TESTOSTERONE THERAPY AND CARDIOVASCULAR RISKS

Abraham Morgentaler, MD, FACSFounder, Men’s Health Boston

Associate Clinical Professor of UrologyBeth Israel Deaconess Medical Center

Harvard Medical School

November 6, 2013

January 29, 2014

January 31, 2014

Survival of treated vs untreated T-deficient men

N=1031 Men>40y T<250 ng/dl (8 nmol/L) Mortality:

10.3% T treated 20.7% untreated P<0.0001

Shores et al, J Clin Endocrin Metab 2012

N=55,593 Insurance claims data-diagnosis codes, prescriptions No clinical info (eg, smoking, obesity, lab results) Compared rates of non-fatal MI 12 mo prior to T

Rx vs up to 90d after T Rx (until 1st refill) Primary result- increased MI rate after T Rx Comparison with men Rx PDE5i- no increase

T Rx

12 months 90 days

Pre T Rx MI RatePost T Rx MI Rate

Finkle et al, PLoS One

STUDY DESIGN

RESULTS: Post-rate/Pre- rate= 1.36 (95% CI 1.03, 1.81)CONCLUSION: T prescription associated with

36% increased rate of MI

T Rx

12 months 90 days

Pre T Rx MI RatePost T Rx MI Rate

PRE AND POST RX PERIODS ARE UNRELATED

STUDY DESIGN

T Rx

12 months 90 days

Pre T Rx MI RatePost T Rx MI Rate

PRE AND POST RX PERIODS ARE UNRELATED

NOT AN EXPERIMENTAL STUDY!•Pre Rx: How often MDs offered T Rx within 12mo of MI •Post Rx: MI rates after T Rx•These two periods have no relationship to each other•Prescribing patterns vs natural rates of MI •Comparison is meaningless

WAS MI RATE HIGH AFTER T Rx?

4.75 MI/1000 person-years: Finkle et al 13 MI/1000 person-years: NIH Heart Attack Risk

Calculator MI rate was LOW- a fraction of expected rate

No control group Unknown whether T Rx associated with MI rate

that is higher, lower, or unchanged compared with untreated men

COMPARISON WITH PDE5I

Dissimilar groups (men with low T vs men with ED) Dissimilar treatments (T vs PDE5I) Dissimilar indications for treatment Classic case of apples and oranges Comparison is non-informative

FINKLE ET AL

Pre- Rx rate: 3.48 events/1000 person-years Post-Rx rate: 4.75 events/1000 person-years Difference: 1.27 events/1000 person-years Clinical significance?

One excess event per 1000 person‐years of exposure‐What does it mean?

2014

His son uses T for 10y=20 person‐yearsof exposure

Man applies T for 10y= 10 person‐yearsof exposure

2034

Grandson applies T for 10y= 30 person‐yearsof exposure

2054 2074

Great grandson applies T for 10y=40 person‐years of exposure

This means that if a son in every generation was treated with T for 10y, then one additional MI would occur in this family …

2014

In 100 generations , by the Year 4014!

No increased risk of MI following T therapy More accurate title:

“Physicians Are Unlikely to Prescribe Testosterone Within 12 Months

Following MI”

Vigen R et al. J Am Med Assoc 310(17): 1829-1836 (2013)

Rates of death, myocardial infarction, and stroke in men treated with testosterone and untreated men

Vigen R et al. J Am Med Assoc 310(17): 1829-1836 (2013)

19.9

15.4

10.1

25.7

18.5

11.3

0

5

10

15

20

25

30

at 1 year at 2 years at 3 years

no TRT TRT

“Of 7486 patients not receiving testosterone therapy, 681died, 420 had MIs, and 486 had strokes. Among 1223patients receiving testosterone therapy, 67 died, 23 hadMIs, and 33 had strokes. The absolute rate of events were19.9%in the no testosterone therapy group vs 25.7%in thetestosterone therapy group”

“Of 7486 patients not receiving testosterone therapy, 681died, 420 had MIs, and 486 had strokes. Among 1223patients receiving testosterone therapy, 67 died, 23 hadMIs, and 33 had strokes. The absolute rate of events were19.9%in the no testosterone therapy group vs 25.7%in thetestosterone therapy group”

No T (N=7486) T (N= 1223)

Died 681 67

MI 420 23

Stroke 486 33

Total 1587 123

Absolute rate 1587/7486=21.2% 123/1223= 10.1%

Rates After Statistical Modelling Using Stabilized Inverse Propensity of Treatment Weighting Adjusting for >50 Variables*

Vigen R et al. J Am Med Assoc 310(17): 1829-1836 (2013)

19.9

15.4

10.1

25.7

18.5

11.3

0

5

10

15

20

25

30

at 1 year at 2 years at 3 years

no TRT TRT

*adjusting for: age, race, comorbidities: (prior MI, congestive heart failure, diabetes, renal failure, depression, posttraumatic stress disorder, hyperlipidemia, peripheral vascular disease, chronic pulmonary disease, chronic obstructive pulmonary disease, obstructive sleep apnea, hypertension, cerebrovascular disease, overweight, dialysis, ever smoker, alcohol, anemia, blood loss anemia, coagulation disorder, complicated diabetes, uncomplicated diabetes, drug abuse, fluid electrolyte disorder, human immunodeficiency syndrome or AIDS, hypothyroidism, liver disease, lymphoma, metastatic cancer, neurological disorder, paralysis,peptic ulcer disease, psychoses, pulmonary circulatory disorder, renal failure, rheumatoid arthritis, nonmetastatic tumor, and weight loss), and procedures (prior revascularization, prior catheterization, prior percutaneous coronary intervention [PCI], prior coronary artery bypass graft surgery, cardiac transplant, prior stress test, prior cardiac blood pool imaging, cardiac magnetic resonanceimaging, cardiac computed tomography [CT], CT coronary angiography, prior myocardial perfusion imaging,,prior transthoracic echocardiogram, and prior transesophageal echocardiogram

EXCLUDED MEN SKEW RESULTS

Once MI or stroke occurred, men were no longer in the risk-set

Irrelevant whether or not they received T

If included, this increases number of events in no-T group by 71% (1132 + 1587)

CORRECTION #2 (Mar 5, 2014):LARGE ERRORS IN DATA

In response to challenge re excluded group of 1132 men, authors reviewed data for this group and acknowledge series of errors

1132 to 128 men: error involving >1000 men 397 to 1301 men: error involving >900 men Discovery of 100 women= 9% of population!

“My room IS clean!” 

World’s Experts Petition JAMA to Retract T Study

Recommendation to retract article submitted Mar 25, 2014 to JAMA editor-in-chief, Dr. Howard Bauchner

Cited “Gross data mismanagement and contamination” Study “no longer credible”Signed by: 29 Medical Societies >160 distinguished researchers/clinicians >60 full professors, 8 emeritus 9 journal editors 32 countries (all continents except Antarctica)

SOCIETIES PETITIONING JAMA TO RETRACT STUDY

American Society for Men’s Health (ASMH)

Brazilian Society of Endocrinology and Metabolism

Canadian Men's Sexual Health Council, an affiliate of the CUA

Canadian Society for the Study of Men’s Health (CSSAM)

European Society for the Study of the Aging Male (ESSAM)

European Society for Sexual Medicine (ESSM)

German Society for Men’s Health

Indonesian Andrologist Association

International Society for Men’s Health (ISMH)

International Society for Sexual Medicine (ISSM)

International Society for the Study of the Aging Male (ISSAM)

Italian Society of Andrology

Italian Society of Andrology and Sexual Medicine

Japan ASEAN Council for Men’s Health and Aging

UNPRECEDENTED GLOBAL ACTION TO REPUDIATE STUDY

Japanese Society for Men’s Health

Korean Society for Sexual Medicine and Andrology

Malaysian Men’s Health Initiative

Malaysian Society of Andrology and the Study of the Aging Male

Mens Health Initiative of British Columbia (Canada)

Mexican Association of Bone and Mineral Metabolism

Middle East Society for Sexual Medicine

Russian Society for Men’s Health

South Asian Society for Sexual Medicine

Sexual Medicine Society of North America

Latin American Society for Sexual Medicine

The Society for Men's Health, Singapore

Society for the Study of Androgen Deficiency

Society for the Study of Andrology and Sexology, Singapore (SSASS)

Meta-Analysis T and CV Risk

Largest meta-analysis to date 75 RCTs T group: 3016 men Placebo: 2448 menResult No increased CV risk with T Protective effect among men with metabolic

abnormalities

Corona et al Expert Opin Drug Safety 2014

Androgen Study Group Submission to FDA May 7, 2014

Review of literature submitted to FDA Detailed analysis of studies reporting increased

CV risks Supplemented by overview of 30y of literature

that has shown beneficial effects of higher endogenous T or T therapy

Compilation of 3 appendices, 8 tables

Malkin CJ et al. Heart 96: 18231-1825 (2010)

CUMULATIVE SURVIVAL BASED ON BIOAVAILABLE T

N=930 MEN WITH CORONARY HEART DISEASE

FOLLOWED FOR 6.9 ± 2.6 Y

MORTALITY: LOW T 21%, NORMAL T 12%

0.85

0.9

0.95

1

0 500 1000 1500 2000 2500 3000 3500Survival time

Cum

ulat

ive

Surv

ival

Bio T < 2.6 nmol/L(n=194)

Bio T < 2.6 nmol/L(n=194)

Bio T > 2.6 nmol/L(n=736)

Bio T > 2.6 nmol/L(n=736)

Log rank, p=0.007, HR 2.2 (1.2-3.9)

Low T As A Predictive Marker For Cardiovascular Mortality

N = 11,606 men (no cancer or CVD) 825 men died matched

with 1489 living men in control group

Mean follow-up 7 years “In men, endogenous testosterone

concentrations are inversely related to mortality due to cardiovascular disease and all causes”

Khaw KT, et al. Circulation. 2007;116:2694-2701.

0 2 4 6 8 10

1234

Multivariate-adjusted survival by quartile of endogenous T concentration (4 is highest)

Years of follow up

Testosterone group

.5

.6

.7

.8

.9

1.0

Cum

ulat

ive

surv

ival

1.1

Overall mortality

P < .001 for trend after adjusting for multiple variables, including age, BMI, blood pressure, cigarette smoking, etc.

Low Testosterone and Increased Mortality (N >500)

Recent Studies HR (95% CI) Nature Men, n Follow-

up, y Mortality

Shores, 2006 1.88 (1.34–2.63) Retrospective 858 8 All-cause

Laughlin, 2008 1.38 (1.02–1.85) Prospective 794 20 CVD

Khaw, 2007 2.29 (1.60–3.26) Prospective 2314 of 11,606 10 All-cause and

CVD

Haring, 2010 2.32 (1.38–3.89) Prospective 1954 7.2 All-cause

2.56 (1.15-6.52) CVD

Malkin, 2010 2.27 (1.45–3.60) Prospective 930 6.9

All-cause in men with coronary disease

Tivesten, 2009 1.65 (1.29–2.12) Prospective 3014 4.5 All-cause

Menke, 2010 1.43 (1.09–1.87) Prospective 1114 9 All-cause

Vikan, 2009 1.24 (1.01–1.54) Prospective 1568 11.2 All-cause

Corona, 2010 7.1 (1.8–28.6) Prospective 1687 4.3 CVD

No. of Studies with Beneficial or Harmful CV Effects with Higher T (Endogenous or Treated)

Cardiovascular Beneficial Harmful

Mortality

Coronary Artery Disease (CAD)

Severity CAD

Carotid Plaque/Intima Media Thickness

Fat mass/Obesity

Glycemic control

Total

No. of Studies with Beneficial or Harmful CV Effects with Higher T (Endogenous or Treated)

Cardiovascular Beneficial Harmful

Mortality 8 0

Coronary Artery Disease (CAD) 6 0

Severity CAD 4 0

Carotid Plaque/Intima Media Thickness

8 0

Fat mass/Obesity 14 0

Glycemic control 6 0

Total 46 0

Summary

No credible evidence in the scientific literature that T therapy is associated with CV risks

FDA: no evidence increased risk Literature supports beneficial effects of T

Low T associated with increased mortality Higher endogenous T is protective against CV risk T therapy improves CV risk factors

Why Is There A Controversy?

Claims of increased CV risk promoted by those who are not involved in the care of men with T deficiency : Anti-pharma advocates Media Plaintiff attorneys Anti-sex

ACCURATE REPORTING OF T RESEARCH

Androgen Study Group formed to provide accurate reporting of T research

www.androgenstudygroup.org

ACCURATE REPORTING OF T RESEARCH

Androgen Study Group formed to provide accurate reporting of T research

www.androgenstudygroup.org

“If you don't read the newspaper you are uninformed. If you do read the newspaper you are misinformed.”Mark Twain (1835-1910), US author, humorist