and undertreated BPH on clinical, economic, and quality of life outcomes

• Describe the epidemiology and clinical correlation between LUTS/BPH and ED

• Implement health plan policies aimed at educating in-plan clinicians and covered patients on symptoms and evidence-based treatments for LUTS/BPH

• Translate evidence on the benefits and limitations of traditional and newer BPH therapies to formulary discussions and review

Improving Men’s Health,Quality of Life, and Cost Outcomes:

Evolving Treatment Strategies for Benign Prostatic Hyperplasia

Claus G. Roehrborn Professor and Chairman

UT Southwestern Medical CenterDepartment of Urology

A Modern View of Male LUTS and BPHClinical, Anatomic, and Pathophysiologic Changes

• BPH

– Histologic:stromoglandular hyperplasia1

• May be associated with

– Clinical:presence of bothersome LUTS2

– Anatomic:enlargement of the gland (BPE = Benign Prostatic Enlargement)2

– Pathophysiologic:compression of urethra and compromise of urinary flow (BOO = Bladder Outlet Obstruction)2

BOO = bladder outlet obstruction; BPE = benign prostatic enlargement; BPH = benign prostatic hyperplasia; LUTS = lower urinary tract symptoms.1. Roehrborn C (reviewer). Rev Urol. 2002;3:139-145. 2. Nordling J, et al. In: Chatelain C, et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001:107-166.

HistologicBPH

All Men>40 y

BOOObstruction

BPEEnlargement

LUTS/Bother

Epidemiology of BPHHistologic Prevalence around the World

Lepor H. Rev Urol. 2004;6(suppl 9):S3-S10; Roehrborn CG, McConnell JD. Etiology, pathophysiology, epidemiology and natural history of benign prostatic hyperplasia. In: Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia, PA: WB Saunders Co; 2002:1297-1336; Roehrborn CG. Int J Impot Res. 2008;20(suppl 3):S11-S18.

Holund1980

Franks1954

Karube1961

Harbitz1972

Fang-Lui1991

Baron1941

Moore1943

Swyer1944

Pradhan1975

Pre

vale

nce

(%

)

20-29 30-39 40-49 50-59 60-69 70-79 80-89

Age (years)

80

70

90

60

50

40

30

20

0

10

100

LUTS Increases with AgePresence of Bothersome LUTS(Moderate to Severe, IPSS >7)

IPSS = International Prostate Symptom Score.Oishi K, Boyle P, Barry JM, et al. Epidemiology and natural history of benign prostatic hyperplasia. In: Denis L, Griffiths K, Khoury S, et al. eds. Fourth International Consultation on BPH, Paris, July 1997. Plymouth, UK: Health Publications. 1998:25-59.

50-59 60-69 70-79

Canada FranceUSA HollandChinaAsia Australia

Pat

ien

ts (

%)

80

40

30

0

70

20

10

60

50

15

2731

2630

36

8

14

2729

40

56

24

33

49

3633

37

3136

44

Age (years)

Negative Impact of BPH on Daily QoLIncreases with Symptom Severity

QoL = quality of life. N = 2115.*Reported as 2% to 4%.Girman CJ. et al. Urology. 1994;44:825-831.

Mild Symptoms

Moderate orSevere Symptoms

25

20

10

0Getting

Enough Sleep

Men

Rep

ort

ing

Mo

re T

han

a L

ittl

eIn

terf

eren

ce w

ith

Act

ivit

ies

(%)

15

5

Going Placeswith No Toilet

PlayingOutdoor Sports

**

Q44 “Now I’m going to read you a series of statements and I would like you to tell me whether youagree strongly, agree somewhat, disagree somewhat or disagree strongly with the statement”

Concerns of Men with BPH by LUTS Severity(Agree Strongly or Somewhat)

Worry aboutenlarged prostate

Prostate symptomsare embarrassing

Worry conditionmay be prostate cancer

Prostate conditionreduces QoL

Worry conditionmay get worse

Expect conditionto get worse

0 5 10 15 20 25 30 35 40 45

24

10

13

7

24

9

Percent (%)

25

17

28

33

42

39

Moderate / Severe

(n=419)

LUTZ Severity:

Mild

ConsequencesProblems

AUR = acute urinary retention; UTI = urinary tract infection.1. AUA Practice Guidelines Committee. J Urol. 2003;170:530-547. 2. Rosen R, et al. Eur Urol. 2003;44:637-649. 3. Lepor H, Lowe FC. In: Walsh PC, et al, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa: Saunders; 2002:1337-1377.

LUTS1,2

BPH

BOO3

BothersomeInterference with

daily activities andsexual function

AURSurgery

Nonfunctioning bladderUTI

StonesRenal failure

AUR in Population-Based Studies

Author/Source

Description of Cohort Cases CohortYears of

f/uPercentOverall

Percent /Year

IR/1,00ptyrs

95% CI

Ball,1981

Watchful Waiting Study 2 107 5 1.9 0.37% 3.7

Craigen,1969

Watchful Waiting Study 15.0

Birkhoff,1976

Watchful Waiting Study 10 26 3 39% 13% 130

Wasson,1995

TURP vs Watchful WaitingVA COOP

8 276 3 2.8% 0.9% 9.6

Hunter,1997

Self reported prior eventsin Spanish men

102 2002 ? 5.1 50.9

Barry,1997

Prostatectomycandidates

40 500 4 8% 2.5% 25

Meigs,1999

Physicians Health Study,Self reported

82 6,100 3 1.3% 4.5 3.1; 6.2

Olmsted,1997

Community Cohort40-49 years old

57 2,115 4 6.8 5.2; 8.9

McConnell,1998

Placebo group ofPless Study

99 1,376 4 7.2% 1.8% 18

Andersen,1997

Placebo groups oftwo year BPH studies

57 2,109 2 2.7% 1.35% 13.5

Impact of AUR on QoL

Thomas, et al. BJU Int. 2005;95:72-76.

AUR (n=43)

Interference of painwith enjoyment of life

during the past 24 hours

2 4

8

7

10

9

5

3

0

0 6 8 10

Mea

n I

nte

rfer

ence

Follow-up (years)

2

1

6

4

Elective BPH Surgery (n=35) Renal Colic (n=17)

Feeling about spendingthe rest of your life withyour urinary condition

2 4

7

6

4

1

0 6 8 10

Follow-up (years)

3

2

5

Terrible

Unhappy

EquallySatisfied and

Dissatisfied

Delighted

MostlySatisfied

Pleased

MostlyDissatisfied

RetenFrance: Immediate Complications by Duration of Catheterization

Desgrandchamps F, et al. BJU Int. 2006;97:727-733.

Catheter≤3 Days(n=817)

Catheter>3 Days(n=1600)

P

Haematuria

Asymptomatic bacteriuria

Lower UTI

Urosepsis

Urine leak

Catheter obstruction

6.1%

4.9%

1.1%

0.9%

2.2%

0.4%

12.0%

14.1%

4.3%

2.0%

4.6%

2.1&

<.001

<.001

<.001

.03

.003

<.001

Prolongation of hospitalization

Median prolongation (in days)

3.2%

5

6.5%

7

<.001

Use of Treatment Options United States vs Europe

US Market Europe

MIST 1%

SurgeryMIST3%

WaWa40%

WaWa24%

Surgery 2%

Drugs57%

Drugs73%

Center for Disease Control and PreventionHospital procedures, all-listed: US, 1990-2010

(Source: NHDS) Rate per 10,000

The data are from the National Hospital Discharge Survey (NHDS). The NHDS collects data from a sample of inpatient records acquired from a national sample of short stay, non-federal hospitals in the United States. Additional information on technical aspects of the survey, including definitions of terms, is available at the National Hospital Discharge Survey web page .Procedures have been coded using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). Up to four procedures were coded per discharge in the NHDS through 2009. Beginning in 2010, up to eight procedures are coded per discharge in the NHDS. Some estimates of all-listed procedures in 2010 may therefore exhibit marked increases if compared with prior years.

1990

80

120

100

0

Pro

ced

ure

s (p

er 1

0,00

0)

20

60

40

2000 2010

Bariatric Surgery

Removal of Prostate

Transurethral Prostatectomy

Hysterectomy

Vaginal Hysterectomy

Repair of Cystocele(bladder) and Rectocele(rectum)

Excision of IntervertebralDisc and Spinal Fusion

Total Hip Replacement

Total or Partial KneeReplacement

8.6

95.7

53.0

42.2

18.412.311.9

6.1

13.7

16.922.2

25.231.0

38.2

60.1

8.713.315.418.1

26.9

84.6

91.9

30.1

7.0

The Demographic Burden of Urologic Diseases in AmericaNational Physician Office and Hospital

Outpatient Visits for BPH or LUTS

Rate per 100,000 based on 1994, 1996, 1998, and 2000 population estimates from Current Population Survey for relevant demographic categories of American male civilian noninstitutionalized population ≥40 years old.Data from Litwin MS, Saigal CS, editors. Urologic diseases in America. NIH Publication No. 07–5512. Washington: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, US Government Publishing Office; 2007.Miller DC, et al. Urol Clin North Am. 2009;36:11-27.

1994

7,000,000

9,000,000

8,000,000

0

1,000,000

4,000,000

2,000,000

1998 2000

Primary Reason

Any Reason

3,000,000

6,000,000

5,000,000

1996

4,603,426

2,899,300

6,112,287

3,658,367

6,443,185

3,990,359

4,418,425

7,797,781

The Demographic Burden of Urologic Diseases in America (cont)

Urologic Clinics of North America Volume 36, Issue 1, February 2009, Pages 11–27

No. Visits to Office-Based Physicians (NAMCS) Plus Hospital Outpatient Clinics (NHAMCS)

No. Visits toEmergency Rooms

(NHAMCS)

No. Hospital Stays

Total Expenditures

(Million $)Primary Diagnosis Any Diagnosis

ProstateChronic and acute prostatitis — 1,841,066 — — $84,452,000Benign prostatic hyperplasia 4,418,425 7,797,781 117,413 105,185 $1099.5Prostate cancer 3,330,196 — — — $1,295,800,312BladderInterstitial cystitis, painful bladder syndrome — — — — $65,927,937Urinary incontinence in women 1,159,877 2,130,929 — 46,470 $452.8Urinary incontinence in men 207,595 353,065 — 1332 $10.3Bladder cancer — — — — —Lower tract transitional cell cancer — 832,416 — — $1,073,803,094Upper tract transitional cell cancer — — — — $64,309,807KidneyUrolithiasis 1,996,907 2,682,290 617,647 177,496 $2067.4Kidney cancer — 279,564 — — $401,390,672Pediatric urologic disordersVesicoureteral reflux 83,791 140,098 — — $41,725,663Undescended testis 148,551 215,482 — — —Hypospadias — 17,364 — — $16,563,330Ureterocele — — — — $16,803,712Male reproductive healthInfertility — 158,413 — — $17,046,404Erectile dysfunction — 2,904,896 — — $327,626,849Peyronie's disease — — — — —Urethral stricture — 364,389 — — $191,074,350Testicular cancer — 14,790 — — $21,745,500InfectionsUrinary tract infections in women 6,860,160 8,966,738 1,311,359 245,879 $2474Urinary tract infections in men 1,409,963 2,049,232 424,705 121,367 $1027.9

The Cost of Treating the 10 Most PrevalentDiseases in Men 50 Years of Age or Older

*Categories are not exclusive; patients may exist in more than one cohort.SD = standard deviation; CAD = coronary artery disease; GERD = gastroesophageal reflux disease.Fenter TC, et al. Am J Manag Care. 2006;12:S90-S98.

Age, Diagnoses, and Prescription Drug Use by Disease State

Disease* NMead Age

(SD)

Non-Disease-Specific

Prescriptions

Prescription Categories

Diagnoses

Arrhythmias 13,202 63.63 (8.48) 9.9 (10.72) 4.07 (3.52) 11,31 (7.87)

Osteoarthritis 26,835 60.39 (7.7) 7.64 (8.91) 2.91 (2.75) 6.61 (5.22)

Cataracts 68,866 65.46 (7.9) 10.29 (11.53) 3.77 (3.47) 5.97 (5.21)

CAD 21,074 61.78 (8.1) 5.65 (7.98) 2.46 (2.74) 8.32 (6.15)

Bursitis 26,449 58.01 (6.59) 8.26 (9.66) 3.2 (3.03) 5.81 (4.76)

Type 2 Diabetes 22,476 60.16 (7.42) 8.93 (10.48) 3.45 (3.25) 6.12 (4.97)

Enlarged Prostate 25,886 63.56 (8.02) 9.56 (10.59) 3.83 (3.34) 7.63 (5.74)

GERD 23,575 59.29 (7.37) 8.55 (9.58) 3.49 (3.12) 7.48 (5.88)

Depression 25,838 58.92 (7.72) 10.48 (11.04) 4.17 (3.61) 7.2 (6.78)

Hypertension 59,084 59.6 (7.46) 4.47 (6.56) 2.04 (2.37) 5.79 (5.03)

Overall 259,480 60.48 (7.86) 7.77 (9.78) 3.04 (3.09) 5.91 (5.08)

The Cost of Treating the 10 Most PrevalentDiseases in Men 50 Years of Age or Older

CAD = coronary Artery disease; GERD = gastroesophageal reflux disease.Fenter TC, et al. Am J Manag Care. 2006;12:S90-S98.

One-year Disease-specific Medical Costs for the10 Most Prevalent Diagnoses in Men ≥50 Years of Age

Co

st (

$)

1800

1600

1400

800

600

400

0

200

1200

1000 885989

1699

463463

782

217316

401

213

The Cost of Treating the 10 Most PrevalentDiseases in Men 50 Years of Age or Older (cont)

CAD = coronary Artery disease; GERD = gastroesophageal reflux disease.Fenter TC, et al. Am J Manag Care. 2006;12:S90-S98.

Percent Contribution of Disease-specific Total Costs byMedical vs Prescription Costs for each of the

10 Most Prevalent Diagnoses in Men ≥50 Years of Age

Per

cen

t (%

)

100

80

70

40

30

20

0

10

90

60 Prescription

Medical50

0

10088

12

84

16

49

51

82

18

52

48

29

71

33

67

52

48

41

59

The Cost of Treating the 10 Most PrevalentDiseases in Men 50 Years of Age or Older (cont)

CAD = coronary Artery disease; GERD = gastroesophageal reflux disease; MI = myocardial infarction; N/A = not applicable; GI = gastrointestinal.Fenter TC, et al. Am J Manag Care. 2006;12:S90-S98.

One-Year Disease-Specific Medical and Prescription Costs

Definition List of Significant Events after Initiation of Pharmocotherapy for Each Disease

DiseaseMedical Cost ($)

Prescription Cost ($)

Arrhythmias 1699 312

Osteoarthritis 989 131

Cataracts 885 0

CAD 782 710

Bursitis 463 101

Type 2 Diabetes 463 474

Enlarged Prostate 401 371

GERD 316 655

Depression 217 529

Hypertension 213 310

Significant Events

Cardioversion

Arthroscopy, knee replacement

N/A

Acute MI, stroke

Removal or drainage of the bursa sac

Nephropathy, neuropathy, retinopathy, lower extremity amputation

Prostate-related acute urinary retention, surgery

Endoscopy, upper GI surgery

Depression-related inpatient hospitalization

Stroke, acute MI, congestive heart failure, ischemic heart disease

The Cost of Treating the 10 Most PrevalentDiseases in Men 50 Years of Age or Older (cont)

CAD = coronary Artery disease; GERD = gastroesophageal reflux disease.Fenter TC, et al. Am J Manag Care. 2006;12:S90-S98.

Liklihood of Experiencing a Significant Eventwithin 1 Year Classified by Diagnosis

Per

cen

t (%

)

25

20

15

0

5

10

13.5

19.2

23

6.5

8.79.5

0.11.1

2.2

Evaluating Use Patterns of and Adherence to Medications for BPH

Nichol MB, et al. J Urol. 2009;181:2214-2222.

0.4

1.0

0.6

0.2

0

0.8

0 200 400 600

Su

rviv

al

Pro

bab

ility

Time to Discontinue/Censored

Logrank P = .0003

Doxazosin

Finasteri

Multipled

Tamsulosi

Terazosin

0.7

0.9

0.5

0.3

0.1

Population ≥65 Years for Developed andDeveloping Countries by Age

2000 to 2050

US Department of Health and Human Services. 65+ in the United States. 2005. http://www.census.gov/prod/2006pubs/p23-209.pdf. Accessed September 5, 2014.

Po

pu

lati

on

(M

illio

ns)

≥80 Years

65-79 Years

Total ≥65 Years

Developed Countries1200

800

600

0

1000

400

2000

200

238.2

64.8

2010 2020 2030 2040 2050

284.6

81.9

312.7

105.3

326.5

121195.1

52.9171.4

37.4

Year

Developed Countries1200

800

600

0

1000

400

2000

200

476.0

395.9

80.1

2010 2020 2030 2040 2050

689.5

568.5

121

950.7

752.2

198.5

1175.7

870.4

305.3

327.8

274.6

53.2249.0

214.6

34.4

Year

173.4 202.7 207.4 205.5142.2133.7

In the US, the population aged≥65 y is projected to increasefrom 35 million to 71 million

between 2000-2030

≥80 Years

65-79 Years

Total ≥65 Years

The Urologic IcebergDifferentiating the True and Observed

Prevalence of Urologic Conditions

Symptoms Presented, Diagnosed, Treated, and

Counted as Cases

Symptoms Presented, Diagnosed, Treated, and

Counted as Cases

Symptoms Not Recognized and Not Presented

Symptoms Not Recognized and Not Presented

Symptoms RecognizedBut Not Presented(possible self care)

Symptoms RecognizedBut Not Presented(possible self care)

Symptoms PresentedBut Not Diagnosed, Treated,

or Counted

Symptoms PresentedBut Not Diagnosed, Treated,

or Counted

The TruePrevalenceof UrologicConditions

in thePopulation

Note: Iceberg concept adapted from Last (1963; 2001).

Unobservedand

Not Counted

Observedand

Counted

ED = erectile dysfunction.Feldman et al. J Urol. 1994;151:54-61.

Major Risk Factor for ED: Aging

Severe ED

Moderate ED

Mild ED

80

70

40

040

Pre

vale

nce

(%

) 60

20

60 70

39

4850

30

10

Age (years)

50

57

67

(n=1209)

Kohler and McVary. European Urology 55. (2009)38-48.

The Relationship Between ED and LUTS andthe Role of Phosphodiesterase Type 5 Inhibitors

Epidemiology of Erectile Dysfunction:Results of the ‘Cologne Male Survey’

M Braun et al, Int J of Imptence Res 12:305, 2000

Odds Ratio (OR) with 95% confidence intervals (CI) for erectile dysfunctionassociated with age group, pelvic surgery, lower urinary tract symptoms (LUTS),

hypertension, and diabetis mellitus.All odds ratios are significantly different from 1 (P<.0001)

OR 95% CI

Age 40-49 y vs 30-39 y 3.72 (2.37-5.86)

Age 50-59 y vs 30-39 y 5.16 (3.35-7.95)

Age 60-69 y vs 30-39 y 11.02 (7.26-16.75)

Age 70-80 y vs 30-39 y 22.42 (14.35-35.02)

Pelvic surgery 6.03 (4.37-8.31)

LUTS 2.11 (1.75-2.55)

Hypertension 1.58 (1.29-1.93)

Diabetis mellitus 3.95 (2.98-5.23)

Correlates for Erectile and Ejaculatory Dysfunction in Older Dutch Men: A Community-based Study

Blanker et al J Am Geriatr Soc. 2001 Apr;49(4):436-42

†Lower urinary tract symptoms: no symptoms (IPSS 0), mild (1-7), moderate (8-19), severe (>19).CI = confidence interval; TURP = transurethral resection of the prostate; IPSS = International Prostate Symptom Score.Blanker MH, et al. J Am Geriatr Soc. 2001;49:436-442.

NOTE: Significant erectile dysfunction = patient report of erections with severely reduced rigidity or no erections.*Smoker = current smoker or stopped smoking <5 years ago. Non-smoker = never smoked or stopped >5 years ago.

NOTE: Significant ejaculatory dysfunction = reportof ejaculations of significantly reduced volume or no ejaculations.

Correlates for SignificantErectile Dysfunction, Yielded by

Multiple Logistic Regression Models

Correlates for SignificantEjaculatory Dysfunction, Yielded byMultiple Logistic Regression Models

CharacteristicAdjusted Odds Ratio

(95% CI)

Age (stratum vs 50-54 years)55-5960-6465-6970-78

2.3 (1.0-5.2)4.6 (2.1-10.1)8.9 (4.1-19.5)

14.3 (6.4-32.1)

Smoking habits* (smokers vs non-smokers)

1.6 (1.1-2.3)

Body mass index (kg/m2)25-30 vs <25>30 vs <25

1.5 (1.0-2.3)3.0 (1.7-5.4)

Lower urinary tract symptomsMild vs no symptomsModerate vs no symptomsSevere vs no symptoms

1.8 (0.8-4.3)3.4 (1.4-8.4)7.5 (2.5-22.5)

Under treatment forCardiac symptoms (yes vs no)COPD (yes vs no)

2.5 (1.5-4.3)1.9 (1.1-3.6)

CharacteristicAdjusted Odds Ratio

(95% CI)

Age (stratum vs 50-54 years)55-5960-6465-6970-78

2.3 (1.0-5.2)4.6 (2.1-10.1)8.9 (4.1-19.5)

14.3 (6.4-32.1)

Erectile functionReduced vs normal rigiditySeverely reduced rigidity orno erections vs normal rigidity

3.5 (2.1-5.1)29.5 (18.3-47.8)

Lower urinary tract symptomsMild vs no symptomsModerate vs no symptomsSevere vs no symptoms

1.0 (0.5-2.3)1.9 (0.8-4.2)4.2 (1.4-12.9)

Previous TURP (yes vs no)

26.7 (13.2-54.4)

Under treatment forDiabetis mellitus (yes vs no) 0.2 (0.1-0.7)

MSAM-7: Erectile Function Declines with LUTS Severity, Independent of Age

Base: Men sexually active/sexual intercourse during past 4 weeks, *as measured by IIEF.Rosen R, et al. Eur Urol. 2003;44:637-649.

Average Score on a Scale from 1-30 (6 questions) Measured by IIEF

Mea

n E

rect

ile F

un

ctio

n S

core

(IIE

F)*

30

20

15

0

25

10

5

18.9

50-59 Years

15.9

50-59 Years

10.3

50-59 Years

Mild SevereLUTS None Moderate

Best

Worse

15

12.6

7.5

22.3

19.3

15.2

21

18.3

13.2

DAN-PSSsex:ED

Per

cen

t (%

)

100

80

70

40

30

20

0

10

90

60

50

Net Reduction of Stiffness No Erection

50

5

45

50-59 Years

65

12

53

60-69 Years

83

31

52

70-79 Years

70

17

53

83

19

64

89

44

45

14

212

40

7

33

57

16

41

27

2

25

49

6

43

70

20

50

Relationship between Lower Urinary Tract Symptoms and Erectile Dysfunction:

Results from the Boston Area Community Health Survey

Brookes ST, et al. J Urol. 2008;179:250-255.

Per

cen

t (%

)

100

80

40

20

0

60

AUA-SI

Mild/Moderate

Moderate

SevereNone

Mild

Erectile Dysfunction

(IEFF-5)

30-39 Years 40-49 Years 50-59 Years 60-69 Years 70-79 Years

90

70

30

10

50

AR = adrenoreceptor; NO = nitric oxide; NOS = nitric oxide synthase; SMC = smooth muscle cell.Andersson KE, et al. Neurourol Urodyn. 2011;30(3):292-301.

Atherosclerosis/Pelvic ischemia

BPH-LUTSPotential Pathophysiologic Pathways

Increased sympathetic tone

Enhancedα-AR-sensitivity

Increased SMC proliferation• Structural change in the prostate• Bladder

hypertrophy/noncompliance

Increasedsmooth muscle tone

• Detrusor overactivity• Elevated prostatic tone

Autonomic Overactivity

Inflammationof LUT tissue

Inflammation/Androgen/Rho Kinase

Alteredandrogen

environment

Increased Rhokinase activity

Reduced NOS/NO in bladder and prostate

Risk Factors: age, diabetes, hypertension

Pelvic reduction in NOS/NO

Increased SMC proliferation

• Structural change in the prostate

• Bladder hypertrophy/ noncompliance

Increasedsmooth

muscle tone• Elevated

prostatic tone

Enhanced bladder afferent activity

Chronic hypoxia/ischemia Nerve growth factor

Reduced prostate/bladder perfusion

AtherosclerosisPelvic arterial insufficiency

Bladder outlet obstructionElevated intravesical

pressure

LUTS

Increased SMC proliferation• Structural change in the prostate• Bladder

hypertrophy/noncompliance

Increasedsmooth muscle tone

• Detrusor overactivity• Elevated prostatic tone

Increased SMC proliferation• Structural change in the prostate• Bladder

hypertrophy/noncompliance

Increasedsmooth muscle tone

• Detrusor overactivity• Elevated prostatic tone

Treatments for Moderate to SevereMale LUTS Associated with BPH

• Watchful waiting– Lifestyle and behavioral

changes

• Medical therapy– Oral therapies

• Food supplements, etc

• α-receptor (AR) blockers

• 5-α Reductase inhibitors

• PDE 5 inhibitors

• Antimuscarinics

• Combination therapies

– Injectables

• Parenteral

– LHRH antagonists

• Intraprostatic

– Nymox

– Protox

– Botox

• Minimally invasive therapies– Heat based

• Transurethral radiofrequency needle ablation

• Transurethral microwave heat treatments

• NxThera Vapor treatment

– Mechanical• Neotract UroLift

• Urolume stent

• Surgical therapies– TU incision of bladder neck/prostate

– TU resection of prostate

– TU laser vaporization

– TU laser resection

– TU laser enucleation

– Lap/Robotic enucleation

– Open enucleation

α-Adrenergic Receptor Antagonists

α1-Blockerα1-Receptor Selectivity

Side Effects*

Doxazosin α1A=α1D=α1B

Dizziness, dyspnea, edema, fatigue,

somnolence

Terazosin α1A=α1D=α1BAsthenia, dizziness, postural hypotension

Alfuzosin α1A=α1D=α1BDizziness, upper

respiratory tract infection

Tamsulosin α1A=α1D>α1B

Abnormal ejaculation†, asthenia, back pain, dizziness, increased

cough, infection‡, rhinitis, sinusitis,

somnolence

Silodosin α1A>α1D>α1B Retrograde ejaculation

Vascular Receptors Prostate Receptors

Prostatic α1A-receptors

Vascular α1B-receptors

α1A Prostatic smooth muscle contractionα1B Vascular smooth muscle contractionα1D Bladder muscle contraction and sacral

spinal cord innervation

*Adverse effects present in ≥2% of treated vs non-treated subjects; †Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation, and ejaculation disease; ‡Terms also include cold, common cold, head cold, flu, and flu-like symptoms.Cardura package insert. 2009; Flomax package insert. 2009; Hatano A, et al. Br J Pharmacol. 1994;113(3):723-728; Hytrin package insert. 2009; Lepor H. Rev Urol. 2011;13(1):20-33; Rapaflo package insert. 2011; Schwinn DA, MichelottiGA. BJU Int. 2000;85(suppl 2):6-11; Uroxatral package insert. 2010; Yoo TK, Cho HJ. Korean J Urol. 2012;53:139-148.

5α-Reductase Inhibitors RegulateProstate Growth and BPH Development

*Adverse effects present in ≥2% of treated vs non-treated subjects.DHT = dihydrotestosterone; DNA = deoxyribonucleic acid; T = testosterone.Avodart package insert. 2012; Azzouni F, et al. Adv Urol. 2012:530121; Gravas S, Oelke M. World J Urol. 2010;28:9-15; Proscar package insert. 2012; Roehrborn CG. Int J Impot Res. 2008;20(suppl 3):S11-S18; Rosenberg MT, et al. Int J ClinPract. 2010;64(4):488-496.

Dutasteride Finasteride

5α-Reductasespecificity

Type I and II Type II

Half-life 5 weeks <1 day

Serum DHT ~95% reduction ~70% reduction

IntraprostaticDHT

~98% reduction 68%-85% reduction

PSA ~50% reduction

Prostate volume

~25% reduction

Adverse events*

Reduced libido, impotence

Abnormal ejaculation,

decreased ejaculate volume, impotence,

reduced libidoDHT produced peripherally by Type 1

and Type 2 5α-reductase

Testosterone

DNA

Nucleus

5α-ReductaseType 2

DHT

Androgen receptor Androgen receptor

DNA

Nucleus

Growth factors Growth factors

STROMALCELLS

EPITHELIALCELLS

T T

Combination Therapy Provides Dual Mechanism of Action

Alphablockade

5-reductaseinhibition

Dynamic componentand

irritative symptoms

Static componentand

obstructive symptoms

Polling Question

Which of the following is true of alpha blockers?

a) They reduce PV and maintain reductions in PV

b) They prevent symptomatic progression in the short term

c) Reduce longer-term risk of AUR and surgery

d) All of the above are true of alpha blockers

Polling Question

Which of the following is true of alpha blockers?

a) They reduce PV and maintain reductions in PV

b) They prevent symptomatic progression in the short term

c) Reduce longer-term risk of AUR and surgery

d) All of the above are true of alpha blockers

Two Different Patterns of EffectCombination Therapy: The Best of Both Worlds?

1. Madersbacher S, et al. Eur Urol. 2004;46:547-554. 2. Roehrborn CG, et al. J Urol. 2008;179:616-621.3. Roehrborn C, et al. Eur Urol Suppl. 2006;5:716-721.

Alpha blockers

5ARIs

Improve symptoms/flow

Onset of symptom relief

in 1–2 weeks

Prevent symptomatic

progression in the short term

Sustained symptomatic

benefit

Reduce PV

Maintain reductions in PV

Reduce longer-term risk of

AUR and surgery

Time

Magnitude of benefit

Time

Magnitude of benefit

GiGs

Sympathetic Nerve Terminal

tone

cAMP

Ca2+

Ca2++

–

M23

NE

NE

AC Gq

Ca2+

contractionSRCa2+

IP3

Ca2+

Ca2+

Ca2+

IP3

PIPM3

ACh

DG

+

ROC channel

Muscarinic Receptor Signaling

Parasympathetic Nerve Terminal

M1 M2/4

ACh

+ –

AC = adenylate cyclase; Ach = acetylcholine; β3 = β3 adreneregic receptor; cAMP = cyclic adenosine monophosphate; DG = diacylglycerol; IP3 = inositol triphosphate; M1, M2, M2/4, and M3 are muscarinic receptor subtypes; NE = norepinephrine; PIP = phosphatidylinositol; PLC = phospholipase C; ROC = receptor-operated calcium channel; SR = sarcoplasmic reticulum.Andersson K-E. Lancet Neurol. 2004;3:46-53. Ouslander JG. N Engl J Med. 2004;350:786-799; Sellers DJ, et al. J AutonPharmacol. 2000;20:171-176.

PLC

OAB is defined as urgency, with or without urgency incontinence, usually with frequency and nocturia (ICS 2002 definition)

OAB = overactive bladder.Irwin DE, et al. Eur Urol. 2006;50:1306-1315. Abrams P, et al. Urology. 2003;61:37-49.

Most Men with LUTS Have Both Storage and Voiding/Post-Micturition Symptoms

67% of Men

Experience Symptoms

of Both OABand BPH

Storage Symptoms Related

to the Bladder

Voiding/Post-Micturition

Symptoms Related to the Prostate

• Slow stream

• Intermittency

• Straining

• Terminal dribble

• Post-micturition dribble

• Incomplete emptying

• Urgency

• Frequency

• Nocturia

• Urgency urinary

incontinence

• Other incontinence

Phosphodiesterase Type 5 Inhibitors Relax Smooth Muscle and Increase Vascularity

• Smooth muscle cell relaxation in bladder neck, prostate, and urethra

• Smooth muscle cell relaxation of these organs’ vascular supply and increased blood perfusion and oxygenation

• Modulation of the sensory output from the LUT is likely to play a role in both the short and long term

ReviewRelationship between ED and LUTS and the

Role of PDE5 Inhibitors

BII = BPH Impact Index; GAQ = Global Assessment Question; PVR = postvoid residual; Qmax = maximum flow rate.Kohler TS, et al. Eur Urol. 2009;55:38-48.

StudyAgent Dose

DurationN, PDE-I

nInclusion

Placebo Run-in

IPSS ∆: PDE-I vs Placebo(P value)

Other Findings

McVaryet al

Sildenafil50–100 mg qday 12 wk

369189

Age ≥45,history of ED:≤25 IIEF

(EF domain), IPSS ≥12

No6.3 vs 1.9(P<.0001)

No change in Qmax; IIEF, BII, mean IPSS QoL score,

and GAQ all significantlyimproved

Stiefet al

Vardenafil10 mg

bid 8 wk

222109

Age 45–64, IPSS ≥12,

no history of ED required

No5.9 vs 3.6(P=.0013)

No change in Qmax or PVR;IIEF, QoL, irritative and

obstructive IPSS subscoresall significantly improved

McVaryet al

Tadalafil5 mg → 20 mg

qday 4-wk run-in +

12 wk(6 → 6)

281138

Age ≥45, IPSS ≥12 from BPH for 6 mo,

no history of ED required

Yes

5 mg 2.8 vs 1.2 (P=.003)

20 mg 3.8 vs 1.7 (P≤.001)

7.1 vs 4.5 (P≤.001):includes run-in

No change in Qmax; IIEF,irritative and obstructive IPSS

subscores, mean IPSSQoL score all significantly

improved

Roehrbornet al

Tadalafil2.5, 5, 10,

20 mg qday4-wk run-in +

12 wk

1058~212/ group

Age ≥45, IPSS >12 from BPH for 6 mo,

Qmax: 4–15 mL/s

Yes

2.5 mg 3.9 vs. 2.3 (P<.05)

5 mg 4.9 vs 1.8 (P<.05)

10 mg 5.2 vs 4.5 (P<.05)

20 mg 5.3 vs 4.5 (P<.05)

No change in Qmax; IIEF,mean IPSS QoL score, BII,LUTS GAQ all significantly

improved (≥5 mg); dose>5 mg minimal ∆ improvement

but ↑ side effects

IPSS Total Score Mean Change from Baselineto Endpoint after 4, 8, and 12 Weeks

*Tadalafil 2.5 mg, P<.05 at Weeks 4, 8, and 12, and Tadalafil 5, 10, and 20 mg P<.001 for Weeks 4, 8, and 12 compared with placebo. Compared with placebo (Ancova analysis).Broderick GA, et al. Urology. 2010;75:1452-1458.

-2

-3

0

-1

-4

-5

-6

-7

Mea

n C

han

ge

in T

ota

l IP

SS

Sco

refr

om

Bas

elin

e to

En

dp

oin

tBaseline 4 8 12

Week

Placebo

Tad 2.5

Tad 5.0

Tad 10.0

Tad 20

Clinically MeaningfulImprovement

Top 5 Treatment-EmergentAdverse Events

Nasopharyngitis

Myalgia

Back Pain

Dyspepsia

Headache

Roehrborn CG, et al. J Urol. 2008;180:1228-1234.

20

18

14

10

6

2

0212

Placebo

Pat

ien

ts (

%)

16

12

8

4

212.82.4

≥1 TEAE (%)≥1 SAE (%)Discontinued

Patients with

209Tadalafil2.5 mg

212Tadalafil

5 mg

216Tadalafil10 mg

209Tadalafil20 mg

212.82.4

212.82.4

212.82.4

212.82.4

n = 9

n = 20

n = 25

n = 35

n = 40

Placebo

Tad 2.5

Tad 5.0

BIID

Total IPSSB

SEP Q3 (% “Yes” Responses)C

IIEF EF Domain ScoreA

Tadalafil 2.5 or 5 mg Administered Once Daily for 12 Weeksin Men with Both Erectile Dysfunction and

Signs and Symptoms of Benign Prostatic Hyperplasia:Results of a Randomized,Placebo-Controlled, Double-Blind Study

*P<.001 vs placebo; P<.01 vs placebo.LS = least squares.Egerdie RB, et al. J Sex Med. 2012;9:271-281.

Change from baseline in co-primary (International Index of Erectile Function-erectile function [IIEF-EF] domain (A)and total International Prostate Symptom Score [IPSS] (B) and key secondary (Sexual Encounter Profile Question 3

[SEPQ3] (C) and Benign Prostatic Hyperplasia Impact Index [BII] (D) measures at weeks 4, 8, and 12/end-point visits.

0

-1

-2

-4

Weeks Post-Baseline

-3

0 4 12/Endpoint

8

0

-2

-8

-4

-6

0 4 12/Endpoint

82

40

20

0

LS

Mea

n C

han

ge

fro

m B

asel

ine

Weeks Post-Baseline

30

10

0 4 12/Endpoint

8

8

6

0

LS

Mea

n C

han

ge

fro

m B

asel

ine

4

2

0 4 12/Endpoint

8

* * ** *

***

*

*

**

* ***

****

Tadalafil Administered Once Daily for Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia:

A 1-Year, Open-Label Extension Study

Donatucci CF, et al. BJU Int. 2011;107:1110-1116.

Wk 12 to EP

BL to 12 Wk

Change in IPSS from BL – Wk 12 – EP2

1

-1

-3

-5

-7PrevPlac

IPS

S S

core

0

-2

-4

-6

PrevTad 2.5

PrevTad 5.0

PrevTad 10

PrevTad 20

Changes in IPSS and BII for Menwith or without ED

Population: All randomized men.n = number randomized to therapy group. Broderick GA, et al. Urology. 2010;75:1452-1458.

Placebo(n=210)

2.5 mg(n=208)

5 mg(n=212)

20 mg(n=208)

Tadalafil

10 mg(n=216)

-4

-6

0

-2

-1

-3

-5

-7

Ch

ang

e in

IP

SS

(LS

Mea

n ±

SE

)

-2.4 -2.4

-3.2-4.3

-5.3-4.8

-5.1 -5.3-4.5

-5.6

0

-1.0

-0.5

-1.5

-2.0

Ch

ang

e in

BII

(LS

Mea

n ±

SE

)

-1

-0.7 -0.7 -0.9

-1.3 -1.3 -1.3 -1.3 -1.2 -1.4Without ED

With ED

0.352 / 0.644

0.753 / 0.852

Subgroup/Interactionp-values

*P<.05 vs placebo.LS = least square.Oelke M, et al. Eur Urol. 2012;61(5):917-925.

Monotherapy with Tadalafil or Tamsulosin Similarly Improves Symptoms and Maximum Urinary Flow Rate in Men with Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: Results of an International,

Randomized, Double- Blind, Placebo-Controlled Clinical Trial

Mean Change

Placebo (n=172)

Tadalafil5 mg

(n=171)

Tamsulosin0.4 mg(n=168)

Qmax, mL/s

1.2 ± 4.8 2.4 ± 5.5* 2.2 ± 4.1*

Vvoid, mL

4.6 ± 110.9 8.2 ± 101.5 21.4 ± 109.3

Bladder capacity, mL

4.2 ± 123.7 3.5 ± 113.8 11.9 ± 130.4

PVR, mL

-1.2 ± 56.5 -4.6 ± 47.0 -10.2 ± 59.2

0

0

-1

-2

-3

-4

-5

-6

-7

1 4 12/EP

Placebo

Tadalafil 5 mg

Tamsulosin 0.4 mg

IPS

S T

ota

lL

S M

ean

Ch

ang

e fr

om

Bas

elin

e

Duration of Treatment (weeks)

Storage symptoms• c/w overactive bladder (OAB)• No evidence of bladder outlet

obstruction (BOO)

1. Lifestyle intervention2. Behavioral therapy

3. Antimuscarinic monotherapy

Treatment failure

Success: Reassuranceand annual follow up

Evidence of BOODiscuss Rx options

Share decision

Medical Therapy

MIST or surgical intervention

Consider:• Botulinum toxin

• Neuromodulation• Other invasive therapies

Mixed OAB and BOO

Mixed BOOand ED

PredominantBOO

Larger gland Higher PSA

Alpha blocker +5 AR inhibitor

Small gland Low PSA

Alpha blocker

PDE5 inhibitorAlone or withAlpha blocker

Antimuscarinics and

Alpha blocker

Success: Reassurance and annual follow up

Treatment failure

Recommended Tests:1. Validated questionnaire

2. Frequency volume charts (FVC)3. Flow rate recording (FRR)4. Postvoid residual check

Additional optional tests:5. Urethrocystoscopy

6. Transrectal ultrasound (TRUS)7. Urodynamic studies

Improving Men’s Health,Quality of Life, and Cost Outcomes:

Evolving Treatment Strategies for Benign Prostatic Hyperplasia

William J. Cardarelli, PharmDDirector of Pharmacy Revenue and Supply

Atrius HealthHarvard Vanguard Medical Associates

Watertown, Massachusetts

Prevalence of BPH

• Prevalence of BPH

– 4th most prevalent disease in men >50 years

• 50% of men >60 years

• 90% of men >85 years

– Begins in middle age and continues throughout later life

• Goals: improve LUTS, reduce risk of BPH-related surgery, slow progression of disease

• Significant QoL issues: affecting physical, social, and psychological well being

BPH = benign prostatic hyperplasia; LUTS = lower urinary tract symptoms; QOL = quality of life.McVary KT. Am J Manag Care. 2006;12:S122‐S128. Medscape BPH, http://emedicine.medscape.com/article/437359-overview#a0156. Accessed July 21, 2014.

Data from Berry SJ, Coffey DS, Walsh PC, et al. The development of human benign prostatic hyperplasia with age. J Urol. 1984;132:474. Cunningham GR, et al. http://www.uptodate.com/contents/epidemiology-and-pathogenesis-of-benign-prostatic-hyperplasia?source=search_result&search=benign+prostatic+hyperplasia&selectedTitle=3~96. Updated September 10, 2013. Accessed September 1, 2014.

Prevalence of Benign Prostatic Hyperplasia Pathology with Age

Age-associated increase in pathologic evidence of benign prostatic hyperplasia in 1075 men at autopsy.The percentage with benign prostatic hyperplasia was determined during 10-year intervals

from five different studies; the mean values are shown.

11-20 21-30

80

70

100

90

50

30

0

1-10 31-40 51-60 81-90

Per

cen

t o

f P

rost

ates

(%

)

Age Range in Years

20

10

60

40

41-50 61-70 71-80

Economic Burden of BPH

• Annual cost per patient

– $1536 to $2577 (in 1999 Dollars)

• Annual healthcare expenditure to treat BPH

– $3.4 Billion (1999)

• Urologic Diseases in America Project

– Studied BPH in 2000

– Estimated that the disease carried an economic burden of $1.1 Billion in direct annual expense exclusive of outpatient pharmacotherapy costs

• While costs are important, they should not overshadow the negative impact of BPH on QOL

Issa MM, et al. Am J Manag Care. 2007;13:S4‐S9.

Approved Drug Therapies

• Alpha blockers –

– Alpha-blockers help relieve BPH symptoms, but they do not reduce the size of the prostate. They can help improve urine flow and reduce risk of bladder obstruction.

– Terazosin, doxazosin, tamsulosin, alfuzosin, and silodosin

• 5-alpha reductase inhibitors –

– Block the conversion of testosterone to dihydrotestosterone

– Finasteride and dutasteride

• Combination drug –

– Dutasteride 0.5 mg/tamsulosin 0.4 mg

• Phosphodiesterace 5 inhibitors (PDE-5) –

– Recently approved for men with BPH and ED

– Tadalafil 5 mg

http://www.nytimes.com/health/guides/disease/enlarged-prostate/medications.html Accessed July 21, 2014.

Polling Question

According to National Guideline Clearinghouse, it is recommended that BPH should not be treated with ____ in men with LUTS secondary to BPH without prostatic enlargement.

a) Alpha-adrenergic Blockers

b) 5-alpha Reductase Inhibitors

c) Combination therapy [Alpha-adrenergic Blockers and 5-alpha reductase inhibitors]

d) None of the above

Polling Question

According to National Guideline Clearinghouse, it is recommended that BPH should not be treated with ____ in men with LUTS secondary to BPH without prostatic enlargement.

a) Alpha-adrenergic Blockers

b) 5-alpha Reductase Inhibitors

c) Combination therapy [Alpha-adrenergic Blockers and 5-alpha reductase inhibitors]

d) None of the above

Guideline on the Management ofBenign Prostatic Hyperplasia (BPH)National Guideline Clearinghouse

Alpha-adrenergic blockers (Alpha-blockers)

• Option: The older, less costly, generic alpha blockers remain reasonable choices. These require dose titration and blood pressure monitoring. [Based on Panel consensus]

5-ARIs

• Option: 5-ARIs may be used to prevent progression of LUTS secondary to BPH and to reduce the risk of urinary retention and future prostate-related surgery. [Based on review of the data and Panel consensus]

• Recommendation: 5-ARIs should not be used in men with LUTS secondary to BPH without prostatic enlargement. [Based on review of the data and Panel consensus]

• Option: The 5-ARIs are appropriate and effective treatment alternatives for men with LUTS secondary to BPH who have demonstrable prostate enlargement. [Based on review of the data and Panel consensus]

Combination

• Option: The combination of an alpha-blocker and a 5-alpha reductase inhibitor (5-ARIs) (combination therapy) is an appropriate and effective treatment for patients with LUTS associated with demonstrable prostatic enlargement based on volume measurement, prostate-specific antigen (PSA) level as a proxy for volume, and/or enlargement on digital rectal exam (DRE). [Based on review of the data and Panel consensus]

http://www.guideline.gov/content.aspx?id=25635#Section434. Accessed September 1, 2014.

Case Study of Tadalafil

• You’ve been asked to review a newly approved BPH therapy for your company’s P&T Committee

– It was previously approved for ED with a quantity limit of 4 tablets/30 days supply

– Its new indication is for the treatment of BPH and ED when the symptoms occur simultaneously

– As an ED drug, it already has a moderate financial impact on your drug spend

– You’ve been asked to develop coverage language to provide access given the new indication

Case Study of Tadalafil (cont)

• Background

– ED and BPH commonly coexist in older men

– Current therapies address the BPH component but not ED

– ED is a common side effect of current therapies

• Study Design

– Men aged 45 years or older

– Experienced both ED and BPH symptoms

– Random assignment after 4-week washout into 1 of 3 arms

• Tadalafil 2.5 mg

• Tadalafil 5 mg

• Placebo

Egerdie RB, et al. J Sex Med. 2012;9:271‐281.

Case Study of Tadalafil (cont)

• Outcomes

– Improvements in the International Prostate Symptom

– Score (IPSS) and International Index of Erectile Function (IEFF) score at 12 weeks compared with placebo

– Improvement was maintained throughout study

– Improvement scores were significant for the 5-mg dose (P<.001) but not for the 2.5-mg dose

– Drug was well tolerated with no clinically adverse changes in orthostatic vital signs or uroflow parameters

Egerdie RB, et al. J Sex Med. 2012;9:271‐281.

IPSS Total Score Mean Change fromBaseline to Endpoint Using Placebo and

Different Dosages of Tadalafil

*Tadalafil 2.5 mg, P<.05 at Weeks 4, 8, and 12, and Tadalafil 5, 10, and 20 mg P<.001 for Weeks 4, 8, and 12 compared with placebo. Compared with placebo (Ancova analysis).Broderick GA, et al. Urology. 2010;75:1452-1458.

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En

dp

oin

tBaseline 4 8 12

Week

Placebo

Tad 2.5

Tad 5.0

Tad 10.0

Tad 20

Clinically MeaningfulImprovement

Potential Concerns/Benefits

• Pharmacy adjudication at point of sale does not include diagnosis codes; therefore, a drug can’t be covered differentially by indication

• Providing unrestricted access to this drug may result in patients with ED diagnosis receiving much larger supplies of medication than previously, resulting in inappropriate use and increased cost

• Allowing appropriate, defined access will improve the QOL for those patients with simultaneous BPH and ED

Considerations for Managed Care

• Comparative effectiveness

• Cost impact

• Benefit design

• Coverage issues

• Utilization controls

• Patient-reported outcomes?

All of these help to assess

VALUE

Medical Care vs “Lifestyle” Care

• Benefit language has difficulty separating the two

• Need to balance the “mission and margin”

• Fundamental values of benefit management

– Accepting resource constraints

– Helping the sick

– Protecting the worse off

– Respecting autonomy of both patients and physicians

– Promoting inclusive decision making

Burton SL, et al. Health Aff. 2001;20:150‐163.

Utilization Controls

• Prior authorization

– Including molecular testing requirements

• Step therapy

• Formulary design

– Open vs closed formularies

• P&T review process

– Efficacy, tolerability, and safety

– Financial

How Does Comparative Effectiveness Benefit Managed Care?

• Provides meaningful comparisons between healthcare interventions instead of comparing interventions with placebos

• Offers the advantage of pooling findings from various studies and grades the quality of evidence

• Educates payers and providers about different strategies and interventions to treat and monitor patients in “real-world” settings

Oderda GM, et al. J Manag Care Pharm. 2011;17(9‐b):S19‐S24.

Limitations of CER

• Too many trials compare active agents with placebo

• Drugs shown to be equivalent to an average group of patients does not necessarily imply that they are equivalent for all patients

• Broad scope of research makes quality ratings important

• Must place a high value on effectiveness and internal validity

Oderda GM, et al. J Manag Care Pharm. 2011;17(9‐b):S19‐S24.

Pharmacoeconomic Evaluations: Are We Wasting Our Time?

• Resources are scarce

– People, time, facilities, equipment, knowledge

• Many medications are expensive

– Over 20 therapies with cost >$4000 per year

– Is $1000/day acceptable?

• Assists in making the decision process explicit

– Can take into account preferences and attributes

International Society For Pharmacoeconomics And Outcomes Research. Value in Health. http://www.ispor.org/publications/value/abstracts.asp. Accessed April 2, 2012.

What about HRQOL?

• Assesses an individual’s perceived effect of the illness on their physical, psychological, and social daily lives

– In a VA study, PD patients scored lower on the physical and mental health dimensions than patients with 8 other chronic diseases, including diabetes, heart failure, coronary artery disease, and stroke

• Used in determining the effectiveness of therapies both at an individual and population level

• Managed care can use this to measure the effectiveness of treatment strategies and quality of care

• Can be used in determining the appropriate placement of medications on formularies

• Preservation of HRQOL can reduce the need for healthcare resource use and lower total expenditures

VA = Veterans’ Affairs; PD = Parkinson’s disease.Chen JJ. Am J Manag Care. 2010;16(Suppl Implications):S87-S93. Weintraub D, et al. Am J ManagCare. 2008;14(2 Suppl):S49-S58.

So What’s Your Case for Access?

• Is Product X superior to already approved products?

• Where does its cost land?

• Do you need to put in place any utilization controls?

• If all other things are equal, does superior patient-reported outcomes change the analysis?

Algorithm forFormulary Decision-Making

NO

Drug review—oral/writtenpresentation by clinical pharmacist

Experience/opinion—oral comments byinvited consultants and committee members

Does drug offer substantial improvement in therapy overexisting formulary drugs for like indications, or is it a

completely new therapy not previously covered by medications?

Add to formulary with guidelines forcost-effective and safe use if needed

Does drug offer at least equal clinical benefit toexisting formulary drugs for like indications?

Add to formulary with guidelines forcost-effective use if needed

Do not add toformulary

Do not add toformulary

Can any safety concernsbe managed?

Does financial impact of drugsupport formulary addition?

NO

NO

NO

NO

YES

NO

YES

YES

YES

Conclusion

• Managed Care Organizations can contribute to cost-effective improved care in BPH by better understanding the current treatment options, evaluating the value of newer agents, and designing benefit language to address the needs of those patients with concomitant symptomology

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