Journal ClubJim Hoehns, Pharm.D.

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

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

N Engl J Med 2010;363:109-22.

Journal Article

JAMA 2013;310:1829-36.

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

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

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

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

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%)

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%

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

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

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

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

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

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