mario maggi sexualmedicine & andrology university of ... · pdf filemario maggi...

Mario MaggiSexual Medicine &

AndrologyUniversity of Florence,[email protected]

Cardiovascular risk associated with testosterone boosting medications: a meta‐analysis of the available evidence

G. RastrelliG. Corona Cardiovascular risk associated with testosterone boosting medications: a meta‐analysis of the available evidence

[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.


• 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 RISKS FOR ADVERSE EVENTS

(including peripheral oedema)

• ELDERLY MEN WITH LIMITED MOBILITY

Is there an increased CV risk in patients on TRT?

• 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)

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

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


Is there an increased CV risk in patients on TRT?

• 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 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

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