Journal Club Jim Hoehns, Pharm.D .
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Transcript of Journal Club Jim Hoehns, Pharm.D .
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Journal ClubJim Hoehns, Pharm.D.
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What Adverse Effects Are Related to Testosterone Administration?
CV: DVT, edema, HTN, vasodilation CNS: aggression, depression, insomnia, anxiety,
sleep apnea, memory loss, mood swings Endo: breast pain, gynecomastia, hyperlipidemia,
libido change GI: nausea, weight gain, increased appetite GU: priapism, impotence, PSA increased, BPH,
impaired urination, testicular atrophy Hepatic: cholestatic jaundice Heme: anemia, bleeding, polycythemia,
suppression of clotting factors, Hgb/Hct increased Other: creatinine increased
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Background Men have gradual declines in average
testosterone as they age Testosterone therapy prescribed for 2.9% of
men aged ≥40 years No equivalent of Women’s Health Initiative for
men Inadequate information of effect of testosterone
replacement on clinical outcomes One recent study of T replacement in older
frail men was stopped prematurely due to CV events
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N Engl J Med 2010;363:109-22.
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Journal Article
JAMA 2013;310:1829-36.
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Methods
Retrospective national cohort (VA system) 76 VA cath labs
Patients Male patients with angiography (2005-
2011), had subsequent [testosterone] checked, and had value <300 ng/mL
Study comparison: Those that started testosterone Rx vs. those who did not
CAD: ≥20% stenosis in epicardial vessel
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Methods
Exclusion criteria Started testosterone before angiography Missing data on coronary anatomy Prescribed testosterone after an MI Hct >50% PSA of 4.0 ng/mL or higher
Follow-up Mean: 27.5 months
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Methods
Covariates Weighted adjustment
▪ Age, race, prior MI, CHF, diabetes, renal failure, MDD, PTSD, hyperlipidemia, PAD, COPD, OSA, HTN, cerebrovascular disease, overweight, dialysis, ever smoker, alcohol, anemia, drug abuse, electrolyte abnormalities, AIDS, hypothyroidism, liver disease, lymphoma, cancer, neurological disorder, PUD, RA, and procedures: prior CABG, revascularization, transplant, cardiac MRI, echocardiogram, TEE
Primary exposure variable Initiated Rx for testosterone gel, injection, or
patch▪ ?once initiated, assumed to have continued until
event or end of follow-up
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Methods
Primary endpoint Time to all-cause mortality or
hospitalization for MI or stroke▪ Obtained from VA inpatient files (ICD-9)▪ Last day of follow-up: 1/23/12
Statistics Treated testosterone as a time varying
covariate Tested for interaction between CAD
status and testosterone therapy
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Methods
Statistics (cont.): Separated testosterone exposure▪ Injections, patch, or gel
Sensitivity analyses▪ Evaluated if results due to differential
treatment of CV risk factors▪ LDL, BP, statin use, beta-blocker use
▪ Included subsequent PCI/CABG as additional outcome▪ Assessed dose of T prescribed and duration of
treatment▪ Gel (1.1%), injections (35.7%), and patches (63.3%)
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Primary EndpointGroup Died MI Stroke
No testosterone(N=7,486)
9.1% 5.6% 6.5%
Testosterone(N=1,223)
5.4% 1.8% 2.6%
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Primary EndpointGroup 1 Year† 2 Years 3 Years
No testosteron
e
10.1% 15.4% 19.9%
Testosterone
11.3%* 18.5% 25.7%
Abolute Risk
Difference
1.3% (-7.1% to 9.7%)
3.1% (-4.9% to 11.0%)
5.8% (-1.4% to 13.1%)
† years after coronary angiography* Kaplan-Meier estimated cumulative percentages
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Results
Same elevated risk observed in patients in those with and without CAD Test for interaction, P=0.41
No difference in risk among types of T replacement
T values 60% of those prescribed T had another [T]
checked Among them, T increased from mean of
176 ng/dL to 332 ng/dL
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Discussion
Potential explanations for results T may increase platelet aggregation T may increase vascular inflammation T may worsen breathing in patients with
OSA First observational study to suggest
that testosterone is associated with adverse cardiovascular outcomes
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Limitations
Unmeasured confounders may exist Outcomes not validated by chart review
Used ICD-9 codes Small number of patients with extended
follow-up time Uncertain generalizability
Sizable burden of comorbidities Poor characterization of testosterone
usage from pharmacy claims Uncertain how to rectify the statistics
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My Thoughts
Weighting of comorbidities Complex methodology I am uncertain of validity of this method to
adjust for unmeasured confounders Unclear what individual components of
composite outcome were driving observed differences in their model
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Summary
Use of testosterone was associated with increased risk of mortality, MI, or ischemic stroke
Association was not modified by presence or absence of CAD