Arkansas Association of HealthSystem Pharmacists 2017 Fall Seminar Alicia Sutterfield MT PharmD PGY2 Ambulatory C are P harmacy R esident Central Arkansas Veterans Healthcare System ID: 929825
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Slide1
Clinical Pearls: Testosterone Replacement TherapyArkansas Association of Health-System Pharmacists 2017 Fall Seminar
Alicia Sutterfield, MT, PharmDPGY2 Ambulatory Care Pharmacy ResidentCentral Arkansas Veterans Healthcare System
1
Slide2DisclosureI have no financial or non-financial conflicts of interest to disclose.
2
Slide3Pharmacist ObjectivesDescribe recent trends in prescribing of testosterone replacement
therapy.Appraise the current evidence for the use of testosterone replacement therapy in aging males.Formulate a patient care plan for testosterone replacement therapy, balancing the risks vs benefits.3
Slide4Technician ObjectivesDiscuss recent trends in prescribing of testosterone replacement therapy.
Evaluate the current evidence for the use of testosterone replacement therapy in aging males.Create a patient care plan which balances the risks vs benefits of testosterone replacement therapy.4
Slide5Testosterone Replacement Therapy5
Handelsman
, 2013
Slide62016 Update on Medical Overuse:A Systematic Review6
Overuse of testingImaging for low-risk headachesHospitalization for low-risk syncopeToo frequent colonoscopy screeningsOvertreatment
Anticoagulation for
Afib
with a CHADS
2
or CHA
2
DS
2
-VASc = 0
Inappropriate testosterone replacement prescribing
Continued prescribing of opioids after over-dose
Intensive glycemic control in older adults
Services to question
Oxycodone/acetaminophen and cyclobenzaprine for acute low back pain
Over-diagnosis of C. diff with molecular testing
Serial follow-up of benign thyroid nodules
Morgan et al., 2016
Slide7Testosterone Marketing7
“Testosterone is the life source for the male body... …It’s what makes a man a man”“There are countless studies that have shown not only the safety of hormone therapy, but also the long-term health benefits.” ”It is medical science at its best.”
https://
www.renewyouth.com
Slide8Male Testosterone Levels
8An Introduction to Clinical
Medicine,
McGraw
Hill 2013
Lower-Limit of Normal
Total
Testosterone
Free Testosterone
280
– 300 ng/
dL
5 – 9
pg
/mL
Slide9Androgen Deficiency9
PrimarySecondaryFailure of testicular tissue
Failure of hypothalamus
or
pituitary gland
LH & FSH
LH
& FSH
Congenital
or Acquired
Pathological
Functional
Identifiable defect
of hypothalamus-pituitary-testicular axis
Intact reproductive tract
Normal FSH/LH levels
Adaptive response to aging or disease state
An Introduction to Clinical
Medicine,
McGraw
Hill 2013
Slide10Endocrine Society Clinical Practice Guidelines for Male Hypogonadism
Diagnosis: Signs and symptoms consistent with androgen deficiency Low morning levels of total serum testosterone x2 Luteinizing Hormone Follicle Stimulating Hormone
10
Bhasin
et al., 2010
Slide11Endocrine Society Clinical Practice Guidelines for Male Hypogonadism
Signs and symptoms consistent with androgen deficiency11
Specific
Less
Specific
Reduced
libido/ sexual activity
Gynecomastia
Loss of body hair
Shrinking testes
Low or no sperm count
Low bone mineral density
Hot flashes/sweats
Decreased energy/motivation
Depressed mood
Poor concentration/memory
Sleep disturbances
Mild
anemia (normochromic/
cytic
)
Reduced muscle mass/strength
Increased body fat/BMI
Diminished physical/work performance
Bhasin
et al., 2010
Slide12Endocrine Society Clinical Practice Guidelines for Male Hypogonadism
12
Testosterone replacement therapy
NOT
recommended if:
Hx
of breast or prostate cancer
High risk for prostate cancer
PSA > 4 ng/ml
PSA > 3 ng/ml + risk factors (race, family history)
Hematocrit > 50%
Severe lower urinary tract symptoms
Untreated severe obstructive sleep apnea
Uncontrolled/poorly controlled heart failure
Bhasin
et al., 2010
Slide13Endocrine Society Clinical Practice Guidelines for Male Hypogonadism
13
Monitoring
Serum Testosterone
3-6
months after initiation, then annually
Target Testosterone Level
Mid-normal range
Preferred Dosage
Form
Patient’s preference
Bone Mineral Density
Baseline, then repeat in
1-2 years
Prostate Specific Antigen
& Digital Rectal Exam
Age
>
40 y/o AND PSA > 0.6 ng/mL:
Baseline, then repeat in 3-6
months
(further evaluation per current guidelines)
Bhasin
et al., 2010
Slide14Testosterone Replacement Therapy14
Adverse EffectsEdema
HDL, LDL
Hepatic dysfunction
Acne
Polycythemia
Behavioral effects:
Psychological dependence
Aggression
Psychosis
Venous thromboembolic events
Sleep apnea
Benign
prostatic hyperplasia
Secondary exposure
Linnebur
et al., 2009
Chrousos et al., 2009
Slide15FDA Drug Safety Communication
Caution: Use of testosterone products to relieve symptoms in men with low testosterone for no apparent reason other than aging is not an FDA-approved indication.Labeling change required to inform of possible increased risk of heart attack and stroke with use.
15
U.S. Food and Drug Administration, 2015
Slide16The Testosterone TrialsEligibility Requirements:
Males > 65 years old Average serum testosterone < 275 ng/dLIntervention:1% Testosterone Gel (1.25g/pump)
5g daily, titrated
to a maximum of 15g
daily
vs
Placebo Gel
16
Testosterone Trials
n
= 788
Physical Function Trial
788
Sexual Function Trial
788
Vitality Trial
788
Cognitive Function Trial
493
Anemia
Trial
62
Cardiovascular
Trial
170
Bone Trial
211
Snyder et al., 2014
Slide1717
Testosterone TrialsPrimary OutcomeResults
Physical Function
Snyder
et al., 2016
Percentage of men who achieved an increase in 6 minute walking distance by at least 50 meters from baseline
Absolute Difference
= 7%;
p = 0.20
Change in score from baseline for sexual activity (PDQ-Q4)
0.58 mean increase; p<0.001 (
MDTD* = 0.75
)
Sexual Function
Percentage of men whose FACIT-Fatigue score increased by at least 4 points
Absolute Difference =
9.6%;
p = 0.30
Vitality
Cognitive Function
Resnick et al., 2017
Mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI.
−0.07
mean decrease in change from baseline;
p
=
0
.88
Anemia
Roy et al., 2017
Percentage
of men with unexplained anemia (baseline
Hgb
10.0 to 12.7) whose
Hgb
increased by at least 1g/
dL
Absolute Difference =
39%
AOR
=
31.5, 95% CI, 3.7-277.8; p = 0.002
CV
Budoff
et al., 2017
Mean change in
noncalcified
plaque volume from baseline to 12 months
41mm
3
mean increase;
p = 0.003
Bone
Snyder et
al., 2017
Percent change from baseline in
vBMD
of trabecular bone in the lumbar spine, as assessed by means of quantitative computed tomography
Absolute Difference = 6.8%; p
< 0.001
* Minimum detectable treatment difference
Slide18The TOM TrialTestosterone in Older Men with Mobility Limitations Trial
Community dwelling men > 65 years old Limited mobility Total testosterone 100-350 ng/dL 10g
t
estosterone
g
el
(1%)
daily
vs
placebo
x6
months
18
Basaria
et al., 2013
Slide19The TOM TrialTestosterone in Older Men with Mobility Limitations
Trial Enrollment terminated Increased incidence of cardiovascular events in testosterone arm19
#
of Subjects
Testosterone
Placebo
Randomized
106
103
Cardiovascular
Event
23
5
Increase in Free Testosterone
10.6
p = 0.05
5.2
Basaria
et al. 2013
Slide20Systematic Review & Meta-AnalysisAssociation Between TRT and Cardiovascular Events
27 Randomized Controlled Trials 2,994 Men 180 Cardiovascular Events20
Risk
of CVE
95% CI
All Trials
OR 1.54
1.09 – 2.18
Non-Industry
Sponsored Trials
OR 2.06
1.34 – 3.17
Industry
Sponsored Trials
OR 0.89
0.50 –
1.60
Xu et
al., 2013
Slide21Testosterone Replacement Therapy in Aging Males
Summary Androgen deficiency is a normal process of aging Evidence does not support a clear benefit for use of TRT in aging males TRT may be associated with increased risk for cardiovascular events Not an FDA-approved indication
21
Slide22Testosterone Replacement Therapy in Aging Males
Recommendations Judicious selection of candidates for TRT therapy Pharmacist involvement to improve patient outcomes Management of comorbidities Weight loss Glycemic control
Blood pressure control
Smoking cessation
Avoid alcohol
TRT should not be used to treat side-effects of other medications
22
Slide23Patient Case
LT – 39 y/o CMCCFatigue, sexual dysfunction, “could I have Low-T?”PMH
T2DM
(dx 2015), HPLD, HTN, CLBP
SH
(+) tobacco – 1ppd
(+)
EtOH
– 2-3 beers/night
PE
Ht
: 70 in.,
Wt
: 102kg, BMI: 30.4
BP: 145/96, HR: 65
HgbA1c = 10.3%
Testosterone = 256 ng/
dL
Medication List:
cyclobenzaprine 10mg PO TID
metformin 500mg PO BID
metoprolol tartrate 50mg PO BID
oxycodone 10mg/APAP 325mg PO q 4-6 hours prn pain
simvastatin 20mg PO QHS
23
Slide24Patient Case - Question #1Mr. LT’s PCP has requested the clinic pharmacist to provide a treatment recommendation.Testosterone 4mg/
hr patch applied once daily QHSTestosterone 1.62% gel, 2 pumps applied once daily QAMTestosterone injectable solution, 200mg IM q 2 weeksNone of the above24
Slide25Patient Case - Question #2What additional information is recommended prior to initiating TRT?Repeat testosterone level in 1 week, collected 8-10AM
Luteinizing and follicle-stimulating hormone levelsBaseline hgb/hct, LFT’s, BUN/serum creatinineComplete medical and family historyAll of the above
25
Slide26Patient Case - Question #3What is the likely etiology for Mr. LT’s symptoms?
ObesityPoor glycemic controlHTNSmokingChronic opioid useAll of the above26
Slide27Patient Case - Question #4What is the best treatment for Mr. LT’s symptoms?
Increase metformin to 1000mg BID and replace metoprolol with HCTZ 25mg QAMWeight loss to obtain a healthy weightSmoking cessationReduced alcohol consumptionTaper-off opioid therapyAll of the above27
Slide28Questions?
Alicia Sutterfield, MT, PharmDPGY2 Ambulatory Care Pharmacy ResidentCentral Arkansas Veterans Healthcare Systemalicia.sutterfield@va.gov
28
Slide29ReferencesHandelsman
DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med J Aust. 2013;199:548-51. doi: 10.5694 /mja13.10111 .Morgan DJ, Dhruva SS, Wright SM, Korenstein D. 2016 Update on medical overuse: a systematic review. Jama Intern Med. 2016. doi: 10.1001/jamainternmed.2016.5381.Male Hormones. Renew Youth Centers, LLC. Renew Youth
. https://
www.renewyouth.com. Accessed August, 26, 2017.
Pathophysiology
of Disease: An Introduction to Clinical Medicine, Seventh Edition.
New York, NY: McGraw-Hill; 2013. http://
accesspharmacy.mhmedical.com.libproxy.uams.edu/content.
aspx?bookid
=961&Sectionid=53555704
. Accessed November 15, 2016
.
Bhasin
S, Cunningham GR, Hayes FJ, et al., Testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab
. 2010:95(6):2536-2559.
doi
:
10.1210/jc.2009-2354.
29
Slide30References30
Linnebur SA, Wallace JI. Chapter 30. Erectile Dysfunction. In: Linn WD, Wofford MR, O'Keefe M, Posey L. eds. Pharmacotherapy in Primary Care.New York, NY: McGraw-Hill; 2009.http://access pharmacy.mhmedical.com.libproxy.uams.edu/content.aspx?bookid= 439&Sectionid=3996867Accessed July 24, 2016.
Chrousos
GP. The Gonadal Hormones & Inhibitors. In:
Katzung
BG, Trevor AJ. eds.
Basic & Clinical Pharmacology, 13e.
New York, NY: McGraw-Hill; 2015.http://
accesspharmacy. mhmedical.com.libproxy.uams.edu/
content.aspx?bookid
=1193&Sectionid=69110111
. Accessed July 24,
2016
U.S. Food & Drug Administration. FDA drug safety communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. http://
www.fda.gov/Drugs/ DrugSafety/ucm436259.htm
. Published March 2015. Accessed October 10, 2016
.
Snyder PJ,
Ellenberg SS, Cunningham GR, et al. The Testosterone Trials: seven coordinated trials of testosterone treatment in elderly men.
Clin
Trials.
2014; 11:362-75
.
Slide31References31
Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment on older men. N Eng J Med. 2016;374(7)611-624. doi: 10.1056/NEJMoa1506119.Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA. 2017;317(7):717-27.
doi
: 10.1001/jama.2016.21044.
Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of testosterone levels with anemia in older men.
JAMA Intern Med
. 2017;177(4):480-90.
doi
: 10.1001/jamainternmed.2016. 9540.
Budoff
MJ,
Ellenberg
SS, Lewis CE, et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone.
JAMA
. 2017;317(7):708-16. doi:10.1001/jama. 2016.21043.
Snyder PJ,
Kopperdahl
DL, Stephens-Shields AJ, et al. Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone.
JAMA Intern Med. 2017;177(4):471-79. doi
: 10.1001/jamainternmed.2016.9539.
Slide32References32
Basaria S, Davda MN, Travison TG, Ulloor J, Singh R, Bhasin S. Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation. J Gerontol A Biol Sci Med Sci. 2013 February; 68(2):153-60.
doi:10.1093/
gerona
/gls138.
Xu
L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.
BMC Medicine
.
2013;11:108.
http://www.biomedcentral.com/1741-7015/11/108