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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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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
N Engl J Med 2010;363:109-22.
JAMA 2013;310:1829-36.
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Retrospective national cohort (VA system)
 76 VA cath labs
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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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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
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Follow-up
 Mean: 27.5 months
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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
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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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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
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Statistics
 Treated testosterone as a time varying covariate
 Tested for interaction between CAD status and
testosterone therapy
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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%)
Group
Died
MI
Stroke
No testosterone
(N=7,486)
9.1%
5.6%
6.5%
Testosterone
(N=1,223)
5.4%
1.8%
2.6%
Group
1 Year†
2 Years
3 Years
No
testosterone
10.1%
15.4%
19.9%
Testosterone
11.3%*
18.5%
25.7%
Abolute Risk
Difference
1.3% (-7.1% to 3.1% (-4.9% to 5.8% (-1.4% to
9.7%)
11.0%)
13.1%)
† years after coronary angiography
* Kaplan-Meier estimated cumulative percentages
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Same elevated risk observed in patients in those
with and without CAD
 Test for interaction, P=0.41
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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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Potential explanations for results
 T may increase platelet aggregation
 T may increase vascular inflammation
 T may worsen breathing in patients with OSA
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First observational study to suggest that
testosterone is associated with adverse
cardiovascular outcomes
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Unmeasured confounders may exist
Outcomes not validated by chart review
 Used ICD-9 codes
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Small number of patients with extended
follow-up time
Uncertain generalizability
 Sizable burden of comorbidities
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Poor characterization of testosterone usage
from pharmacy claims
Uncertain how to rectify the statistics
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Weighting of comorbidities
 Complex methodology
 I am uncertain of validity of this method to adjust for
unmeasured confounders
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Unclear what individual components of composite
outcome were driving observed differences in
their model
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Use of testosterone was associated with increased
risk of mortality, MI, or ischemic stroke
Association was not modified by presence or
absence of CAD