Associations of serum sclerostin and Dickkopf-related protein-1 proteins with future cardiovascular events and mortality in haemodialysis patients: a prospective cohort study

Abstract Background Sclerostin and Dickkopf-related protein-1 (Dkk-1) proteins are inhibitors of the canonical Wnt/β-catenin bone pathway. Sclerostin but not Dkk-1 is associated with increased arterial stiffness. This study examined the prognostic significance of sclerostin and Dkk-1 levels for cardiovascular outcomes and mortality in haemodialysis (HD) patients. Methods Serum sclerostin and Dkk-1 levels were measured with enzyme-linked immunosorbent assay in 80 HD patients that were followed-up for a median of 45 months. Factors that could interfere with the association of sclerostin and Dkk-1 with outcomes [including carotid–femoral pulse wave velocity (PWV), parathyroid hormone (PTH), calcium–phosphate product and others] were assessed at baseline. The primary endpoint was a combination of all-cause death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, hospitalization for decompensated heart failure and new-onset atrial fibrillation. Secondary endpoints included cardiovascular and all-cause mortality. Results Cumulative freedom from the primary endpoint was significantly lower for higher tertiles of sclerostin (77.8, 69.2 and 40.7%; Tertiles 1–3, respectively; log-rank P = 0.004). The risk for the primary outcome gradually increased for higher sclerostin tertiles [Tertile 3: hazard ratio (HR) = 3.847, 95% confidence interval (CI) 1.502–9.851]. No significant association was evident between sclerostin and all-cause mortality, whereas higher sclerostin levels presented a trend towards higher risk for cardiovascular mortality. Dkk-1 levels exhibited no association with the risk of the primary or secondary endpoints. In stepwise Cox regression modelled analysis, sclerostin levels were associated with the primary outcome, independently of PTH, calcium–phosphate product, serum albumin, C-reactive protein and PWV levels (HR = 2.921, 95% CI 1.401–6.090; P = 0.004). Conclusions High sclerostin levels are associated with lower cumulative freedom and higher risk for a composite endpoint of cardiovascular events and mortality. Dkk-1 exhibited no association with the future risk of adverse outcomes.

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P1252ASSOCIATIONS OF SERUM SCLEROSTIN AND DKK-1 PROTEIN WITH FUTURE CARDIOVASCULAR EVENTS AND MORTALITY IN HEMODIALYSIS PATIENTS; A PROSPECTIVE COHORT STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1252 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

EIRINI STAVRINOU ◽

Panteleimon Sarafidis ◽

Charalampos Loutradis ◽

Evangelos Memmos ◽

Danai Faitatzidou ◽

...

Keyword(s):

Cardiovascular Events ◽

Primary Outcome ◽

Cox Regression ◽

Coronary Revascularization ◽

Prognostic Significance ◽

Decompensated Heart Failure ◽

Hemodialysis Patients ◽

High Serum ◽

All Cause Mortality ◽

Cardiovascular Endpoint

Abstract Background and Aims Sclerostin and Dickkopf-1 (Dkk-1) protein are inhibitors of the canonical Wnt/β-catenin bone pathway. Sclerostin but not Dkk-1 is associated with increased arterial stiffness. This study examined the prognostic significance of serum sclerostin and Dickkopf-related protein-1 (Dkk-1) levels for cardiovascular outcomes and mortality in hemodialysis patients. Method Serum sclerostin and Dkk-1 levels were measured with ELISA in 80 hemodialysis patients that were followed-up for a median of 45 months. Several factors that could interfere in the association of sclerostin and Dkk-1 with outcomes (including carotid-femoral pulse-wave-velocity (PWV), parathyroid hormone, calcium-phospate product and others) were assessed at baseline The primary end-point was a combination of all-cause death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, hospitalization for decompensated heart failure and new-onset atrial fibrillation. Secondary end-points included cardiovascular and all-cause mortality. Results Cumulative freedom from the primary endpoint was significantly lower for higher tertiles of sclerostin (77.8%, 69.2%, and 40.7% for tertiles 1 to 3 respectively; log-rank-p=0.004). The corresponding risk for the primary outcome was gradually increasing for higher tertiles of sclerostin (Tertile 3: HR: 3.847, 95%CI: 1.502-9.851). No significant association was evident between sclerostin and all-cause mortality, whereas higher sclerostin levels presented a trend towards higher risk for cardiovascular mortality. Dkk-1 levels exhibited no association with the risk of the primary or the secondary endpoints. In stepwise Cox regression modeled analysis, sclerostin levels were associated with the primary outcome, independently of PTH, calcium-phosphate product, serum albumin, CRP and PWV levels (HR: 2.921, 95%CI: 1.401–6.090; p=0.004). Conclusion High serum sclerostin levels are associated with lower cumulative freedom and higher risk for a composite cardiovascular endpoint but not for all-cause mortality. Dkk-1 protein exhibited no association with the future risk of cardiovascular events.

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Mortality in patients with atrial fibrillation with or without heart failure following hospital discharge

European Heart Journal ◽

10.1093/ehjci/ehaa946.0362 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A Kartas ◽

A Samaras ◽

D Vasdeki ◽

G Dividis ◽

G Fotos ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Primary Endpoint ◽

Cox Regression ◽

Cross Sectional ◽

Tertiary Center ◽

All Cause Mortality ◽

Endpoint Event ◽

Secondary Endpoints ◽

Sectional Analysis

Abstract Background The association of heart failure (HF) with the prognosis of atrial fibrillation (AF) remains unclear. OBJECTIVES To assess all-cause mortality in patients following hospitalization with comorbid AF in relation to the presence of HF. Methods We performed a cross-sectional analysis of data from 977 patients discharged from the cardiology ward of a single tertiary center between 2015 and 2018 and followed for a median of 2 years. The association between HF and the primary endpoint of death from any cause was assessed using multivariable Cox regression. Results HF was documented in 505 (51.7%) of AF cases at discharge, including HFrEF (17.9%), HFmrEF (16.5%) and HFpEF (25.2%). A primary endpoint event occurred in 212 patients (42%) in the AF-HF group and in 86 patients (18.2%) in the AF-no HF group (adjusted hazard ratio [aHR] 2.27; 95% confidence interval [CI], 1.65 to 3.13; P<0.001). HF was associated with a higher risk of the composite secondary endpoint of death from any cause, AF or HF-specific hospitalization (aHR 1.69; 95% CI 1.32 to 2.16 p<0.001). The associations of HF with the primary and secondary endpoints were significant and similar for AF-HFrEF, AF-HFmrEF, AF-HFpEF. Conclusions HF was present in half of the patients discharged from the hospital with comorbid AF. The presence of HF on top of AF was independently associated with a significantly higher risk of all-cause mortality than did absence of HF, irrespective of HF subtype. Funding Acknowledgement Type of funding source: None

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Nurse-based secondary preventive follow-up by telephone reduced recurrence of cardiovascular events: a randomised controlled trial

Scientific Reports ◽

10.1038/s41598-021-94892-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anna-Lotta Irewall ◽

Anders Ulvenstam ◽

Anna Graipe ◽

Joachim Ögren ◽

Thomas Mooe

Keyword(s):

Randomised Controlled Trial ◽

Primary Endpoint ◽

Cardiovascular Events ◽

Controlled Trial ◽

Control Group ◽

Coronary Syndrome ◽

Secondary Endpoints ◽

Randomised Controlled

AbstractEnhanced follow-up is needed to improve the results of secondary preventive care in patients with established cardiovascular disease. We examined the effect of long-term, nurse-based, secondary preventive follow-up by telephone on the recurrence of cardiovascular events. Open, randomised, controlled trial with two parallel groups. Between 1 January 2010 and 31 December 2014, consecutive patients (n = 1890) admitted to hospital due to stroke, transient ischaemic attack (TIA), or acute coronary syndrome (ACS) were included. Participants were randomised (1:1) to nurse-based telephone follow-up (intervention, n = 944) or usual care (control, n = 946) and followed until 31 December 2017. The primary endpoint was a composite of stroke, myocardial infarction, cardiac revascularisation, and cardiovascular death. The individual components of the primary endpoint, TIA, and all-cause mortality were analysed as secondary endpoints. The assessment of outcome events was blinded to study group assignment. After a mean follow-up of 4.5 years, 22.7% (n = 214) of patients in the intervention group and 27.1% (n = 256) in the control group reached the primary composite endpoint (HR 0.81, 95% CI 0.68–0.97; ARR 4.4%, 95% CI 0.5–8.3). Secondary endpoints did not differ significantly between groups. Nurse-based secondary preventive follow-up by telephone reduced the recurrence of cardiovascular events during long-term follow-up.

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Lipoprotein(a) and Cardiovascular Outcomes after Revascularization of Carotid and Lower Limbs Arteries

Biomolecules ◽

10.3390/biom11020257 ◽

2021 ◽

Vol 11 (2) ◽

pp. 257

Author(s):

Marat V. Ezhov ◽

Narek A. Tmoyan ◽

Olga I. Afanasieva ◽

Marina I. Afanasieva ◽

Sergei N. Pokrovsky

Keyword(s):

Primary Endpoint ◽

Cardiovascular Events ◽

Cardiovascular Outcomes ◽

Lower Limbs ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Cox Regression Analysis ◽

Lipoprotein A ◽

Secondary Endpoints

Background: Despite high-intensity lipid-lowering therapy, there is a residual risk of cardiovascular events that could be associated with lipoprotein(a) (Lp(a)). It has been shown that there is an association between elevated Lp(a) level and cardiovascular outcomes in patients with coronary heart disease. Data about the role of Lp(a) in the development of cardiovascular events after peripheral revascularization are scarce. Purpose: To evaluate the relationship of Lp(a) level with cardiovascular outcomes after revascularization of carotid and lower limbs arteries. Methods: The study included 258 patients (209 men, mean age 67 years) with severe carotid and/or lower extremity artery disease, who underwent successful elective peripheral revascularization. The primary endpoint was the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The secondary endpoint was the composite of primary endpoint and repeated revascularization. Results: For 36-month follow-up, 29 (11%) primary and 128 (50%) secondary endpoints were registered. There was a greater risk of primary (21 (8%) vs. 8 (3%); hazard ratio (HR), 3.0; 95% confidence interval (CI) 1.5–6.3; p < 0.01) and secondary endpoints (83 (32%) vs. 45 (17%), HR, 2.8; 95% CI 2.0–4.0; p < 0.01) in patients with elevated Lp(a) level (≥30 mg/dL) compared to patients with Lp(a) < 30 mg/dL. Multivariable-adjusted Cox regression analysis revealed that Lp(a) was independently associated with the incidence of cardiovascular outcomes. Conclusions: Patients with peripheral artery diseases have a high risk of cardiovascular events. Lp(a) level above 30 mg/dL is significantly and independently associated with cardiovascular events during 3-year follow-up after revascularization of carotid and lower limbs arteries.

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Abstract 967: Parathyroidectomy Reduces Cardiovascular Events And All-cause Mortality In Renal Hyperparathyroidism

Circulation ◽

10.1161/circ.116.suppl_16.ii_191-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Jose Lima ◽

Valeria Costa-Hong ◽

Vanda Jorgetti ◽

Luis Henrique W Gowdak ◽

Rosa Maria A Moyses ◽

...

Keyword(s):

Cardiovascular Events ◽

Mineral Metabolism ◽

Cardiovascular Complications ◽

Maintenance Hemodialysis ◽

Major Cardiovascular Events ◽

All Cause Mortality ◽

Phosphate Product ◽

Cardiovascular Variables ◽

Overall Mortality

Background: Secondary hyperparathyroidism (SHPT) and its associated abnormalities in mineral metabolism increase the risk of cardiovascular morbidity and death in chronic kidney disease (CKD). The effect of parathyroidectomy (PTX) on the incidence of major cardiovascular events in CKD patients with SHPT is unknown. We tested the hypothesis that PTX reduces the incidence of cardiovascular complications and death in CKD patients with severe SHPT scheduled for PTX, comparing the outcome of patients treated or not treated by surgery. Methods: The study comprised 118 CKD patients with SHPT on maintenance hemodialysis, unresponsive to medical treatment, and scheduled for PTX. Patients underwent comprehensive cardiovascular evaluations at baseline. They were followed up until death, occurrence of major cardiovascular events, or kidney transplantation. Results: No deaths related to surgery occurred. After a median follow-up of 30 months, 50 patients (42.4%) had undergone PTX while 68 (57.9%) had not. The groups were comparable in terms of age, sex, race, parathyroid hormone (PTH), calcium, phosphate, calcium x phosphate product, and all major cardiovascular variables, except diastolic blood pressure. PTX was associated with a reduced incidence of major cardiovascular events (log-rank= 0.02) and overall mortality (log-rank= 0.001). Cox proportional multivariate analysis showed that variables significantly and independently associated with events were PTX (RR=2.36, CI 1.11–6.32, p=0.02) and age (RR=1.07, IC 1.02–1.14, p=0.009). All-cause mortality was related to PTX (RR=2.34, CI 1.25–5.14, p=0.007) and hematocrit (RR=1.15, CI 1.03–1.29, p=0.01). Conclusion: PTX confers protection against future major cardiovascular events and death in select CKD patients with severe refractory SHPT.

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Risk for cardiovascular disease associated with metabolic syndrome and its components: a 13-year prospective study in the RIVANA cohort

Cardiovascular Diabetology ◽

10.1186/s12933-020-01166-6 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

María J. Guembe ◽

◽

Cesar I. Fernandez-Lazaro ◽

Carmen Sayon-Orea ◽

Estefanía Toledo ◽

...

Keyword(s):

Myocardial Infarction ◽

Metabolic Syndrome ◽

Cardiovascular Event ◽

Primary Endpoint ◽

Cardiovascular Mortality ◽

International Diabetes Federation ◽

Major Cardiovascular Event ◽

Mediterranean Population ◽

All Cause Mortality ◽

Secondary Endpoints

Abstract Background We aimed to investigate the association of metabolic syndrome (MetS) and its single components with cardiovascular risk and estimated their impact on the prematurity of occurrence of cardiovascular events using rate advancement periods (RAPs). Methods We performed prospective analyses among 3976 participants (age range: 35–84, 55% female) in the Vascular Risk in Navarre (RIVANA) Study, a Mediterranean population-based cohort. MetS was defined based on the modified criteria of the American Heart Association/National Heart, Lung, and Blood Institute and the International Diabetes Federation. The primary endpoint was major cardiovascular event (a composite of myocardial infarction, stroke, or mortality from cardiovascular causes). Secondary endpoints were incidence of non-fatal myocardial infarction and non-fatal stroke, cardiovascular mortality, and all-cause mortality. Cox proportional hazards models, adjusted for potential confounders, were fitted to evaluate the association between MetS and its single components at baseline with primary and secondary endpoints. Results During a median follow-up of 12.8 years (interquartile range, 12.5–13.1), we identified 228 primary endpoint events. MetS was associated with higher risk of incidence of major cardiovascular event, cardiovascular and all-cause mortality, but was neither associated with higher risk of myocardial infarction nor stroke. Compared with participants without MetS, the multivariable hazard ratio (95% confidence interval [CI]) among participants with MetS was 1.32 (1.01–1.74) with RAP (95% CI) of 3.23 years (0.03, 6.42) for major cardiovascular event, 1.64 (1.03–2.60) with RAP of 3.73 years (0.02, 7.45) for cardiovascular mortality, and 1.45 (1.17–1.80) with RAP of 3.24 years (1.21, 5.27) for all-cause mortality. The magnitude of the associations of the single components of MetS was similar than the predicted by MetS. Additionally, for each additional trait of MetS, incidence of major cardiovascular event relatively increased by 22% (1.22, 95% CI 1.09–1.36) with RAP of 2.31 years (0.88, 3.74). Conclusions MetS was independently associated with CVD risk, cardiovascular and all-cause mortality. Components of the MetS were associated with similar magnitude of increased CVD, which suggests that MetS was not in excess of the level explained by the presence of its single components. Further research should explore the association of different combinations of the components of MetS with CVD.

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Prognostic value of left ventricular remodelling index in idiopathic dilated cardiomyopathy

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeaa144 ◽

2020 ◽

Author(s):

Yuanwei Xu ◽

Jiayi Lin ◽

Yaodan Liang ◽

Ke Wan ◽

Weihao Li ◽

...

Keyword(s):

Heart Transplantation ◽

Dilated Cardiomyopathy ◽

Primary Endpoint ◽

Prognostic Value ◽

Extracellular Volume ◽

Left Ventricular ◽

Secondary Endpoint ◽

Idiopathic Dilated Cardiomyopathy ◽

All Cause Mortality ◽

Secondary Endpoints

Abstract Aims To evaluate the prognostic value of left ventricular (LV) remodelling index (RI) in idiopathic dilated cardiomyopathy (DCM) patients. Methods and results We prospectively enrolled 412 idiopathic DCM patients and 130 age- and sex-matched healthy volunteers who underwent cardiovascular magnetic resonance imaging between September 2013 and March 2018. RI was defined as the cubic root of the LV end-diastolic volume divided by the mean LV wall thickness on basal short-axis slice. The primary endpoint included all-cause mortality and heart transplantation. The secondary endpoint included the primary endpoint and heart failure (HF) readmission. During the median follow-up of 28.1 months (interquartile range: 19.3–43.0 months), 62 (15.0%) and 143 (34.7%) patients reached the primary and secondary endpoints, respectively. Stepwise multivariate Cox regression showed that RI [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.11–1.30, P < 0.001], late gadolinium enhancement (LGE) presence and log (N-terminal pro-B-type natriuretic peptide) were independent predictors of the primary endpoint, while RI (HR 1.15, 95% CI 1.08–1.23, P < 0.001) and extracellular volume were independent predictors of the secondary endpoint. The addition of RI to LV ejection fraction (EF) and LGE presence showed significantly improved global χ2 for predicting primary and secondary endpoints (both P < 0.001). Furthermore, RI derived from echocardiography also showed independent prognostic value for primary and secondary endpoints with clinical risk factors. Conclusions RI is an independent predictor of all-cause mortality, heart transplantation, and HF readmission in DCM patients and provides incremental prognostic value to LVEF and LGE presence.

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P1513Exercise-induced cardiac troponin I release and incident cardiovascular morbidity and mortality

European Heart Journal ◽

10.1093/eurheartj/ehz748.0275 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

V Aengevaeren ◽

M T E Hopman ◽

P D Thompson ◽

E A Bakker ◽

K P George ◽

...

Keyword(s):

Risk Factors ◽

Myocardial Infarction ◽

Primary Endpoint ◽

Cardiac Troponin ◽

Cardiovascular Events ◽

Troponin I ◽

Long Distance ◽

Post Exercise ◽

All Cause Mortality ◽

Exercise Induced

Abstract Background Blood concentrations of cardiac troponin I (cTnI) above the 99th percentile (upper reference limit, URL) are a key criterion for the diagnosis of acute myocardial injury and infarction. cTnI concentrations, even below the URL, also predict adverse outcomes in general and patient populations. cTnI increases after exercise, but the clinical significance of this exercise-induced cTnI increase is unknown. We examined the association between exercise-induced cTnI elevations and clinical outcomes in long-distance walkers. Methods cTnI was measured in 726 participants (median 61 [54–69] yrs) before and immediately after 30–55 km of walking. The primary endpoint was a composite of all-cause mortality and major adverse cardiovascular events (MACE, i.e. myocardial infarction, stroke, heart failure, revascularization or sudden cardiac arrest). Results Participants walked 498 [440–555] min at 68±10% of their maximum heart rate. Baseline cTnI concentrations were 2 [0–8] ng/L, with 9 participants (1%) demonstrating a baseline cTnI value above the URL (>40 ng/L). cTnI increased after walking (8 [1–18] ng/L, p<0.001) and 63 participants (9%) had a post-exercise cTnI value >URL. During 43 [23–77] months of follow-up, 62 participants (9%) experienced a primary endpoint; 29 died and 33 had MACE. 27% of participants with post-exercise cTnI >URL experienced a primary endpoint compared to only 7% with cTnI below the URL (log-rank p<0.001). The hazard ratio was 2.35 (95% CI: 1.21–4.53) after adjusting for age, sex, cardiovascular risk factors (hypertension, hypercholesterolemia or diabetes mellitus), cardiovascular diseases (myocardial infarction, stroke or heart failure) and baseline cTnI. Kaplan-Meier of Mortality and MACE Conclusion Post-exercise cTnI concentrations >URL were associated with higher all-cause mortality and MACE, independent of age, sex, presence of cardiovascular risk factors or cardiovascular diseases and baseline cTnI concentrations in a large cohort of older long-distance walkers. Exercise-induced increases in cTnI may not be a benign physiological response to exercise in all, but an early marker of future mortality and cardiovascular events. Acknowledgement/Funding V.L.A was supported by a grant from the Radboud Institute for Health Sciences, T.M.H.E by a Horizon 2020 grant from the European Commission

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A prospective cohort study on effects of gemigliptin on cardiovascular outcomes in patients with type 2 diabetes (OPTIMUS study)

Scientific Reports ◽

10.1038/s41598-020-75594-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Eun Heui Kim ◽

Sang Soo Kim ◽

Dong Jun Kim ◽

Young Sik Choi ◽

Chang Won Lee ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiovascular Events ◽

Primary Outcome ◽

Cardiovascular Death ◽

Cox Proportional Hazard Model ◽

Proportional Hazard ◽

Proportional Hazard Model ◽

Cox Proportional Hazard ◽

All Cause Mortality

Abstract This study was performed to evaluate the long-term cardiovascular safety of gemigliptin in patients with type 2 diabetes mellitus (T2DM). After screening, eligible patients with T2DM were enrolled, received gemigliptin, and were followed up for a median of 2.50 years. The primary outcome was a composite of confirmed cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke (3-point major adverse cardiovascular event [MACE]). The key secondary outcomes were incidence of all-cause mortality and any other cardiovascular events. A total of 5179 patients were included in the study and 5113 were treated with gemigliptin. Overall, the primary outcome occurred in 26 patients within 12 months (estimated incidence by Cox proportional hazard model 0.49%, 95% CI 0.29–0.69%) and in 54 patients within 54 months (estimated incidence from Cox proportional hazard model 1.35%, 95% CI 0.92–1.77%). During the study period, the incidence rates of each component of the primary composite outcome were 0.04% (0.2 events per 1000 person-years) for cardiovascular death, 0.51% (2.2 events per 1000 person-years) for nonfatal myocardial infarction, and 0.61% (2.5 events per 1000 person-years) for nonfatal ischemic stroke. The incidence of all-cause mortality was 0.82% (3.2 events per 1000 person-years) and the incidences of other cardiovascular events were all less than 0.3%. In conclusion, T2DM patients who received gemigliptin exhibited a low incidence of the primary composite MACE and all-cause mortality. Therefore, the use of gemigliptin is expected to be safe without an increase in cardiovascular risk. Trial registration: The study was registered at ClinicalTrials.gov (identifier: NCT02290301).

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Does Testosterone Therapy Increase Risk of Cardiovascular Events among Men? A Meta-analysis

Cardiology and Angiology An International Journal ◽

10.9734/ca/2018/v7i421317 ◽

2018 ◽

pp. 1-16

Author(s):

Nader Makki ◽

Wassef Karrowni

Keyword(s):

Heart Disease ◽

Ischemic Heart Disease ◽

Primary Endpoint ◽

Cardiovascular Events ◽

Observational Studies ◽

Meta Analysis ◽

Ischemic Heart ◽

Testosterone Therapy ◽

Cerebrovascular Events ◽

All Cause Mortality

Importance: There has been increasing interest in use of testosterone therapy (TT) beyond patients with hypogonadism to include younger men without documented hormone measurements for the purpose of improving libido, sexual function, bone density, and body mass. However, there is no conclusive data about safety of TT due to lack of adequately powered randomized clinical trials (RCTs) specifically designed for this purpose. Objective: To examine the overall risk of cardiovascular events associated with TT via meta-analysis of published randomized and observational studies. Data Sources: We searched MEDLINE, EMBASE, CINAHL, the Cochrane Controlled Trials Register and the National Institute of Health Clinical Trials.gov database from 1966 to 2014. Study Selection: Out of the initial 2,800 studies identified, we obtained a total of 34 studies for detailed analysis after applying our inclusion/exclusion criteria. Two reviewers used eligibility criteria to assess all titles, abstracts, and full texts and resolved disagreements by discussion. Data Extraction and Synthesis: One reviewer did data abstractions and quality assessments, which were confirmed by a second reviewer. Data were then collected and analyzed using random and fixed effect model, as appropriate. Risk estimates were extracted as adjusted hazard ratios (HRs) from included studies. Main Outcome and Measures: Association of TT with cardiovascular events as a primary endpoint and association of TT with ischemic heart disease, all-cause mortality and cerebrovascular events as secondary endpoints. Results: TT was associated with increased incidence of cardiovascular events (adjusted hazard ratio (HR) = 1.41, 95% CI = 1.19-1.67, p = 0.0004), all-cause mortality (adjusted HR = 1.29, 95% CI = 1.03-1.62, p = 0.02), and ischemic heart disease (adjusted HR=1.51, 95% CI = 1.05-2.18, p = 0.02) but there was no clear association with cerebrovascular events (adjusted HR=0.91, 95% CI = 0.66-1.25, p=0.54). Subgroup analyses of our primary endpoint by study type (randomized versus observational studies) did not change our results (adjusted HR=1.40, 95% CI = 1.05-1.87, p = 0.02 and adjusted HR=1.54, 95% CI = 1.09-2.17, p = 0.01 respectively). Additional analysis using meta-regression and sensitivity analyses to account for factors such as history of prior CV events, indication for TT and duration of follow up did not change our results. However, we did notice lack of association between CV events and Intramuscular testosterone. Conclusions and Relevance: TT may be associated with an increased risk of all-cause mortality, cardiovascular events, and ischemic heart disease. These findings support the need for an adequately powered randomized study.

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