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Abstract

Background:

Testosterone deficiency is associated with heart failure (HF) progression and poor prognosis. Testosterone therapy has been shown to improve exercise capacity in patients with chronic HF, but no trial has evaluated the impact of replacement in patients with demonstrated testosterone deficiency.

Methods:

Prospective, randomized, double-blind, placebo-controlled, and parallel-group trial comparing testosterone replacement with placebo in males with chronic HF with reduced ejection fraction (HFrEF) and testosterone deficiency (NCT01813201). Long-acting undecanoate testosterone at a fixed dose of 1000 mg was supplied by intramuscular injection at inclusion and then every 3 months. The placebo group received isotonic saline serum. Patients were randomly allocated 1:1 to testosterone or placebo while receiving optimal medical therapy, and the study was conducted for 12 months.

Results:

The final sample comprised 29 patients, 15 in the placebo group and 14 in the testosterone group (aged 65 ± 8, 62% with an ischemic etiology, left ventricular ejection fraction [LVEF] 30% ± 6%, 69% New York Heart Association functional [NYHA II]). After 12 months, testosterone replacement increased testosterone levels (P = .002) but was not associated with benefit in terms of clinical symptoms and functional capacity including NYHA class, Framingham score, Minnesota Living Heart Failure Questionnaire, 6-minute walk test, or LVEF and N-terminal pro-B-type natriuretic peptide levels. No significant side effects associated with testosterone treatment were observed. No effects were found in other hormonal, metabolic, and bone turnover biomarkers.

Conclusion:

In patients with HFrEF and testosterone deficiency, replacement therapy was not associated with any significant improvement.

Keywords

testosterone heart failure anabolism randomized

Submitted February 09, 2018; Accepted May 30, 2018. Heart failure (HF) represents a progressive and disabling disease and is associated with high mortality, despite the existence of evidence-based therapies.¹ Besides hemodynamic impairment and the activation of several compensatory neurohormonal systems, the progression of HF includes an anabolic derangement.² Testosterone, the main anabolic hormone, has been reported to be below the 10th percentile of the age-adjusted normal population in about 20% to 30% of males with chronic HF and reduced left ventricular ejection fraction (LVEF) .^3,4 In addition, testosterone deficiency has been repeatedly associated with decreased functional class, exercise capacity, and muscle strength as well as higher mortality during follow-up.^3,5

–8

In light of the above, correcting testosterone deficiency has been proposed as an attractive approach.^8,9 The administration of testosterone exerts inotropic and vasodilatory actions, has anti-inflammatory and immunomodulatory effects, and improves symptoms and exercise capacity.¹⁰ Several clinical trials have evaluated the effect of testosterone supplementation in patients with HF with reduced ejection fraction (HFrEF).^11,12 These studies evaluated different routes of administration and reported an improved functional capacity but no improvement in cardiac function or related clinical events. The accumulated safety data point has no significant concerns. However, none of the previous studies were designed to assess the effect of testosterone replacement in patients with biochemical evidence of testosterone deficiency. Since this was not an inclusion criterion in previous trials, the role of testosterone replacement in testosterone-deficient patients has not been specifically evaluated yet.

This study sought to assess the clinical benefits of prolonged testosterone replacement in ambulatory male patients with demonstrated testosterone deficiency and HFrEF.

Methods

Study Design and Intervention

This study represents a phase IV, prospective, randomized, double-blind, placebo-controlled, and parallel-group trial comparing testosterone with placebo in males with HFrEF and testosterone deficiency. Intervention consisted of the administration of long-acting undecanoate testosterone at a fixed dose of 1000 mg, administered by intramuscular injection at inclusion and then every 3 months until the last study visit at 12 months. The placebo group received isotonic saline serum. Patients were enrolled at 4 specialized HF clinics in Spain. Patients were randomly allocated 1:1 to testosterone or placebo while receiving optimal medical therapy. The study received the approval by the ethics committee of each institution, and written informed consent was obtained from all patients prior to enrollment. This clinical trial was registered at http://www.clinicaltrials.gov (NCT01813201).

Study Population

Participants eligible for enrollment were ambulatory male patients, with an established diagnosis of chronic symptomatic HFrEF who fulfilled all following criteria: (1) at least 1 prior hospitalization for acute decompensated HF; (2) stable ambulatory clinical condition and New York Heart Association functional (NYHA) class II-IV; (3) LVEF <40% in the previous 6 months; (4) N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration >400 pg/mL at inclusion; (5) testosterone deficiency, defined as the presence of low levels of both total testosterone (<3.2 ng/mL for <46 years, <3.0 ng/mL for 46-55 year), <2.7 ng/mL for 56-65 years and <2.6 ng/mL for >66 years) and free testosterone (<77 pg/mL for <46 years, <64 pg/mL for 46-55 years, <59 pg/mL for 56-65 years, and <52 pg/mL for >66 years), that is, values below the 10th percentile adjusted by age³; and (6) older than 18 years and written informed consent. Exclusion criteria were valvular disease assessed as severe and amenable to surgery, noncardiac illness with a life expectancy lower than 1 year, history of androgen-dependent prostate adenocarcinoma, benign prostate hyperplasia under treatment or a prostate-specific antigen (PSA)> 3 ng/mL, history of breast or liver cancer, renal insufficiency with an estimated glomerular filtration rate <30 mL/kg/min.1.73, acute coronary syndrome in the previous year, hepatic insufficiency Child-Pugh C, uncontrolled hypertension, hematocrit >50%, or hypersensivity to the active treatment or any excipient.

Randomization Method and Masking

Patients who fulfilled the inclusion and none of the exclusion criteria, and who gave written informed consent, were randomized 1:1 to receive active treatment (testosterone replacement) or placebo (saline). Randomization was performed by the coordinating center using the “minimization” method,¹³ and adjudication was controlled for the following predefined variables: age (> or < 65 years old), LVEF (>25% or <25%), NYHA class (II or III-IV), and spironolactone therapy (yes or no). Testosterone and placebo were dispensed by the pharmacy department, which was also responsible for the randomization codes. The blinded drug was administered by a nurse, and all the investigators were kept blinded to patient treatment.

Procedures and Follow-Up

All study variables were registered at inclusion and at programmed visits every 3 months, in accordance with the predefined study flow-chart (Supplemental, Table 1). The last visit occurred at 12 months, 3 months after the last treatment. At each visit, all variables were recorded including treatment administration, clinical variables (weight, NYHA class, blood pressure, heart rate, and modified Framingham score), and laboratory variables (creatinine, sodium, potassium, urea, hepatic enzymes, PSA, hemogram, troponin T, NT-proBNP). The following procedures were performed at inclusion and at 6 and 12 months: 6-minute walking test (6-MWT), echocardiography, Minnesota Living With Heart Failure questionnaire (MLHF), and electrocardiogram. At each programmed visit, before administration of the medication, venous blood samples were taken following the predefined protocol and stored at −80°C until analysis. After completion of the study, additional biochemical measures were performed including hormonal, metabolic, and bone turnover biomarkers (Supplemental Material, expanded methods). Total testosterone (Testosterone II; Roche Diagnostics, Mannheim, Germany) was measured in a Modular Analytics E170 (Roche Diagnostics; lower limit of detection: 0.025 ng/mL, intraassay and interassay coefficient of variability: 4.1% and 4.4%, respectively). Free testosterone was calculated according to the Vermeulen’s formula.¹⁴

Study Outcomes

The main clinical outcome was the composite of all-cause mortality, hospitalization due to HF, or ambulatory decompensation requiring intravenous medication. The outcome measurements were: (1) clinical status assessment using a modification of the Framingham cumulated score, (2) cardiac function parameters (LVEF and NT-proBNP), (3) functional status assessment by the NYHA class and 6-MWT; and (4) quality-of-life evaluation by the MLHF. In addition, a safety end point was predefined.

Statistical Analysis

Variables were tested for normality using the Kolmogorov-Smirnov test. Continuous variables are presented as mean and standard deviation (SD) or median and quartiles (25th-75th) as appropriate. Categorical variables are presented as numbers (percentage). Differences in baseline characteristics between treatment and placebo groups were evaluated by the χ² and unpaired t test. In addition, a mixed-design analysis of variance model was performed according to treatment and time (basal, 3 months, and 12 months). Mauchly Test of sphericity was performed to assess whether the variances in the differences between all combinations of related groups (levels) were equal. The degree to which sphericity was present or not was represented by the epsilon statistic (ε). If violation of the assumption of sphericity was found, that is a statistically significant Mauchly test (P < .05), Greenhouse-Geisse and Huynh-Feldt corrections were used. Within-group changes in the reported variables were evaluated by the paired t test or Wilcoxon-signed rank test for nonnormally distributed variables. Based on the initial planning, an expected event rate of 50% at 12 months, a relative risk reduction of 25%, with a significance level (α) of 5% and power (1-β) of 80%, the planned sample size was 126 patients (bilateral hypothesis). Data were statistically analyzed using SPSS statistics 22 (IBM Corp, Armonk, New York).

Results

The study was halted without having achieved the expected sample size due to inclusion difficulties (Consort diagram; Supplemental Figure S1). The final study population consisted of 29 patients, 15 in the placebo group and 14 in the testosterone group (age 65 ± 8 years, 62% ischemic etiology, LVEF 30% ± 6%, and 69% NYHA II). Baseline characteristics are presented in Table 1 with no significant differences between the groups.

Table 1.

Baseline Clinical Characteristics of Study Patients.

Variables	Testosterone, n = 14	Placebo, n = 15	P Value
Clinical characteristics
Age, years	65 (7)	64 (9)	.66
Body mass index, kg/m²	29 (4)	31 (4)	.13
Abdominal perimeter, mm	105 (13)	109 (10)	.47
NYHA class I/II/III/IV (%)	0/11/3/0	0/9/6/0	.28
Hypertension	11 (78%)	13 (86%)	.56
Diabetes Mellitus	8 (57%)	6 (40%)	.35
Dyslipidemia	9 (64%)	8 (53%)	.55
Ischemic etiology	11 (78%)	7 (46%)	.19
Atrial fibrillation	4 (28%)	7 (46%)	.60
Peripheral vascular disease	2 (14%)	1 (6%)	.25
Chronic renal disease	6 (43%)	4 (26%)	.35
COPD	2 (14%)	2 (13%)	.94
Cerebrovascular disease	0 (0%)	3 (20%)	.07
Electrochardiography
PR interval	188 (24)	193 (19)	.65
QRS width, milliseconds	125 (26)	131 (43)	.36
QTc, (milliseconds	454 (27)	468 (38)	.30
Echochardiography
LV ejection fraction (%)	30 (6)	28 (6)	.22
LV end-diastolic volume, mL	196 (86)	197 (86)	.94
Left atrial volume, mL	83 (34)	88 (40)	.54
Treatments
ACE inhibitors or ARB	14 (100%)	15 (100%)	1.00
β-blockers	13 (93%)	15 (100%)	.29
Antialdosteronics	12 (85%)	13 (86%)	.63
Loop diuretics	14 (100%)	15 (100%)	1.00
Digoxin	4 (28%)	4 (26%)	.81
Nitrates	8 (57%)	6 (40%)	.45
Laboratory
Hemoglobin, g/dL	12.6 (1.7)	13.6 (1.2)	.12
Creatinine, mg/dL	1.47 (0.52)	1.24 (0.38)	.18
Urea, mg/dL	79 (45)	62 (28)	.21
GFR, mL/min.1.73m²	52 (17)	66 (24)	.11
Sodium, mEq/L	139 (3)	141 (3)	.25
Potasium, mEq/L	4.7 (0.9)	4.7 (0.5)	.93
AST, U/L	21 (6)	23 (6)	.53
Troponin T, pg/mL	25 (19)	28 (20)	.62
NT-proBNP, pg/mL	1469 (1209-2414)	1444 (992-4986)	.92

Abbreviations: AST, aspartate aminotransferase; ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; LV, left ventricular; PR, interval, milliseconds; QRS, interval, milliseconds; QTc, interval, milliseconds.

^a Data are expressed as number (%), mean (standard deviation) or median (interquartile range).

Testosterone Replacement and Outcomes

Testosterone deficiency was confirmed in all participants, with levels of total testosterone of 2.4±0.9 ng/mL and free testosterone of 25.5±17.2 pg/mL at inclusion. Table 2 shows changes in end point measurements in the 2 study arms. After 12 months, the therapy group exhibited a significant increase in testosterone levels, which differed significantly from the placebo group (Figure 1). However, testosterone replacement was not associated with any improvement in terms of symptoms (NYHA class, modified Framingham score), functional capacity (6-MWT), perceived quality of life (MLHFQ), or objective cardiac function measures (LVEF, NT-proBNP; Figure 1). During the follow-up, adverse clinical events occurred in 4 (29%) patients in the testosterone group and 6 (40%) patients in the placebo group (P = .851): 1 patient died and another patient was admitted to hospital due to decompensated HF, both of them in the placebo group; 4 patients in each group required ambulatory intravenous diuretics. The PSA levels did not change, and no other adverse side effects of long-acting intramuscular testosterone administration were observed.

Table 2.

Main Outcome Measures According to Treatment Group.^a

Variables	Baseline		12 Months		Change (Δ)
Variables	Testosterone	Placebo	Testosterone	Placebo	Testosterone	Placebo
Testosterone Total, ng/mL	2.20 (1.02)	2.57 (0.97)	5.31 (2.52)^b	3.14 (1.49)	3.10 (2.04)^c	0.54 (0.95)
NYHA class	2.18 (0.39)	2.40 (0.51)	2.08 (0.30)	2.13 (0.52)^b	−0.08 (0.51)	−0.27 (0.46)
Clinical score	0.95 (0.99)	1.11 (0.94)	0.82 (0.84)	0.82 (1.07)	−0.14 (1.27)	−0.29 (1.28)
6-MWT, meters	378 (150)	385 (107)	356 (140)	382 (152)	− 23 (51)	− 2 (134)
MLHF physical	14.20 (9.32)	14.50 (10.02)	9.10 (9.40)	9.29 (10.25)	− 5.10 (9.75)	− 5.21 (12.36)
MLHF emotional	6.80 (7.45)	6.43 (7.24)	5.60 (5.10)	3.21 (4.98)	−1.20 (7.46)	−3.21 (8.63)
LVEF, %	29.88 (6.82)	27.84 (6.68)	29.90 (9.27)^c	35.26 (8.47)^b	0.02 (6.43)	7.42 (6.76)
NT-proBNP, pg/mL	1470 (1210, 2414)	1444 (992, 4986)	1172 (896, 5080)	1067 (792, 3357)	−378 (−760, 480)	−362 (−1324, 612)
PSA, ng/mL	1.55 (1.07)	0.84 (0.60)	1.83 (1.53)	0.91 (0.80)	0.28 (0.98)	0.08 (0.35)

Abbreviations: 6MWT, 6-minute walk test; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PSA, prostate-specific antigen; hsTnT, high-sensitivty Troponin T; MLHF, Minnesota Living with Heart Failure.

^a Values are means (standard deviation).

^b P < .05 significantly different from baseline time within the same group.

^c P < .05 significantly different between the groups.

Figure 1.

Changes in concentrations of total testosterone and main outcome measures, according to treatment group. Data are mean (standard deviation).

Effect on Other Related Parameters

As shown in Table 3, of the studied anabolic parameters, lipids, insulin resistance, and bone turnover, none showed significant change in response to testosterone replacement. Systolic blood pressure showed a trend to increase in the testosterone group versus placebo (+7.7 ± 12 vs −2.7±14; P = .07), without significant changes in diastolic blood pressure (+2.6 ± 12 vs +1.5 ± 12; P = .50) or heart rate (−3.18 ± 12 vs −6±11; P = .82). Changes in body mass index (+0.43 ± 2.02 vs +0.69 ± 1.2; P = .78) and abdominal perimeter (+4.2 ± 5.1 vs +2.2 ± 5.9; P = .52) did not significantly differ between the groups. At inclusion, the QTc interval was slightly prolonged (461 ± 34 milliseconds), but changes at 12 months did not differ between the testosterone and placebo arms (−18 ± 29 milliseconds vs −4.9 ± 44 milliseconds; P = .43). None of other baseline parameters showed differences.

Table 3.

Biochemical Measures Related to Anabolism, Lipids, Insulin Resistance, and Bone Turnover.^a

Variables	Baseline		12 Months		Change (Δ)
Variables	Testosterone	Placebo	Testosterone	Placebo	Testosterone	Placebo
SHBG, nMol/L	68 (59)	82 (56)	67 (58)	76 (59)^b	−0.5 (6.6)	−5.8 (7.5)
Free Testosterone. pg/mL^c	30.9 (18.0)	34.6 (18.9)	86.7 (54.1)^b	66.1 (53.6)	60.1 (38.4)^d	33.8 (48.4)
IGFBP-3, ng/mL	2496 (626)	2864 (774)	2233 (618)^b	2936 (658)	−263 (99)	72 (457)
Somatomedine, ng/mL	115 (75)	96 (25)	82 (255)	90 (29)	−33 (59)	−6 (44)
Insulin, µIU/mL	28.2 (7.6)	28.6 (21.5)	23.6 (10.9)	31.0 (23.1)	−4.6 (9.3)	2.3 (36.4)
HOMA-IR	9.4 (2.0)	9.4 (7.1)	8.0 (4.3)	7.4 (4.4)	−1.4 (6.0)	−2.1 (9.5)
Cholesterol, mg/dl	140 (19)	139 (33)	143 (63)	146 (38)	3 (46)	7 (21)
HDL-c, mg/dL	35 (3)	29 (12)	32 (5)	33 (13)	−3 (3)	3 (7)
LDL-c, mg/dL	73 (12)	79 (18)	83 (48)	86 (26)	10 (39)	7 (14)
Tryglicerides, mg/dL	162 (42)	182 (140)	143 (66)	146 (57)	−19 (31)	−36 (154)
Albumin, g/dL	4.4 (0.2)	4.4 (0.4)	4.1 (0.1)	4.3 (0.3)	−0.3 (0.2)	−0.1 (0.2)
Prealbumin, mg/dL	26.0 (0.8)	30.7 (8.6)	21.2 (5.1)	30.3 (7.9)	−4.8 (5.5)	−0.4 (5.5)
Albumin/prealbumin	0.17 (0.01)	0.15 (0.04)	0.20 (0.05)	0.15 (0.03)	0.03 (0.04)	−0.00 (0.01)
Haemoglobin, g/L	12.6 (1.8)	13.6 (1.3)	13.8 (2.3)	14.3 (1.0)	0.32 (1.0)	0.49 (1.6)
P1NP, ng/mL	98 (97)	48 (22)	85 (84)	55 (31)	−13 (17)	7 (13)
Osteocalcin, ng/mL	35 (30)	25 (14)	30 (25)	22 (12)	−4.2 (8.2)	−2.3 (22.5)
β-CTX, ng/mL	0.47 (0.45)	0.42 (0.34)	0.49 (0.35)	0.40 (0.31)	0.49 (0.35)	0.02 (0.28)
NTX, Nmeco	28 (23)	20 (6)	25 (19)	18 (4)	−2.6 (4.3)	−2.2 (2.9)
ALP total, IU/L	130 (63)	81 (28)	160 (85)	77 (26)	−4 (28)	−4 (15)
ALP isoenzyme, µg/L	24 (23)	13 (8)	26 (28)	16 (13)	1.5 (4.9)	2.5 (8.7)

Abbreviations: ALP, alkaline phosphatase; β-CTX, Beta-CrossLaps; HDL-c, high density lipoproteins; IGFBP-3, insulin-like growth factor binding protein 3; LDL-c, low-density lipoporteinsç; P1NP, procollagen type 1 N propeptide.

^a Values are means (standard deviation).

^b P < .05 significantly different from basal time within the same group.

^c Calculated using the Vermeulen’s formula.

^d P < .05 significantly different between the groups.

Discussion

The role of testosterone therapy in HF remains a relevant but still unresolved question. The present study assessed the role of this therapy in patients with established testosterone deficiency, a population not specifically evaluated previously. In this setting, the study did not have sufficient statistical power to detect an impact on clinical outcomes, but it has added new findings to previous results as regards secondary end points. Long-term testosterone replacement in deficient male patients with HFrEF was well tolerated after 12 months, but despite a significant increase in testosterone levels, no significant improvements were observed in exercise capacity, quality of life, cardiac, or metabolic parameters.

Testosterone therapy in patients with HFrEF, as a hormonal supplement regardless of baseline testosterone levels, has been studied in several randomized placebo-controlled trials.^11,12 Pugh et al¹⁵ administered intramuscular testosterone in 10 patients and found an improvement in the distance walked and the MLHF scores after 3 months, with no effect on forearm muscle strength. In a larger study, Malkin et al¹⁶ also found an improvement in functional capacity and symptoms in 29 men with moderately severe HF using a testosterone adhesive skin patch preparation during a 12-month period. Caminiti et al¹⁷ investigated the effect of long-acting intramuscular testosterone in 31 males over 3 months and observed an improvement in exercise capacity, muscle strength, glucose metabolism, and baroreflex sensitivity. Iellamo et al¹⁸ supplemented 32 females with transdermal testosterone for 6 months and also found an improvement in exercise capacity. Finally, Mirdamadi et al found a marginally significant improvement in exercise capacity with intramuscular testosterone supplementation in 25 patients.^19,20

The present study did not assess testosterone supplementation but testosterone replacement given to patients who were testosterone deficient. This approach is the same that has led to promising results with the replacement of growth hormone deficiency.²¹ However, we did not find any improvement after a 12-month treatment period. We explored several measures but pointed to a lack of benefit in terms of symptoms, quality of life, exercise capacity, and cardiac and metabolic measures. These results contrast with previous studies showing an improvement in exercise capacity and symptoms. Several reasons for this discrepancy in our results might be argued. The first one is that none of these studies treated testosterone deficiency given that it was not included in the inclusion criteria. In fact, only 21 (30%) patients in the study of Caminiti et al and 18 (24%) patients in the study of Malkin et al had testosterone deficiency. In another double-blind randomized study, Stout et al evaluated the effect of testosterone versus placebo when added to an exercise rehabilitation program in 28 elderly patients with HFrEF and low testosterone status (total testosterone <432 ng/dL).¹⁹ In this study, 61% of patients were androgen deficient, and although testosterone supplementation seemed to have a positive impact on exercise capacity, there were no significant differences between the testosterone and placebo groups. It might have been expected that testosterone deficiency would show a more pronounced response to testosterone therapy. Indeed, Caminiti et al reported an interaction between lower testosterone levels and greater improvement in V02max but not in 6-MWT and other end points.¹⁷ However, Pugh et al found no relationship between baseline hormone levels and improvement in measures and neither did the rest of the studies mentioned.¹⁶ The findings of our study support the idea that testosterone deficiency may identify a stage of the disease where any benefit of testosterone therapy will be lost. In other words, testosterone replacement and testosterone supplementation are associated with different responses.

Another relevant point in that we used the same doses as the study of Caminiti et al but with a longer interdose interval (6 weeks vs 12 weeks) and a longer duration of treatment (3 months vs 12 months). It is possible that a longer interval between doses could affect the results. However, this is not supported by the fact that levels of both total and free testosterone increased significantly in response to treatment and differed from the placebo group. Therefore, an improvement in parameters such as functional capacity and insulin resistance might have been expected but was not the case. Similarly, an assessment of lipid parameters and biomarkers of bone turnover pointed out no positive response to testosterone replacement. In agreement with previous studies, left ventricular ejection fraction (LVEF) and NT-proBNP levels did not improve in response to testosterone. The lack of effects on left ventricular function in all studies published to date seems to confirm the previously stated hypothesis that testosterone acts mainly through peripheral mechanisms. In agreement with other studies, too, we observed no significant effects on blood pressure.¹⁶ Giraldi et al²² demonstrated that lower testosterone levels are associated with longer QTc intervals, which is congruent with the prolonged QTc interval observed in our population. Bai et al showed that testosterone might be able to reduce the QTc interval,²³ but, as with other parameters, we found no evidence of this.

As regards side effects, testosterone administered intramuscularly was safe in a manner comparable to other trials using the same administration route. Together with the study of Malkin et al,¹⁶ the present study is the longest (12 months). Prostate levels remained unchanged in our trial after 12 months, but it must be underlined that prostatic malignancy was excluded prior to initiating the treatment. There has been growing concern that testosterone therapy could be associated with increased risk of cardiovascular events, especially in elderly patients.^24,25 However, with the doses used in patients with HFrEF, any such side effects should be negligible.

Finally, previous trials provided few data on the effects of testosterone replacement therapy on raw HF end points, including hospitalization, HF decompensation, and death. We did not find significant differences between the groups, but the small sample size and the low number of events preclude any fair conclusion regarding it. Nevertheless, the sample size is enough to compare the data about secondary end points, and our trial has strengths as the enrollment of patients with advanced HFrEF and unequivocally low testosterone concentrations, the double-blind and placebo-controlled design, and the longer follow-up compared with previous studies. The major limitations of our trial are the small sample size, reflecting the difficulties for recruitment observed in previous published trials, where a low recruitment rate of 4% has been reported.¹⁹

In conclusion, taking into account the small sample size, the results of our pilot study suggest that long-term testosterone replacement in deficient patients with HFrEF did not improve cardiac function, functional capacity, quality of life, or metabolic parameters. The small sample size or a refractory state associated with testosterone deficiency might account for these negative results. Hence, sufficient evidence in this field is still lacking.

Supplemental Material

supplementary_material - Testosterone Replacement Therapy in Deficient Patients With Chronic Heart Failure: A Randomized Double-Blind Controlled Pilot Study

supplementary_material for Testosterone Replacement Therapy in Deficient Patients With Chronic Heart Failure: A Randomized Double-Blind Controlled Pilot Study by Marina Navarro-Peñalver, M. Teresa Perez-Martinez, Manuel Gómez-Bueno, Pablo García-Pavía, Josep Lupón-Rosés, Eulalia Roig-Minguell, Josep Comin-Colet, Antoni Bayes-Genis, Jose A. Noguera, and Domingo A. Pascual-Figal in Journal of Cardiovascular Pharmacology and Therapeutics

Footnotes

Authors’ Note

The authors state that the views expressed in this article are of their own.

Acknowledgment

The authors thank to Antonio Maurandi for his technical support.

Authors’ Contribution

Marina Navarro-Peñalver contributed to acquisition and interpretation, drafted the manuscript, and gave final approval; M. Teresa Perez-Martinez contributed to design, contributed to acquisition and interpretation, and gave final approval. Manuel Gómez-Bueno contributed to acquisition, critically revised manuscript, and gave final approval; Pablo García-Pavía, Josep Lupón-Rosés, Eulalia Roig-Minguell, Josep Comin-Colet, and Jose A. Noguera contributed to acquisition, critically revised the manuscript, and gave final approval. Antoni Bayes-Genis contributed to conception and design, contributed to analysis, critically revised manuscript, and gave final approval. Domingo A. Pascual-Figal contributed to conception and design, drafted the manuscript, critically revised the manuscript, and gave final approval. All authors agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by a grant from the Instituto de Salud Carlos III, Madrid, Spain (TRA-168) and by a grant from Fundación Séneca (Agencia de ciencia y tecnología de la Región de Murcia; 19334/PI/14).

ORCID iD

Domingo A. Pascual-Figal

Supplemental Material

Supplemental material for this article is available online.

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