Physician Reference Guide

Transcription

1 Physician Reference Guide

2 Physician Reference Guide TABLE OF CONTENTS Basics of BPH Patient Workup Management of BPH Anatomy Prostatic Artery Embolization Complications Additional Resources Dr. Shivank Bhatia is a paid consultant of Merit Medical. The text, graphics, images and other material contained in this Reference Guide represent the collective work of healthcare professionals and is provided for informational purposes only. This information does not constitute medical advice and does not guarantee that this information is accurate, complete, without errors, or that relying on such information will ensure or support a favorable medical outcome.

3 Physician Reference Guide BASICS OF BPH

4 BENIGN PROSTATIC HYPERPLASIA (BPH) Benign prostatic hyperplasia (BPH) is a condition in which the prostate gland is enlarged and not cancerous. 1 As the prostate gets bigger, the gland may constrict or partly block the urethra. The bladder wall becomes thicker, and eventually may weaken and lose the ability to empty completely. The narrowing of the urethra and urinary retention cause many of the lower urinary tract symptoms (LUTS) associated with BPH. Bladder Enlarged Prostate Constricted Urethra Urethra An enlarged prostate can constrict or block the urethra, possibly causing urinary symptoms. REFERENCES 1. American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH), Revised

5 SCOPE OF THE PROBLEM BPH is the most common prostate problem for men older than age 50 1 BPH affects more than 20% of American men aged 40 to 79 years roughly 15 million men 2 Prevalence appears to increase with aging, as approximately 80% of men are affected by BPH/LUTS by age 70 3 By 2030, 20% of the US population will be 65 years or older, including more than 20 million men 4 In 2000, BPH accounted for $1.1 billion in direct health-care expenditures, 4.4 million office visits, 117,000 emergency room visits, 105,000 hospitalizations and million hours in lost productivity in the US. Estimated annual costs of BPH treatment totals $2.9 billion 5,6 RISK FACTORS Known risk factors associated with BPH/LUTS include: 1,7-8 Age Sedentary lifestyle Smoking Excessive alcohol consumption Medical conditions such as hypertension, type 2 diabetes, heart and circulatory disease, obesity Ethnicity African American and Hispanic men are at a higher risk Family history of BPH REFERENCES 1. American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH), Revised Centers for Disease Control and Prevention (CDC). Trends in aging United States and worldwide. Morb Mortal Wkly Rep 2003 Feb 14; 52(6):101-4, Wei JT, Calhoun E, Jacobsen SJ. Urologic diseases in America project: benign prostatic hyperplasia. J Urol 2005 Apr; 173(4): Hu TW, Wagner TH, Bentkover JD, et al. Estimated economic costs of overactive bladder in the United States. Urology 2003 Jun; 61(6): NIH Publication No ; August 2014; 6. Krista AR, Arnold KB, Schenk JM, et al. Race/ethnicity, obesity, health related behaviors and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. J Urol 2007; 177(4): Parsons JK, Sarma AV, McVary K, et al. Obesity and benign prostatic hyperplasia: clinical connections, emerging etiological paradigms and future directions. J Urol 2013; 189(1): S102-S Patel ND and Parsons JK. Epidemiology and etiology of benign prostatic hyperplasia and bladder outlet obstruction. Indian J Urol (2):

6 PATHOLOGY OF BPH The Problem All Men >40 yrs BPE Histologic BPH BOO LUTS/Bother Roehrborn CG. Pathology of benign prostatic hyperplasia. Int J Impot Res 2008;20[Suppl. 3]:S11 8) Patients must have all four conditions to be a candidate for prostatic artery embolization 6

7 LOWER URINARY TRACT SYMPTOMS (LUTS) Two components are responsible for lower urinary tract symptoms (LUTS): 1 STATIC COMPONENT Related to the enlargement of the prostate and urethral compression, causing storage or irritative symptoms. Urinary Frequency Urinary Urgency Incontinence Nocturia DYNAMIC COMPONENT Related to the tension of prostatic smooth muscle in the prostate, prostate capsule, and bladder neck, causing voiding or obstructive symptoms. Inability to Urinate Difficulty Starting Urination Straining to Urinate or Weak Urine Stream Intermittent Urine Flow Incomplete Emptying of Bladder Benign prostatic hyperplasia (BPH), also known as benign prostatic obstruction (BPO), is not the only contributing factor to lower urinary tract symptoms (LUTS). 2 Detrusor underactivity Benign prostatic obstruction Others Overactive bladder / detrusor overactivity Distal ureteric stone Nocturnal polyuria LUTS Bladder tumor Chronic pelvic pain syndrome Urethral stricture Neurogenic bladder dysfunction Urinary tract infection Foreign body REFERENCES 1. Caine M. The present role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. J Urol 1990 Jul; 136(1): EAU Guidelines. Edn. presented at the EAU Annual Congress London ISBN

8 Basic Management of LUTS in Men LUTS CAUSE LITTLE OR NO BOTHER REASSURANCE AND FOLLOW UP RECOMMENDED TESTS: RELEVANT MEDICAL HISTORY ASSESSMENT OF LUTS SEVERITY AND BOTHER (i.e. AUA-SI) PHYSICAL EXAMINATION INCLUDING DRE URINALYSIS SERUM PSA 1 FREQUENCY/VOLUME CHART 2 Complicated LUTS: SUSPICIOUS DRE HEMATURIA ABNORMAL PSA PAIN INFECTION 3 PALPABLE BLADDER NEUROLOGICAL DISEASE PREDOMINANT SIGNIFICANT NOCTURIA FREQUENCY-VOLUME CHART BOTHERSOME LUTS POLYURIA NO POLYURIA 1 2 Polyuria 24-hour output >_ 3 liters Lifestyle and fluid intake is to be reduced 4 Nocturnal polyuria >_ 33% output at night Fluid intake to be reduced Consider other causes STANDARD TREATMENT ALTER MODIFIABLE FACTORS - DRUGS - FLUID & FOOD INTAKE LIFESTYLE ADVICE DRUG TREATMENT 5 FAILURE SUCCESS IN RELIEVING BOTHERSOME LUTS: 1. When life expectancy is >10 years and if the diagnosis of prostate cancer can modify the management. For the AUA PSA Best Practice Statement: 2009 Update, see 2. When significant nocturia is predominate symptom. 3. Assess and start treatment before referral. CONTINUE TREATMENT DETAILED MANAGEMENT 4. In practice, advise patients with symptoms to aim for a urine output of about 1 liter/24 hours. 5. See Detailed Management algorithm Copyright 2010 American Urological Association Education and Research, Inc. 8

9 Detailed Management for Persistent Bothersome LUTS after Basic Management RECOMMENDED TESTS: OAB (Storage Symptoms) No Evidence of BOO Validation Questionnaires FVC (Frequency-Volume Chart) Flow Rate Recording Residual Urine Lifestyle Intervention Behavioral Therapy Antimuscarinics Evidence of BOO Discuss Rx Options Shared Decision MIST or Surgery Option FAILURE Mixed OAB and BOO Medical Therapy Option Predominant BOO Reassess and Consider Invasive Therapy of OAB (Botulinum Toxin and Neuromodulation) Antimuscarinics 1 and α-blockers Small gland/ and/or low PSA 2 α-blocker Larger gland/ and/or higher PSA 3 α-blocker and/or 5α-Reductase Inhibitors FAILURE Offer MIST or Surgery to Patient Evaluation clearly suggestive of obstruction? (Qmax <10 ml/s) Yes NO Pressure-flow studies BOO: Bladder outlet obstruction MIST: Minimally invasive surgical treatment OAB: Overactive bladder PSA: Prostate-specific antigen PVR: Post void residual Rx: Treatment 1. Consider checking PVR prior to initiation 2. PSA < 1.5 ng/ml 3. PSA > 1.5 ng/ml NO Obstruction? Treat appropriately. If intervention therapy is pursued, patients need to be informed of possibly higher failure rates. Yes Proceed with selected techniques Copyright 2010 American Urological Association Education and Research, Inc. 9

10 Physician Reference Guide PATIENT WORKUP 10

11 International Prostate Symptom Score (IPSS) PATIENT NAME: DOB: TODAY S DATE: PATIENT INSTRUCTIONS Each question has several possible responses. Circle the number of the response that best describes your own situation. Please be sure that you select one and only one response for each question. In the past month: 1. Incomplete Emptying How often have you had the sensation of not emptying your bladder? 2. Frequency How often have you had to urinate less than every two hours? 3. Intermittency How often have you found you stopped and started again several times when you urinated? 4. Urgency How often have you found it difficult to postpone urination? Not at All Less than 1 in 5 Times Less than Half the Time About Half the Time More than Half the Time Almost Always Weak Stream How often have you had a weak urinary stream? Straining How often have you had to strain to start urination? 7. Nocturia How many times did you typically get up at night to urinate? None 1 Time 2 Times 3 Times 4 Times 5 Times Add the numbers corresponding to questions 1-7. TOTAL: SCORE 1-7 Mild 8-19 Moderate Severe Quality of Life Due to Urinary Symptoms If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that? Delighted Pleased Mostly Satisfied Mixed Mostly Dissatisfied Unhappy Terrible This information, including the questions, structure and completeness of the sample survey, is based on forms and/or scoring systems developed by independent organizations of relevance to the diagnosis and treatment of benign prostatic hyperplasia (BPH). This material is not a substitute for a consultation or physical examination by a physician. Merit Medical disclaims any liability for the decisions a patient makes based on this information. 11

12 International Index of Erectile Function (IIEF) Questionnaire PATIENT NAME: DOB: TODAY S DATE: The first five questions refer to erectile function. 1. Over the last month, how often were you able to get an erection during sexual activity? 2. Over the last month, when you had erections with sexual stimulation, how often were your erections hard enough for penetration? 3. Over the last month, when you attempted intercourse, how often were you able to penetrate your partner? 4. Over the last month, during sexual intercourse, how often were you able to maintain your erection after you had penetrated your partner? 5. Over the last month, during sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? No sexual activity Almost always or always Most times (much more than half the time) Sometimes (about half the time) A few times (much less than half the time) Almost never or never No sexual activity Extremely difficult The next three questions refer to satisfaction with intercourse. Very difficult Difficult Slightly difficult Not difficult No attempts 1-2 times 3-4 times 5-6 times 7-10 times times 6. Over the last month, how many times have you attempted sexual intercourse? 7. Over the last month, when you attempted sexual intercourse how often was it satisfactory for you? No sexual activity Almost always or always Most times (much more than half the time) Sometimes (about half the time) A few times (much less than half the time) Almost never or never No intercourse Very highly enjoyable Highly enjoyable Fairly enjoyable Not very enjoyable No enjoyment 8. Over the last month, how much have you enjoyed sexual intercourse? CONTINUED 12

13 The next two questions refer to orgasmic function 9. Over the last month, when you had sexual stimulation or intercourse, how often did you ejaculate? 10. Over the last month, when you had sexual stimulation or intercourse, how often did you have the feeling of orgasm (with or without ejaculation)? No sexual stimulation/ intercourse Almost always or always Most times (much more than half the time) Sometimes (about half the time) A few times (much less than half the time) Almost never or never The next two questions ask about sexual desire. In this context, sexual desire is defined as a feeling that may include wanting to have a sexual experience (for example masturbation or sexual intercourse), thinking about having sex, or feeling frustrated due to lack of sex. 11. Over the last month, how often have you felt sexual desire? 12. Over the last month, how would you rate your level of sexual desire? Almost always or always The next two questions refer to overall sexual satisfaction. 13. Over the last month, how satisfied have you been with your overall sex life? 14. Over the last month, how satisfied have you been with your sexual relationship with your partner? Most times (much more than half the time) Sometimes (about half the time) A few times (much less than half the time) Almost never or never Very high High Moderate Low Very low or not at all Very satisfied The last question refers to erectile function. Moderately satisfied About equally satisfied and dissatisfied Moderately dissatisfied Very dissatisfied Very high High Moderate Low Very low 15. Over the last month, how do you rate your confidence that you can get and keep your erection? ADD YOUR SCORES All the questions break down into five specific areas, as follows. Add your scores in the appropriate column. Area Questions Score Range Maximum Score Your Score Erectile Function 1-5 & Orgasmic Function Sexual Desire Intercourse Satisfaction Overall Satisfaction SCORING TOTAL 1-10: Severe Erectile Dysfunction 11-16: Moderate dysfunction 17-21: Mild to moderate dysfunction 22-25: Mild dysfunction 26-30: No dysfunction This information, including the questions, structure and completeness of the sample survey, is based on forms and/or scoring systems developed by independent organizations of relevance to the diagnosis and treatment of benign prostatic hyperplasia (BPH). This material is not a substitute for a consultation or physical examination by a physician. Merit Medical disclaims any liability for the decisions a patient makes based on this information. 13

14 SEXUAL HEALTH INVENTORY FOR MEN (SHIM) PATIENT NAME: TODAY S DATE: PATIENT INSTRUCTIONS Sexual health is an important part of an individual s overall physical and emotional well-being. Erectile dysfunction, also known as impotence, is one type of very common medical condition affecting sexual health. Fortunately, there are many different treatment options for erectile dysfunction. This questionnaire is designed to help you and your doctor identify if you may be experiencing erectile dysfunction. If you are, you may choose to discuss treatment options with your doctor. Each question has several possible responses. Circle the number of the response that best describes your own situation. Please be sure that you select one and only one response for each question. 1. How do you rate your confidence that you could keep an erection? 2. When you had erections with sexual stimulation, how often were your erections hard enough for penetration (entering your partner)? 3. During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? 4. During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? 5. When you attempted sexual intercourse, how often was it satisfactory for you? No Sexual Activity Very Low Low Moderate High Very High Almost Never or Never A Few Times (Much Less Than Half The Time) Sometimes (About Half The Time) Most Times (Much More Than Half The Time) Almost Always or Always Did Not Attempt Intercourse Almost Never or Never A Few Times (Much Less Than Half The Time) Sometimes (About Half The Time) Most Times (Much More Than Half The Time) Almost Always or Always Did Not Attempt Intercourse Extremely Difficult Very Difficult Difficult Slightly Difficult Not Difficult Did Not Attempt Intercourse Almost Never or Never A Few Times (Much Less Than Half The Time) Sometimes (About Half The Time) Most Times (Much More Than Half The Time) Almost Always or Always Add the numbers corresponding to questions 1-5. TOTAL: The SHIM questionnaire further classifies erectile dysfunction (ED) severity with the following breakpoints: 1-7 Severe ED 8-11 Moderate ED Mild to Moderate ED Mild ED This information, including the questions, structure and completeness of the sample survey, is based on forms and/or scoring systems developed by independent organizations of relevance to the diagnosis and treatment of benign prostatic hyperplasia (BPH). This material is not a substitute for a consultation or physical examination by a physician. Merit Medical disclaims any liability for the decisions a patient makes based on this information. 14

15 PATIENT WORKUP - INITIAL EVALUATION BASELINE Age of symptom onset, duration and severity International Prostate Symptom Score (IPSS) Sheet Current prostate medications History of sexual dysfunction International Index of Erectile Function (IIEF) Questionnaire Sexual Health Inventory for Men (SHIM) Sheet IPSS SCORE AND RECOMMENDED TREATMENTS Offer PAE to score 13 or higher Stage Mild Moderate Severe Recommendations as provided by American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH), Revised 2010 and Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor. 15

16 PATIENT WORKUP Diagnostic Tests Urinalysis to check for urinary tract infection Prostate-specific antigen (PSA) blood test Post-void residual (PVR) test Digital rectal exam (DRE) Uroflowmetry or Urodynamic testing (Qmax) 16

17 PATIENT WORKUP - LABS Post-Void Residual (PVR) Assessment of bladder emptying Elevation indicates a problem with emptying, but does not tell why PVR greater than 50mL is a significant amount of residual urine PVR >300 ml is chronic retention Post-Void Residual (PVR) is the amount of urine left in your bladder after urination. The test can be done by draining the bladder with a catheter or by using ultrasound. Goals of Urodynamic Studies: Reproduce patient s symptoms to help make an accurate diagnosis of the primary cause of LUTS Distinguish benign prostatic obstruction (BPO) from other causes of LUTS Evaluate bladder storage and emptying, which can impact treatment success or complications Determine if serious or irreversible damage to upper and lower urinary tract has already occurred or is at risk A knowledge of urodynamics and interpretation of urodynamic studies assists the interventional radiologist in selecting appropriate patients for PAE and predicting outcome success and symptom improvement. It is equally important to evaluate urodynamics in treatment failures to recommend retreatment modalities appropriately. 1 REFERENCE 1. Gomez C, Bhatia S, Carnevale F, et al. Role of Urodynamic Studies in Management of Benign Prostatic Obstruction: A Guide for Interventional Radiologists. J Vasc Interv Radiol 2017 Jan;28(1):

18 Uroflowmetry <10mL/s is predictive of BOO >15mL/s can still be present but in <1% of population Improved accuracy with voided volumes > 150mL Specificity of 70%, PPV 70% Recommendations as provided by Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor Uroflowmetry is a simple test that requires a device for catching and measuring urine and a computer to record the data. The equipment creates a graph that shows changes in flow rate from second to second so the health care provider can see when the flow rate is the highest and how many seconds it takes to get there. Results of this test will be abnormal if the bladder muscles are weak or urine flow is blocked. Uroflowmetry REFERENCE Uroflowmetry in a normal individual diagram above and actual reading below Lawrentschuk N, Perera M. Benign Prostate Disorders. [Updated 2016 Mar 14]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; Available from: NBK279008/ 18

19 Figure 1. Uroflowmetry curve showing a normal-appearing flow pattern with a continuous bell-shaped curve. Figure 2. Uroflowmetry curve showing a flattened or plateau-shaped flow pattern that is common in men with BPO. Figure 3. Uroflowmetry curve showing an intermittent flow pattern in a man with BPO. Gomez C, Bhatia S, Carnevale F, et al. Role of Urodynamic Studies in Management of Benign Prostatic Obstruction: A Guide for Interventional Radiologists. J Vasc Interv Radiol 2017 Jan;28(1):

20 Invasive Urodynamic Studies Invasive Urodynamic studies include cystometry and a pressure-flow study. During these tests, a catheter with a pressure-measuring device called a manometer is placed in the bladder, while another catheter is placed in the rectum to record pressure there. These studies are performed in a healthcare provider s office, clinic, or hospital with local anesthesia. Filling Phase (Cystometry) Measures how much urine the bladder can hold, how much pressure builds up inside the bladder as it stores urine, and how full it is when the urge to urinate begins Gomez C, Bhatia S, Carnevale F, et al. Role of Urodynamic Studies in Management of Benign Prostatic Obstruction: A Guide for Interventional Radiologists. J Vasc Interv Radiol 2017 Jan;28(1): Cystometrogram the constant rise and fall of the detrusor pressure (indicated by arrows) is consistent with phasic detrusor overactivity in a patient with BPO. This is often present in men with urinary urgency. Voiding Phase (Pressure-Flow Study) Measures the bladder pressure required to urinate and the flow rate a given pressure generates Determines if obstructive symptoms and urinary retention are secondary to BOO or detrusor underactivity = Pves Pabd Pdet Abdominal pressure (Pabd) is subtracted from intravesical pressure (Pves) to obtain a measurement of true detrusor pressure (Pdet). U.S. Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), Urodynamic Testing, NIH Publication No January

21 The Bladder Outlet Obstruction Index is a simple equation that objectively calculates the degree of obstruction. BOOI = PdetQmax - 2 Qmax International Continence Society nomogram categorizes patients into 3 groups: Obstructed (BOOI >40) Equivocal (BOOI 20-40) Unobstructed (BOOI < 20) International Continence Society nomogram of the pressure-flow relationship to evaluate for BOO Gomez C, Bhatia S, Carnevale F, et al. Role of Urodynamic Studies in Management of Benign Prostatic Obstruction: A Guide for Interventional Radiologists. J Vasc Interv Radiol 2017 Jan;28(1): Schafer nomogram quantifies the urethral resistance relation and is divided into 7 zones: Zones 0 and 1 represent no obstruction Zone 2 is equivocal or mild obstruction Zones 3 6 represent increasing severity of obstruction Schafer nomogram of the pressure-flow relationship to evaluate for BOO (0-VI) and detrusor contractility (VW-ST). Zones 3-6 are diagnostic for BOO. Pdet = detrusor pressure; ST = strong; VW = very weak. Griffiths CJ, Pickard RS. Review of invasive urodynamics and progress towards non-invasive measurements in the assessment of bladder outlet obstruction. Indian J Urol 2009 Jan;25(1):

22 Volume Calculations important to have consistent reporting \ Ellipsoid volume = L x W x H x π 6 Bullet (cylinder + half ellipsoid) volume = L x W x H x 5π 24 The bullet volume may be a better representation of prostate volume for prostate glands smaller than 55 cc. 22

23 PATIENT WORKUP - IMAGING TRUS/TRAS MRI - provides a good image of the prostate gland to assess asymmetry, volume and the gland s median lobe CTA - if patient has documented severe DAD Asymmetry the shape of the gland can help rule out or diagnose malignancy MRIs courtesy Hitachi Medical Systems America, Inc. (image A) Coronal T2-weighted normal prostate; high signal of peripheral zone and heterogeneous intermediate signal in central gland caused by benign prostatic hyperplasia; (image B) Axial T2-weighted image displays prostate cancer of right peripheral zone, which appears as a low signal (white arrow). Bhatia S, Dalal R, Gomez C, Narayanan G. Prostatic Artery Embolization After Failed Urlogical Interventions for Benign Prostatic Obstruction: A Case Series of Three Patients. Cardiovasc Intervent Radiol 2016 Aug;39(8): Axial T2 image of the prostate demonstrating an asymmetrically enlarged left lobe. 23

24 PI-RADS PI-RADS - Prostate Imaging-Deporting And Data System - uses a 5-point scale based on the probability that a combination of mpmri findings on T2W, DWI, and DCE correlates with the presence of a clinically significant cancer for each lesion in the prostate gland. The original PI-RADS score was revised and published as the second version, PI-RADS v2. PI-RADS v2 Assessment Categories PIRADS 1 Very low (clinically significant cancer is highly unlikely to be present) PIRADS 2 Low (clinically significant cancer is unlikely to be present) PIRADS 3 Intermediate (the presence of clinically significant cancer is equivocal) PIRADS 4 High (clinically significant cancer is likely to be present) PIRADS 5 Very high (clinically significant cancer is highly likely to be present) 24

25 POTENTIAL PAE CANDIDATES 1 PAE CANDIDACY - IR PERSPECTIVE IPSS score 13 Failed medical therapy (must try for minimum of 3 months) Uroflow <10mL/sec PVR >100mL Prostate size >50 g Median lobe <3 cm Contraindications include: 2 Active urinary tract infection or prostatitis Prostate cancer Bladder cancer Chronic renal failure Bladder atonia, neurogenic bladder disorder, or other neurological disorder impacting bladder function Bladder stones Urinary obstruction due to causes other than BPH Excessive vessel tortuosity or severe atherosclerosis When to Say NO 1 (in addition to contraindications listed above) IPSS 12 Signs/symptoms of prostatitis High PVR and patient is asymptomatic Prostate <50g Median lobe >3cm REFERENCES 1. Recommendations as provided by Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor 2. Embosphere PRO Prostatic Artery Embolization Kit Instructions for Use 25

26 PAE CANDIDACY - UROLOGIST PERSPECTIVE Poor surgical candidates Urinary retention - indwelling bladder catheter (IBC) Refractory hematuria of prostatic origin (RHPO), chronic Prior surgical history Large/giant prostatic hyperplasia (>150 g) PAE CANDIDACY - PATIENT PERSPECTIVE Men who do not want or are ineligible for surgery Men who have tried medication, but have found it to be ineffective or the side effects too burdensome! Men who want to avoid higher risk of possible adverse events such as retrograde ejaculation, impotence and urinary incontinence that are associated with surgical treatments Men wishing to preserve fertility 26

27 Physician Reference Guide MANAGEMENT OF BPH 27

28 BPH TREATMENT OPTIONS Watchful Waiting Pharmaceutical Treatments Less-Invasive Treatments Surgical Procedures Patient does not receive active intervention for BPH Patient is advised to make lifestyle changes to help relieve LUTS. Symptoms should be reevaluated at annual follow-up exam or sooner if symptoms worsen. WATCHFUL WAITING First-line treatment to target LUTS Alpha Blockers 5-Alpha Reductase Inhibitors Phosphodiesterase-5 Inhibitors Minimally Invasive Surgical Treatments (MIST) 1 Laser Treatment PVP- Photoselective Vaporization of the Prostate - Greenlight Laser HoLEP - Holmium Laser Enucleation of the Prostate Microwave Therapy TUMT - Transurethral Microwave Therapy Ablation TUNA - Transurethral Needle Ablation Steam Therapy Rezum Permanent Implants UroLift Prostatic Artery Embolization Recommended for patients with mild symptoms (IPSS score 7) or those with moderate or severe symptoms not bothered by their LUTS. 1,2 Patient does not receive active intervention for BPH, but is advised to make certain lifestyle changes that can help relieve LUTS, including: 2-4 Limiting daily fluid intake to about two quarts Limiting or avoiding caffeine or alcohol Avoiding drinking fluids in the evening Trying to urinate at least once every three hours Double voiding after urinating, wait and try to urinate again Avoiding medications that can aggravate symptoms such as decongestants, antihistamines, antidepressants, diuretics, and narcotics including oxycodone and morphine Exercising pelvic floor muscles Prostate tissue is cut away or the prostate gland is surgically removed to relieve pressure on the urethra TURP - Transurethral Resection of the Prostate (The Gold Standard) Open Prostatectomy Additional lifestyle modifications that could ward off or decrease risk factors such as obesity, lack of physical activity, diabetes, and hypertension are also recommended. 4 REFERENCES 1. American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH), Revised U.S. Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), Urodynamic Testing, NIH Publication No January Harvard Health Publications. Better Bladder and Bowel Control Moyad MA. Lifestyle changes to prevent BPH: Heart healthy = prostate healthy. Urol Nurs 2003 Dec;23(6):

29 MEDICATIONS Recommended by AUA Guidelines as first-line treatment for LUTS associated with BPH. Medication Use Examples Advantages Side-Effects Dizziness 1,2 Alpha Blockers 5-Alpha Reductase Inhibitors Target the dynamic component of BPH by relaxing the smooth muscles of the prostate and bladder neck to improve urine flow Address the static component of BPH by blocking the production of dihydrotestosterone (DHT), a male hormone that accumulates in the prostate and may cause growth of the gland Terazosin (Hytrin ) Doxazosin (Cardura ) Tamsulosin (Floxmax ) Alfuzosin (Uroxatral ) Silodosin (Rapaflo ) Finasteride (Proscar ) Dutasteride (Avodart ) Fastest-acting treatment for BPH, improving both symptoms and flow rate within one week 1,2 Useful for moderately enlarged prostates, but act much slower than alpha blockers 1,2 Fatigue 1,2 Decreased libido or erectile dysfunction 1,2 Increased risk of hospitalization or emergency room visits after a fall 3 Increased risk of fracture by 16% 3 Increased risk of head trauma by 15% during first 90 days of use 3 Erectile dysfunction 4 Ejaculatory dysfunction 4 Decreased libido 4 Depression and/or anxiety 4 Phosphodiestrerase-5 (PDE5) Inhibitors Relax smooth muscles in the lower urinary tract Tadalafil (Cialis ) Vardenafil (Levitra ) Sildenafil (Viagra ) Mainly prescribed for erectile dysfunction, but can help reduce LUTS Headache 4 Nasal congestion 4 Back pain 4 Dizziness 4 Combination medications Combining two classes of medications such as Finasteride and Doxazosin or Dutasteride and Tamsulosin or alpha blockers and antimuscarinics, a class of medications that relax the bladder muscles. REFERENCES 1. American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH), Revised Roehrborn CG. Efficacy of α-adrenergic Receptor Blockers in the Treatment of Male Lower Urinary Tract Symptoms. Rev Urol 2009 Fall; 11 (Suppl1):S1-S8 3. Welk B, McArthur E, Fraser LA, et al. The risk of fall and fracture with the initiation of prostate-selective α antagonist: a population based cohort study. BMJ 2015 Oct 26;351:h Trost L, Saitz TR, Hellstron WJ. Side Effects of 5-Apha Reductase Inhibitors: A Comprehensive Review. Sex Med Rev 2013 May;1(1):

30 MINIMALLY INVASIVE SURGICAL TREATMENTS (MIST) 1 There are many types of MISTS that use various types of energy to remove prostate tissue, including: Laser Treatment PVP - Photoselective Vaporization of the Prostate - Greenlight Laser HoLEP - Holmium Laser Enucleation of the Prostate Microwave Therapy TUMT - Transurethral Microwave Therapy Ablation TUNA - Transurethral Needle Ablation enlarged prostate bladder laser enlarged prostate bladder balloon catheter laser resectoscope urethra PVP - Greenlight Laser microwave antenna enlarged prostate tissue removed on this side urethra TUMT heated protstate tissue HoLEP HoLEP - Holmium Laser Enucleation of the Prostate Unlike TURP, indicated for larger ( 100g) prostates 2 Shortened catheterization times, decreased length of hospital stay and fewer serious post-operative complications 2 Difficult learning curve 2 REFERENCES 1. American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH), Revised Michalak J, Tzou D, Funk J. HoLEP: the gold standard for the surgical management of BPH in the 21st Century. Am J Clin Exp Urol 2015 v.3(1) 30

31 MINIMALLY INVASIVE SURGICAL TREATMENTS (MIST) UroLift small permanent implants lift the enlarged prostate out of the way so it no longer blocks urine flow Limited to prostates 80 cc Cannot treat prostates with obstructive or protruding median lobe 5-year IPSS improvement 36% 1 5-year Qmax improvement 44% 1 UroLift bladder bladder neck adronergic nerves blood vessels Rezum uses steam therapy to treat BPH not widely available in United States 2-year IPSS improvement 51% 2 hyperplastic tissue veru montanum urethra Rezum central zone peripheral zone transition zone REFERENCES 1. Roehrborn CG, Barkin J, Gange SN, et al. Five year results of the prospective randomized controlled prostatic urethral L.I.F.T. study. Can J Urol 2017 Jun;24(3): Roehrborn CG, Gange SN, Gittelman MC, et al. Convective Thermal Therapy: Durable 2-Year Results of Randomized Controlled and Prospective Crossover Studies for Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia. J Urol 2017 Jun;197(6):

32 PROSTATIC ARTERY EMBOLIZATION (PAE) 1-10 PAE hopes to address both components of BPH: Static Component ischemia can lead to apoptosis, necrosis, and subsequent volume reduction Dynamic Component ischemia with prostate cell death, which can decrease α1-adrenergic receptors leading to decreased neuromuscular tone BENEFITS Outpatient procedure with conscious sedation Performed via femoral or radial access Potential symptom improvement within days Low risk of erectile dysfunction Low risk of urinary incontinence Faster recovery time versus surgery Demonstrated success on larger prostate glands, hematuria, and patients with acute urinary retention CHALLENGES Anatomy identification of prostatic feeders Preventing non-target embolization Determining when to coil Steep learning curve Technique Pre-embolization Post-embolization Pre- and post-embolization angiograms courtesy Dr. Shivank Bhatia REFERENCES 1. McWilliams JP, Kuo MD, Rose SC, et al. Society of Interventional Radiology Position Statement: Prostate Artery Embolization for Treatment of Benign Disease of the Prostate. J Vasc Interv Radiol 2014; 25: Bhatia S, Harward SH, Sinha VK, Narayanan G. Prostate Artery Embolization via Transradial or Transulnar versus Transfemoral Arterial Access: Technical Results. J Vasc Interv Radio Jun;28(6): Carnevale FC, Iscaife A, Yoshinaga EM, et al. Transurethral Resection of the Prostate (TURP) Versus Original and PErFecTED Prostate Artery Embolization (PAE) Due to Benign Prostatic Hyperplasia (BPH): Preliminary Results of a Single Center, Prospective, Urodynamic-Controlled Analysis. Cardiovasc Intervent Radiol 2016 Jan;39(1): Gao YA, Huang Y, Zhang R,et al. Benign prostatic hyperplasia: prostatic arterial embolization versus transurethral resection of the prostate a prospective, randomized, and controlled clinical trial. Radiology 2014; 270: Golzarian J, Antunes AA, Bilhim T, et al. Prostatic artery embolization to treat lower urinary tract symptoms related to benign prostatic hyperplasia and bleeding in patients with prostate cancer: proceedings from a multidisciplinary research consensus panel. J Vasc Interv Radiol 2014; 25: Bhatia S, Kava B, K Pereira, et al. Prostate Artery Embolization for Giant Prostatic Hyperplasia. J Vasc Interv Radiol 2015 Oct;26(10: Isaacson AJ, Raynor MC, Yu H, et al. Prostatic Artery Embolization Using Embosphere Microspheres for Prostates Measuring cm3: Early Results from a US Trial. J Vasc Intervent Radiol 2016;27: Carnevale FC, Soares GR, de Assis AM, et al. Anatomical Variants in Prostate Artery Embolization: A Pictorial Essay. Cardiovasc Intervent Radiol 2017 Sep;40(9): de Assis AM, Moreira AM, de Paula Rodrigues VC, et al. Pelvic Arterial Anatomy Relevant to Prostatic Artery Embolisation and Proposal for Angiographic Classification. Cardiovasc Intervent Radiol 2015 Aug;38(4): Bhatia S, Sinha V, Bordegaray M, et al. Role of Coil Embolization during Prostatic Artery Embolization: Incidence, Indications, and Safety Profile. J Vasc Interv Radiol 2017 May;28(5):

33 SURGICAL TREATMENT OPTIONS Appropriate and effective for patients with moderate or severe symptoms (IPSS score 8) who are bothered by their LUTS Open Prostatectomy involves the surgical removal of the the prostate. Typically performed on patients with larger prostates (80-100g). 1 Usually requires a longer hospital stay and can result in a larger loss of blood. Retrograde ejaculation is common after procedure. 1,5 TURP (Transurethral Resection of the Prostate) still considered the gold standard for treating symptomatic BPH. 1,2 A wire-loop electrode is used to remove prostate tissue that is obstructing or pressing against the urethra. Retrograde ejaculation occurs in most patients. 1-3 TURP is performed much less frequently as new treatment options become available and physician reimbursement has dropped from a high of $2000-$3000 to approximately $650, while alternative surgical procedures, such as laser treatment options, are reimbursed at much higher levels. 4 bladder wire loop resectoscope enlarged prostate urethra TURP REFERENCES 1. American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH), Revised El-Hakim A. TURP in the new century: an analytical reappraisal in light of lasers. Can Urol Assoc J 2010 Oct 4(5): Rassweiler J, Teber D, Kuntz R, Hofmann R. Complications of Transurethral Resection of the Prostate (TURP) Incidence, Management, and Prevention. Eur Uro : Downs TM, O Leary MP. Sexual dysfunction in patients with benign prostatic hyperplasia. Curr Opin Urol 199;9: Emberton M, Neal DE, Black N, et al. The effect of prostatectomy on symptom severity and quality of life. Br J Urol 1996;77:

34 TREATMENT OUTCOMES BIPOLAR VS MONOPOLAR TURP Bipolar Monopolar IPSS Equal Equal Flow Rate Bipolar has fewer complications with at least equal results. POSSIBLE TURP ADVERSE EVENTS Bipolar Monopolar Transfusion/Clot Retention 2% 4% TUR Syndrome 0 1.4% Stricture Formation 4% 4% LONG-TERM TURP OUTCOMES Initial improvement sustained at 5 years Retreatment after TURP 1 Qmax improved 125% Symptom Score decreased by 70% QOL improved by 69% PVR reduced by 77% 6% at 1 year 12% at 5 years 15% at 10 years UROLIFT 5-YEAR OUTCOMES 2 IPPS improvement after Prostatic UroLift (PUL) was 88% greater than that of SHAM at 3 months. Improvement in IPSS, QOL and Qmax were durable through 5 years with improvements of 36%, 50% and 44%, respectively. Surgical retreatment was 13.6% over 5 years. Sexual function was stable over 5 years with no de novo, sustained erectile or ejaculatory dysfunction. REFERENCES 1. Reich O, Gratzke C, Stief CG. Techniques and Long-Term Results of Surgical Procedures for BPH. European Urology ; Roehrborn CG, Barkin J, Gange SN, et al. Five year results of the prospective randomized controlled prostatic urethral L.I.F.T. study. Can J Urol 2017 Jun;24(3):

35 Physician Reference Guide ANATOMY 35

36 PROSTATE ANATOMY ZONES CENTRAL ZONE BPH NODULES - related to hyperplasia of the stroma and glandular epithelium (2:1 ratio), which leads to enlargement of the prostrate gland, urethral compression, and obstructive symptoms Median lobe - portion which protrudes into urinary bladder PERIPHERAL ZONE Over 80 percent of prostate cancers occur in the peripheral zone TRANSITION ZONE Surrounds the part of the urethra that passes through the prostate Gets larger with age and can cause urinary problems Central Zone Bladder Ejaculatory Duct Transitional Zone Anterior Zone Prostate Peripheral Zone Urethra 36

37 PAE ANATOMY PROVISO Illustration showing the PROVISO arteries and their relationship to the prostate using the Foley balloon as a guide under the ipsilateral oblique view. PROVISO ip internal pudendal mr middle rectal O obturator VI inferior vesical Sv superior vesical O oblique view Carnevale FC, Antunes AA. Prostatic artery embolization for enlarged prostates due to benign prostatic hyperplasia. How I do it. Cardiovasc Intervent Radiol 2013 Dec;36(6);

38 MICROCATHETER POSITION FOR EMBOLIZATION Illustration showing the ideal positioning of the distal tip of the microcatheter (asterisk) for a safe and effective direct flow embolic agent injection during prostatic artery embolization. Urethral Branches Capsular Branches Urethral Branches: These run parallel to the urethra These branches supply the transition zone (BPH) Capsular Branches: Posterolateral aspects of the prostrate gland Peripheral zone Some of these vessels may pass to the rectum and anal canal Digital subtraction angiography showing the microcatheter inserted in the left inferior vesical artery before the origin of bladder (white arrow) and rectal (white arrowhead) branches. Asterisk indicates ideal microcatheter tip position to start embolic agent injection. Carnevale FC, Antunes AA. Prostatic artery embolization for enlarged prostates due to benign prostatic hyperplasia. How I do it. Cardiovasc Intervent Radiol 2013 Dec;36(6);

39 PROSTATIC ARTERY ORIGINS Schematic drawing of the different prostate artery origins and their incidence. Bilhim T, Pisco JM, Rio Tinto H, et al. Prosatic Arterial Supply: Anatomic and Imaging Findings Relevant for Selective Arterial Embolization. J Vasc Interv Radiol 2012 Nov;23(11): Angiographic Anatomical Classification Classification Incidence Anatomic Description Type I 28.7% IVA originating from anterior division of IIA, in a common trunk with SVA Type II 14.7% IVA originating from anterior division of IIA, inferior to SVA Type III 18.9% IVA originating from obturator artery Type IV 31.1% IVA originating from IPA Type V 5.6% Less common origins Carnevale FC, Soares GR, de Asses AM, et al. Anatomical Variants in PRostate Artery Embolization: A Pictorial Essay. Cardiovasc Intervent Radiol 2017 Sep;40(9):

40 UTILIZING A FOLEY BALLOON CATHETER Anterior-posterior Rx showing the Foley balloon (F) placed in the bladder (filled with 30% iodinated contrast medium and 70% normal saline solution) and its relationship with the rectum (arrows). The Inferior Vesical Artery (IVA) is considered the main prostatic artery, and it usually arises as the second or third branch of the anterior trunk of the internal iliac artery (white arrows). Generally, one main prostatic artery is found on each side in that position, but the main prostatic artery or additional prostatic branches arising from the superior vesical, internal pudendal, obturator, and middle rectal arteries also can be found in some patients. Carnevale FC, Antunes AA. Prostatic artery embolization for enlarged prostates due to benign prostatic hyperplasia. How I do it. Cardiovasc Intervent Radiol 2013 Dec;36(6);

41 PAE Anatomy PROVISO Ipsilateral Oblique View P - Internal Pudendal R - Middle Rectal O - Obturator V - Vesical + I - Inferior S - Superior Vesical O - Oblique View = Inferior Vesical (IV) Foley Prostatic S IV O R P PROVISO is an acronym developed by Dr. Francisco Carnevale to remember the arteries and their relationship to the prostate while using a Foley balloon catheter as an anatomical landmark in the ipsilateral oblique view. The Inferior Vesical (IV) leads to the intra-prostatic arteries. Here are two tips to help you locate the Inferior Vesical Artery: 1. Find the Foley balloon (filled with contrast and saline mixture) and identify the arteries (prostatic branches) immediately below it. Follow these branches back to identify the origin of the prostatic artery. 2. Because not all physicians will use a Foley, you can also locate the Inferior Vesical by first finding the Obturator Artery (it resembles a fork). Usually, the IV is superior to the Obturator. TYPE I ORIGIN - IVA Left Ipsilateral Oblique IVA SVA IVA The Inferior Vesical Artery originates from the Anterior Division of the Internal Iliac Artery in a common trunk with the Superior Vesical Artery. Foley O Merit Medical does not dispense medical or legal advice, and the text, illustrations, photographs, animations and other information ( Content ) presented above is for general information purposes only. All angiogram images courtesy Francisco Carnevale, MD, PhD, Interventional Radiologist, São Paulo, Brazil. All anatomical illustrations courtesy Junior Falcetti, medical illustrator, São Paulo, Brazil. 41

42 TYPE II ORIGIN - ANTERIOR DIVISION - LEAST COMMON Left Ipsilateral Oblique S Anterior Division IIA* U R The Inferior Vesical Artery originates from the Anterior Division of the Internal Iliac Artery, inferior to the Superior Vesical Artery. *IIA Internal Iliac Artery Foley Prostatic * O VI P IG TYPE III ORIGIN - OBTURATOR Right Ipsilateral Oblique NOTE: This is a right ipsilateral oblique view, without a Foley. In this case, locate the Obturator Artery (O) and the Superior Vesical (S). The Inferior Vesical (which leads to the prostatic arteries) orignates from the Obuturator in this type III origin. IG P S * O U Prostatic U TYPE IV ORIGIN - IPA - MOST COMMON Left Ipsilateral Oblique S Foley IV * R The Inferior Vesical Artery originates from the Internal Pudendal Artery. Prostatic O P IG Merit Medical does not dispense medical or legal advice, and the text, illustrations, photographs, animations and other information ( Content ) presented above is for general information purposes only. All angiogram images courtesy Francisco Carnevale, MD, PhD, Interventional Radiologist, São Paulo, Brazil. All anatomical illustrations courtesy Junior Falcetti, medical illustrator, São Paulo, Brazil. 42

43 MOST COMMON TYPES OF PROSTATIC ARTERY ORIGINS Type IV anatomy. DSA in 44-degree right oblique view shows IVA originating from the internal pudendal artery (IPA arrow). Type III anatomy. DSA in 35-degree right oblique view shows IVA originating from the obturator artery (arrow). De Assis AM, Moreira AM, de Paula Rodrigues VC, et al. Pelvic Arterial Anatomy Relevant to Prostatic Artery Embolisation and Proposal for Angiographic Classification. Cardiovasc Intervent Radiol Aug;38(4):

44 MOST COMMON TYPES OF PROSTATIC ARTERY ORIGINS Type II anatomy. DSA in 44-degree right oblique view shows the IVA originating from the anterior division of IIA (arrow), inferior to SVA. Type I anatomy. DSA in 45-degree left oblique view shows inferior vesical artery (arrow) originating from the anterior division of internal iliac artery (IIA), in a common trunk (arrowhead) with the superior vesical artery (SVA). De Assis AM, Moreira AM, de Paula Rodrigues VC, et al. Pelvic Arterial Anatomy Relevant to Prostatic Artery Embolisation and Proposal for Angiographic Classification. Cardiovasc Intervent Radiol Aug;38(4):

45 LESS-COMMON ANATOMICAL PATTERNS DSA in 44-degree left oblique view shows IVA (arrows) originating from the accessory internal pudendal artery (aipa). DSA in 42-degree right oblique view shows the anterior division of the IIA ending in a trifurcation: IVA, internal pudendal artery (IPA) and inferior gluteal artery (IGA). De Assis AM, Moreira AM, de Paula Rodrigues VC, et al. Pelvic Arterial Anatomy Relevant to Prostatic Artery Embolisation and Proposal for Angiographic Classification. Cardiovasc Intervent Radiol Aug;38(4):

46 Physician Reference Guide PROSTATIC ARTERY EMBOLIZATION 46

47 PAE TIPS & TRICKS FOLEY CATHETER When first learning and performing PAE, a Foley catheter is recommended to serve as an anatomical landmark during the procedure. It is also recommended to use a Foley if the patient has PVR 300 or the patient has experienced previous episodes of retention. Consider sedating the patient before Foley placement using ultrasound guidance. National Institute of Diabetes and Digestive and Kidney Diseases, NIH Carnevale FC, Antunes AA. Prostatic artery embolization for enlarged prostates due to benign prostatic hyperplasia. How I do it. Cardiovasc Intervent Radiol 2013 Dec;36(6); The inflated Foley balloon is filled with a 30/70 mixture of iodinated contrast and saline solution. MEDICATIONS Pre-Procedure: Dulcolax (2 tabs) for 2 nights before the procedure to prevent constipation Day of Procedure: antibiotics such as Ciprofloxacin or Levofloxacin IV (one dose) During the Procedure: Nitroglycerine Administer right after catheterization of the prostatic artery and before injecting embolic Sedation Versed and Fentanyl Heparin IV ready Recommendations as provided by Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor. 47

48 STEP 1: ACCESS Radial Access Tumescent Anesthesia: 100mcg Nitro 9mL 1% Lidocaine 10mL syringe Inject along length of radial artery under palpation for length of needle (4cm) Anti-Spasmodic Radial Cocktail 200mcg Nitro 2000IU Heparin Hemodilute with aspirated blood to 20mL and slowly reinject 2.5mg Verapamil Recommendations as provided by Dr. Darren Klass, Merit Medical s ThinkRadial IR Proctor. Dr. Darren Klass is a paid consultant of Merit Medical. STEP 2: HYPOGASTRIC ANGIOGRAM Identification of prostatic artery and origin critical First injection 30 degrees ipsilateral oblique Second 45 degrees if necessary Rarely ipsilateral oblique Imaging Start with an angiogram from the common internal iliac trunk to help identify the prostatic artery and origin, and to help avoid missing any branch arising from the anterior and posterior division. A view of ipsilateral oblique view is recommended to identify the internal vesical artery and all possible accessory branches. A caudal view (10 20 ) can help identify some bladder branches. Carnevale FC, Antunes AA. Prostatic artery embolization for enlarged prostates due to benign prostatic hyperplasia. How I do it. Cardiovasc Intervent Radiol 2013 Dec;36(6);

49 STEP 3: CATHETERIZATION OF THE PROSTATIC ARTERY Less or equal to 2.4F Shapable tip wire Trackable Proximal support STEP 4: SELECTIVE INJECTION OF THE PROSTATIC ARTERY STEP 5: CONE BEAM PROTOCOLS 0.3mL/sec for a total of 5.4mL (8 second delay) Hand injection: 3 to 5cc of 50% diluted, starting 2 seconds before rotation and for the duration of the spin 6 sec spin with very slow hand injection 3-5cc Recommendations as provided by Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor. 49

50 STEP 6: EMBOLIZATION OF THE PROSTATIC ARTERY Recommended Embolic Mixture 9 cc saline + 9 cc contrast + 2 cc Embosphere Microspheres = 20 cc Embolic Mixture Embosphere Microspheres are contained in a sterile, 20 ml pre-filled syringe with saline. AP projection recommended for embolic injection Very slow embolic injection: 1cc/2 minutes Recommended injection protocol: 1cc embolic mixture / 1cc saline delivered slowly / 3cc saline delivered quickly repeat until near stasis endpoint Recommend using µm microspheres for prostate glands 60g Identify potential non target Embolize with coils if necessary (have coils ready) Foley Removal At the end of the PAE procedure Next day if keeping patient overnight One week after PAE for patients with acute urinary retention (remove indwelling catheter and patient should attempt spontaneous voiding) If the catheter can t be removed, another attempt is tried every week for 4 weeks Recommendations as provided by Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor. 50

51 PErFecTED Technique Proximal Embolization First, Then Embolize Distal, developed by Dr. Francisco Carnevale. 1,2 Technique involves: 1. Embolizing the IVA from a single position distal to any bladder or rectal branches, but proximal to individual prostatic branches 2. Then advancing the microcatheter deeper into the gland, into the intraprostatic branches to deliver additional embolic agent Inject embolic mixture without nitro Deliver 2-4cc more embolics REFERENCES 1. Carnevale FC, Antunes AA. Prostatic artery embolization for enlarged prostates due to benign prostatic hyperplasia. How I do it. Cardiovasc Intervent Radiol 2013 Dec;36(6); Carnevale FC, Moreira AM, Antunes AA. The PErFecTED Technique : Proximal Embolization First, Then Embolize Distal for BPH. Cardio vasc Intervent Radiol 2014 Dec;37(6):

52 STEP 7: HEMOSTASIS Sheath Removal Band Placement Patent Hemostasis Achieved Foley Removal Patient Transferred to Post-Care Unit 52

53 TIPS & TRICKS POST-PROCEDURE MORNING AFTER PROCEDURE Check the groin site (femoral) / Remove Foley catheter Prescription: Ibuprofen 800 mg TID, Nexium 40 mg OD: Antibiotics (ciprofloxacin) x 5 days and if required: Percocet Labs: PSA and CBC morning after the procedure POST-PROCEDURE CARE Remove Foley, if used Medication Ibuprofen 800mg TID x 7 days Ciprofloxacin 500mg BID x 7 days - longer for patients with indwelling Foley Pyridium mg TID Vesicare 5 mg once a day Dulcoalx 20mg OD Normal post-procedure fluids Dehydration can result in acute renal failure Restrict activity for 2-3 days Patient will feel tired 5-7 days after procedure Call patient next day PATIENT FOLLOW-UP Patients return in to clinic 4-6 weeks after PAE Patients with indwelling catheters return 1 week after PAE Attempt catheter removal and spontaneous voiding If catheter cannot be removed, another attempt is tried every week If patient cannot urinate spontaneously after 1 month; PAE considered clinical failure 1-month follow-up appointment: patient questionnaires, labs and stop medications 3-month follow-up appointment: MRI, uroflowmetry, PVR and patient questionnaires Recommendations as provided by Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor. 53

54 Physician Reference Guide COMPLICATIONS 54

55 POSSIBLE PROBLEMS DURING PAE Spasm Smaller vessels more likely to spasm Use nitro immediately, cone beam sooner and use µm microspheres Stenosis in the vessel or at origin Systemic Heparin, IU Careful catheterization Have embolics ready Collaterals Common with smokers and vasculopathy Carefully watch direction of flow Use µm microspheres and coils if necessary Prostatic rectal trunk Larger vessel but difficult to catheterize Recommendations as provided by Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor. 55

56 EXPECTATIONS - POST-PROCEDURE PROSTATE-SPECIFIC ANTIGEN POST PAE Dramatically increases (up to 20x) 24 hours after PAE Drops to normal value (50% of baseline) 1 month after PAE Carnevale et al 1 has reported higher PSA values at day 1 after PAE results and better outcomes in AUR patients PROSTATE REDUCTION POST PAE % reduction in prostate volume Most evident 3 months post-pae Larger prostates (>90g) usually experience higher volume reduction REFERENCES 1. Carnevale FC, Antunes AA. Prostatic artery embolization for enlarged prostates due to benign prostatic hyperplasia. How I do it. Cardiovasc Intervent Radiol 2013 Dec;36(6); Carnevale FC, da Motta-Leal-Filho JM, Antunes AA, et al. Quality of Life and Clinical Symptom Improvement Support Prostatic Artery Embolization for Patients with Acute Urinary Retention Caused by Benign Prostatic Hyperplasia. J Vasc Interv Radiol 2013 Apr;24(4): Antunes AA, Carnevale FC, da Motta-Leal-Filho JM, et al. Clinical, Laboratorial, and Urodynamic Findings of Prostatic Artery Embolization for the Treatment of Urinary Retention Related to Benign Prostatic Hyperplasia. A Prospective Single-Center Pilot Study. Cardiovasc Intervent Radiol 2013 Aug;36(4): McWilliams JP, Kuo MD, Rose SC, et al. Society of Interventional Radiology Position Statement: Prostate Artery Embolization for Treatment of Benign Disease of the Prostate. J Vasc Interv Radiol 2014; 25:

57 POSSIBLE ADVERSE EVENTS 1-6 Dysuria Urinary urgency or frequency Lower abdominal spasm Fever Blood in urine, stool or ejaculate Fatigue Will persist 5-7 days after procedure Urinary Tract Infection (UTI) Higher-risk patients include: those with indwelling catheters or self-catheterizing, have undergone recent instrumentation procedure, and have had prostatitis, urinary retention or previous UTI Baseline urine culture a must Non-targeted embolization Bladder, penile, or rectal Urethral obstruction after PAE caused by sloughing prostate tissue MEDICATIONS TO COMBAT ADVERSE EVENTS:* Phenazopyridine (Pyridium ) mg/2-3 days. Relieves pain, burning and discomfort. Will cause urine to be dark or turn orange. Can cause dizziness, headache, indigestion, itchy stomach, cramps or pain. Solifenacin (Vesicare ) or Oxybutynin (Ditropan ) 5mg/day. Can help reduce urinary urgency and bladder spasms. Can cause dry mouth and constipation. Not recommended for patients older than 85 years old, as it can cause confusion. Bisacodyl (Dulcolex ) 20mg. Laxative to help prevent constipation. Uribel also for urinary burning and urgency. Can turn urine blue/bluish-green. Azo over the counter medication for urinary pain relief. URINARY RETENTION* Need to catheterize patients who can t urinate after more than 4 hours after PAE Leave indwelling catheter in place for 1 week and wait for inflammation to decrease Predictors of Urinary Retention Higher PVR and/or IPSS at baseline Self-catheterization Bigger prostate glands Stopping Flomax Recommended to double dose first 3 days after procedure *Recommendations as provided by Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor. REFERENCES 1. McWilliams JP, Kuo MD, Rose SC, et al. Society of Interventional Radiology Position Statement: Prostate Artery Embolization for Treatment of Benign Disease of the Prostate. J Vasc Interv Radiol 2014; 25: Lebdai S, Delongchamps NB, Sapoval M, et al. Early results and complications of prostatic arterial embolization for benign prostatic hyperplasia. World J Urol 2016 May;34(5) Moreira AM, de Assis AM, Carnevale FC, et al. A Review of Adverse Events Related to Prostatic Artery Embolization for Treatment of Bladder Outlet Obstruction Due to BPH. Cardiovasc Intervent Radiol 2017 Aug;40: Moreira AM, Marques CFS, Antunes AA, et al. Transient Ischemic Rectitis as a Potential Complication after Prostatic Artery Embolization: Case Report and Review of the Literature. Cardiovasc Interent Radiol : Carnevale FC, Da Motta-Leal-Filho JM, Antunes AA, et al. Quality of Life and Clinical Symptom Improvement Support Prostatic Artery Embolization for Patients with Acute Urinary Retention Caused by Benign Prostatic Hyperplasia. J Vasc Interv Radiol 2013 Apr;24(4): Leite LC, de Assis AM, Moreira AM, et al. Prostatic Tissue Elimination After Prostatic Artery Embolization (PAE): A Report of Three Cases. Cardiovasc Intervent Radiol 2017 Jun;40(6):

58 POST-PAE ADVERSE EVENT FORM PATIENT NAME: TODAY S DATE: ADVERSE EVENT Start Date End Date Any Medications Pain After Procedure Painful Urination Fever Fatigue Leakage of Urine Lower Abdominal Spasm Blood in Urine Blood in Stool Blood in Ejaculate Groin Swelling/Discoloration Inability to Urinate Problems with Erection / Ejaculation Recommendations as provided by Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor. This information, including the questions, structure and completeness of the sample survey, is based on forms and/or scoring systems developed by independent organizations of relevance to the diagnosis and treatment of benign prostatic hyperplasia (BPH). This material is not a substitute for a consultation or physical examination by a physician. Merit Medical disclaims any liability for the decisions a patient makes based on this information. 58

59 Physician Reference Guide ADDITIONAL RESOURCES 59

60 UROLOGY OUTREACH & PATIENT AWARENESS BUILDING PATIENT AWARENESS Collaboration with Urology Department Outreach Patient Experience Know your basics Reach Out to Urology Staff Physicians Fellows/Residents Physician Assistants Surgical Schedulers/Nurse Managers Collaboration with Urologists Baseline and follow up multiple times with Urology Share coding and reimbursement rate information IRs should collaborate with urologists for patients - cannot treat without joint effort Consider a joint clinic - pick the same clinic day as the urologist Additional Outreach Create awareness Grand rounds to primary care/geriatrics Centralized Number Hospital newsletter TV ads Radio interviews Recommendations as provided by Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor. 60

61 PAE EQUIPMENT TABLE SET-UP* RADIAL OR FEMORAL 1 Procedure Table 1 Table or Mayo Stand for Embolization Procedure Pack with Wire Bowl, 2 Smaller Bowls, 3 Specimen Cups 4x4's Wire Wipe or Telfa Pad Dump Bag for Waste and - if possible - Spikes for Contrast and Hepranized Saline Contrast and Hepranized Saline for the Table Pressurized Hepranized Saline Flush Bags to Connect to Sheath (Only Tubing is Sterile) Load Contrast Injector 1% Lidocaine Nitro for IA to Prevent Spasm Radial Cocktail (Only if Radial Access) (4) 3cc Medallion Syringes for Contrast/Saline (6) 1cc Medallion Syringes for Embolization/Contrast/Saline (6) 10cc Medallion Syringes for Contrast/Saline (2) Stopcocks US Probe Cover 4Fr or 5Fr Sheath 4Fr or 5Fr Mini Access Kit or Micropuncture Hydrophilic Guide Wire (180cm) or Physician's Wire of Choice Flush Catheter (Pigtail, Mod Hook) 4Fr or 5Fr 125cm Bernstein (Radial) 4Fr or 5Fr UAC, RUC, Simmons, Cobra (Femoral) Hemostasis Valve Microcatheter/Microwire Embosphere Microspheres (recommended) or Separate Table (so there is no cross contamination of particles) Closure or Hemostasis Device Tegaderm/Clean 4x4 to Cover Access Site * Merit Medical does not dispense medical or legal advice, nor endorse or guarantee the suitability of any of the above-listed products for any specific patient or procedure. Before using, refer to the Instructions for Use (IFU) for indications, contraindications, warnings, precautions, and directions for use. The above equipment set-up suggestions and other information, which may include both Merit and third-party products, are for the practitioner s convenience and for general information purposes only. 61

62 PAE EQUIPMENT TABLE SET-UP* RADIAL 4Fr Radial Set-Up Embosphere Procedure Pack Rad Board 2 Radial Arm Board Rad Rest 5Fr Radial Set-Up Embosphere Procedure Pack Rad Board 2 Radial Arm Board Rad Rest Procedure 4Fr PreludeEASE Laureate Guide Wire 4Fr Performa Bernstein 125cm 2.1Fr Maestro - 45, Straight or Swan 150cm True Form Microwire 180cm Angled or Straight (Physician Preference) Hemostasis Valve- FLO 30 Medallion Syringes Stopcock Procedure 5Fr PreludeEASE Laureate Guide Wire 5Fr Performa Bernstein 125cm 2.1Fr Maestro - 45, Straight or Swan 150cm True Form Microwire 180cm Angled or Straight (Physician Preference) Hemostasis Valve- FLO 30 Medallion Syringes Stopcock Embosphere PRO PAE Kit Embosphere PRO PAE Kit (Recommended) OR Embosphere Microspheres Embosphere Microspheres (Recommended) Embosphere PRO PAE Kit Embosphere PRO PAE Kit (Recommended) OR Embosphere Microspheres Embosphere Microspheres (Recommended) Closure/Hemostasis PreludeSYNC Closure/Hemostasis PreludeSYNC Each Embosphere PRO PAE Kit includes: (1) prefilled syringe of Embosphere Microspheres (1) 10 ml Medallion Syringe (1) 3 ml Medallion Syringe (2) 1 ml Medallion Syringes (1) 3-way Medallion Stopcock, 1050 psi * Merit Medical does not dispense medical or legal advice, nor endorse or guarantee the suitability of any of the above-listed products for any specific patient or procedure. Before using, refer to the Instructions for Use (IFU) for indications, contraindications, warnings, precautions, and directions for use. The above equipment set-up suggestions and other information, which may include both Merit and third-party products, are for the practitioner s convenience and for general information purposes only. 62

63 PAE EQUIPMENT TABLE SET-UP* FEMORAL 4Fr Femoral Set-Up Embosphere Procedure Pack 5Fr Femoral Set-Up Embosphere Procedure Pack Procedure 4Fr Prelude InQwire or Benston C Laureate Standard.035/180cm 4Fr Mod Hook 4Fr UAC 4Fr Sim 1, 2 4Fr C1, 2 2.1Fr Maestro - 45, Straight or Swan 130cm SwiftNINJA True Form Microwire 180cm Angled or Straight (Physician Preference) Hemostasis Valve Access Plus and MBA Large Bore Honor and Passage Small Bore Medallion Syringes Stopcock Embosphere PRO PAE Kit Embosphere PRO PAE Kit (Recommended) OR Embosphere Microspheres Embosphere Microspheres (Recommended) Closure/Hemostasis Safeguard Femoral Procedure 5Fr Prelude InQwire or Benston C Laureate Standard.035/180cm 5Fr Mod Hook 5Fr UAC 5Fr Sim 1, 2 5Fr C1, C2 2.1Fr Maestro - 45, Straight or Swan 130cm SwiftNINJA True Form Microwire 180cm Angled or Straight (Physician Preference) Hemostasis Valve Access Plus and MBA Large Bore Honor and Passage Small Bore Medallion Syringes Stopcock Embosphere PRO PAE Kit Embosphere PRO PAE Kit (Recommended) OR Embosphere Microspheres Embosphere Microspheres (Recommended) Closure/Hemostasis Safeguard Femoral Each Embosphere PRO PAE Kit includes: (1) prefilled syringe of Embosphere Microspheres (1) 10 ml Medallion Syringe (1) 3 ml Medallion Syringe (2) 1 ml Medallion Syringes (1) 3-way Medallion Stopcock, 1050 psi * Merit Medical does not dispense medical or legal advice, nor endorse or guarantee the suitability of any of the above-listed products for any specific patient or procedure. Before using, refer to the Instructions for Use (IFU) for indications, contraindications, warnings, precautions, and directions for use. The above equipment set-up suggestions and other information, which may include both Merit and third-party products, are for the practitioner s convenience and for general information purposes only. 63

64 Glossary of Terms Acute Urinary Retention (AUR) a severe complication of benign prostatic hyperplasia (BPH); the inability to voluntarily pass urine. Benign Prostatic Enlargement (BPE) when the prostate gland is enlarged; usually a presumptive diagnosis based on the size of the prostate. Benign Prostatic Hyperplasia (BPH) a common noncancerous condition in which the prostate gland becomes enlarged. (aka Benign Prostatic Hypertrophy) Benign Prostatic Obstruction (BPO) when obstruction has been proven by pressure flow studies, or is highly suspected from flow rates and enlargement of the gland. Bladder Outlet Obstruction (BOO) a general term used to describe all types of bladder obstruction. For example, benign prostatic obstruction or BPO is a type of BOO. Bladder Outlet Obstruction Index (BOOI) also known as the Abrams-Griffiths (AG) number, is the most widely used index for predicting BOO. BOOI = Qmax 2 Qmax. Dihydrotestosterone (DHT) a male hormone that plays a role in prostate development and growth. Some research has indicated that the buildup of DHT may be a factor in BPH. International Index of Erectile Function (IIEF) a brief 15-question self-administered survey used to help diagnose erectile dysfunction by addressing the four areas of male sexual function: erectile function, orgasmic function, sexual desire, and intercourse satisfaction. The SHIM (Sexual Health Inventory for Men) also known as IIEF-5, is an abbreviated questionnaire used as a diagnostic tool for erectile dysfunction. IPSS (International Prostate Symptom Score) a brief 7-question self-administered survey concerning urinary symptom severity and one question addressing quality of life (QoL). LUTS (Lower Urinary Tract Symptoms) range of symptoms related to problems with the lower urinary tract (bladder, prostate, urethra). LUTS are broadly grouped into voiding (obstructive) symptoms or storage (irritative) symptoms. Common LUTS include: Urinary frequency urination eight or more times a day Urinary urgency the inability to delay urination Trouble starting a urine stream An interrupted or weak urine stream Dribbling at the end of urination Urinary retention inability to completely empty bladder Urinary incontinence the accidental loss of urine Nocturia excessive urination at night during sleep Pain during urination or after ejaculation Overactive Bladder (OAB) a condition in which the bladder muscles contract uncontrollably and cause urinary frequency, urinary urgency and urinary incontinence. The symptoms of OAB can be mistakenly attributed to BPH, but men can also suffer from both. Pdet (detrusor pressure) an important concept of urodynamics, it is the subtracting of abdominal pressure (or extrinsic forces) from the intravesical pressure (or bladder pressure) to obtain the detrusor pressure (Pves Pabd = Pdet). Detrusor pressure can be normal, overactive or underactive. For normal function, the bladder volume increases during the filling phase without a significant rise in bladder pressure. Post Void Residual (PVR) measures the amount of urine remaining in the bladder after voiding. PVR can be measured by sonogram or by inserting a catheter through the urethra and into the bladder, draining and measuring any remaining urine. Prostate Volume (PV) indicates prostate size and is measured by TRUS (Transrectal Ultrasound), MRI, or CT. Common and interchangeable units of measurement you may see for prostate volume include: grams (g), cubic centimeters (cc or cm3), and milliliters (ml). PSA (Prostate-Specific Antigen) protein produced by the prostate gland. A PSA test measures the level of PSA proteins circulating in the blood. Most physicians consider 4.0ng/ml and lower as normal. (ng/ml nanograms per milliliter) Quality of Life (QoL) general well-being of a person. In terms of BPH, it s used as part of the International Prostate Symptom Score (IPSS) assessment tool, which helps patients communicate how their symptoms are affecting everyday life. Urodynamics - studies that assess how the bladder and urethra are performing their job of storing and releasing urine. Urodynamic tests can help explain symptoms such as frequent urination or incontinence. Uroflowmetry test that measures the volume of urine released from the body, the speed it is released, and how long the release takes. Qmax is the single most useful parameter of uroflowmetry and indicates the maximum flow rate and is more significantly correlated with age and voided volume than average flow rate (Qavg). 64

65 PHARMACEUTICAL TREATMENTS 5-Alpha Reductase Inhibitors medications that block the production of DHT and can prevent the progression of prostate growth or shrink the prostate in some men. Examples include finasteride (Proscar ) and dutasteride (Avodart ). These medications act more slowly than alpha blockers and are useful for only moderately enlarged prostates. Alpha Blockers medications mainly used to treat hypertension but also work to improve LUTS by relaxing the smooth muscles of the prostate and bladder neck to improve urine flow and reduce bladder blockage. Examples include: doxazosin (Cardura ), terazosin (Hytrin ), tamsulosin (Flomax ), alfuzosin (Uroxatral ), and silodosin (Rapaflo ). Phosphodiesterase-5 Inhibitors (PDE-5 Inhibitors) medications prescribed mainly for erectile dysfunction but can reduce LUTS by relaxing smooth muscles in the lower urinary tract. Examples include Viagra and Cialis. Combination Therapy several studies have shown that combining medications can more effectively improve symptoms, urinary flow, and quality of life. LESS-INVASIVE TREATMENTS Holmium Laser Enucleation of the Prostate (HoLEP) modern alternative to TURP and minimally invasive surgical technique for BPH. The surgeon will use a laser to enucleate the prostate tissue, leaving just the capsule in place. The surgeon will push the excised prostate tissue into the bladder and use a morcellator device to grind up and remove the tissue. Photoselective Vaporization of the Prostate (PVP) commercially known as the GreenLight Laser PVP treatment. This minimally invasive surgery for BPH uses a laser to vaporize the prostate tissue to restore natural urine flow. Prostatic Artery Embolization (PAE) minimally invasive procedure for BPH. Using a small incision in the patient s upper thigh or wrist, an interventional radiologist (IR) guides a catheter to the vessels supplying blood to the prostate. Embosphere Microspheres are then delivered through the catheter into the vessels, decreasing the prostate s blood flow, causing it to shrink and improving lower urinary tract. opae (original prostatic artery embolization) superselective catheterization and embolization of the inferior vesical arteries (IVAs) from a single position distal to any bladder or rectal branches, but proximal to individual prostatic branches. PErFecTED (Proximal Embolization First, then Embolize Distal) technique developed by Dr. Francisco Carnevale that includes embolization of the IVAs from two microcatheter positions: first from the proximal position used for opae, and then distally from individual branches to the prostate. Transurethral Microwave Therapy (TUMT) minimally invasive surgical treatment for BPH. A cystoscope is inserted through the penis and into the urethra. The doctor then guides a pair of needles through the cystoscope and into the obstructing prostate tissue to deliver radio frequency energy to heat and kill the prostate tissue. Transurethral Needle Ablation (TUNA) minimally invasive surgical treatment for BPH. The doctor guides a thin catheter with a microwave generator through the penis and into the urethra to the prostate to deliver heat to destroy the prostate tissue. UroLift a procedure that uses tiny implants to hold the prostate lobes apart to relieve compression on the urethra, allowing urine to flow normally again. SURGICAL PROCEDURES Prostatectomy surgical procedure that involves removing part or all of the prostate. It may be performed to treat prostate cancer or BPH. Transurethral Resection of the Prostate (TURP) a surgery in which a resectoscope (a combined surgical instrument used to visualize and cut) is inserted into the penis and passed through the urethra into the bladder. The prostate surrounds the urethra and the physician will use the resectoscope to cut away the excess prostate tissue blocking the urine flow. 65

66 PAE Bibliography 1. Amouyal G, et al. Bilateral Arterial Embolization of the Prostate Through a Single Prostatic Artery: A Case Series. Cardiovasc Intervent Radiol 2016 Dec. 2. Amouyal G, et al. Safety and Efficacy of Occlusion of Large Extra-Prostatic Anastomoses During PAE for Symptomatic BPH. Cardiovasc Intervent Radiol 2016 Sep;39(9): Amouyal G, et al. Clinical Results After Prostatic Artery Embolization Using the PErFecTED Technique: A Single-Center Study. Cardiovasc Intervent Radiol 2016 Mar;39(3): Antunes AA, et al. Clinical, Laboratorial, and Urodynamic Findings of Prostatic Artery Embolization for the Treatment of Urinary Retention Related to Benign Prostatic Hyperplasia. A Prospective Single-Center Pilot Study. Cardiovasc Intervent Radiol 2013 Aug;36(4); Bhatia S, et al. Prostate Artery Embolization via Transradial or Transulnar versus Transfemoral Arterial Access: Technical Results. J Vasc Interv Radiol 2017 Jun;28(6): Bhatia S, et al. Role of Coil Embolization during Prostatic Artery Embolization: Incidence, Indications, and Safety Profile. J Vasc Interv Radiol 2017 May;28(5): Bhatia S, et al. Prostate Artery Embolization for Giant Prostatic Hyperplasia. J Vasc Interv Radiol 2015 Oct;26(10): Brook OR, et al. Embolization Therapy for Benign Prostatic Hyperplasia: Influence of Embolization Particle Size on Gland Perfusion. J Magn Reson Imaging 2013 Aug; 38(2): Camara-Lopes G, et al. The Histology of Prostate Tissue Following Prostatic Artery Embolization for the Treatment of Benign Prostatic Hyperplasia. Int Braz J Urol 2013 Mar-Apr; 39(2): Carnevale FC, et al. Recurrence of Lower Urinary Tract Symptoms Following Prostate Artery Embolization for Benign Hyperplasia: Single Center Experience Comparing Two Techniques. Cardiovasc Intervent Radiol 2017 Mar;40(3): Carnavale FC, et al. Transurethral Resection of the Prostate (TURP) Versus Original and PErFecTED Prostate Artery Embolization (PAE) Due to Benign Prostatic Hyperplasia (BPH): Preliminary Results of a Single Center, Prospective, Urodynamic- Controlled Analysis. Cardiovasc Intervent Radiol 2016 Jan;39(1): Carnevale FC, et al. The PErFecTED Technique : Proximal Embolization First, Then Embolize Distal for Benign Hyperplasia. Cardiovasc Intervent Radiol Dec; 37(6): Carnevale FC, et al. Quality of Life and Clinical Symptom Improvement Support PAE for Patients with Acute Urinary Retention Caused by Benign Prostatic Hyperplasia. J Vasc Interv Radiol 2013 Apr;24(4): Carnevale FC, et al. Prostatic Artery Embolization for Enlarged Prostates Due to Benign Prostatic Hyperplasia. How I do it. Cardiovasc Intervent Radiol 2013 Dec;36(6): Carnevale FC, et al. Midterm Follow-up After Prostate Embolization in Two Patients with Benign Prostatic Hyperplasia. Cardiovasc Intervent Radiol 2011 Dec;34(6): Carnevale FC, et al. Prostatic Artery Embolization as a Primary Treatment for Benign Prostatic Hyperplasia: Preliminary Results in Two Patients. Cardiovasc Intervent Radiol 2010 Apr;33(2): De Assis AM, et al. Pelvic Arterial Anatomy Relevant to Prostatic Artery Embolisation and Proposal for Angiographic Classification. Cardiovasc Intervent Radiol 2015 Aug; 38(4): De Assis AM, et al. Prostatic Artery Embolization for Treatment of Benign Prostatic Hyperplasia in Patients with Prostates >90g: A Prospective Single-Center Study. J Vasc Interv Radiol 2015 Jan;26(1): Feng S, et al. Prostatic Arterial Embolization Treating Moderate-to-Severe Lower Urinary Tract Symptoms Related to Benign Prostatic Hyperplasia: A Meta-Analysis. Cardiovasc Intervent Radiol 2017 Jan;40(1): Frenk NE, et al. MRI Findings After Prostatic Artery Embolization for Treatment of Benign Hyperplasia. Am J Roentgenol 2014 Oct; 203(4): Gabr AH, et al. Prostatic Artery Embolization: A Promising Technique in the Treatment of High-Risk Patients with Benign Prostatic Hyperplasia. Urol Int 2016 Jun;97(3): Golzarian J, et al. Prostatic Artery Embolization to Treat Lower Urinary Tract Symptoms Related to Benign Prostatic Hyperplasia and Bleeding in Patients with Prostate Cancer: Proceedings from a Multidisciplinary Research Consensus Panel. J Vasc Interv Radiol 2014 May;25(5): Gonçalves OM, et al. Comparative Study Using Versus μm Microspheres for Symptomatic Patients Due to Enlarged BPH Prostates. Cardiovasc Intervent Radiol 2016 Oct;39(10): Isaacson AJ, et al. Technical Feasibility of Prostatic Artery Embolizaton From a Transradial Approach. AJR 2016;206: Grosso M, et al. Prostatic Artery Embolization in Benign Prostatic Hyperplasia: Preliminary Results in 13 Patients. Radiol Med 2014 Apr;120(4): Isaacson AJ, et al. Prostatic Artery Embolization using Embosphere Microspheres for Prostates Measuring cm: Early Results from a US Trial. J Vasc Interv Radiol May;27(5): Kably I, et al. Prostate Artery Embolization (PAE) in the Management of Refractory Hematuria of Prostatic Origin Secondary to Liatrogenic Urological Trauma: A Safe and Effective Technique. Urology 2016 Feb;88: Kurbatov D, et al. Prostatic Artery Embolization for Prostate Volume Greater than 80cm: Results from a Single-Center Prospective Study. Urology 2014 Aug;84(2): Laborda A, et al. Radiodermitis after prostatic artery embolization: case report and review of the literature. Cardiovasc Intervent Radiol 2015 Jun;38(3): Lin YT, et al. Intra-vesical Prostatic Protrusion (IPP) Can Be Reduced by Prostatic Artery Embolization. Cardiovasc Intervent Radiol 2015 Nov. 31. Leite LC, et al. Prostatic Tissue Elimination After Prostatic Artery Embolization (PAE): A Report of Three Cases. Cardiovasc Intervent Radiol Jan doi: /s McWilliams JP, et al. Society of Interventional Radiology Position Statement: Prostate Artery Embolization for Treatment of Benign Disease of the Prostate. J Vasc Interv Radiol Sept 2014;25(9): Sun F, et al. Prostatic Artery Embolization (PAE) for Symptomatic Benign Prostatic Hyperplasia (BPH): Part 2, Insights into the Technical Rationale. Cardiovasc Intervent Radiol 2016 Feb;39(2): Sun F, et al. Prostatic Artery Embolization (PAE) for Symptomatic Benign Prostatic Hyperplasia (BPH): Part 1, Pathological Background and Clinical Implications. Cardiovasc Intervent Radiol 2016 Jan;39(1): Moreira AM, et al. Transient Ischemic Rectitis as a Potential Complication after PAE: Case Report and Review of the Literature. Cardiovasc Intervent Radiol 2013 Dec;36(6): Rampoldi A, et al. Prostatic Artery Embolization as an Alternative to Indwelling Bladder Catheterization to Manage Benign Prostatic Hyperplasia in Poor Surgical Candidates. Cardiovasc Intervent Radiol 2017 Jan 27. doi: /s Russo GI, et al. Prostatic Arterial Embolization vs Open Prostatectomy: A 1-Year Matched-Pair Analysis of Functional Outcomes and Morbidities. Urology 2015 Aug;86(2): Sun F, et al. Transarterial Prostatic Embolization: Initial Experience in a Canine Model. AM J Roentgenol 2011 Aug; 197(2): Teoh JY, et al. Prostatic artery embolization in treating benign prostatic hyperplasia: a systematic review. Int Urol Nephrol 2016 Nov Uflacker A, et al. Meta-Analysis of Prostatic Artery Embolization for Benign Prostatic Hyperplasia. J Vasc Interv Radiol 2016 Nov;27(11): This bibliography is a partial list of published journal articless; it is not all inclusive. Highlighted articles are recommended by Dr. Shivank Bhatia, Merit Medical s ThinkPAE Proctor Merit Medical Systems, Inc. All rights reserved. 66

67 Prostatic Artery Embolization Coding & Reimbursement Information 2017 ANGIOGRAM CPT Code Description 1 Medicare Physician Payment 2 APC Code 3 (Status Indicator) Angiography, visceral, selective or supraselective (with or without flush aortogram), radiological supervision and interpretation Angiography, selective, each additional vessel studied after basic examination, radiological supervision and interpretation (list separately in addition to code for primary procedure) $ (Global) $56.70 (Prof) $87.57 (Global) $69.62 (Tech) $17.94 (Prof) OPPS Payment /Q2 $3, N N/A CATHETER ACCESS Medicare APC Code CPT Code Description 1 Physician Payment 2 (Status Indicator) OPPS Payment Selective catheter placement, arterial system; each first order abdominal, pelvic, or lower $ N N/A extremity artery branch, within vascular family Initial second order abdominal $ N N/A Initial third order $ N N/A additional second order, third order, and beyond (list in addition to code for initial second or third ordervessel as appropriate) $51.32 N N/A EMBOLIZATION PROCEDURES Medicare APC Code CPT Code Description 1 Physician Payment 2 (Status Indicator) OPPS Payment Vascular embolization or occlusion, inclusive of all radiological supervision and interpretation, intraprocedural roadmapping, and imaging guidance necessary to complete the intervention; for tumors, organ ischemia, or infarction $ /J1 $9, * 75898* *Do not report in the same operative field. Transcatheter therapy, embolization, any method, radiological supervision and interpretation Angiography through existing catheter for followup study for transcatheter therapy, embolization or infusion, other than thrombolysis $69.62 (Prof) $88.29 (Prof) N N/A 5181/Q2 $ APC=Ambulatory Payment Classification. Status indicator: Q2 is paid under OPPS when services are separately payable and packaged if there is a status T procedure on the same claim. S is a significant procedure. T separate payment but multiple procedure reduction applies. Effective January 1, 2015, Medicare implemented the packaged code classification: Status Code J1. This is a comprehensive APC (C-APC). All associated services are to be packaged within the primary code (assigned as J1 status indicator). All pretreatment and mapping services will be packaged when billed on the same day as CPT code (J1). Physician payment is not impacted by APC status indicators. 67

68 Prostatic Artery Embolization Coding & Reimbursement Information 2017 PROSTATIC ARTERY EMBOLIZATION ICD-10-CM Diagnosis Codes 4 N400 N401 ICD-10-CM Procedure Codes 4 0V503ZZ 0VH433Z Description Benign prostatic hyperplasia without lower urinary tract symptoms Benign prostatic hyperplasia with lower urinary tract symptoms Description Destruction of Prostate, Percutaneous Approach Insert infusion device into prostate/seminal vesicles Embosphere PRO Prostate Artery Embolization Kit First and only FDA-cleared embolic for PAE Possible MS-DRG Assignment MS-DRG 726 MS-DRG 725 Description Benign prostate hypertrophy without MCC Benign prostate hypertrophy with MCC 2017 Medicare National Average Payment Rate 5 $4, $7, REFERENCES 1. CPT 2017 American Medical Association (AMA). All rights reserved. CPT is a registered trademark of the AMA. Applicable FARS/DFARS restrictions apply to government use. Fee schedules, relative value units, conversion factors and/or related components are not assigned by the AMA, are not part of the CPT, and the AMA is not recommending their use. The AMA does not directly or indirectly practice medicine or dispense medical services. The AMA assumes no liability for data contained or not contained herein. 2 Source: January 01, 2017 Medicare physician relative value scale conversion factor $ Rates are effective from January 1, April 1, When an Angiography procedure is performed in an office-based setting, the physician would bill for a global (professional and technical payment). When a procedure is performed in a hospital based or ambulatory surgical center (ASC), the physician would bill the professional payment signified by the place of service code on the CMS 1500 form. If the physician is only performing the supervision and interpretation of an imaging study, the physician would bill the appropriate code using modifier 26. If the procedure was done in an ASC and the ASC bills separately, then the ASC would receive the technical component payment CMS Ambulatory Payment Classification Addendum B effective January 1, CMS 2017 ICD-10-PCS, CDC 2017 ICD-10-CM. 5. FY 2017 Hospital Inpatient Final Rule, Correction Notice. MS-DRG estimated payments National average (wage index greater than 1) MS-DRG rates calculated using the national adjusted full update standardized labor, non-labor and capital amounts reflecting an average community hospital reporting quality data. MS-DRG assignment will depend on the admitting diagnosis and surgical procedures provided. Merit Medical Systems, Inc. gathers reimbursement information from third-party sources and presents this information for illustrative purposes only. This information does not constitute reimbursement or legal advice and does not guarantee that this information is accurate, complete, without errors, or that use of any of the codes provided will ensure coverage or payment at any particular level. Medicare may implement policies differently in various parts of the country. Physicians and hospitals should confirm with a particular payor or coding authority, such as the American Medical Association or medical specialty society, which codes or combinations of codes are appropriate for a particular procedure or combination of procedures. Reimbursement for a product or procedure can be different depending upon the setting in which the product is used. Coverage and payment policies also change over time and Merit Medical Systems, Inc. assumes no obligation to update the information provided herein. 68

69 RADIAL PAE EQUIPMENT LIST Product Name Part Number Description Set-Up Embosphere Procedure Pack K12T Procedure Tray RadBoard 2 Radial Arm Board RB050 Reusable Mini Radial Arm Board Rad Rest RR811 Radial Arm Cushion Access PreludeEASE Hydrophilic Sheath Introducers* PHR4F11018SS 4F x 11cm Sheath; 0.018" x 40cm SS/SS Guide Wire PreludeEASE Hydrophilic Sheath Introducers PHR5F11018SS 5F x 11cm Sheath; 0.018" x 40cm SS/SS Guide Wire PreludeEASE Hydrophilic Sheath Introducers PHR6F11018SS 6F x 11cm Sheath; 0.018" x 40cm SS/SS Guide Wire PreludeEASE Hydrophilic Sheath Introducers PHR4F11018NTPD 4F x 11cm Sheath; 0.018" x 40cm NT/PD Guide Wire PreludeEASE Hydrophilic Sheath Introducers PHR5F11018NTPD 5F x 11cm Sheath; 0.018" x 40cm NT/PD Guide Wire PreludeEASE Hydrophilic Sheath Introducers PHR6F11018NTPD 6F x 11cm Sheath; 0.018" x 40cm NT/PD Guide Wire Diagnostic Imaging InQwire Diagnostic Guidewires IQ35F210J1O5 J-TIP: 1.5mm,.035" 210cm Fixed Core InQwire Diagnostic Guidewires IQ35F260J3 J 3.0mm,.035", 260cm, Fixed Core Merit Laureate Hydrophilic Guidewires LWSTDA " 220 cm Shaft Standard Angled Tip Performa Angiographic Catheters PV412538BERN Berenstein 4F.042"/1.07 mm 125 cm.038" 1 Bumper Tip Performa Angiographic Catheters PV512538BERN Berenstein 5F.046"/1.17 mm 125 cm.038" Impress Diagnostic Peripheral Catheters PV512538U3 5F, 125 cm,.038, Ultimate 3 Impress Diagnostic Peripheral Catheters PV512538COB2 5F, 125 cm,.038, Cobra 2 Navigation TrueForm Reshapable Guidewire TF14180S.014", 180 cm, Straight Tip TrueForm Reshapable Guidewire TF14180A.014", 180 cm, Angled Tip Merit Maestro Microcatheters 28MC24150ST 2.8F Prox 2.4F Distal 150cm Straight Merit Maestro Microcatheters 28MC F Prox 2.4F Distal 150cm 45 degree Diameter.018" Guide Wire.038 Guide Catheter Merit Maestro Microcatheters 28MC24150SN 2.8F Prox 2.4F Distal 150cm Swan Neck Diameter.018" Guide Wire.038 Guide Catheter Merit Maestro Microcatheters 28MC21150ST 2.8F Prox 2.1F Distal 150cm Straight Merit Maestro Microcatheters 28MC F Prox 2.1F Distal 150cm 45 degree Merit Maestro Microcatheters 28MC21150SN 2.8F Prox 2.1F Distal 150cm Swan Neck Embolotherapy Embosphere PRO Prostatic Artery Embolization Kit S220PRO Embosphere PRO PAE Kit, µm, 2ml, Yellow Embosphere PRO Prostatic Artery Embolization Kit S420PRO Embosphere PRO PAE Kit, µm, 2ml, Blue Hemostasis PreludeSYNC Radial Compression Device SRB24MED Compression Device, 24 cm, 20 ml, Standard Luer Safeguard Radial Compression Device SRB29MED Compression Device, 29 cm, 20 ml, Standard Luer Safeguard Radial Compression Device SGR26 Safeguard Radial Compression Device 26cm (*) All PreludeEASE kits include 21G x 4cm Advance Needle. SS/SS = stainless steel mandrel wire with stainless steel coils. NT/PD = nitinol mandrel wire with palladium coils. 69

70 FEMORAL PAE EQUIPMENT LIST Product Name Part Number Description Set-Up Embosphere Procedure Pack K12T Procedure Tray Access PreludePRO Sheath Introducers** PRO-4F F x 11cm Sheath;.035" x 50cm Guide Wire Prelude Sheath Introducers PSI-4F F x 11cm Sheath;.035" x 50cm Guide Wire PreludePRO Sheath Introducers PRO-5F F x 11cm Sheath;.035" x 50cm Guide Wire Prelude Sheath Introducers PSI-5F F x 11cm Sheath;.035" x 50cm Guide Wire PreludePRO Sheath Introducers PRO-6F F x 11cm Sheath;.035" x 50cm Guide Wire Prelude Sheath Introducers PSI-6F F x 11cm Sheath;.035" x 50cm Guide Wire Diagnostic Imaging InQwire Diagnostic Guidewires IQ35F180B.035", 180cm, 23cm Taper, Standard Benston InQwire Diagnostic Guidewires IQ35F150J3 J 3.0mm,.035", 150cm, Fixed Core Merit Laureate Hydrophilic Guidewires LWSTDA " 150 cm Shaft Standard Angled Tip Impress Diagnostic Peripheral Catheters 46538BER Berenstein 4F 65cm.038 Impress Diagnostic Peripheral Catheters 56538BER Berenstein 5F 65cm.038 Impress Diagnostic Peripheral Catheters 56538CB2 Cobra 2 5 Fr x 65cm x.038" 0 SH Impress Diagnostic Peripheral Catheters 58035MHK2 Modified Hook 2, 5,046 /1.17 mm 80 cm 0 SH Impress Diagnostic Peripheral Catheters 56535SIM1 Impress Braided 5F 65cm Simmons 1.0 Side Ports.035" (0.89mm) Impress Diagnostic Peripheral Catheters 57538CPC5 Impress Braided 5F 75cm CPC-5.0 Side Ports.038" (0.97mm) Impress Diagnostic Peripheral Catheters 57538CPC10 Impress Braided 5F 75cm CPC-10.0 Side Ports.038" (0.97mm) Navigation Tenor Steerable Guidewires TNR " Straight, 165cm Long Taper Tenor Steerable Guidewires TNR " Straight, 165cm Long Taper Tenor Steerable Guidewires TNR '' Angled, 165cm Long Taper Tenor Steerable Guidewires TNR " Angled, 165cm Long Taper TrueForm Reshapable Guidewires TF14180S.014", 180 cm, Straight Tip TrueForm Reshapable Guidewires TF14180A.014", 180 cm, Angled Tip TrueForm Reshapable Guidewires TF14165S.014", 165 cm, Straight Tip Merit Maestro Microcatheters 28MC24150ST 2.8F Prox 2.4F Distal 150cm Straight Diameter.018" Guide Wire.038 Guide Catheter Merit Maestro Microcatheters 28MC F Prox 2.4F Distal 150cm 45 degree Diameter.018" Guide Wire.038 Guide Catheter Merit Maestro Microcatheters 28MC24150SN 2.8F Prox 2.4F Distal 150cm Swan Neck Diameter.018" Guide Wire.038 Guide Catheter Merit Maestro Microcatheters 28MC24130ST 2.8F Prox 2.4F Distal 130cm Straight Diameter.018" Guide Wire.038 Guide Catheter Merit Maestro Microcatheters 28MC F Prox 2.4F Distal 130cm 45 degree Diameter.018" Guide Wire.038 Guide Catheter Merit Maestro Microcatheters 28MC24130SN 2.8F Prox 2.4F Distal 130cm Swan Neck Diameter.018" Guide Wire.038 Guide Catheter Merit Maestro Microcatheters 28MC21150ST 2.8F Prox 2.1F Distal 150cm Straight Merit Maestro Microcatheters 28MC F Prox 2.1F Distal 150cm 45 degree Merit Maestro Microcatheters 28MC21150SN 2.8F Prox 2.1F Distal 150cm Swan Neck Merit Maestro Microcatheters 28MC21130ST 2.8F Prox 2.1F Distal 130cm Straight Merit Maestro Microcatheters 28MC F Prox 2.1F Distal 130cm 45 degree Merit Maestro Microcatheters 28MC21130SN 2.8F Prox 2.1F Distal 130cm Swan Neck SwiftNINJA Steerable Microcatheter MIV SwiftNINJA, Steerable Microcatheter, 2.9F-2.4F 125 cm Embolotherapy Embosphere PRO Prostatic Artery Embolization Kit S220PRO Embosphere PRO PAE Kit, µm, 2ml, Yellow Embosphere PRO Prostatic Artery Embolization Kit Hemostasis S420PRO Safeguard Pressure Assisted Device Safeguard Pressure Assisted Device 24cm Safeguard Pressure Assisted Device Safeguard Pressure Assisted Device 12cm Clo-Sur PLUS P.A.D. SCV22P-AB Clo-Sur P.A.D. Antimicrobial Topical Hemostatic Dressing (**) PRO sheaths made with polypropylene tubing. PSI sheaths made with polyethylene tubing. 70

71 Embosphere PRO Prostatic Artery Embolization Kit INSTRUCTIONS FOR USE 71

72 Embosphere PRO English Prostatic Artery Embolization Kit INSTRUCTIONS FOR USE CAUTION Federal (U.S.A.) law restricts this device to use by or on the order of a licensed physician INTENDED USE The Embosphere PRO Prostatic Artery Embolization Kit, which includes Embosphere Microspheres, is indicated for use in the embolization of prostatic arteries for symptomatic benign prostatic hyperplasia (BPH). CLINICAL APPLICATIONS FOR BENIGN PROSTATIC HYPERPLASIA (BPH) Prostatic artery embolization (PAE) is an alternative treatment for men requiring treatment for relief of lower urinary tract symptoms (LUTS) attributed to BPH, such as urinary frequency, inability to urinate, incomplete emptying of bladder, difficulty starting urination, and straining to urinate or weak urine stream. MAGNETIC RESONANCE IMAGING Embosphere Microspheres are made of tris-acryl polymer impregnated with porcine gelatin and have no ferrous composition. DEVICE DESCRIPTION Embosphere Microspheres are part of a family of embolic materials based on Merit Medical s proprietary microsphere technology. These spheres are designed to offer controlled, targeted embolization. Embosphere Microspheres are biocompatible, hydrophilic, nonresorbable, microspheres produced from an acrylic polymer and impregnated with porcine gelatin. DEVICE PACKAGING Each Embosphere PRO Prostatic Artery Embolization Kit contains (1) syringe of Embosphere Microspheres ( microns or microns), (1) 10 ml syringe, (1) 3 ml syringe, (2) 1 ml syringes, and (1) 3-way stopcock. Embosphere Microspheres are contained in a sterile, 20 ml pre-filled syringe, packaged in a peel-away tray. Each syringe contains approximately 2.0 ml of Embosphere Microspheres in a pyrogen-free, sterile, physiological saline. The kit s syringes and stopcock are sterilized and packaged in a sterile poly pouch. The following contraindications, warnings, precautions, and instructions for use are applicable to the embolization of prostatic arteries for symptomatic BPH. CONTRAINDICATIONS Patients intolerant to occlusion procedures Vascular anatomy or blood flow that precludes catheter placement or embolic agent injection Presence or likely onset of vasospasm Presence or likely onset of hemorrhage Presence of severe atheromatous disease Presence of arteries supplying the lesion not large enough to accept Embosphere Microspheres Presence of collateral vessel pathways potentially endangering normal territories during embolization Vascular resistance peripheral to the feeding arteries precluding passage of Embosphere Microspheres into the lesion In large diameter arteriovenous shunts (i.e., where the blood does not pass through an arterial/capillary/venous transition but directly from an artery to a vein) In the pulmonary vasculature PAE Specific Contraindications Active urinary tract infection or prostatitis Prostate cancer Bladder cancer Chronic renal failure Bladder atonia, neurogenic bladder disorder, or other neurological disorder impacting bladder function Bladder stones Urinary obstruction due to causes other than BPH, including urethral stricture Excessive vessel tortuosity or severe atherosclerosis WARNINGS Embosphere Microspheres contain gelatin of porcine origin, and therefore could cause an immune reaction in patients who are hypersensitive to collagen or gelatin. Careful consideration should be given prior to using this product in patients who are suspected to be allergic to injections containing gelatin stabilizers. Studies have shown that Embosphere Microspheres do not form aggregates, and, as a result, penetrate deeper into the vasculature as compared to similarly sized PVA particles. Some of the Embosphere Microspheres may be slightly outside of the range, so the physician should be sure to carefully select the size of Embosphere Microspheres according to the size of the target vessels at the desired level of occlusion in the vasculature and after consideration of the arteriovenous angiographic appearance. The size of Embosphere Microspheres should be selected to prevent passage from artery to vein. Serious radiation induced skin injury may occur to the patient due to long periods of fluoroscopic exposure, large patient diameter, angled x-ray projections, and multiple image recording runs or radiographs. Refer to your facility s clinical protocol to ensure the proper radiation dose is applied for each specific type of procedure performed. Physicians should monitor patients that may be at risk. Onset of radiation-induced injury to the patient may be delayed. Patients should be counseled on potential 72

73 radiation side effects and whom they should contact if they show symptoms. Pay careful attention for signs of mistargeted embolization. During injection carefully monitor patient vital signs to include SaO2 (e.g., hypoxia, CNS changes). Consider terminating the procedure, investigating for possible shunting, or increasing microsphere size if any signs of mistargeting occur or patient symptoms develop. Consider upsizing the microspheres if angiographic evidence of embolization does not quickly appear evident during injection of the microspheres. PAE Specific Warnings A thorough clinical evaluation should be performed on all patients presenting for embolization for BPH (e.g., urinalysis, digital rectal exam, symptom scores, prostate imaging, prostate-specific antigen test, transrectal ultrasound) to rule out prostate cancer. Because of the tortuous vessels and duplicative feeding arteries in the pelvic area, extreme caution should be used when performing prostatic artery embolization (PAE). Complications of mistargeted embolization include ischemia of the rectum, bladder, scrotum, penis or other areas. When using Embosphere Microspheres for prostatic artery embolization, do not use microspheres smaller than 100 microns. It is recommended to use microns. Warnings About PAE and Fertility The effects of PAE on fertility have not been determined. Therefore, this procedure should not be performed on men wanting to father a child. Warnings About Use of Small Microspheres Careful consideration should be given whenever use is contemplated of embolic agents that are smaller in diameter than the resolution capability of your imaging equipment. The presence of arteriovenous anastomoses, branch vessels leading away from the target area or emergent vessels not evident prior to embolization can lead to mistargeted embolization and severe complications. Microspheres smaller than 100 microns will generally migrate distal to anastomotic feeders and therefore are more likely to terminate circulation to distal tissue. Greater potential of ischemic injury results from use of smaller sized microspheres and consideration must be given to the consequence of this injury prior to embolization. The potential consequences include swelling, necrosis, paralysis, abscess and/or stronger post embolization syndrome. Post embolization swelling may result in ischemia to tissue adjacent to target area. Care must be given to avoid ischemia intolerant, nontargeted tissue such as nervous tissue. PRECAUTIONS Patients with known allergy to contrast medium may require corticosteroids prior to embolization. Additional evaluations or precautions may be necessary in managing periprocedural care for patients with the following conditions: Bleeding diathesis or hypercoagulative state Immunocompromise Do not use if the Embosphere syringe, plunger seal, or tray package appear damaged. Do not use if the kit s syringes, stopcock, or pouch appear damaged. For single patient use only - contents supplied sterile - never reuse, reprocess, or resterilize the contents of a syringe that has been opened. Reusing, reprocessing or resterilizing may compromise the structural integrity of the device and or lead to device failure, which in turn may result in patient injury, illness or death. Reusing, reprocessing or resterilizing may also create a risk of contamination of the device and or cause patient infection or cross infection including, but not limited to, the transmission of infectious disease(s) from one patient to another. Contamination of the device may lead to injury, illness or death of the patient. All procedures must be performed according to accepted aseptic technique. Do not connect the 20 ml syringe with Embosphere Microspheres directly to a microcatheter for embolic delivery, as a catheter occlusion may result. The syringe is intended for embolic use only. Do not use for any other application. Embolization with Embosphere Microspheres should only be performed by physicians who have received appropriate interventional embolization training in the region to be treated. PAE Specific Precautions The PAE procedure should only be performed by interventional radiologists who have received appropriate training. Collateral circulation may be present and can dilate and supply adjacent arteries as resistance within the prostatic bed increases. Therefore, there is potential for severe complications with nontargeted embolization. There is an increased chance of retro-migration of Embosphere Microspheres into unintended blood vessels as prostatic artery flow diminishes. Embolization should be stopped when the vasculature surrounding the prostate can no longer be visualized but before complete stasis in the prostatic artery. POTENTIAL COMPLICATIONS Vascular embolization is a high-risk procedure. Complications may occur at any time during or after the procedure, and may include, but are not limited to, the following: Paralysis resulting from untargeted embolization or ischemic injury from adjacent tissue edema Undesirable reflux or passage of Embosphere Microspheres into normal arteries adjacent to the targeted lesion or through the lesion into other arteries or arterial beds, such as the internal carotid artery, pulmonary, or coronary circulations Pulmonary embolism due to arterial venous shunting Ischemia at an undesirable location, including ischemic stroke, ischemic infarction (including myocardial infarction), and tissue necrosis Capillary bed occlusion and tissue damage Vessel or lesion rupture and hemorrhage Vasospasm Recanalization Foreign body reactions necessitating medical intervention 73

74 Infection necessitating medical intervention Complications related to catheterization (e.g., hematoma at the site of entry, clot formation at the tip of the catheter and subsequent dislodgment, and nerve and/or circulatory injuries, which may result in leg injury) Allergic reaction to medications (e.g., analgesics) Allergic reaction to contrast media or embolic material Pain and/or rash, possibly delayed from the time of embolization Death Blindness, hearing loss, loss of smell, and/or paralysis Additional information is found in the Warnings section PAE Specific Potential Complications Non-targeted embolization of the rectum, bladder, scrotum, penis, or other areas The most frequent post-procedure complication includes Post-PAE Syndrome, which includes nausea, vomiting, fever, pelvic pain, burning sensation, dysuria, and frequent or urgent urination Skin burn (radiation exposure) from prolonged fluoroscopy time Blood in urine, semen, or stool Bladder spasm Hematoma at the catheter site Urinary tract infection Urinary retention Constipation STORAGE AND STERILITY Embosphere Microspheres must be stored in a cool, dry and dark place in their original syringe and packaging. Use the Embosphere Microspheres by the date indicated on the syringe label. Do not freeze the Embosphere Microspheres. Do not resterilize the Embosphere Microspheres. Use the kit s syringes and 3-way stopcock by the date indicated on the pouch. Do not resterilize the syringes and 3-way stopcock. INSTRUCTIONS FOR USE Inspect packaging prior to use to ensure seal integrity for maintenance of sterility. Carefully evaluate the vascular network associated with the lesion using high resolution imaging prior to beginning the embolization procedure. The Embosphere PRO Prostatic Artery Embolization Kit contains Embosphere Microspheres in microns or microns size ranges. Because of the potential for misembolization and the inherent variability in sphere sizes, the physician should be sure to carefully select the size of Embosphere Microspheres according to the size of the target vessels at the desired level of occlusion in the vasculature. For prostatic artery embolization, it is recommended to use Embosphere Microspheres microns. Choose a delivery catheter based on the size of the target vessel and the microsphere size being used. Embosphere Microspheres can tolerate temporary compression of up to 33% to facilitate passage through the delivery catheter. Introduce the delivery catheter into the target vessel according to standard techniques. Position the catheter tip as close as possible to the treatment site to avoid inadvertent occlusion of normal vessels. Embosphere Microspheres are not radiopaque. It is recommended that the embolization be monitored using fluoroscopic visualization by adding the appropriate amount of contrast medium to the physiologic suspension fluid. To Deliver Embosphere Microspheres Match the total volume in the syringe with the same volume of undiluted contrast, which will result in a 50% microsphere/saline and 50% contrast solution. Remove all air from the syringe. To evenly suspend the Embosphere Microsphere/contrast solution, gently invert the 20 ml syringe several times. Attach the 20 ml syringe to one port of the 3-way stopcock. Attach a 1 ml or 3 ml injection syringe to another port on the stopcock and, if desired, a delivery catheter may be attached to the remaining port on the stopcock. Wait several minutes to allow the Embosphere Microspheres to suspend in the solution. Draw the Embosphere Microspheres/contrast solution into the injection syringe slowly and gently to minimize the potential of introducing air into the system. Purge all air from the system prior to injection. Inject the Embosphere Microspheres/contrast solution under fluoroscopic visualization with the injection syringe using a slow pulsatile injection while observing the contrast flow rate. If there is no effect on the flow rate, repeat the delivery process with additional injections of the Embosphere Microspheres/contrast solution. If the Embosphere Microspheres/contrast solution requires re-suspension, gently invert the 20 ml syringe several times. Exercise conservative judgment in determining the embolization endpoint. Femoral puncture can result in arterial spasm. This may predispose to femoral thrombosis (e.g., leg injury). Femoral patency should be re-assessed prior to final catheter removal. Upon completion of the treatment, remove the catheter while maintaining gentle suction so as not to dislodge Embosphere Microspheres still within the catheter lumen. Apply pressure to the puncture site until hemostasis is complete. Discard any open, unused Embosphere Microspheres. Additional PAE Specific Instructions A Foley catheter, with its balloon inflated with a mixture of contrast and saline, may be placed prior to PAE for use as a landmark during the embolization procedure. PAE can be performed by either radial or femoral access. PATIENT COUNSELING INFORMATION Patients should have a clear understanding prior to embolization of who will provide their post procedure care and whom to contact in case of an emergency after embolization. Embolization patients should have an understanding of the potential benefits, risks, and adverse events associated with embolization. In particular, patients should understand that there is a chance their symptoms will not improve following embolization. 74

75 PAE CLINICAL SUMMARY A Composite database from clinical trials and published literature containing information from a total of 286 patients who underwent prostatic artery embolization (PAE) using Embosphere Microspheres for treatment of symptomatic benign prostatic hyperplasia (BPH) was analyzed to evaluate clinical outcomes. All patients were suffering from lower urinary tract symptoms (LUTS) due to BPH, with International Prostate Symptom Scores (IPSS) of moderate to severe. Prostate or bladder cancer, active urinary tract infections or prostatitis, bladder stones, and atonia or other neurogenic conditions impacting bladder function, and intolerance to contrast media or catheter-based interventions were exclusionary. Prior to embolization, patients underwent clinical evaluation, imaging of the prostate, and completed validated symptom and quality of life questionnaires. Follow-up evaluations included the IPSS and its quality of life (QOL) questionnaire and prostate imaging at a minimum. The primary effectiveness evaluations were change in IPSS and QOL scores post embolization, with reduction in prostate size as a secondary objective. Safety was assessed from reported adverse events. RESULTS Mean age of the evaluated cohort was in the seventh decade, lower urinary tract symptoms were severe as reflected in a mean IPSS score over 20, and quality of life was dissatisfied to unhappy. Fifty-four patients had indwelling bladder catheters at baseline. Table 1 Baseline Characteristics of the Patient Population Characteristic Mean ± SD n Age (years) 67.7 ± IPSS 21.5 ± Quality of life 4.8 ± Prostate volume (gms) 85.1 ± PSA (ng/ml) 5.4 ± Qmax (ml/s) 6.9 ± The majority of patients underwent bilateral embolization. Table 2 Unilateral versus Bilateral Embolization Embolization Patients (%) Unilateral 29 (10.1) Bilateral 254 (88.9) No data 3 (1.0) Mean symptom scores, which were severe at baseline, improved compared to pretreatment values at every followup interval. Values at the 9-16 month evaluation period were mildly symptomatic. A reduction of IPSS by at least 3 points was achieved at this latest evaluation in 97% of patients, and 90% dropped by at least 1 symptom category. Table 3 Mean IPSS at Baseline and Follow-up Time Window Mean ± SD n Baseline 21.5 ± to 3 months f/u 6.3 ± to 16 months f/u 6.2 ± Table 4 Proportion of Patients Achieving 3-point Improvement in IPSS Time Point Proportion (95% CI) 1 to 3 months f/u ( ) 9 to 16 months f/u ( ) Table 5 Proportion of Patients Achieving 1 IPSS Category Improvement Time Point Proportion (95% CI) 1 to 3 months f/u ( ) 9 to 16 months f/u ( ) Not surprisingly, the reduction of lower urinary tract symptoms reflected in the IPSS changes affected mean quality of life. Mean QOL scores, which were categorized as mostly dissatisfied to unhappy pre-embolization, improved at every follow-up interval to pleased/mostly satisfied. Table 6 Mean Quality of Life at Baseline and Follow-up Time Point Mean ± SD n Baseline 4.8 ± to 3 months f/u 1.4 ± to 16 months f/u 1.4 ± Mean prostate size at baseline was 85.1g, and demonstrated reduction throughout follow-up. Table 7 Mean Prostate Volume at Baseline and Follow-up Time Point Mean ± SD n Baseline 85.1 ± to 3 months f/u 62.4 ± to 16 months f/u 65.2 ± In addition to the overall Composite population, analyses were done for subsets of patients age 80 or older, with prostates 90g or larger, and those with indwelling catheters at baseline for management of acute urinary retention. These categories are not mutually exclusive. Patients in these groups were of particular interest because they frequently are contraindicated for TURP: elderly patients have higher incidence rates of comorbid conditions, patients with prostate size larger than 90g are typically referred for open surgery, and patients in acute retention are not generally treated by transurethral procedures. For these reasons the successful outcomes from PAE in these cohorts is notable. Other than being older, baseline evaluations of the 80-year subset were similar to those of the Composite group, including IPSS reflecting severe symptoms and mostly dissatisfied to unhappy quality of life. Table 8 Baseline Characteristics of Patients Age 80 Years Characteristic Mean ± SD n Age (years) 84.6 ± IPSS 23.9 ± Quality of life 4.6 ± Prostate volume (gms) 78.1 ± PSA (ng/ml) 3.9 ± * 13 of 39 patients (33.3%) had indwelling bladder catheters at baseline 75

76 Although elderly patients might be limited in treatment options and/or might be more fragile due to comorbidities, this cohort achieved reduction in LUTS at all follow-up intervals. Over 80% had at least a 3-point reduction in IPSS and a substantial majority dropped by at least one symptom category. Table 9 Mean IPSS at Baseline and Follow-up of Patients Age 80 Years Time Window Mean ± SD n Baseline 23.9 ± to 3 months f/u 13.4 ± to 16 months f/u 7.0 ± Table 10 Proportion of Patients Age 80 Years Achieving 3 Point IPSS Improvement Time Window Proportion (95% CI) 1 to 3 months f/u ( ) 9 to 16 months f/u ( ) Table 11 Proportion of Patients Age 80 Years Achieving 1 IPSS Category Improvement Time Point Proportion (95% CI) 1 to 3 months f/u ( ) 9 to 16 months f/u ( ) The mean quality of life for this group trended toward improvement from mostly dissatisfied to mostly satisfied. Table 12 Mean Quality of Life at Baseline and Follow-up of Patients Age 80 Years Time Point Mean ± SD n Baseline 4.6 ± to 3 months f/u 1.4 ± to 16 months f/u 1.1 ± Bilateral embolization was possible in 80% of this group, and prostate size reduction was seen throughout follow-up. Table 13 Unilateral versus Bilateral Embolization in Patients Age 80 Years Embolization Patients (%) Unilateral 8 (20.5) Bilateral 31 (79.5) No data 0 (0) Table 14 Mean Prostate Volume at Baseline and Followup of Patients Age 80 Years Time Point Mean ± SD n Baseline 78.1 ± to 3 months f/u 55.1 ± to 16 months f/u 64.6 ± Among the subset of patients with prostate size larger than 90g, baseline characteristics were similar to those of the entire Composite group, other than gland volume. Table 15 Baseline Characteristics of Patients with Prostate Size 90g Characteristic Mean ± SD n Age (years) 68.4 ± IPSS 19.8 ± Quality of life 4.6 ± Prostate volume (gms) ± PSA (ng/ml) 7.4 ± * 12 of 95 patients (12.6%) had indwelling bladder catheters at baseline Symptoms improved in this cohort post embolization at all time points, and a minimum 3-point reduction and drop of at least one symptom category in IPSS was achieved by 96% and 89% of patients respectively. Table 16 Mean IPSS at Baseline and Follow-up of Patients with Prostate Size 90g Time Window Mean ± SD n Baseline 19.8 ± to 3 months f/u 5.0 ± to 16 months f/u 4.6 ± Table 17 Proportion of Patients with Prostate Size 90g Achieving 3 Point IPSS Improvement Time Window Proportion (95% CI) 1 to 3 months f/u ( ) 9 to 16 months f/u ( ) Table 18 Proportion of Patients with Prostate Size 90g Achieving 1 IPSS Category Improvement Time Point Proportion (95% CI) 1 to 3 months f/u ( ) 9 to 16 months f/u ( ) Mean quality of life scores also improved and prostate size demonstrated a reduction at each evaluation point, consistent with the reduced lower urinary tract symptoms. Table 19 Mean Quality of Life at Baseline and Follow-up of Patients with Prostate Size 90g Time Point Mean ± SD n Baseline 4.6 ± to 3 months f/u 1.1 ± to 16 months f/u 1.2 ± Table 20 Mean Prostate Size at Baseline and Follow-up of Patients with Prostate Size 90g Time Point Mean ± SD n Baseline ± to 3 months f/u 85.9 ± to 16 months f/u 91.0 ± The difference in size of the prostates relative to the entire Composite group did not impact technical success of embolization. Over 90% of patients underwent bilateral embolization. 76

77 Table 21 Unilateral versus Bilateral Embolization of Patients with Prostate Size 90g Embolization Patients (%) Unilateral 6 (6.3) Bilateral 87 (91.6) No data 2 (2.1) Patients with indwelling catheters at baseline tended to be older than the Composite population as a whole, and the catheters led to unhappy to quality of life scores categorized as terrible. Table 22 Baseline Characteristics of Patients with Indwelling Catheters at Baseline Characteristic Mean ± SD n Age (years) 73.8 ± Quality of life 5.8 ± Prostate volume (gms) 79.0 ± PSA (ng/ml) 6.3 ± Baseline IPSS data were not analyzed for patients with indwelling catheters because their acute urinary retention made questions about urination habits moot. Consequently, no analyses of the proportions of patients whose symptoms improved from baseline could be conducted. Post embolization, patients went from inability to answer IPSS questions to being only mildly symptomatic, and quality of life scores improved from categorization of unhappy to terrible at baseline to pleased after treatment. Table 23 Mean IPSS During Follow-up of Patients with Indwelling Catheters at Baseline Time Window Mean ± SD n 1 to 3 months f/u 6.0 ± to 16 months f/u 5.9 ± Table 24 Mean QOL at Baseline and Follow-up of Patients with Indwelling Catheters at Baseline Time Point Mean ± SD n Baseline 5.8 ± to 3 months f/u 1.0 ± to 16 months f/u 1.0 ± Table 25 Mean Prostate Size at Baseline and Follow-up of Patients with Indwelling Catheters at Baseline Time Point Mean ± SD n Baseline 79.0 ± to 3 months f/u 64.3 ± to 16 months f/u 54.3 ± Table 26 Unilateral versus Bilateral Embolization of Patients with Indwelling Catheters at Baseline Embolization Patients (%) Unilateral 9 (16.7) Bilateral 44 (81.5) No data 1 (1.8) Table 27 Adverse Events Event PAE Congenital, familial and genetic disorders 1 (0.3%) Hydrocele 1 (0.3%) Ear and labyrinth disorders 2 (0.7%) Ear pain 2 (0.7%) Endocrine disorders 1 (0.3%) Hypogonadism 1 (0.3%) Gastrointestinal disorders 33 (11.5%) Abdominal pain lower 1 (0.3%) Abdominal pain upper 1 (0.3%) Abdominal rigidity 2 (0.7%) Anorectal discomfort 1 (0.3%) Constipation 4 (1.4%) Dental necrosis 1 (0.3%) Diarrhea 2 (0.7%) Hematochezia 14 (4.9%) Hemorrhoids 1 (0.3%) Nausea 5 (1.7%) Vomiting 1 (0.3%) General disorders and administration site 18 (6.3%) conditions Catheter site inflammation 1 (0.3%) Chest pain 1 (0.3%) Chills 1 (0.3%) Facial pain 1 (0.3%) Local swelling 3 (1.0%) Pain 1 (0.3%) Pyrexia 8 (2.8%) Suprapubic pain 2 (0.7%) Infections and infestations 13 (4.5%) Cellulitis 1 (0.3%) Localized infection 1 (0.3%) Nasopharyngitis 2 (0.7%) Sepsis 1 (0.3%) Urinary tract infection 8 (2.8%) Injury, poisoning and procedural complications 217 (75.9%) Bladder injury 1 (0.3%) Fall 1 (0.3%) Post prostatic artery embolization syndrome 212 (74.1%) Procedural pain 1 (0.3%) Pubic bone injury 1 (0.3%) Rectal injury 1 (0.3%) Investigations 1 (0.3%) Blood urine present 1 (0.3%) Musculoskeletal and connective tissue disorders 11 (3.8%) Arthralgia 1 (0.3%) Chest wall mass 1 (0.3%) Flank pain 1 (0.3%) Groin pain 2 (0.7%) Muscle spasms 1 (0.3%) Musculoskeletal chest pain 1 (0.3%) Musculoskeletal discomfort 1 (0.3%) Musculoskeletal pain 1 (0.3%) Pain in extremity 2 (0.7%) 77

78 Event PAE Nervous system disorders 4 (1.4%) Dizziness 2 (0.7%) Headache 1 (0.3%) Sciatica 1 (0.3%) Renal and urinary disorders 65 (22.7%) Bladder discomfort 3 (1.0%) Bladder spasm 5 (1.7%) Dysuria 22 (7.7%) Hematuria 10 (3.5%) Micturition urgency 6 (2.1%) Pollakuria 2 (0.7%) Renal failure acute 1 (0.3%) Terminal dribbling 1 (0.3%) Urethral pain 2 (0.7%) Urethral trauma 1 (0.3%) Urinary incontinence 2 (0.7%) Urinary retention 9 (3.1%) Urinary straining 1 (0.3%) Reproductive system and breast disorders 36 (12.6%) Decreased ejaculatory volume 14 (4.9%) Epididymal cyst 1 (0.3%) Hematospermia 12 (4.2%) Pelvic pain 3 (1.0%) Penile burning sensation 1 (0.3%) Penile pain 1 (0.3%) Perineal pain 1 (0.3%) Prostatitis 1 (0.3%) Testicular pain 1 (0.3%) Varicocele 1 (0.3%) Respiratory, thoracic and mediastinal disorders 6 (2.1%) Chronic obstructive pulmonary disease 2 (0.7%) Dyspnoea 2 (0.7%) Nasal congestion 1 (0.3%) Pulmonary mass 1 (0.3%) Skin and subcutaneous tissue disorders 2 (0.7%) Skin discoloration 2 (0.7%) Surgical and medical procedures 1 (0.3%) Arthroscopic surgery 1 (0.3%) Vascular disorders 2 (0.7%) Hematoma 1 (0.3%) Hypertension 1 (0.3%) The most common adverse event was Post-PAE Syndrome. REFERENCES 1. Amouyal G, Thiounn N, Pellerin O, et al. Clinical results after prostatic artery embolization using the PErFecTED technique: a single-center study. Cardiovasc Intervent Radiol 2015; 39(3): DOI /s Antunes AA, Carnevale FC, da Motta Leal Filho JM, et al. Clinical, laboratorial, and urodynamic findings of prostatic artery embolization for the treatment of urinary retention related to benign prostatic hyperplasia. A prospective single-center pilot study. Cardiovasc Intervent Radiol 2013; 36(4): DOI /s Bhatia S, Kava B, Pereira K, et al. Prostate artery embolization for giant prostatic hyperplasia. J Vasc Interv Radiol 2015; 26(10): DOI /j.jvir Camara-Lopes G, Mattedi R, Antunes AA, et al. The histology of prostate tissue following prostatic artery embolization for the treatment of benign prostatic hyperplasia. Int Braz J Urol 2013; 39(2): DOI /S IBJU Carnevale FC, Antunes AA, da Motta Leal Filho JM, et al. Prostatic artery embolization as a primary treatment for benign prostatic hyperplasia: preliminary results in two patients. Cardiovasc Intervent Radiol 2010; 33(2): DOI /s z. 6. Carnevale FC, da Motta Leal Filho JM, Antunes AA, et al. Midterm follow-up after prostate embolization in two patients with benign prostatic hyperplasia. Cardiovasc Intervent Radiol 2011; 34(6): DOI /s Carnevale FC, da Motta Leal Filho JM, Antunes AA, et al. Quality of life and clinical symptom improvement support prostatic artery embolization for patients with acute urinary retention caused by benign prostatic hyperplasia. J Vasc Interv Radiol 2013; 24(4): DOI /j. jvir Carnevale FC, Iscaife A, Yoshinaga EM, et al. Transurethral resection of the prostate (TURP) versus original and PErFecTED prostate artery embolization (PAE) due to benign prostatic hyperplasia (BPH): preliminary results of a single center, prospective, urodynamic-controlled analysis. Cardiovasc Intervent Radiol 2016; 39(1): DOI / s de Assis AM, Moreira AM, de Paula Rodrigues VC, et al. Prostatic artery embolization for treatment of benign prostatic hyperplasia in patients with prostates > 90 g: a prospective single-center study. J Vasc Interv Radiol 2015; 26(1): DOI /j.jvir Frenk NE, Baroni RH, Carnevale FC, et al. MRI findings after prostatic artery embolization for treatment of benign hyperplasia. Am J Roentgenol 2014; 203(4): DOI /AJR Grosso M, Balderi A, Arnò M, et al. Prostatic artery embolization in benign prostatic hyperplasia: preliminary results in 13 patients. Radiol Med 2014; 120(4): DOI /s Kably I, Pereira K, Chong W, et al. Prostate artery embolization (PAE) in the management of refractory hematuria of prostatic origin secondary to iatrogenic urological trauma: a safe and effective technique. Urology 2016; 88: DOI /j.urology Khayrutdinov ER, Zharikov SB, Vorontsov IM, et al. Our first experience with prostatic artery embolization via transradial access. Cardioangiology 2015; 41:

79 14. Kurbatov D, Russo GI, Lepetukhin A, et al. Prostatic artery embolization for prostate volume greater than 80 cm3: results from a single-center prospective study. Urology 2014; 84(2): DOI /j.urology Laborda A, de Assis AM, Ioakeim I, et al. Radiodermitis after prostatic artery embolization: case report and review of theliterature. Cardiovasc Intervent Radiol 2015; 38(3): DOI /s Lin YT, Amouyal G, Thiounn N, et al. Intra-vesical prostatic protrusion (IPP) can be reduced by prostatic artery embolization. Cardiovasc Intervent Radiol 2016; 39(5): DOI /s McWilliams JP, Kuo MD, Rose SC, et al. Society of Interventional Radiology position statement: Prostate artery embolization for the treatment of benign disease of the prostate. J Vasc Interv Radiol 2014; 25(9): DOI /j.jvir Moreira AM, Marques CFS, Antunes AA, et al. Transient ischemic rectitis as a potential complication after prostatic artery embolization: case report and review of the literature. Cardiovasc Intervent Radiol 2013; 36(6): DOI / s Russo GI, Kurbatov D, Sansalone S, et al. Prostatic arterial embolization vs open prostatectomy: a 1-year matched-pair analysis of functional outcomes and morbidities. Urology 2015; 86(2): DOI /j.urology All serious or life-threatening adverse events or deaths associated with use of the device should be reported to the U.S. Food and Drug Administration under the MedWatch program and to the device manufacturer. Information about the MedWatch program and forms for reporting adverse events can be obtained at www. fda.gov/safety/medwatch/howtoreport/ucm htm or by calling toll free Reports to Merit Medical, Inc. can be made by calling toll free INFORMATION ON PACKAGING Symbol Designation Manufacturer: Name & Address Use by date: year-month-day LOT REF Batch code Catalog number Do not resterilize Do not use if package is damaged Keep away from sunlight Keep dry Single Use Do not re-use Caution - Refer to Instructions For Use Non-pyrogenic Sterilized using steam Sterilized using Ethylene Oxide Lower limit of temperature 79

80 Biosphere Medical, S.A. Parc des Nations - Paris Nord rue de la Belle Etoile Roissy en France France Manufactured for: Merit Medical Systems, Inc West Merit Parkway, South Jordan, Utah U.S.A U.S.A. Customer Service

81 Embosphere PRO Prostatic Artery Embolization Kit FIRST AND ONLY FDA-CLEARED EMBOLIC INDICATED FOR PROSTATIC ARTERY EMBOLIZATION Predictable. Targeted. Established. Convenient. 81

82 Embosphere PRO Prostatic Artery Embolization Kit Prostatic artery embolization (PAE) is a technically challenging procedure that demands a predictable, targeted, and established microsphere like Embosphere Microspheres. The first and only embolic cleared by the U.S. Food & Drug Administration for PAE, Embosphere Microspheres are available in Merit s exclusive Embosphere PRO Prostatic Artery Embolization Kit, which brings additional convenience to the power and predictability of Embosphere Microspheres. PREDICTABLE Embosphere Microspheres temporarily compress to facilitate smooth microcatheter passage (A). 1 Once through the microcatheter, Embosphere Microspheres return to their original spherical shape and stated diameter (B) for predictable, targeted delivery. 1 A B TARGETED Embosphere Microspheres have consistently demonstarted a direct correlation between the level of arterial occlusion and the size of the microspheres used, allowing for consistent, targeted occlusion. 2,4 Pre-embolization Post-embolization Pre- and post-embolization angiograms courtesy Dr. Shivank Bhatia, Interventional Radiologist, Miami, FL 82

83 ESTABLISHED Embosphere Microspheres are the most clinically studied and clinically utilized spherical embolic, having been proven: During more than 20 years of clinical use In more than 250 clinical articles, with more than 35 PAE-related 5 PAE Clinical Summary with Embosphere Microspheres 5 A composite database of 286 patients who underwent PAE using Embosphere Microspheres for treatment of symptomatic benign prostatic hyperplasia (BPH) was analyzed to evaluate clinical outcomes. All patients were suffering from lower urinary tract symptoms (LUTS) due to BPH with International Prostate Symptom Scores (IPSS) of moderate to severe. Post embolization, 97% of patients reported a decrease in their IPSS by at least 3 points, and 90% of patients dropped at least 1 symptom category, from severe to moderate or moderate to mild. Most patients also experienced improvement in their Quality of Life score and a substantial decrease in prostate volume. Mean Prostate Volume at Baseline and Follow-Up Time Window Mean ± SD n Baseline 85.1 ± to 3 months f/u 62.4 ± to 16 months f/u 65.2 ± Mean Quality of Life at Baseline and Follow-Up Time Window Mean ± SD n Baseline 4.8 ± to 3 months f/u 1.4 ± to 16 months f/u 1.4 ± Mean IPSS at Baseline and Follow-Up Time Window Mean ± SD n Baseline 21.5 ± to 3 months f/u 6.3 ± For more information about the composite database and clinical outcomes, refer to the Embosphere PRO Prostatic Artery Embolization Kit Instructions for Use (IFU). CONVENIENT Merit Medical s new Embosphere PRO Prostatic Artery Embolization Kit combines the power and predictability of Embosphere Microspheres with basic preparation and delivery tools for added convenience. Each kit includes: (1) prefilled syringe of Embosphere Microspheres, μm or μm (1) 10 ml Medallion Syringe (2) 1 ml Medallion Syringes (1) 3 ml Medallion Syringe (1) 3-way Marquis Stopcock, 1050 psi 83

84 Embosphere PRO Prostatic Artery Embolization Kit First and only embolic indicated for PAE Ordering Information Product Number Item Description Color Code S220PRO Embosphere PRO Prostatic Artery Embolization Kit with prefilled syringe of Embosphere Microspheres, µm, 2 ml volume S420PRO Embosphere PRO Prostatic Artery Embolization Kit with prefilled syringe of Embosphere Microspheres, µm, 2 ml volume Sold 1 per box. It is recommended to use µm Embosphere Microspheres for PAE. Navigate the Challenges of PAE PAE is a technically demanding procedure because of complex anatomical variations and thin prostatic arteries often blocked by atherosclerosis. PAE is also time-consuming with long fluoroscopy time and multiple imaging such as conebeam computed tomography and digital subtraction angiography, which can lead to high radiation exposure to physicians and patients. 6-8 With its steerable articulating tip, Merit Medical s SwiftNINJA Steerable Microcatheter is designed to simplify and shorten the PAE procedure. SwiftNINJA Steerable Microcatheter Catheter Specifications Part Number MIV Outer Diameter Proximal Portion 2.9F (0.97 mm) Outer Diameter Distal Portion 2.4F (0.80 mm) Usable Length Hydrophilic Coating Length Distance From Tip To 1 st Markerband Distance Between 1 st And 2 nd Markerbands 125 cm 80 cm 0.5 mm 13.5 mm Recommended Guide Cath. ID (1.07 mm -1.09mm) Inner Diameter Max. Guide wire (0.54 mm) (0.46 mm) Max. Injection Pressure 6,900 kpa (1,000 psi) Max. Microsphere Size 700 µm Max. Coil Size.018 (0.46 mm) Cath Vol ml Before using, refer to Instructions for Use (IFU) for indications, contraindications, warnings, precautions, and directions for use. REFERENCES 1. Laurent A, et al. Trisacryl Gelatin Microspheres for Therapeutic Embolization, I: Development and In Vitro Evaluation. Am J Neuroradial 1996 Mar; 17: Pelage JP, et al. Uterine Artery Embolization in Sheep: Comparison of Acute Effects with Polyvinyl Alcohol Particles and Calibrated Microspheres. Radiol 2002;224: Verret V, et al. The Arterial Distribution of Embozene and Embosphere Microspheres in Sheep Kidney and Uterus Embolization Models. J Vasc Interv Radiol 2011 Feb;22(2): Yamamoto A, et al. Evaluation of Tris-acryl Gelatin Microsphere Embolizaton with Monochromatic X Rays: Comparison with Polyvinyl Alcohol Particles. J Vasc Interv Radiol 2006 Nov;17(11 pt 1): Data on file. 6. Garzón W, et al. Prostatic artery embolization: radiation exposure to patients and staff. J Radiol Prot 2016; 36: Laborda A, et al. Radiodermitis after prostatic artery embolization: case report and review of the literature. Cardiovasc Intervent Radiol 2015; 38: Andrade G, et al. Radiation Exposure of Patients and Interventional Radiologists during Prostatic Artery Embolization: A Prospective Single-Operator Study. J Vasc Interv Radiol 2017; 28: Australia +61 (0) Denmark Italy Spain Austria Finland Korea Sweden Merit Medical Systems, Inc West Merit Parkway South Jordan, Utah MERIT merit.com Merit Medical Europe, Middle East, & Africa (EMEA) Amerikalaan 42, 6199 AE Maastricht-Airport The Netherlands Merit Medical Ireland Ltd. Parkmore Business Park West Galway, Ireland +353 (0) Belgium (Dutch) (Français) Brazil Canada China France Germany Hong Kong India Ireland (Republic) Luxembourg Netherlands Norway Portugal Russia Switzerland (Deutsch) (Français) (Italiano) UK /C ID