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Secondary Polycythemia in Men Receiving Testosterone Therapy Increases Risk of Major Adverse Cardiovascular Events and Venous Thromboembolism in the First Year of Therapy

2022; Lippincott Williams & Wilkins; Volume: 207; Issue: 6 Linguagem: Inglês

10.1097/ju.0000000000002437

1527-3792

Jesse Ory, Sirpi Nackeeran, Navin C. Balaji, Joshua M. Hare, and Ranjith Ramasamy,

Hemoglobinopathies and Related Disorders

Open AccessJournal of UrologyAdult Urology1 Jun 2022Secondary Polycythemia in Men Receiving Testosterone Therapy Increases Risk of Major Adverse Cardiovascular Events and Venous Thromboembolism in the First Year of TherapyThis article is commented on by the following:Editorial Comment Jesse Ory, Sirpi Nackeeran, Navin C. Balaji, Joshua M. Hare, and and Ranjith Ramasamy Jesse OryJesse Ory https://orcid.org/0000-0002-9176-4334 University of Miami, Department of Urology, Miami, Florida Dalhousie University, Department of Urology, Halifax, Nova Scotia, Canada , Sirpi NackeeranSirpi Nackeeran University of Miami Miller School of Medicine, Miami, Florida , Navin C. BalajiNavin C. Balaji University of Miami Miller School of Medicine, Miami, Florida , Joshua M. HareJoshua M. Hare University of Miami, Division of Cardiology, Department of Medicine, Interdisciplinary Stem Cell Institute, Miami, Florida , and and Ranjith Ramasamyand Ranjith Ramasamy *Correspondence: Department of Urology, University of Miami,1150 NW 14th St, Suite 309, Miami, Florida 33136 (telephone:305-243-6630; FAX: 305-243-3381; E-mail Address: [email protected] University of Miami, Department of Urology, Miami, Florida View All Author Informationhttps://doi.org/10.1097/JU.0000000000002437AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: An unsafe hematocrit threshold for men receiving testosterone therapy (TT) has never been tested. This study seeks to determine whether secondary polycythemia among men receiving TT confers an increased risk of major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE). Materials and Methods: Using a multi-institutional database of 74 million patients, we identified 2 cohorts of men with low testosterone (total testosterone <350 ng/dl) who received TT and subsequently either developed polycythemia (5,887) or did not (4,2784). Polycythemia was defined as hematocrit ≥52%. As a secondary objective, we identified 2 cohorts of hypogonadal men without polycythemia, who either did (26,880) or did not (27,430) receive TT. Our primary outcome was the incidence of MACE and VTE in the first year after starting TT. We conducted a Kaplan-Meier survival analysis to assess differences in MACE and VTE survival time, and measured associations following propensity score matching. Results: A total of 5,842 men who received TT and developed polycythemia were matched and compared to 5,842 men who did not develop polycythemia. Men with polycythemia had a higher risk of MACE/VTE (number of outcomes: 301, 5.15%) than men who had normal hematocrit (226, 3.87%) while on TT (OR 1.35, 95% CI 1.13–1.61, p <0.001). In hypogonadal men who received testosterone, no increased risk of MACE and VTE was identified as compared to hypogonadal men naïve to TT. Conclusions: Developing polycythemia while on TT is an independent risk factor for MACE and VTE in the first year of therapy. Future research on the safety of TT should include hematocrit as an independent variable. Abbreviations and Acronyms LDL low-density lipoprotein MACE major adverse cardiovascular events MI myocardial infarction RCT randomized controlled trial TT testosterone therapy VTE venous thromboembolism Whether testosterone therapy (TT) causes major adverse cardiovascular events (MACE) or venous thromboembolism (VTE) is highly debated and a source of controversy amongst clinicians. Meta-analyses of randomized controlled trials (RCTs) do not support an association between MACE/VTE and TT.1 Alternatively, some large cohort studies have suggested at an association between TT and VTE.2 Meanwhile, other large database studies fail to find an association,3 while some studies support TT in hypogonadal men as cardioprotective.4 Regardless of the findings, none of these studies investigated the possible role of polycythemia as a causative factor of these adverse events. It is possible that secondary polycythemia due to TT is a leading factor in causing MACE or VTE because increasing hematocrit can increase blood viscosity, and polycythemia has been shown to cause thrombosis in men with idiopathic erythrocytosis.5–7 Because of this, multiple professional organizations have established guidelines on safe prescribing of TT and include an upper safe limit for hematocrit during therapy. The upper limit of safe hematocrit varies between 48% to 55% and is based off population data of individuals who were not taking TT.5,8–10 To date, no studies have tested whether the presence of polycythemia during TT leads to adverse events as a primary outcome. We hypothesized that TT is a potential risk factor for MACE/VTE due to its ability to increase hematocrit levels. This elevation in hematocrit occurs primarily during initiation of and through the first year of TT,11 supporting our hypothesis that MACE and VTE risk is highest in the first year of therapy.2,11,12 Therefore, we evaluated men who developed secondary polycythemia (which we defined as a hematocrit over 52%)10 while receiving TT using a large national database. METHODS We accessed data from the TriNetX Analytics Network, a global federated database that captures anonymized data from electronic medical records amongst 54 health care organizations in the U.S. totaling 74 million patients. Patient data were available from 2002 through 2020. Details of this database have been described previously.13 The TriNetX data include diagnoses (using ICD-10-CM [International Classification of Diseases, 10th Edition, Clinical Modification] codes), demographics, procedures, medications and measurements. The data from a typical health care organization generally go back around 7 years, with some going back 13 years. The data are continuously updated every 1–4 weeks. The analyses in this manuscript were run July 31, 2021. Additional analyses were run later in the year and are included in the supplementary materials (https://www.jurology.com). We evaluated 2 separate cohorts for comparison. The first cohort included men over 18 with a testosterone <350 ng/dl who subsequently received 2 prescriptions for TT within 9 months of each other and had at least 1 hematocrit above 52% following initiation of TT. We used 2 prescriptions within 9 months to ensure that men were continuing to use TT throughout the first year of therapy. We used a testosterone of 350 ng/dl in keeping with some national society guidelines, and to be able to include a larger cohort.14,15 The second cohort was identical to the first, except these men never developed a hematocrit over 52%. Men were excluded if they had ICD-10-CM codes for an acute myocardial infarction (MI; I21), VTE (I26 or I82 or Z86.718), stroke (I63), transient ischemic attack (G45) or polycythemia vera (D45) within a year before their first testosterone prescription. While the definition varies, we defined polycythemia as a hematocrit above 52% in keeping with the American Urological Association guideline definition and that of other publications.10,16 Our primary outcome was the odds of MACE and VTE within the first year of receiving TT. Secondary outcomes included the individual components of MACE and VTE. The index event was the first prescription of TT. MACE were defined as a composite of death from any cause, MI (I21–I23) and stroke (I63, G45). VTE included deep vein thrombosis (I82 and Z86.718) and pulmonary embolism (I26). We used propensity-score matching to control for risk factors of MACE/VTE prior to comparison.17 The risk factors we used included a series of established risk factors for MACE/VTE: dyslipidemia (E78), diabetes (E08–E13), hypertension (I10), obesity (E66), age, ethnicity, tobacco use (F17), sleep apnea (G47.33), use of statins (CV350), beta-blockers (CV100), aspirin (1191), clopidogrel (32968) and angiotensin-converting enzyme inhibitors (CV800). We controlled for the effects of TT by creating 2 additional cohorts of hypogonadal men (E29.1 or E23.0) with testosterone 17.5 gm/dl). Second, we tested 2 alternative definitions of polycythemia: a hematocrit at or above 50% and 54%. Third, we assessed whether the differences in outcomes could be attributable to cardiovascular risk factors that were not accounted for during propensity-score matching. We compared low-density lipoprotein (LDL) and blood pressure levels at 1 year after TT in the propensity-matched cohorts, comparing the high hematocrit and normal hematocrit groups using t-tests. Additionally, we evaluated use of anticoagulants (warfarin, dabigatran, apixaban, rivaroxaban) during the first year of TT as alternative but related outcome to MACE/VTE. To address potentially confounding variables, we utilized 1:1 greedy nearest-neighbor propensity-score matching through the TriNetX platform, which is powered through Python (Python Software Foundation, Fredericksburg, Virginia) and R software (R Foundation for Statistical Computing, Vienna, Austria).17 This technique uses logistic regression to develop 2 equally matched cohorts based on demographics, comorbidities and medication use. We determined that the 2 groups had minimal differences after balancing when standardized differences between propensity scores were less than 0.1.18 Statistical associations between index events and outcome variables were determined through the calculation of odds ratios for comparative analysis between the exposure and control cohorts. All confidence intervals for odds ratios were calculated with an alpha of 0.05. Survival analysis within a 1-year period was performed through the Kaplan-Meier method, with statistically significant differences between survival probabilities of the control and exposure cohorts assessed by the log-rank test. We utilized propensity-score matching to control for confounders for survival analysis as well. RESULTS We identified 48,671 men over 18 years of age who received TT: 5,887 of whom had at least 1 recorded hematocrit above 52% after starting TT and 42,784 of whom never had a hematocrit above 52% after starting TT. Matching for the 14 risk factors was achieved resulting in 5,842 men in each group (table 1). Table 1. Baseline characteristics of men on testosterone who did and did not develop polycythemia Before Propensity-Score Matching After Propensity-Score Matching Elevated Hematocrit after Starting TT Normal Hematocrit after Starting TT Elevated Hematocrit after Starting TT Normal Hematocrit after Starting TT No. pts 5,887 42,343 5,842 5,842 Mean±SD yrs age 53.4±12.4 51.6±14.6 53.5±12.4 53.8 ±13.1 No. race/ethnicity (%): Caucasian 4,905 (83) 33,253 (79) 4,870 (83) 4,836 (83) African American 302 (5.1) 4,194 (10) 302 (5.2) 281 (4.8) Latino 232 (3.9) 1,713 (4.1) 230 (3.9) 239 (4.1) Comorbidities: Hypogonadism 4,643 (79) 17,425 (41) 4,601 (79) 4,644 (79) Hypertension 3,216 (55) 18,276 (43) 3,178 (54) 3,154 (54) Dyslipidemia 3,206 (55) 18,040 (43) 3,172 (54) 3,084 (53) Obesity 2,031 (35) 9,761 (23) 1,992 (34) 1,967 (34) Obstructive sleep apnea 1,490 (25) 6,213 (15) 1,462 (25) 1,398 (24) Diabetes 1,354 (23) 8,947 (21) 1,348 (23) 1,292 (22) Nicotine use 783 (13) 4,200 (10) 770 (13) 679 (12) Heart failure 255 (4.3) 1,662 (3.9) 253 (4.3) 225 (3.9) Medications: Statin 2,476 (42) 14,044 (33) 2,447 (42) 2,418 (41) ACE inhibitor 1,816 (31) 9,673 (23) 1,788 (31) 1,752 (30) β blocker 1,681 (29) 9,664 (23) 1,661 (28) 1,594 (27) Aspirin 1,478 (25) 9,157 (22) 1,461 (25) 1,383 (24) Clopidogrel 199 (3.4) 1,356 (3.2) 196 (3.4) 180 (3.1) As expected, baseline hematocrit was higher in the men who developed polycythemia vs those who did not (47.4% and 42.5%, respectively). In the first year following TT and after propensity-score matching, the risk of MACE/VTE was 5.2% in men who developed polycythemia vs 3.9% in those men who did not (OR 1.35; 95% CI 1.13–1.61; see figure). Kaplan-Meier survival analysis showed time to survival was significantly different between the 2 groups, and the survival probability (probability of 1 year without MACE/VTE) was significantly lower in the polycythemia group (95% vs 97%, log-rank p 52%, blue line) versus men with a normal hematocrit (hematocrit 17.5 gm/dl) yielded similar results, showing higher incidence of MACE/VTE in men who developed polycythemia compared to those who did not (OR 1.21, 95% CI 1.02–1.36). Additionally, we tested different definitions of polycythemia. Odds of MACE remained higher in the polycythemia group when defined as hematocrit >54% (OR 0.78, 95% CI 0.62–0.98, p=0.03). We were unable to demonstrate a difference between groups when hematocrit >50% was used as the cutoff (OR 0.90, 95% CI 0.78–1.03, p=0.13). A third sensitivity analysis on use of anticoagulants during the first year of therapy as a surrogate for MACE/VTE yielded similar results, as men with polycythemia used more anticoagulants (288) than men with normal hematocrit (230; OR 1.27, 95% CI 1.06–1.51, p <0.01). Finally, LDL and blood pressure were measured at baseline as additional surrogates of comorbidity. We were unable to demonstrate a difference between LDL and systolic blood pressure at 1 year post-TT, while diastolic blood pressure was higher in men with polycythemia (table 2). The majority of men who developed polycythemia while receiving TT were under 65 years of age (72%). Thus, we performed a post hoc analysis of our primary objective in younger (18–64 years) and older (65+) men. Men under 65 years receiving TT had a higher rate of MACE/VTE if they developed secondary polycythemia (OR 1.27, 95% CI 1.0–1.6). Interestingly, a difference was not demonstrated in men over 65 years (OR 1.15, 95% CI 0.96–1.38). Table 2. Mean (standard deviation) blood pressure and LDL levels among patients within the first year of testosterone use, after propensity-score matching Normal Hematocrit Elevated Hematocrit p Value Mean mmHg blood pressure (SD): Systolic 130 (16.7) 130 (16.8) 0.62 Diastolic 77.9 (10.9) 78.4 (10.5) 0.04 Mean mg/dl LDL (SD) 96 (34.1) 97 (35.3) 0.17 DISCUSSION Whether or not exogenous testosterone causes MACE or VTE is actively debated, with different evidence showing that TT is either protective, neutral or dangerous for cardiovascular or thrombotic outcomes.19 It is possible that a concurrent, independent risk factor may be driving these adverse events. Whether or not secondary polycythemia may be driving this potential risk has never been evaluated in a population of men using TT. Understanding the factors that may cause MACE or VTE in men on TT is critical to understand, not only for patient and prescribers but for future trial designs investigating this association. We demonstrated that developing secondary polycythemia while receiving TT, defined as a hematocrit over 52%, was associated with increased risk of developing MACE and VTE during the first year of therapy. TT itself, in the absence of polycythemia, did not appear to increase risk of MACE/VTE in hypogonadal men. To our knowledge, this is the first study to establish secondary polycythemia from TT as an independent risk factor for MACE/VTE using a specific hematocrit-based cutoff. We used a large national database to answer this question, hypothesizing that real-world data would be best suited to address this issue. Men with high baseline hematocrit are often excluded from randomized trials, and in clinical practice pre-treatment blood work is often not done, and guidelines are frequently not followed.20,21 This leaves a large population of men using TT who are not represented by RCTs. Our findings are somewhat supported by prior literature. The TOM (Testosterone in Older Men with Sarcopenia) trial, an RCT that was stopped early due to increased risk of cardiovascular adverse events, included older men with a high incidence of comorbid conditions.22 While this trial only included 209 men, their demographic information is similar in nature to our study, which included a large proportion of men with comorbid conditions. Like most RCTs on testosterone, the TOM trial did not report hematocrit values in those men with cardiovascular events. One systematic review on this topic did not find overall increased cardiovascular risk, however they did find an increased event rate in the first 12 months of therapy, supporting our window of 1 year for evaluation of MACE/VTE.23 Another review reinforced the value of using large databases in answering this question, highlighting that all published RCTs on this topic are underpowered to assess any association with treatment and cardiovascular outcomes.24 This will hopefully be addressed by the TRAVERSE (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men) trial (NCT03518034), however polycythemia or hematocrit-based adverse events are not listed as an outcome. It is well established that TT increases the risk of secondary polycythemia,25 with higher rates in longer-acting modalities and lower rates in shorter-acting modalities.16 Multiple national guidelines use elevation in hematocrit as a trigger to stop or change TT in men. TT cessation triggers include 55% from Canadian guidelines,9 54% from endocrine society guidelines and European urology guidelines,5,26 and between 50%–54% from American urological guidelines.10 While the rationale for these cutoffs is not cited in these guidelines, they appear to come from the Framingham heart study, which found an increase in adverse cardiovascular outcomes with a hematocrit of 49% or higher.8 These findings were confirmed in a more recent prospective cohort study, which found an increased rate of overall and cardiovascular-related mortality once hematocrit entered the range of 50%–54%.27 Neither of these studies specifically studied men on testosterone, and thus the currently existing hematocrit cutoffs amongst TT users is arbitrary. For the purposes of our study, we chose a cutoff of 52%, reflecting other published literature, and to ensure a relatively large comparator arm.10,16 The strengths of this study include its use of a large multi-institutional database and being a real-world snapshot of the effects of TT in a U.S. cohort. There is increasing evidence that nonrandomized evidence from large databases can accurately emulate a large-scale RCT, lending validity to these results.28 Detailed propensity-score matching increased the validity of our findings. Lastly, our sensitivity analyses, and analysis of TT-naïve men, support the role of polycythemia as an independent, critical factor in the development of MACE/VTE. Limitations include the inability to segregate results by type of testosterone prescription. In addition, a large percentage of the men included are Caucasian (86%), and the matched populations have a relatively high comorbidity index, limiting the generalizability of the findings to minorities and healthy individuals. Furthermore, we were not able to match the 2 groups by baseline hematocrit, as the men in the polycythemia group had a higher baseline hematocrit. Therefore, we cannot definitively determine whether the increased risk of MACE/VTE is due to hematocrit reaching 52% or due to men with higher baseline hematocrit starting TT. Regardless, the baseline hematocrit in the polycythemia group was 47.4%, which according to U.S., Canadian and European guidelines does not warrant further investigation before starting TT. Lastly, due to the limitations of the TriNetX database, we were unable to analyze hematocrit as a continuous variable. Regardless of these limitations, this study lends prescribers a practical approach to informing about risks of TT, and reinforces existing guideline practices of checking hematocrit prior to prescribing.5 It also provides a hematocrit-based cutoff that comes directly from a population of men using TT, and can hopefully allow future guideline statements to remain consistent across recommendations. Future studies that aim to assess cardiovascular outcomes in men on testosterone (such as the ongoing TRAVERSE study, NCT03518034) should perform detailed analysis on hematocrit change to investigate this as a possible association. CONCLUSION Men using TT should be aware that they are at a higher risk for MACE/VTE if their hematocrit reaches or exceeds 52% during the first year of therapy. This is especially relevant in men with cardiovascular comorbidities. Hematocrit-based cutoffs should be incorporated into the outcomes of future RCTs investigating MACE/VTE and TT. 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Google Scholar Support: Funding to access the TriNetX database was provided in part by an educational grant from Acerus Pharmaceuticals. Acerus Pharmaceuticals was not involved in the planning, design, writing or any other aspect of this project. Conflict of Interest: RR: consultant and grant recipient for Acerus, Boston Scientific, Endo Pharmaceuticals and Coloplast; grant recipient from Empower Pharmacy and Olympus; consultant for Nestle Health; advisory board of Hims, Inc.; Recipient of NIH funding (1R01DK130991-01). JMH: consultant, shareholder and board member for Longeveron, Vestion and Heart Genomics; grant recipient from NHLBI. Ethics Statement: In lieu of a formal ethics committee, the principles of the Helsinki Declaration were followed. Editor's Note: This article is the fifth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1357 and 1358. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.© 2022 The Author(s). Published on behalf of the American Urological Association, Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of UrologyMar 15, 2022, 12:00:00 AMEditorial Comment Volume 207Issue 6June 2022Page: 1295-1301Supplementary Materials Supplementary Video Supplementary Video Advertisement Copyright & Permissions© 2022 The Author(s). Published on behalf of the American Urological Association, Education and Research, Inc.Keywordsadverse effectspolycythemiathromboembolismtestosteronehypogonadismMetricsAuthor Information Jesse Ory University of Miami, Department of Urology, Miami, Florida Dalhousie University, Department of Urology, Halifax, Nova Scotia, Canada More articles by this author Sirpi Nackeeran University of Miami Miller School of Medicine, Miami, Florida More articles by this author Navin C. Balaji University of Miami Miller School of Medicine, Miami, Florida More articles by this author Joshua M. Hare University of Miami, Division of Cardiology, Department of Medicine, Interdisciplinary Stem Cell Institute, Miami, Florida More articles by this author and Ranjith Ramasamy University of Miami, Department of Urology, Miami, Florida *Correspondence: Department of Urology, University of Miami,1150 NW 14th St, Suite 309, Miami, Florida 33136 (telephone:305-243-6630; FAX: 305-243-3381; E-mail Address: [email protected] More articles by this author Expand All Support: Funding to access the TriNetX database was provided in part by an educational grant from Acerus Pharmaceuticals. Acerus Pharmaceuticals was not involved in the planning, design, writing or any other aspect of this project. Conflict of Interest: RR: consultant and grant recipient for Acerus, Boston Scientific, Endo Pharmaceuticals and Coloplast; grant recipient from Empower Pharmacy and Olympus; consultant for Nestle Health; advisory board of Hims, Inc.; Recipient of NIH funding (1R01DK130991-01). JMH: consultant, shareholder and board member for Longeveron, Vestion and Heart Genomics; grant recipient from NHLBI. Ethics Statement: In lieu of a formal ethics committee, the principles of the Helsinki Declaration were followed. Editor's Note: This article is the fifth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1357 and 1358. Advertisement Advertisement PDF DownloadLoading ...