Coronary Heart Disease
Conditions
Brief summary
Testosterone has traditionally been regarded as a risk factor for heart disease due to the fact that males have a higher incidence of this disease than women, at least until the menopause. However recent studies have shown that men with low levels of testosterone may be at an increased risk of developing coronary heart disease (furring up of the blood vessels supplying blood to the heart). Our group has demonstrated a relaxing effect of testosterone in isolated animal coronary arteries (blood vessels supplying blood to the heart). We have shown that short-term testosterone administration can increase coronary artery and brachial artery (blood vessel in the arm) blood flow and can decrease the lack of blood supply to the heart muscle in men with coronary artery disease. These findings indicate a need for similar but longer-term studies to investigate the possible beneficial effects of longer-term testosterone therapy on the heart and blood vessels. Should this treatment be shown to be beneficial to men with coronary artery disease it may be a useful additional therapy for men with the furring up of arteries in the heart and the resulting angina. Aim To investigate our hypothesis that testosterone can beneficially affect myocardial perfusion, vascular reactivity, metabolic risk factors for coronary heart disease and improve quality of life in men with low plasma testosterone levels and coronary heart disease.
Detailed description
The main purpose of this project is to determine whether testosterone treatment over a number of weeks can beneficially affect myocardial perfusion, vascular reactivity, metabolic risk factors and quality of life in men with documented coronary heart disease. Men with documented significant coronary artery disease and a positive exercise test for myocardial ischaemia will be enrolled into the study. They will be randomised to active testosterone therapy (5 mg/day) or placebo for 2 months. After 2 months they will undergo MRI perfusion scanning, radial artery applanation tonometry to assess endothelial function, blood sampling for analysis of metabolic risk factors for coronary heart disease, complete quality of life questionnaires and will cross-over to the opposite treatment. After a further 2 month period these tests will be repeated. Angina diaries will be kept for the duration of the study.
Interventions
DRUGTestosterone undecanoate
Licensed for androgen deficiency
Sponsors
Organon
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Pharmacy dispensing of study medication that was randomized by supplier
Eligibility
Sex/Gender
MALE
Age
35 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Men * Aged 35 to 75 years * Angiographically proven coronary artery disease (70 percent lesion in at least one major coronary artery, or major branch), including patients post-coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) * Plasma testosterone less than or equal to 12 nmol/l * Normal prostate specific antigen (PSA; normal range 0 - 4 g/l) * Willing to give written informed consent
Exclusion criteria
* Significant arrhythmia, particularly those which would affect interpretation of the ST-segment of the ECG * Treatment with digitalis * Treatment with testosterone or similar hormonal therapy * Thoracic or abdominal surgery within the previous 3 months * Haemoglobin \>16 g/dL * Haematocrit \>50 percent * History of hormone-dependent cancer such as prostate or breast cancer * Hypercalcaemia * Nephrosis * Pacemaker or automated implantable cardiac defibrillator * Implanted ferromagnetic arterial clips * Left ventricular hypertrophy * New York Heart Association (NYHA) III or IV functional class * Intolerance of confined spaces * Previous allergic reaction to Gadolinium * Participation in another research study within the previous 60 days * Unwilling to give written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial Perfusion | Testosterone versus placebo (8 week treatment period) | Myocardial perfusion (blood flow in the heart muscle) in subendocardial myocardial segments (one of the inner layers of heart muscle), supplied by coronary arteries without significant obstruction. This was measured using Cardiovascular Magnetic Resonance (CMR) imaging and a dual-bolus gadnolinium infusion protocol. Myocardial perfusion index = the ratio between myocardial perfusion measurements following adenosine-induced stress and rest measurements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Endothelial Function | Testosterone versus placebo (8 week treatment period) | The endothelium is a single layer of cells that line all blood vessels and regulates arterial function. Coronary artery disease causes dysfunction of the endothelium but some substances/drugs help to reverse this dysfunction. In this study, endothelial function was measured by radial applanation tonometry which measures the blood pressure waveform during each cardiac cycle (heart beat). Radial artery pulse recordings were acquired, with an averaged waveform generated from 20 sequential waveforms. Augmentation index (AIx) is derived from this averaged waveform, and is the ratio of the pulse pressure at the second systolic arterial pressure waveform peak to that of the first systolic peak. The change in AIx before and after salbutamol (400mcg) is a measure of endothelial function. |
Countries
United Kingdom
Participant flow
Recruitment details
Outpatients at a tertiary referral NHS hospital in London, UK. Eligible patients were invited to participate by post. Interested participants returned an eligibility questionnaire. Those fulfilling the inclusion/exclusion criteria were invited to attend for a screening/consent appointment.
Pre-assignment details
Blood was taken at a screening visit. Those not fulfulling the inclusion/exclusion criterial were excluded.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants All participants randomized to study medication (n=28), whether randomized to testosterone or placebo first. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Completed Study Protocol | Adverse Event | 1 | 1 |
| Completed Study Protocol | Withdrawal by Subject | 0 | 1 |
| Randomized | Lost to Follow-up | 0 | 1 |
| Randomized | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | All Study Participants | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 8 Participants | — |
| Age, Categorical Between 18 and 65 years | 20 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United Kingdom | 28 participants | — |
| Sex: Female, Male Female | 0 Participants | — |
| Sex: Female, Male Male | 28 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 0 / 28 | 1 / 28 |
| serious Total, serious adverse events | 1 / 28 | 0 / 28 |
Outcome results
Primary
Myocardial Perfusion
Myocardial perfusion (blood flow in the heart muscle) in subendocardial myocardial segments (one of the inner layers of heart muscle), supplied by coronary arteries without significant obstruction. This was measured using Cardiovascular Magnetic Resonance (CMR) imaging and a dual-bolus gadnolinium infusion protocol. Myocardial perfusion index = the ratio between myocardial perfusion measurements following adenosine-induced stress and rest measurements.
Time frame: Testosterone versus placebo (8 week treatment period)
Population: 22 patients had assessable CMR data for both evaluation visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Testosterone | Myocardial Perfusion | 1.83 myocardial perfusion index | Standard Deviation 0.9 |
| Placebo | Myocardial Perfusion | 1.52 myocardial perfusion index | Standard Deviation 0.65 |
Secondary
Endothelial Function
The endothelium is a single layer of cells that line all blood vessels and regulates arterial function. Coronary artery disease causes dysfunction of the endothelium but some substances/drugs help to reverse this dysfunction. In this study, endothelial function was measured by radial applanation tonometry which measures the blood pressure waveform during each cardiac cycle (heart beat). Radial artery pulse recordings were acquired, with an averaged waveform generated from 20 sequential waveforms. Augmentation index (AIx) is derived from this averaged waveform, and is the ratio of the pulse pressure at the second systolic arterial pressure waveform peak to that of the first systolic peak. The change in AIx before and after salbutamol (400mcg) is a measure of endothelial function.
Time frame: Testosterone versus placebo (8 week treatment period)
Population: A total of 17 patients had endothelial function assessments - the same patients took both interventions in a randomized cross-over design.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Testosterone | Endothelial Function | 76.5 Augmentation index | Standard Deviation 9.5 |
| Placebo | Endothelial Function | 79.4 Augmentation index | Standard Deviation 7.8 |