is there an increased cv risk in patients on trt? · pdf filemario maggi sexualmedicine &...

Is there an increased CV

risk in patients on TRT?

Mario MaggiSexual Medicine &

AndrologyUniversity of Florence,[email protected]



G. RastrelliG. Corona

ED subjects: a high CV-risk population

Mario MaggiSexual Medicine &

AndrologyUniversity of Florence,[email protected]

Without CV events at baseline

With CV events at baseline

p<0.0001

Follow up (years)

Prop

ortio

n fr

ee o

f MA

CE

Proportion free of MACE (Kalplan-Meier curves) as a function of baseline positivity for previous CV event in a consecutive series of

1687 ED subjects at the University of Florence, Florence, Italy

Corona et al., Andrology, 2014Sep;2(5):741-7


Is there an increased CV risk in patients on TRT?


• High prevalence of incident MACE in ED

Take homemessages

LH

(U

/L)

Testosterone (nmol/L)

Hypogonadal status in 4173ED subjects studied at the University of Florence

Corona et al.,J. Sex. Med., 2014 Jul;11(7):1823-34.

LH

(U

/L)

Compensated hypogonadism

(4.1%)

Testosterone ≤10.4 nmol/L

Primary hypogonadism

(2.5%)

Secondaryhypogonadism

(17.3%)

LH = 9.4 U/L

Eugonadism(76.1%)Testosterone (nmol/L)

Hypogonadal status in 4173ED subjects studied at the University of Florence




• High prevalence of incident MACE in ED• 20% of men with ED → hypogonadism

17% secondary

3% primary

Take homemessages


Cross-sectional studies

• Are MACE and hypogonadism associated?

Corona et al., Eur J Endocrinol. 2011;165(5):687-701

‐20,00

‐15,00

‐10,00

‐5,00

0,00

5,00

10,00 Diff. in mean LL, 95% CI UL, 95% CI-20 -15 -10 -5 0 5 10SourceTT mean differences (nmol/L)

Favours CHD Favors no CHD

Poggi et al., 1976Ben-Halim et al., 1978Entrican et al., 1978Luria et al., 1982Labropoulos et al., 1982Labropoulos et al., 1982*Zumoff et al., 1982*Phillips et al., 1983Aksut et al., 1986Aksut et al., 1986*Franzen et al., 1986Franzen et al., 1986*Lichatenstein et al., 1987Small et al., 1987Phillips et al., 1988Barrett-Connor et al., 1988Sewdarsen et al., 1990Hauner et al., 1991Rice et al., 1993Hautanen et al., 1994Marques-Vidal et al., 1995Phillips et al., 1996Tripathi et al., 1998*Tripathi et al., 1998**Tripathi et al., 1998***Chearskul et al., 2000Mikulec et al., 2004Cao et al., 2010Overall CHD non-angio documented

-8,75 -13,91 -3,590,00 -2,94 2,942,35 -0,31 5,011,32 -4,06 6,703,00 0,27 5,731,80 -0,38 3,981,46 -1,43 4,350,80 -0,86 2,46-6,36 -8,63 -4,10-7,16 -10,03 -4,283,00 0,57 5,432,00 -0,43 4,43-1,10 -1,81 -0,39-3,30 -7,12 0,52-0,69 -2,57 1,18-0,04 -1,18 1,10-1,51 -2,64 -0,38-1,40 -2,85 0,05-2,15 -3,53 -0,760,50 -1,71 2,71-0,40 -1,95 1,152,64 -2,01 7,29

-13,85 -15,68 -12,02-13,43 -14,97 -11,89-13,56 -15,59 -11,53-5,81 -7,92 -3,700,31 -0,77 1,39-4,06 -5,30 -2,82-2,33 -3,99 -0,68

Weighted differences (with 95% confidence interval [CI]) of mean total testosterone between non-angiographically documented CHD and controls from cross-sectional studies

Overall CHD non‐angio‐documented ‐2.33 ‐3.99 ‐0.68

Corona et al., Eur J Endocrinol. 2011;165:687

‐15,00

‐10,00

‐5,00

0,00

5,00

10,00 Diff. in mean LL, 95% CI UL, 95% CI-15 -10 -5 0 5 10SourceTT mean differences (nmol/L)

Favours CHD Favors no CHD

Luria et al., 1982 *Zumoff et al., 1982Barth et al., 1983Hromadova et al., 1985Sewdarsen et al., 1986Chute et al., 1987Hamalainen et al., 1987Sewdarsen et al., 1988Slowinska-Srzednicka et al., 1989Zhao et al., 1998Kabakci et al., 1999English et al., 2000Dobrzycki et al., 2003Dunajska et al., 2004Dunajska et al., 2004*Fischer et al., 2004 Davoodi et al., 2007He et al., 2007Mohamad et al., 2007Mohamad et al., 2007*Turhan et al., 2007Fallah et al., 2009Overall CHD angio documented

2,99 -0,42 6,39-1,90 -5,87 2,07-5,70 -9,36 -2,04-7,21 -10,85 -3,57-5,00 -7,56 -2,44-4,76 -7,86 -1,66-0,70 -4,36 2,96-3,80 -6,88 -0,72-3,06 -7,32 1,20-5,56 -7,80 -3,321,74 -0,28 3,76-2,00 -4,09 0,09-9,30 -11,97 -6,63-3,60 -7,25 0,05-2,36 -5,23 0,51-0,60 -2,08 0,880,78 -0,64 2,20-0,28 -2,08 1,53-4,50 -6,48 -2,52-1,40 -3,76 0,96-3,48 -5,76 -1,200,78 -0,64 2,20-2,57 -3,82 -1,31

Weighted differences (with 95% confidence interval [CI]) of mean total testosterone between angiographically documented CHD and controls from cross-sectional studies

Overall CHD angio‐documented ‐2.57 ‐3.82 ‐1.31


‐14,00

‐12,00

‐10,00

‐8,00

‐6,00

‐4,00

‐2,00

0,00

2,00

4,00

Diff. in mean LL, 95% CI UL, 95% CI-14 -12 -10 -8 -6 -4 -2 0 2 4

Source

TT mean differences (nmol/L)

Favours other CVD Favors no other CVD

Taggart et al., 1980

Foresta et al., 1982

Elwan et al., 1990

Dash et al., 1991

Jeppesen et al., 1996

Price et al., 1997

Demirbag et al., 2005

Page et al., 2008

Overall other CVD

0,10 -2,15 2,35

-5,49 -8,60 -2,37

-0,87 -4,67 2,93

-6,60 -12,26 -0,94

-2,70 -4,56 -0,84

-1,30 -3,52 0,92

-8,02 -11,73 -4,31

-1,40 -2,28 -0,52

-2,71 -4,26 -1,15

Weighted differences (with 95% confidence interval [CI]) of mean total testosterone between other CVD and controls from cross-sectional studies

Overall other CVD -2.71 -4.26 -1.15




• High prevalence of incident MACE in ED• 20% of men with ED → hypogonadism• Having MACE decreases T by 2-3 nmoles/L

17% secondary

3% primary

Take homemessages

Progetto Cuore risk engineAdjusted for

BMICDS

Adj r=-0.068; p<0.005

Tota

l tes

tost

eron

e nm

ol/L

Total scoreI II III IV

Quartiles

Adj r=-0.091; p<0.0001

Corona et al., J Endocrinol Invest. 2012;35:809

Total testosterone as a function of cardiovascular risk (Progetto Cuore risk engine) in a consecutive series of 2269 ED subjects at the

University of Florence, Florence, Italy



• High prevalence of incident MACE in ED• 20% of men with ED → hypogonadism• Having MACE decreases T by 2-3 nmoles/L• In ED, having ↑CVD risk decreases T by 3-4 nmoles/L

17% secondary

3% primary

Take homemessages



• Is low T associated with MACE morbidity?

Corona et al., J Sex Med. 2010;7:1557

Mean follow up 4.3±2.6 years1687 Male subjects with EDCity of Florence Registry Office:major adverse cardiac events (MACE)- ischemic heart disease (ICD 410-4)- other heart diseases (ICD 420-9)- sudden death for cardiac d. (ICD 798-799)- cerebrovascular diseases (ICD 430-4, 436-8)- peripheral arterial diseseas (ICD 440)

MACE

Observational prospective study (2000-2007) of ED subjects at the University of Florence- SIEDY©- ANDROTEST©- Physical examination, hormonal parameters, psychiatric symptoms (MHQ)- Basal and dynamic penile color Doppler ultrasound

W/O MACE92%

MACE=8% Non fatal89% 11% fatal

Ischemic heart

Cerebrovascular

61%

29%

10% peripheral

MACE

Observational prospective study (2000-2007) of ED subejcts at the University of Florence- SIEDY©- ANDROTEST©- Physical examination, hormonal parameters, psychiatric symptoms (MHQ)- Basal and dynamic penile color Doppler ultrasound

TT 10.4 nMTT 8-10.4 nMTT < 8 nM

p=NS

Proportion free of MACE (Kalplan-Meier curves) as a function of baseline total testosterone in a consecutive series of 1687 ED subjects

at the University of Florence, Florence, Italy

Prop

ortio

n fr

ee o

f MA

CE

Follow up (years)

Baseline total testosterone does notpredict incident MACE (Cox regression HR=NS)

Corona et al.,J. Sex. Med., 20107:1557-64


Longitudinal studies

• Is low T associated with MACE morbidity?

Baseline weighted differences (with 95% confidence interval) of mean total testosterone(TT) between patients with incident MACE and controls

‐12,00

‐10,00

‐8,00

‐6,00

‐4,00

‐2,00

0,00

2,00

4,00Source ‐12 ‐10 ‐8 ‐6 ‐4 ‐2 0 2 4 Diff. in mean LL, 95% CI UL, 95% CI

Higher any CVD incidence Lower any CVD incidence


Cauley et al., 1987

Phillips et al., 1988

Contoreggi et al., 1990

Yarnell et al., 1993

Hautanen et al 1994

Mikulec et al., 2004

Yeap et al., 2009

Corona et al., 2010

Overall

0,60 -1,47 2,67

-0,69 -2,83 1,44

0,35 -1,79 2,49

0,10 -1,19 1,39

0,50 -1,71 2,71

-10,10 -10,77 -9,44

-1,00 -2,02 0,02

-0,70 -1,85 0,45

‐1,40 ‐5,23 2,44




• High prevalence of incident MACE in ED• 20% of men with ED → hypogonadism• Having MACE decreases T by 2-3 nmoles/L• In ED, having ↑CVD risk decreases T by 3-4 nmoles/L• Low T is not associated with incident MACE

17% secondary

3% primary

Take homemessages

Corona et al.,Andrology, 2014Sep;2(5):741-7

Free

from

MA

CE

p=0.034

History of MACE at baseline

C

Free from MACE at baseline

B

Free

from

MA

CE

p=0.462

Total testosterone < 12 nM at baseline

Total testosterone ≥ 12 nM at baseline

Follow up years

Proportion free of MACE (Kalplan-Meier curves) as a function of baseline total testosterone in a consecutive series of 1687 ED subjects

at the University of Florence, Florence, Italy, according to CV events atbaseline


p=0.097

Free from MACE at baseline

A

Free

from

MA

CE

B

History of MACE at baseline

Free

from

MA

CE

p=0.012

Follow up years

Proportion free of MACE (Kalplan-Meier curves) as a function of baseline testis volume in a consecutive series of 1687 ED subjects atthe University of Florence, Florence, Italy, according to CV events at

baseline

Testis volume < 20 cc at baseline

Testis volume ≥ 20 cc at baseline


Proportion free of MACE (Kalplan-Meier curves) as a function of baseline testis volume and/or total testosterone in a consecutive series

of 1687 ED subjects at the University of Florence, Florence, Italy, in subjects reporting CV events at baseline

Free

from

MA

CE

C

p=0.013 Total testosterone < 12 nMand TV < 20 cc at baseline

Total testosterone < 12 nMor TV < 20 cc at baseline

Total testosterone ≥ 12 nMand TV ≥ 20 cc at baseline

Follow up yearsCorona et al.,Andrology, 2014Sep;2(5):741-7

Proportion free of MACE (Kalplan-Meier curves) as a function of baseline testis volume and/or total testosterone in a consecutive series

of 1687 ED subjects at the University of Florence, Florence, Italy, in subjects reporting CV events at baseline

Free

from

MA

CE

C

p=0.013 Total testosterone < 12 nMand TV < 20 cc at baseline

Total testosterone < 12 nMor TV < 20 cc at baseline

Total testosterone ≥ 12 nMand TV ≥ 20 cc at baseline

Follow up yearsCorona et al.,Andrology, 2014Sep;2(5):741-7

HR=0.514 [0.306‐0.864] p<0.02Adjusted for:AgeSmoking & drinking habitChronic Disease Score



• High prevalence of incident MACE in ED• 20% of men with ED → hypogonadism• Having MACE decreases T by 2-3 nmoles/L• In ED, having ↑CVD risk decreases T by 3-4 nmoles/L• Low T is not associated with incident MACE• Hypogonadism is protective from MACE in high-risk

17% secondary

3% primary

Take homemessages



• Is low T associated with MACE lethality?

0

5

10

15

20

25

30

35

40

45

50

55

0

5

10

15

20

25

30

35

40

45

50

55

No Yes No Yes

TT < 10.4 nmol/L TT < 8 nmol/L

Age Adjusted HR=5.9[1.6-21.7]; p=0.007 HR= 12.2[1.9-79.5]; p=0.008

Prevalence of MACE lethality as a function of baseline total testosterone in a consecutive series of 1687 ED subjects at the University of

Florence, Florence, Italy

Non fatal 89% 11% fatal

Prev

alen

ceof

MA

CE

leth

ality

Prop

ortio

n fr

ee o

f MA

CE

leth

ality

TT 10.4 nMTT 8-10.4 nMTT < 8 nM

Proportion free of MACE lethality (Kalplan-Meier curves) as a function of baseline total testosterone in a consecutive series of 1687

ED subjects at the University of Florence, Florence, Italy

Follow up (years)

p<0.05 vs. TT 10.4 nM

p<0.0001 vs. TT 10.4 nM

Baseline hypogonadism increasesMACE lethality

Corona et al.,J. Sex. Med., 7:1557-64, 2010

Corona et al., Best Pract Res Clin Endocrinol Metab. 2011 Apr;25(2):337-53

Corona et al., Eur J Endocrinol. 2011;165(5):687-701


Baseline weighted differences (with 95% confidence interval) of mean total testosterone(TT) between patients with incident CV mortality and controls

-0,61 -1,86 0,64

-1,00 -1,66 -0,34

-3,00 -6,53 0,53

-0,97 -1,55 -0,40

Barrett-Connor et al., 1988

Khaw et al., 2007

Corona et al., 2010

OVERALL

‐7,00

‐6,00

‐5,00

‐4,00

‐3,00

‐2,00

‐1,00

0,00

1,00Source ‐7 ‐6 ‐5 ‐4 ‐3 ‐2 ‐1 0 1 Diff. in mean LL, 95% CI UL, 95% CI

Higher any CVD mortality Lower any CVD mortality





• High prevalence of incident MACE in ED• 20% of men with ED → hypogonadism• Having MACE decreases T by 2-3 nmoles/L• In ED, having ↑CVD risk decreases T by 3-4 nmoles/L• Low T is not associated with incident MACE• Hypogonadism is protective from MACE in high-risk • Hypogonadism is associated with ↑ MACE lethality

17% secondary

3% primary

Take homemessages



• Is compensated hypogonadism associatedwith CVD risk and/or MACE lethality?

A

n=2792

Eugonadism

Pred

icte

d C

V r

isk

(Pro

gett

oC

uore

)

p<0.0001 at ANOVA

p<0.0001p<0.0001

Compensatedhypogonadism

Overthypogonadism

Cardiovascular risk (Progetto Cuore risk engine) as a function of hypogonadal status in a consecutive series of 4173 ED subjects at the

University of Florence, Florence, Italy


EugonadismOvert hypogonadismCompensated hypogonadism

Proportion free of MACE lethality (Kalplan-Meier curves) as a function of baseline hypogonadal status in a consecutive series of 1687

ED subjects at the University of Florence, Florence, Italy

Free

from

MA

CE

deat

h

Follow up (years)

*

*

B

0,01 0,1 1 10

Compensated hypogonadism

0.01 0.1 1 10 100

Overt hypogonadism




• High prevalence of incident MACE in ED• 20% of men with ED → hypogonadism• Having MACE decreases T by 2-3 nmoles/L• In ED, having ↑CVD risk decreases T by 3-4 nmoles/L• Low T is not associated with incident MACE• Hypogonadism is protective from MACE in high-risk • Hypogonadism is associated with ↑ MACE lethality• Compensated HG is associated with ↑ MACE lethality

17% secondary

3% primary

Morbidities:• CVD• T2DM• Obesity• MetS

IncreasedCV mortality

1.: Corona G, Rastrelli G, Maseroli E, Fralassi N, Sforza A, Forti G, Mannucci E, Maggi M. Low testosterone syndrome protects subjects with high cardiovascularrisk burden from major adverse cardiovascular events. Andrology. 2014Sep;2(5):741‐7. doi: 10.1111/j.2047‐2927.2014.00241.x. Epub 2014 Jul 7. PubMedPMID: 25044637.

2: Corona G, Maseroli E, Rastrelli G, Sforza A, Forti G, Mannucci E, Maggi M.Characteristics of compensated hypogonadism in patients with sexual dysfunction. J Sex Med. 2014 Jul;11(7):1823‐34. doi: 10.1111/jsm.12549. Epub 2014 Apr 29.PubMed PMID: 24774537.

3: Corona G, Rastrelli G, Monami M, Maseroli E, Jannini EA, Balercia G, Sforza A,Forti G, Mannucci E, Maggi M. Frequency of sexual activity and cardiovascularrisk in subjects with erectile dysfunction: cross‐sectional and longitudinalanalyses. Andrology. 2013 Nov;1(6):864‐71. doi: 10.1111/j.2047‐2927.2013.00139.x.Epub 2013 Oct 11. PubMed PMID: 24127288.

4: Fisher AD, Rastrelli G, Bandini E, Corona G, Balzi D, Melani C, Monami M,Matta V, Mannucci E, Maggi M. Metabolic and cardiovascular outcomes offatherhood: results from a cohort of study in subjects with sexual dysfunction. JSex Med. 2012 Nov;9(11):2785‐94. doi: 10.1111/j.1743‐6109.2012.02865.x. Epub 2012Aug 15. PubMed PMID: 22897516.

5: Corona G, Rastrelli G, Balercia G, Sforza A, Forti G, Maggi M. Testosteroneand cardiovascular risk in patients with erectile dysfunction. J EndocrinolInvest. 2012 Oct;35(9):809‐16. doi: 10.3275/8063. Epub 2011 Nov 8. PubMed PMID:22082753.

6: Corona G, Rastrelli G, Monami M, Guay A, Buvat J, Sforza A, Forti G, Mannucci E, Maggi M. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta‐analytic study. Eur J Endocrinol. 2011 Nov;165(5):687‐701. doi:10.1530/EJE‐11‐0447. Epub 2011 Aug 18. Review. PubMed PMID: 21852391.

7: Corona G, Rastrelli G, Vignozzi L, Mannucci E, Maggi M. Testosterone,cardiovascular disease and the metabolic syndrome. Best Pract Res Clin EndocrinolMetab. 2011 Apr;25(2):337‐53. doi: 10.1016/j.beem.2010.07.002. Review. PubMedPMID: 21397202.

8: Corona G, Monami M, Boddi V, Balzi D, Melani C, Federico N, Balzi D, Sforza A,Rotella CM, Forti G, Mannucci E, Maggi M. Is obesity a further cardiovascularrisk factor in patients with erectile dysfunction? J Sex Med. 2010Jul;7(7):2538‐46. doi: 10.1111/j.1743‐6109.2010.01839.x. Epub 2010 Apr 26. PubMedPMID: 20456622.

9: Corona G, Monami M, Boddi V, Cameron‐Smith M, Fisher AD, de Vita G, Melani C, Balzi D, Sforza A, Forti G, Mannucci E, Maggi M. Low testosterone is associatedwith an increased risk of MACE lethality in subjects with erectile dysfunction. JSex Med. 2010 Apr;7(4 Pt 1):1557‐64. doi: 10.1111/j.1743‐6109.2009.01690.x. Epub 2010 Jan 25. PubMed PMID: 20102478.

10: Corona G, Mannucci E, Forti G, Maggi M. Hypogonadism, ED, metabolic syndrome and obesity: a pathological link supporting cardiovascular diseases. Int JAndrol. 2009 Dec;32(6):587‐98. doi: 10.1111/j.1365‐2605.2008.00951.x. Epub 2009Feb 10. Review. PubMed PMID: 19226407.

11: Corona G, Rastrelli G, Filippi S, Vignozzi L, Mannucci E, Maggi M. Erectiledysfunction and central obesity: an Italian perspective. Asian J Androl. 2014Jul‐Aug;16(4):581‐91. doi: 10.4103/1008‐682X.126386. PubMed PMID: 24713832;PubMed Central PMCID: PMC4104087.

12: Rastrelli G, Corona G, Lotti F, Boddi V, Mannucci E, Maggi M. Relationship oftestis size and LH levels with incidence of major adverse cardiovascular eventsin older men with sexual dysfunction. J Sex Med. 2013 Nov;10(11):2761‐73. doi:10.1111/jsm.12270. Epub 2013 Jul 11. PubMed PMID: 23844651.

↓

↓




↓

↓

↓ spermatogenesis

↓ testosterone↓ fer lity


↓fatherhood



↓

↓

↓ spermatogenesis

↓ testosterone↓ fer lity

↓ sexualactivity

↓ energy expenditure

Low T syndrome


↓fatherhood



Fisher et al.,J Sex Med. 2012 Nov;9(11):2785‐94

HR=1.018 [1.003‐1.032] p=0.025Adjusted for:AgeSmoking & drinking habitChronic Disease ScoreTestosterone, prolactinPartner’s hypoactive sexual desire

ED subjects a high prevalence of: • CVD• Low T



[01-31-2014] The U.S. Food and Drug Administration (FDA) is investigating therisk of stroke, heart attack, and death in men taking FDA-approved testosteroneproducts. We have been monitoring this risk and decided to reassess this safetyissue based on the recent publication of two separate studies that eachsuggested an increased risk of cardiovascular events among groups of menprescribed testosterone therapy. We are providing this alert while we continueto evaluate the information from these studies and other available data, and willcommunicate our final conclusions and recommendations when the evaluation iscomplete.



Until evidence from large randomized trials becomes available, the EndocrineSociety believes that patients should be made aware of the potential risk ofcardiovascular events in middle-aged and older men who are taking orconsidering testosterone therapy for age-related decline in testosterone levels andsymptoms.




• Is testosterone administration associated withCV outcomes in Heart Failure? (primary endpoint)

• placebo-controlled, randomized studies

Toma et al., Circ Heart Fail 5:315‐21, 2012

Exercise capacity


• Is testosterone administration associated withCV outcomes in CHD? (primary endpoint)


258 patients with a mean follow-up of 23 weeks


• Is testosterone administration associated withCV outcomes in CHD? (primary endpoint)

Diff. in mean LL, 95% CI UL, 95% CI

‐150,00

‐100,00

‐50,00

0,00

50,00

100,00

150,00

200,00

250,00

300,00

350,00Source ‐150 ‐100 ‐50 0 50 100 150 200 250 300 350

Time to 1‐mm ST depression mean differences (seconds)

Favour placebo Favour testosterone

Rosano et al., 1999 (76)

Webb et al., 1999 (77)

English et al., 2000 (78)

Thompson et al., 2002 (79)

Thompson et al., 2002* (79)

Malkin et al., 2004 (80)

Mathur et al., 2009 (81)

Overall

108,00 -108,89 324,89

66,00 -36,90 168,90

69,00 4,82 133,18

6,00 -56,75 68,75

0,00 -64,19 64,19

47,00 -59,55 153,55

186,30 88,68 283,92

57,40 9,90 104,90


‐150,00

‐100,00

‐50,00

0,00

50,00

100,00

150,00

200,00

250,00

300,00

350,00Source ‐150 ‐100 ‐50 0 50 100 150 200 250 300 350 Diff. in mean LL, 95% CI UL, 95% CIExsercise duration mean differences (seconds)

Favour placebo Favour testosterone

Rosano et al., 1999 (76)

Mathur et al., 2009 (81)

Overall

90,00 -111,54 291,54

186,30 88,68 283,92

168,00 80,14 255,86



• Is testosterone administration associated with incidence of CV events?


Fernández‐Balsells et al.,J Clin Endocrinol Metab. 2010Jun;95(6):2560‐75.

• VERY HIGH DOSE OF TRT. CV‐related events in:

4 of 14 subjects (29%) with T levels > 1000 ng/dl

7 of 46 subjects (15%) with T levels < 500 ng/dl

• COMPOSITE RISK FOR ADVERSE EVENTS

(including peripheral oedema)

• ELDERLY MEN WITH LIMITED MOBILITY


• placebo-controlled, randomized studies• 12 wks or more• 27 trials 2994 men 180 adverse events

• Is testosterone administration associated with incidence of composite CV events?

BMC Med. 2013; 11: 108.Published online 2013 April 18. doi: 10.1186/1741-7015-11-108PMCID: PMC3648456Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trialsLin Xu,1 Guy Freeman,1 Benjamin J Cowling,1 and C Mary Schooling 1

,2

Xu et al., BMC Medicine 11:108, 2013

incidence of composite CV events

Xu et al., BMC Medicine 11:108, 2013

IndustrialSupport:

NO

IndustrialSupport:

YES

Corona et al., Expert Opin Drug Saf. 2014 2014 Oct;13(10):1327‐51


• Is testosterone administration associated withmajor CV outcomes? (major adverse cardiovascular events: MACE)

Primary end‐point: major adverse cardiovascular events (MACE)• cardiovascular death, • non‐fatal myocardial infarction• stroke, • acute coronary syndromes and/or heart failure reported as serious adverse events

Secondary end‐points: all cardiovascular‐related events (anything reported as such by the authors):• events reported as cardiac disorders, • cardiovascular complaints, • cardiovascular event• vascular disorders, cardiac or cardiovascular• event description fell within the International Statistical Classification of Disease (ICD) version 10 chapter IX (I00 toI99)


Records identified through different sources

N=2747

Studies included in qualitative synthesis N=101

Full-text artic les excluded: Women N=4 No T use included N=45 No RCT N=21 No placebo (or p-only) arm N=108 No T-only arm N=4 Study duplicates N=18

Records removed: No Clinical Trials N=2287 No Human species N =2 No English language N=13 No Male subjects N=145

Full-text artic les assessed for eligibility N=300

UNPUBLISHED Studies N=649

Ongoing N=202

Study assessed for eligibility N=1

W omen N=21

No results available N=372

No placebo N=26

No T arm N=27

Studies included in quantitative synthesis (meta-analysis) N=75

Studies excluded (see table 6)

N=26


0,00

0,01

0,10

1,00

10,00

100,00

1000,000.01 0.1 1 10 100 Odds ratio for stroke

Source MH-OR LL UL p TRT Placebo

#Events # Patients #Events # Patients

Placebo TS

Hall 1996 0,32 0,01 8,23 0,49

Sih 1997 0,28 0,01 7,31 0,44

Armory 2004 3,13 0,12 80,68 0,49

Kenny 2004 0,23 0,01 7,05 0,40

Brockenbrough 2006 0,35 0,01 9,13 0,53

Malkin 2006 3,25 0,13 82,24 0,48

Basaria 2010 2,94 0,12 73,08 0,51

Overall 0,82 0,24 2,83 0,76

0 35 1 35

0 17 1 15

1 24 0 24

0 6 1 5

0 19 1 21

1 37 0 39

1 106 0 103

3 244 4 242

Placebo TRT

Stroke


Placebo TS

0,00

0,01

0,10

1,00

10,00

100,00

1000,000.01 0.1 1 10 100 Odd ratio for coronary by-pass surgery



Snyder et al., 1999 1,00 0,14 7,37 1,00

Nair et al., 2006 8,27 0,41 167,23 0,17

Basaria et al., 2010 2,94 0,12 73,08 0,51

Overall 2,09 0,48 9,17 0,33

2 54 2 54

3 30 0 32

1 106 1 103

0 6 1 5

Placebo TRT

Coronary by‐pass surgery


0,00

0,01

0,10

1,00

10,00

100,00

1000,000.01 0.1 1 10 100 Odds ratio for acute coronary syndrome



Placebo TRT

Copenaghen SG 1986 1,97 0,08 48,82 0,68

Snyder et al., 1999 2,04 0,18 23,17 0,57

English et al., 2000 3,12 0,12 80,39 0,49

Steidle et al., 2003 2,83 0,11 70,27 0,53

Svartberg et al., 2004 0,29 0,01 7,74 0,46

Malkin et al., 2006 3,25 0,13 82,24 0,48

Nair et al., 2006 5,70 0,26 123,78 0,27

Chapman et al., 2009 1,00 0,05 20,83 1,00

Aversa et al., 2010 JSM 0,08 0,00 2,07 0,13

Aversa et al., 2010 JEI 0,07 0,00 1,97 0,12

Basaria et al.,2010 11,22 0,61 205,49 0,10

Ho et al., 2011 1,00 0,06 16,37 1,00

Jones et al., 2011 0,51 0,05 5,75 0,59

Kaufman et al., 2011 0,52 0,02 13,00 0,69

Hildreth et al, 2013 0,15 0,02 1,53 0,11

Overall 0,92 0,43 1,97 0,83

1 134 0 87

2 54 1 54

1 25 0 25

1 106 0 99

0 15 1 14

1 37 0 39

2 30 0 32

1 6 1 6

0 40 1 10

0 42 1 10

5 106 0 103

1 60 1 60

1 108 2 112

1 234 0 40

1 96 3 47

18 1093 11 738

Acute coronary syndrome


0,00

0,01

0,10

1,00

10,00

100,00

1000,000.01 0.1 1 10 100

Odds ratio for AMI



Placebo TRT

Copenaghen SG 1986 1,97 0,08 48,82 0,68

Snyder et al., 1999 2,04 0,18 23,17 0,57

English et al., 2000 3,12 0,12 80,39 0,49

Seidman et al., 2001 0,41 0,02 10,83 0,59

Svartberg et al., 2004 0,29 0,01 7,74 0,46

Chapman et al., 2009 1,00 0,05 20,83 1,00

Aversa 2010 et al., JSM 0,08 0,00 2,07 0,13

Aversa 2010 et al., JEI 0,07 0,00 1,97 0,12

Basaria et al, 2010 7,00 0,36137,2

2 0,20

Kalinchenko et al., 2010 0,21 0,01 5,15 0,34

Srinivas-Shankar et al., 2010 0,34 0,01 8,31 0,51

Ho et al., 2011 1,00 0,06 16,37 1,00

Jones et al., 2011 0,51 0,05 5,75 0,59

Kaufman et al., 2011 0,52 0,02 13,00 0,69

Overall 0,68 0,30 1,52 0,34

1 134 0 87

2 54 1 54

1 25 0 25

0 13 1 17

0 15 1 14

1 6 1 6

0 40 1 10

0 42 1 10

3 106 0 103

0 113 1 71

0 136 1 138

1 60 1 60

1 108 2 112

1 234 0 40

11 1086 11 747

Acute myocardial infarction


0,00

0,01

0,10

1,00

10,00

100,00

1000,000.01 0.1 1 10 100 Odds ratio for arrhythmia



Placebo TS

Sih et al., 1997 2,82 0,11 74,51 0,54

Snyder et al., 1999 3,12 0,31 30,96 0,33

Armory et al., 2004 3,13 0,12 80,68 0,49

Malkin et al., 2006 0,20 0,01 4,31 0,30

Okun et al., 2006 0,31 0,01 8,28 0,49

Svartberg et al., 2008 3,16 0,12 82,64 0,49

Legros et al., 2009 1,01 0,04 25,01 1,00

Basaria et al., 2010 2,50 0,47 13,19 0,28

Hildreth et al., 2013 0,05 0,00 0,95 0,05

Overall 1,15 0,43 3,05 0,78

1 17 0 15

3 54 1 54

1 24 0 24

0 37 2 39

0 15 1 15

1 19 0 19

1 237 0 79

5 106 2 103

0 96 4 47

12 605 10 395

Placebo TRT

Arrhythmia


0,00

0,01

0,10

1,00

10,00

100,000.01 0.1 1 10 100 Odds ratio for new onset HF

Source MH-OR LL UL pTRT Placebo


Sih 1997 2,82 0,11 74,51 0,54

Srinivas-Shankar 2010 3,07 0,12 76,04 0,49

Kaufman 2011 0,52 0,02 13,00 0,69

Overall 1,64 0,25 10,63 0,60

1 17 0 15

1 130 0 132

1 234 0 40

3 381 0 187

Placebo TRT

New onset HF


0,00

0,01

0,10

1,00

10,00

100,00

1000,000.01 0.1 1 10 100 Odds ratio for MACE

Source MH-OR LL UL pTS Placebo


Copenaghen SG 1986 (27) 1,97 0,08 48,82 0,68Hall et al., 1996 (30) 0,32 0,01 8,23 0,49Sih et al., 1997 (32) 0,88 0,05 15,33 0,93Snyder et al., 1999 (36) 2,04 0,18 23,17 0,57English et al., 2000 (38) 3,12 0,12 80,39 0,49Seidman et al., 2001 (43) 0,41 0,02 10,83 0,59Steidle et al., 2003 (48) 2,83 0,11 70,27 0,53Armory et al., 2004 (50) 3,13 0,12 80,68 0,49Kenny et al., 2004 (52) 0,23 0,01 7,05 0,40Svartberg et al., 2004 (56) 0,29 0,01 7,74 0,46Brockenbrough et al., 2006 (59) 3,75 0,36 39,59 0,27Malkin et al., 2006 (65) 2,17 0,19 25,01 0,53Nair et al., 2006 (68) 5,70 0,26 123,78 0,27Svartberg et al., 2008 (77) 3,16 0,12 82,64 0,49Chapman et al., 2009 (80) 1,00 0,05 20,83 1,00Legros et al., 2009 (81) 1,01 0,04 25,01 1,00Aversa et al., 2010 (85) 0,08 0,00 2,07 0,13Aversa et al., 2010 (86) 0,07 0,00 1,97 0,12Basaria et al., 2010 (10) 13,39 0,74 240,78 0,08Kalinchenko et al., 2010 (88) 0,21 0,01 5,15 0,34Srinivas-Shankar et al., 2010 (89) 1,01 0,14 7,31 0,99Ho et al., 2011 (91) 1,00 0,06 16,37 1,00Jones et al., 2011 (92) 0,51 0,05 5,75 0,59Kaufman et al., 2011 (93) 0,87 0,04 18,48 0,93Behere et al., 2012 (95) 2,95 0,12 72,91 0,51 Hildreth et al., 2013 (97) 0,15 0,02 1,53 0,11 Overall 1,01 0,57 1,77 0,98

Placebo TS

1 134 0 870 35 1 351 17 1 152 54 1 541 25 0 250 13 1 171 106 0 991 24 0 240 6 1 50 15 1 143 19 1 212 37 1 392 30 0 321 19 0 191 6 1 61 237 0 790 40 1 100 42 1 106 106 0 1030 113 1 712 136 2 1381 60 1 601 108 2 1122 234 0 401 183 0 1791 96 3 4731 1895 20 1341

MACE


0,00

0,01

0,10

1,00

10,00

100,00

1000,00

Placebo TS

Associated diaseses

Elderly men 10 1,22 0,49 3,03 0,67

Men with CVD 2 2,48 0,35 17,45 0,36

Frail men 5 2,25 0,72 7,08 0,17

Men with metabolic diseases 4 0,19 0,04 0,85 0,03

Hypogonadism status

Mixed population 14 1,26 0,58 2,73 0,56

TT < 12 nM 12 0,84 0,32 2,23 0,73

da qui

Type of support

Drug company not supported 12 0,94 0,39 2,24 0,88

Drug company supported 14 1,07 0,51 2,24 0,86

Trial duration

≤ 12 weeks 4 1,02 0,20 5,29 0,98

>12 weeks 22 1,01 0,55 1,84 0,98

0.01 0.1 1 10 100

Odds ratio for MACESource # Trials MH-OR LL UL p

TS Placebo #Events # Patients #Events # Patients

13 954 6 549

3 62 1 64

13 401 4 355

1 303 5 203

15 1066 11 865

16 829 9 476

10 437 8 332

21 1458 12 1009

2 147 2 145

29 1746 18 1196

MACE


Trialduration

0,00

0,01

0,10

1,00

10,00

100,00

1000,00

Placebo TS

Associated diaseses

Elderly men 10 1,22 0,49 3,03 0,67

Men with CVD 2 2,48 0,35 17,45 0,36

Frail men 5 2,25 0,72 7,08 0,17


Hypogonadism status


TT < 12 nM 12 0,84 0,32 2,23 0,73

da qui

Type of support



Trial duration

≤ 12 weeks 4 1,02 0,20 5,29 0,98

>12 weeks 22 1,01 0,55 1,84 0,98

0.01 0.1 1 10 100



13 954 6 549

3 62 1 64

13 401 4 355

1 303 5 203

15 1066 11 865

16 829 9 476

10 437 8 332

21 1458 12 1009

2 147 2 145

29 1746 18 1196

MACE


Trialduration

Industrialsupport

0,00

0,01

0,10

1,00

10,00

100,00

1000,00

Placebo TS

Associated diaseses

Elderly men 10 1,22 0,49 3,03 0,67

Men with CVD 2 2,48 0,35 17,45 0,36

Frail men 5 2,25 0,72 7,08 0,17


Hypogonadism status


TT < 12 nM 12 0,84 0,32 2,23 0,73

da qui

Type of support



Trial duration

≤ 12 weeks 4 1,02 0,20 5,29 0,98

>12 weeks 22 1,01 0,55 1,84 0,98

0.01 0.1 1 10 100



13 954 6 549

3 62 1 64

13 401 4 355

1 303 5 203

15 1066 11 865

16 829 9 476

10 437 8 332

21 1458 12 1009

2 147 2 145

29 1746 18 1196

MACE


Trialduration

Industrialsupport

Hypogonadalstatus

0,00

0,01

0,10

1,00

10,00

100,00

1000,00

Placebo TS

Associated diaseses

Elderly men 10 1,22 0,49 3,03 0,67

Men with CVD 2 2,48 0,35 17,45 0,36

Frail men 5 2,25 0,72 7,08 0,17


Hypogonadism status


TT < 12 nM 12 0,84 0,32 2,23 0,73

da qui

Type of support



Trial duration

≤ 12 weeks 4 1,02 0,20 5,29 0,98

>12 weeks 22 1,01 0,55 1,84 0,98

0.01 0.1 1 10 100



13 954 6 549

3 62 1 64

13 401 4 355

1 303 5 203

15 1066 11 865

16 829 9 476

10 437 8 332

21 1458 12 1009

2 147 2 145

29 1746 18 1196

MACE


Trialduration

Industrialsupport

Hypogonadalstatus

Associatedconditions

Men with Metabolic disordes

0,00

0,01

0,10

1,00

10,00

100,000.01 0.1 1 10 100 SourceTS Placebo

#Events # Patients #Events # Patients Odds ratio for MACE in Metabolic disease

MH-OR LL UL p

Placebo TS

Aversa 2010 JSM 0,08 0,00 2,07 0,13

Aversa 2010 JEI 0,07 0,00 1,97 0,12

Kalinchenko 2010 0,21 0,01 5,15 0,34

Jones et al., 2011 0,51 0,05 5,75 0,59

Overall 0,19 0,04 0,85 0,03

0 40 1 10

0 42 1 10

0 113 1 71

1 108 2 112

1 303 5 203

MACE in metabolic disorders


MetS n=483 patients; mean follow up 37 weeks

TRT in Patients with metabolic syndrome and or type 2 diabetesStudy (Ref.)

Boyanov et al

2003

Kapoor et al.,

2006

La Vignera et al.,

2008

Heufelder et al.,

2009

Aversa et al.,

2010

Gopal et al.,

2010

Jones et al.,

2011

Aversa et al.,

2011

Tishova et al.,

2011

LocationSofia,

Bulgaria

Sheffield,

UK

Catania,

Italy

Munich,

Germany

Rome,

Italy

Mumbai,

IndiaMulticenter

Rome,

Italy

Moscow,

Russia

# patients (ID/C) 24/24 12/12 7/5 16/16 32/10 11/11 103/102 40/10 105/65

Hypogonadism

cut off

TT

<15 nM

TT

<12 nM

TT

<8 nM

TT

<12 nM

TT

<11 nM

cFT

<225 pM

TT

< 11 nM

TT

<11 nM

TT

< 12 nM

Trial duration

(weeks)12 12 52 52 52 12 52 104 30

Drugs O-TU i.m T T gel 1% T gel 1% TU i.m T T gel 2% TU TU

Dose 120 mg daily 200 mg/ 2weeks50 mg/

daily

50 mg/

daily

1000 mg/

12 weeks

200 mg/

2weeks

60mg/

Daily

1000 mg/

12 weeks

1000 mg/

12 weeks

Comparator No TRT group Placebo No TRT group No TRT group Placebo Placebo Placebo Placebo Placebo

Metabolic

characteristics T2DM T2DM

NCEP-ATPIII-

MetS

T2DM with

IDF-MetSIDF-MetS T2DM

IDF-MetS

with or

without

T2DM

IDF-MetS IDF-MetS

Corona et al., Best Pract Clin Endocrinol & Metab 2013;27;557T2DM n=263 patients; mean follow up 28 weeks

Effects of TRT on Glycaemia in patients with MetS

Heufelder et al., 2009

Aversa et al., 2010

Jones et al., 2011

Aversa et al., 2011

Tishova et al., 2011

Overall

-0,60 -1,15 -0,05 0,03

-0,60 -1,35 0,15 0,12

-0,31 -1,33 0,71 0,55

-0,70 ‐0,96 ‐0,44 0,00

-0,04 ‐0,49 0,41 0,86

-0,48 ‐0,78 ‐0,19 0,00

‐1,50

‐1,00

‐0,50

0,00

0,50

1,00 Diff. in mean LL, 95% CI UL, 95% CI pSource

Glycaemia mean differences (mmol/L)-1.5 -1.0 -0.5 0 0.5 1.0

Favours no TRT Favors TRT

Corona et al., Best Pract Clin Endocrinol & Metab 2013;27;557

Favours TRT Favors no TRT

‐6,00

‐5,00

‐4,00

‐3,00

‐2,00

‐1,00

0,00

1,00

2,00


HOMA index mean differences-6 -5 -4 -3 -2 -1 0 1 2 3

-2,22 -3,62 -0,81 0,00

-2,22 -3,08 -1,35 0,00

-1,80 -2,62 -0,98 0,00

-0,05 ‐2,31 2,21 0,97

-2,85 ‐5,04 ‐0,66 0,01

-0,32 ‐0,53 ‐0,11 0,00

‐1,54 ‐2,59 ‐0,50 0,00

La Vignera et al., 2009


Aversa et al., 2010

Jones et al., 2011

Aversa et al., 2011


Overall

Effects of TRT on HOMA in patients with MetS



La Vignera et al., 2009


Aversa et al., 2010

Jones et al., 2011

Aversa et al., 2011


Overall

‐1,20

‐1,00

‐0,80

‐0,60

‐0,40

‐0,20

0,00

0,20

0,40

0,60


Triglycerides mean differences (nmol/L)

-1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8

-0,48 -0,82 -0,14 0,01

-0,80 -1,08 -0,52 0,00

0,00 -0,43 0,43 1,00

-0,25 ‐0,65 0,15 0,22

-0,10 ‐0,79 0,59 0,78

-0,52 ‐0,98 ‐0,06 0,03

‐0,40 ‐0,66 ‐0,14 0,00

Effects of TRT on Triglycerides in patients with MetS


Effects of TRT on Glycaemia in patients with T2DM


‐4,00

‐3,00

‐2,00

‐1,00

0,00

1,00


Glycaemia mean differences (mmol/L) -4 -3 -2 -1 0 1 2

Boyanov et al., 2003

Kapoor et al., 2006


Gopal et al., 2010

Jones et al., 2011

Overall

-2,00 -3,09 -0,91 0,00

-1,35 -3,33 0,63 0,18

-0,60 -1,15 -0,05 0,03

-1,98 ‐3,66 ‐0,30 0,02

-0,17 ‐1,42 1,08 0,79

-1,09 ‐1,84 ‐0,35 0,00



Kapoor et al., 2006


Gopal et al., 2010

Jones et al., 2011

Overall

Diff. in mean LL, 95% CI UL, 95% CI pSource

HbA1c mean differences (%) -2.5 -2.0 -1.5 -1.0 -0.5 0 0.5 1 1.5 2


-1,30 -1,99 -0,61 0,00

-0,30 -1,21 0,61 0,52

-0,80 -1,35 -0,25 0,00

-0,02 ‐1,43 1,39 0,98

-0,40 ‐0,55 ‐0,25 0,00

-0,62 ‐1,00 ‐0,24 0,00

Effects of TRT on HbA1c in patients with T2DM


Effects of TRT on Triglycerides in patients with T2DM



Kapoor et al., 2006


Gopal et al., 2010

Jones et al., 2011

Overall

‐2,00

‐1,50

‐1,00

‐0,50

0,00

0,50


Triglycerides mean differences (nmol/L) -2.0 -1.5 -1.0 -0.5 0 0.5 1

-0,51 -0,92 -0,10 0,02

-0,20 -1,23 0,83 0,70

-0,80 -1,08 -0,52 0,00

-0,82 ‐1,61 ‐0,03 0,04

-0,29 ‐0,75 0,17 0,22

-0,60 ‐0,83 ‐0,37 0,00



• Is testosterone administration associated withCV outcomes? (any adverse event)

0,00

0,01

0,10

1,00

10,00

100,00

1000,000.01 0.1 1 10 100 Odds ratio for overall CV events

Source MH-OR LL UL pTS Placebo


Placebo TS

Copenaghen SG 1986 (27) 2,22 0,78 6,31 0,13Hall et al., 1996 (30) 0,19 0,01 4,08 0,29Sih et al.,1997 (32) 0,88 0,05 15,33 0,93Snyder et al., 1999 (36) 1,96 0,61 6,29 0,26English et al.,2000 (38) 5,43 0,25 118,96 0,28Seidman et al., 2001 (43) 0,41 0,02 10,83 0,59Steidle et al., 2003 (48) 4,76 0,23 100,40 0,32Armory et al., 2004 (50) 5,44 0,25 119,63 0,28Kenny et al., 2004 (52) 0,23 0,01 7,05 0,40Svartberg et al., 2004 (56) 0,29 0,01 7,74 0,46Brockenbrough et al., 2006 (59) 1,20 0,34 4,18 0,77Malkin et al., 2006 (65) 0,86 0,24 3,10 0,82Merza et al.,2006 (67) 0,30 0,01 7,85 0,47Nair et al., 2006 (68) 1,32 0,39 4,50 0,66Okun et al., 2006 (69) 0,46 0,04 5,75 0,55Emmelot-Vonk et al., 2008 (75) 2,35 0,59 9,33 0,22Svartberg et al., 2008 (77) 3,16 0,12 82,64 0,49Caminiti et al., 2009 (78) 2,06 0,18 23,83 0,56Chapman et al., 2009 (80) 1,00 0,05 20,83 1,00Legros et al., 2009 (81) 1,01 0,04 25,01 1,00Aversa et al., 2010 (85) 0,08 0,00 2,07 0,13Aversa et al., 2010 (86) 0,07 0,00 1,97 0,12Basaria et al., 2010 (10) 6,05 2,22 16,51 0,00Kalinchenko et al., 2010 (88) 0,12 0,01 2,59 0,18Srinivas-Shankar et al., 2010 (89) 2,60 0,49 13,61 0,26Ho et al., 2011 (91) 1,00 0,14 7,34 1,00Jones et al.,2011 (92) 0,40 0,14 1,19 0,10Kaufman et al., 2011 (93) 1,49 0,33 6,71 0,60Hoyos et al., 2012 (94) 3,18 0,13 81,01 0,48Hildreth et al., 2013 (97) 0,14 0,04 0,48 0,00NCT00957528 0,88 0,05 16,74 0,93Overall 1,07 0,69 1,65 0,76

16 134 5 870 35 2 351 17 1 159 54 5 542 25 0 250 13 1 172 106 0 992 24 0 240 6 1 50 15 1 149 19 9 215 37 6 390 20 1 197 30 6 321 15 2 157 120 3 1171 19 0 192 35 1 351 6 0 61 237 0 790 40 1 100 42 1 10

25 106 5 1030 113 2 715 136 2 1382 60 2 605 108 12 112

17 234 2 401 33 0 344 96 11 471 9 1 8

126 1944 83 1390


Any CV event

0,00

0,01

0,10

1,00

10,00

100,000.01 0.1 1 10 100

Odds ratio for overall CVDSource # Trials MH-OR LL UL p


Placebo TS

Associated diaseses

Elderly men 11 1,13 0,58 2,22 0,71

Men with CVD 3 1,28 0,44 3,71 0,65

Frail men 5 2,62 1,38 4,96 0,00


Hypogonadism status


TT < 12 nM 13 0,80 0,30 2,15 0,66

Type of support



Trial duration

≤ 12 weeks 2 0,18 0,02 1,81 0,15

>12 weeks 29 1,14 0,73 1,77 0,56

52 890 31 487

9 94 7 98

56 395 22 349

6 336 16 237

67 1072 49 879

61 849 34 495

52 575 32 474

76 1343 51 900

0 53 2 27

128 1868 81 1347


Any CV event

Trialduration

0,00

0,01

0,10

1,00

10,00

100,000.01 0.1 1 10 100



Placebo TS

Associated diaseses

Elderly men 11 1,13 0,58 2,22 0,71

Men with CVD 3 1,28 0,44 3,71 0,65

Frail men 5 2,62 1,38 4,96 0,00


Hypogonadism status


TT < 12 nM 13 0,80 0,30 2,15 0,66

Type of support



Trial duration

≤ 12 weeks 2 0,18 0,02 1,81 0,15

>12 weeks 29 1,14 0,73 1,77 0,56

52 890 31 487

9 94 7 98

56 395 22 349

6 336 16 237

67 1072 49 879

61 849 34 495

52 575 32 474

76 1343 51 900

0 53 2 27

128 1868 81 1347


Any CV event

Trialduration

Industrialsupport

0,00

0,01

0,10

1,00

10,00

100,000.01 0.1 1 10 100



Placebo TS

Associated diaseses

Elderly men 11 1,13 0,58 2,22 0,71

Men with CVD 3 1,28 0,44 3,71 0,65

Frail men 5 2,62 1,38 4,96 0,00


Hypogonadism status


TT < 12 nM 13 0,80 0,30 2,15 0,66

Type of support



Trial duration

≤ 12 weeks 2 0,18 0,02 1,81 0,15

>12 weeks 29 1,14 0,73 1,77 0,56

52 890 31 487

9 94 7 98

56 395 22 349

6 336 16 237

67 1072 49 879

61 849 34 495

52 575 32 474

76 1343 51 900

0 53 2 27

128 1868 81 1347


Any CV event

Trialduration

Industrialsupport

Hypogonadalstatus

0,00

0,01

0,10

1,00

10,00

100,000.01 0.1 1 10 100



Placebo TS

Associated diaseses

Elderly men 11 1,13 0,58 2,22 0,71

Men with CVD 3 1,28 0,44 3,71 0,65

Frail men 5 2,62 1,38 4,96 0,00


Hypogonadism status


TT < 12 nM 13 0,80 0,30 2,15 0,66

Type of support



Trial duration

≤ 12 weeks 2 0,18 0,02 1,81 0,15

>12 weeks 29 1,14 0,73 1,77 0,56

52 890 31 487

9 94 7 98

56 395 22 349

6 336 16 237

67 1072 49 879

61 849 34 495

52 575 32 474

76 1343 51 900

0 53 2 27

128 1868 81 1347


Any CV event

Trialduration

Industrialsupport

Hypogonadalstatus


Men with Metabolic disordes


Any CV event in metabolic disorders

0,00

0,01

0,10

1,00

10,00

100,000.01 0.1 1 10 100



Placebo TS

Associated diaseses

Elderly men 11 1,13 0,58 2,22 0,71

Men with CVD 3 1,28 0,44 3,71 0,65

Frail men 5 2,62 1,38 4,96 0,00


Hypogonadism status


TT < 12 nM 13 0,80 0,30 2,15 0,66

Type of support



Trial duration

≤ 12 weeks 2 0,18 0,02 1,81 0,15

>12 weeks 29 1,14 0,73 1,77 0,56

52 890 31 487

9 94 7 98

56 395 22 349

6 336 16 237

67 1072 49 879

61 849 34 495

52 575 32 474

76 1343 51 900

0 53 2 27

128 1868 81 1347


Any CV event in men with frailty

Men with frailty

0,00

0,01

0,10

1,00

10,00

100,000,00

0,01

0,10

1,00

10,00

100,00

1000,00

Copenaghen study group 1986 2,22 0,78 6,31 0,13

Brockenbrough 2006 1,20 0,34 4,18 0,77

Chapman 2009 1,00 0,05 20,83 1,00

Basaria 2010 6,05 2,22 16,51 0,00

Srinivas‐Shankar 2010 2,60 0,49 13,61 0,26

Overall 2,62 1,38 4,95 0,00

16 134 5 87

9 19 9 21

1 6 1 6

25 106 5 103

5 136 2 138

26 159 15 114

0.01 0.1 1 10 100 SourceTS Placebo

#Events # Patients #Events # Patients Odds ratio for CVD in frail men

MH-OR LL UL p

Placebo TS


Any CV event in men with frailty

Does Testosterone Therapy increase CV Risks ?

• TRT might improve CV function in CHD & HF

• TRT is not associated with MACE or any cardiac event

• TRT might decrease MACE and any cardiac event inMetS or T2DM

• TRT might increase any cardiac event (but not MACE)in frail men

Take homemessages

FDA adding general warning to testosterone products about potential for venous blood clots[06/19/2014] The U.S. Food and Drug Administration (FDA) is requiring manufacturers to include a general warning in the drug labeling of all approved testosterone products about the risk of blood clots in the veins. Blood clots in the veins, also known as venous thromboembolism (VTE), include deep vein thrombosis (DVT) and pulmonary embolism (PE). The risk of venous blood clots is already included in the labeling of testosterone products as a possible consequence of polycythemia, an abnormal increase in the number of red blood cells that sometimes occurs with testosterone treatment. Because there have been postmarket reports of venous blood clots unrelated to polycythemia, FDA is requiring a change to drug labeling of all testosterone products to provide a more general warning regarding venous blood clots and to ensure this risk is described consistently in the labeling of all approved testosterone products.

Because these clots occur in the veins, this new warning is not related to FDA’s ongoing evaluation of the possible risk of stroke, heart attack, and death in patients taking testosterone products. We are currently evaluating the potential risk of these cardiovascular events, which are related to blood clots in the arteries and are described in the Drug Safety Communication posted on January 31, 20141.

Testosterone products are FDA‐approved for use in men who lack or have low testosterone levels in conjunction with an associated medical condition. Examples of these conditions include failure of the testicles to produce testosterone for reasons such as genetic problems or chemotherapy.

FDA asks health care professionals and consumers to report any adverse reactions to the FDA’s MedWatch Safety Information and Adverse Event Reporting program:Complete and submit the report online at https://www.accessdata.fda.gov/scripts/medwatch/2Download and complete the form, then submit it via fax to 1‐800‐FDA‐0178

Study name Statistics for each study Events / Total MH odds ratio and 95% CI

MH odds Lower Upper ratio limit limit p-Value TS Placebo

Copenaghen study group 1986 4,66 0,24 91,29 0,31 3 / 134 0 / 87

Brockenbrough 2006 0,29 0,05 1,68 0,17 2 / 19 6 / 21

NCT00957528 0,88 0,05 16,74 0,93 1 / 9 1 / 8

0,74 0,15 3,63 0,71 6 / 162 7 / 116

0,01 0,1 1 10 100

Favours A Favours B

Meta Analysis

Meta Analysis

Odds ratio for deep venous thrombosis

TS Placebo

Corona et al., unpublished

is there an increased cv risk in patients on trt? · pdf filemario maggi sexualmedicine &...

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