Τεστοστερόνη και καρδιαγγειακό σύστημα. Αθηνά Καπράρα

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1 Τεστοστερόνη και καρδιαγγειακό σύστημα Αθηνά Καπράρα

2 T levels and CVS risk T declines with age in men Epidemiological and observational studies: low T - increased CVD risk Μeta-analysis of 70 studies: patients with CVD - significantly lower T and higher 17-β estradiol Relationship between low levels of endogenous T and atherosclerosis, endothelial dysfunction, and higher levels of CRP Negative correlation between T and Framingham Risk Score Araujo AB et al. J Clin Endocrinol Metab 2011;96: Lee WC et al. World J Mens Health 2014;32:139-44

3 this is a causal association or low T is a biomarker of poor health

4 T preparations T preparations available for > 70 y 2.2 million USA citizens were prescribed T in 2013, compared to 1.2 million in T or other androgen prescriptions increased more than threefold, from 0.81% in 2001 to Symphony 2.91% in Healthcare 2011 Solutions Anonymous Patient Longitudinal Database (5/2014) Clinformatics Data Mart Nguyen CP, et al. N Engl J Med 2015;373: Baillargeon J, et al. JAMA Intern Med 2013;173:1465-6

5 ¼ of androgen users did not have a T measurement in the previous 12 months Muram D, et al. J Sex Med 2015;12:

6 Indeed men (January June 2012). 71% had T tested once, 40% twice, Truven and 29% Healthhad no T measurements before TRT MarketscanR Commercial and Medicare Supplemental Insurance Database Only 12% had their gonadotropins measured before the initiation of TRT Following therapy, 46% of men had their T measured at least once Muram D, et al. J Sex Med 2015;12:

7 Marketing The aggressive direct-to-consumer marketing strategy of USA pharmaceutical increase in T use (appropriate diagnosis????) Μedia advertising promises that treating low T can make men feel more alert, energetic, mentally sharp, and sexually functional Corona G, et al. World J Mens Health 2015;33:130-42

8 First warnings Scientific reports suggest that TRT increases CV risk Nonprofit groups the drugs USA FDA warnings for CV risks of Balance between the benefits and risks of medicinal products Corona G, et al. World J Mens Health 2015;33:130-42

9 PROBLEMS... Well-designed, placebo-controlled trials of TRT in men who meet or do not meet the standard criteria for treatment - scant in number, and with inconsistent results RCTs with CV events as a primary endpoint are available, but the majority of information has been derived from trials designed for other purposes Observational clinical research suffers from important biases, including selection, information, and confounding biases Grimes DA, et al. Obstet Gynecol 2012;120:920-7

10 TRT was positively associated with a significant increase in treadmill test duration (168 sec) and time to ST segment depression (57 sec) Small number of patients Different formulations and doses of TRT Randomized, placebo-controlled trials in patients with coronary heart disease (CV events as the primary, prespecified endpoint)

11 Heart failure Randomized, placebocontrolled trials in patients with heart failure (metanalysis of four RCTs) Few Short follow-up duration Significant improvements in exercise capacity after 12 to 52 weeks of TRT Corona G, et al. World J Mens Health 2015;33:130-42

12 In contrast to the trials with CV events as the primary endpoint, which supported a protective effect of TRT on myocardial ischemia and improvement in HF data from trials designed for other purposes have generated recent concerns about the CV safety of TRT

13 neither a protective nor a harmful effect of TRT on CV events Meta-analyses assesing the occurrence of adverse CV events in RCTSs designed for other purposes

14 possible increased risk associated with T treatment Meta-analyses assesing the occurrence of adverse CV events in RCTSs designed for other purposes

15 Xu et al trials 2994 men CV events T increased the risk of CV events, with an odds ratio (OR) of 1.54 (95% confidence interval [CI]= ) But.cases of peripheral edema and self-reported syncope were also included in the category of CV events, leading to an artificial increase of the overall number of events Xu L, et al. BMC Med 2013;11:108

16 neither a protective nor a harmful effect of TRT on CV events (CV death, fatal and non-fatal MI, revascularization procedures, arrhythmia, and cerebrovascular events) Meta-analyses assessing the occurrence of adverse CV events in RCTSs designed for other purposes

17 Calof et al studies 1084 men CV events in the 651 T- treated men and 16 events in the 433 placebo-treated men, with a pooled OR of 1.14 (95% CI= ) Calof OM, et al. A Biol Sci Med Sci 2005;60:1451-7

18 Haddad et al studies 1642 men No significant deference Haddad RM, et al. Mayo Clin Proc 2007;82:29-39

19 Fernández- Balsells et al studies 2679 men No significant deference Fernández-Balsells MM, et al. J Clin Endocrinol Metab 2010;95:

20 Corona et al studies 5464 men The use of TRT was not associated with an increased incidence of MACE compared to placebo (Mantel-Haenzel OR=1.01 [95% CI= ]; p=0.98) Meta-regression analysis showed no difference in the incidence of MACE according to baseline age, body mass index, or level of T A protective role of TRT in subjects with metabolic disease was observed Corona G, et al. Expert Opin Drug Saf 2014;13:

21 Corona et al 2014 Limitations The duration of the available trials - short No information is available on possible longterm effects. The incomplete reporting of the data on MACE in trails marginally designed for non-cv endpoints Corona G, et al. Expert Opin Drug Saf 2014;13:

22 Pharmacoepidemiological studies with myocardial infarction as an outcome Pharmacoepidemiology studies the uses and effects of drugs in a population Their aim to provide a riskbenefit assessment in large numbers of people and to estimate the probability of beneficial effects of a drug and the probability of adverse effects Odds ratios (95% confidence interval [CI]) for acute MI in testosterone untreated vs. treated (tosterone replacement therapy) patients Corona G, et al. World J Mens Health 2015;33:130-42

23 Baillargeon et al men > 66 y 6355 T treated TRT was not linked with any increased risk for MI (HR=0.84 [95% CI= ]) In contrast, men at greater risk for heart problems who underwent TRT actually had a lower rate of heart attacks than similar men who did not receive this treatment Baillargeon J, et al. Ann Pharmacother 2014;48:

24 Finkle et al T treated middle-aged and older men In the first 90 days the study reported a doubled risk of heart attack among men aged 65 years and older and a two- to three-fold increased risk in younger men with a preexisting history of heart disease, but not in those without prior CV events When they followed up men who underwent TRT for another 90 days, the risk declined to the level it was at the study s entry point Finkle WD, et al. PLoS One 2014;9:e85805

25 By combining the results from these studies Corona et al performed a metaanalysis with MI odds as the outcome No relationship between any use of TRT and the risk of MI Corona G, et al. World J Mens Health 2015;33:130-42

26 Erythrocytosis Increase in the total red cell mass secondary to any of a number of non-hematologic systemic disorders in response to a known stimulus (secondary polycythemia) Is the most frequent adverse event associated with T administration T act through the augmentation of erythropoietin and a direct effect on bone marrow, including erythroid progenitors, ferrokinetics, and red cell precursor survival, the suppression of circulating and hepatic hepcidin, an iron regulatory peptide Corona G, et al. World J Mens Health 2013;31:103-25

27 Erythrocytosis Some reports have shown that a higher risk of MI or stroke was associated with T-induced polycythemia Pre-existing erythrocytosis constitutes a risk factor for thrombosis in hypogonadal men Guo W, et al. Aging Cell 2013;12:280-91

28 Corona et al 2014 Standardized mean (95% confidence interval [CI]) differences in hematocrit levels (%) Mantel-Haenzel (MH) odds ratios (95% CI) for pathological hematocrit elevation (>52%) -When the data were limited to the studies enrolling only hypogonadal patients at baseline treated with transdermal preparations, a risk of elevated hematocrit (>52%) was not found - Erythrocytosis has been reported to occur in healthy older men more often after short-action parenteral and oral T administration, but usually not after transdermal T administration Significant increase of hematocrit in comparison to placebo An increased risk of hematocrit levels above 52%

29 Deep Venous Thrombosis It is a potential consequence of polycythemia However, a case-controlled study of 30,572 men, 40 years of age or older, showed that T in the days before the event was not associated with increased risk for venous thromboembolism and was not associated with administration route There are no prospective studies impact unclear Corona G, et al. World J Mens Health 2013;31:103-25

30 FDA-Mandated Change in Labeling for TRT ΤRT is indicated for replacement therapy only in males with On September 17, 2014, the U.S. FDA convened an advisory committee to review the use of conditions associated with a deficiency in endogenous T TRT and its CV risks The committee panel concluded that there was not enough evidence that TRT was a Before significant initiating CV risk TRT, providers must confirm the diagnosis of hypogonadism by measuring serum T in the morning on 2 separate day TRT safety in high CV-risk groups, such as older, diabetic, and obese men, needed further studies Providers should make patients aware of the possible increased CV risk when initiating TRT In March 2015, the FDA clarified recommendations for the use of TRT TRT is approved only for men with documented low T caused by specific medical conditions The benefits and safety of TRT are not clear for the aging male with low T, even if symptomatic In June 2015, the FDA further required manufacturers of TRT products to change their labeling to include additional warnings Bhatt K, et al U.S. Food and Drug Administration, Center for Drug Evaluation and Research

31 Proposed Prospective Study Large, prospective, randomized, placebo-controlled, double-blinded, longterm study (at least 1 year and preferably longer) Entrance criteria: symptomatic hypogonadism, verified by low T (total, free, bioavailable) levels on at least 2 separate morning blood draws At least 2 T-type preparations should be studied (IM injections and gel formulation the 2 most likely candidates) Follow-up T levels throughout the study Primary endpoints: MACE (MI, stroke, CV death) - carefully defined Secondary endpoints: hospitalization, heart rate, BP, ECG, prostate abnormalities, questionnaires related to sexual health (libido and erectile function), tests of muscle strength, muscle mass, adiposity, effects of T on lipid and glucose levels, insulin resistance, PSA, and other biomarkers

32 Conclusions (1) Patients with CVD have lower T levels Lower levels T correlate to atherosclerosis and endothelial dysfunction In patients with coronary heart disease TRT was associated with a significant increase in treadmill test duration and time to ST segment depression

33 Conclusions (2) In patients with heart failure TRT was associated with improvements in exercise capacity The results of meta-analyses which assess the occurrence of adverse CV events in RCTs designed for other purposes are inconsistent In pharmacoepidemiological studies no relationship between any use of TRT and MI risk has been found

34 Conclusions (3) Concerning erythrocytosis, it was found that a significant increase of hematocrit and an increased risk of hematocrit levels above 52% in TRT patients The effect of TRT on deep venus thrombosis is unclear

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