#7 Testosterone Trials – Should we treat age related testosterone deficiency?

Background

Testosterone levels seem to naturally decline as men age. There has been an enormous rise in the amount of testing and treatment of this natural decline in testosterone.  Testosterone clinics have been popping up all over the place and promise that treatment will restore energy, improve depression, increase libido and enhance overall well-being.  In America, the direct to consumer advertising about low T is everywhere- on television, radio, magazines and billboards.  There has been a 100 fold increase in testosterone prescriptions over the past three decades and this is despite the complete lack of any new indications for the drug or any new evidence for the use of testosterone. A trial that looked through the medical records of 112,000 veterans who had been prescribed testosterone. found that only 3% of them met the laboratory  criteria to actually confirm the diagnosis of low testosterone. Around 13% had contraindications to testosterone therapy. Including 1.5% with prostate cancer! And 16% never even had their testosterone levels tested.

So either doctors really believe in testosterone therapy or patients are pressuring doctors to prescribe it. And until now, there has been no good evidence to support OR discredit the treatment of age related testosterone deficiency. The  Testosterone Trials are the first well designed piece of evidence to shed some light on the correct approach. These trials assessed the impact of testosterone treatment on age related testosterone deficiency, not testosterone deficiency due to pathology of the reproductive system.

Study Design

This one study was actually a series of 7 studies. Each was a randomised, placebo controlled trial. They screened 51,085 but only 790 met criteria for inclusion. And then this group 790 men were used across the 7 studies. participants could be included in more than 1 of the trials depending on which inclusion criteria they matched. The general inclusion criteria included:

  • Age >65
  • Low serum testosterone levels on two seperate readings (<9.5nmol/L or <275ng/dL)
  • No past history of prostate cancer and low risk for prostate cancer
  • No cardiovascular disease and low risk for cardiovascular disease

They randomised half of the participants to testosterone and the other half to placebo. The testosterone they used was 1% Androgel in a pump bottle, they initially started 5g topically, daily, but they titrated the dose to keep the serum concentration to a normal level. They considered a normal level as the normal range for someone aged 19 to 40. To maintain placebo, they also did fake dose titrations to those getting the placebo gel.

Vitality Trial

To be recruited to the vitality trial patients had to have low vitality as determined by a vitality scale called the FACIT-fatigue scale (Functional Assessment of Chronic Illness Therapy-fatigue). This is a scale out of 65 which assesses symptoms such as “I feel tired”, “I have trouble starting things because I’m tired”, “I feel weak all over”, “I need help doing my usual activities”, etc. Out of the 790 men in the overall study, 474 qualified for the vitality trial.

The primary outcome was how many men in each group had a greater than 4 point increase in this vitality score. They chose 4 because that is supposed to be the minimally clinically important difference.

Bottom Line: There was no difference in the number of people who had clinically important improvements in vitality with testosterone compared to placebo

Physical Function Trial

To be included in the physical function trial participants had to have difficulty walking or climbing stairs and they had to be slow –  with a gait speed of less than 1.2 metres per second on the 6 minute walk test. 387 patients out of the 790 were enrolled in this trial. The primary outcome was how many people achieved a 50 metre increase in their 6 minute walk test.  This is what was considered to be a clinically important improvement in their gait speed

Bottom line: There was no difference in the number of people who had clinically important improvements in their physical function.

Sexual Function

To be included in the sexual function trial, participants had to have low libido as per a low score on a libido scale called the DISF-M-II scale. They also had to have a partner willing to have sexual intercourse with them at least twice per month. 459 patients qualified for this study. The primary outcome was the improvement on a sexual function scale called the PDQ-Q4 scale (Psychosexual Daily Questionnaire – Question 4). This score asks people about their sexual encounters. For example:  Did you experience any of the following today: sexual daydreams, sexual intercourse, flirting, ejaculation. There are 12 of these in total, each with a “yes” or “no” making a total possible score of 12.

The average baseline score was 1.4 in both groups. In the placebo group, it went to an average of 1.3. In the testosterone group went to 1.9. Making a 0.6 point increase in this 12 point scale over placebo with testosterone therapy.

They assessed erectile dysfunction as a secondary outcome using a score called the IIEF erectile function score. This increase by 2.6 points with testosterone over placebo. Compare this to phosphodiesterase type-5 inhibitors (Viagra, etc.) which in meta-analyses of elderly men has shown to increase this score by 5.7 points.

Bottom Line: Treating men with low testosterone and low libido with testosterone therapy will given them about half an extra flirt, or half an extra spontaneous erection, or half an extra sexual daydream per day. Though direct comparisons have not been done, testosterone appears to be inferior to phosphodiesterase type-5 inhibitors.

The Cardiovascular Trial

By way of background, there are trials which point to an increased risk of cardiovascular disease with testosterone therapy. One randomised controlled trial of 209 elderly men in 2010 found that those in the testosterone trial were 6 times more likely to develop a cardiovascular adverse event than those in the placebo group. Because the Testosterone Trials had men with low cardiovascular risk, it was not powered to pick up a difference in cardiovascular events. So instead they used the surrogate marker of non-calcified coronary artery plaque volume and coronary artery calcification score. 170 men were enrolled in this part of the trial and they put them into a CT coronary angiogram machine at the start of the study and at the end of the study to see who had more atherosclerotic plaque built up in their coronary arteries. There was more atherosclerosis and a higher coronary artery calcification score in those receiving testosterone

Bottom line: Testosterone therapy will increase the amount of atherosclerotic plaque in the coronary arteries as well as the coronary artery calcification score. While this study was not powered to detect a difference in patient oriented outcomes of cardiovascular disease, previous studies have signalled an increase in CVD with testosterone therapy

The Cognition Trial

493 of the 790 men met criteria for Age Associated Memory Impairment and there was no improvement in cognitive functions or memory with testosterone

Bottom Line: testosterone therapy does not improve cognition in men with age associated memory impairment

The anaemia Trial

126 patients out of the cohort of 790 were anaemic, half of which had no known cause. The primary outcome was how many people achieved a rise in haemoglobin by 1g/dL. 54% of men did this when given testosterone versus 15% who were given placebo.

Bottom Line: Treating low testosterone with testosterone therapy in anaemic patients  will improve anaemia with a number needed to treat of 3

The Bone trial

Here they took 211 patients and checked whether their Volumetric Bone Mineral Density changed using quantitative CT scanning. They also checked BMD with DEXA scanning. And there was a slight increase in bone mineral density with testosterone therapy. What we really care about is fractures though, because after all, this is why we care about BMD. They checked for fractures at regular intervals in all the 790 participants. During the 12 months of the study – 6 got a fracture in the testosterone group and 6 got a fracture in the placebo group.

Bottom Line: Testosterone therapy increases bone mineral density but there is no evidence that it reduces fractures

Adverse Events

There was no difference in adverse events between the two groups

Patient Global Impression of Change

In the above summary for each of the trials, only the primary outcomes have been listed. These T-trials had a lot of secondary outcomes and some of them were statistically significant while others were’t. But one of the secondary outcomes deserves mention.

It great when trials actually ask the patient…”did you feel better on this drug?” And this trial did that. They did each of the 790 participants these questions: “Since the beginning of the trial, has your sexual desire been better, not changed or worse?”, “Has your walking ability been better, unchanged or worse?” and “has your energy been better, unchanged or worse.?

With regards to physical functioning, around 11% of those who got placebo said that their walking ability got much better compared to 18% of those who got testosterone. So an absolute difference of 7% in the patients impression of their improvement in physical functioning. Making a number needed to treat of 15.

For vitality, around 10% of those in the placebo group said their energy levels were much better, compared to about 21% in the testosterone group. Making  a number needed to treat of around 10 for patient impression of improvement in vitality.  With regards to sexual function, 5% of those getting placebo said that their sexual desire was much better, compared to 20% of those who got testosterone. The NNT is 7, So for every 7 patients with low testosterone and low libido who are treated with testosterone therapy, 1 will report an improvement sexual function.

Final Bottom Line:

For elderly men who have low testosterone levels that is not due to pathology of the reproductive system, restoring their levels with testosterone therapy to that of a young man, will not improve objective measures of vitality or physical functioning but will result in a slight improvement in objective measures of sexual functioning which is of marginal clinical significance and is likely inferior to phosphodiesterase type-5 inhibitors. But, there will be a subjective improvement in sexual function, vitality and physical function in about 10% of patients. Testosterone will not improve cognition in those with age related memory impairment. It will improve anaemia with a NNT of 3 in those with anaemia. It will improve Bone Mineral Density but not reduce fractures. Concerningly, while this study was not powered to detect a change in cardiovascular disease, it did find an increase in the amount of atherosclerotic plaque in the coronary arteries as well as the coronary artery calcification score with testosterone therapy. This is on a background of previous studies which have showed increased cardiovascular disease with Testosterone therapy.

References:

#2 SPRINT trial – which blood pressure target is best?

In episode 2 of the Evidence Based Medicine Podcast we delve into the SPRINT trial.
This trial assessed whether targeting systolic blood pressure to less than 120mmHg is better than targeting to less than 140mmHg it terms of harms and reduction in cardiovascular disease.

The trial was conducted in 9,361 patients with very a very high risk of cardiovascular disease but who didn’t have diabetes or a past history of stroke. They were randomised to 2 groups: A standard blood pressure group who were targeted to a systolic BP of less than 140mmHg or an intensive blood pressure group who were targeted to less than 120mmHg systolic. They were followed for an average of 3.3 years

In this episode we go through the results of the trial, it’s impact on hypertension guidelines across the world and how it sits in the face of other similar trials, most notably the ACCORD BP trial. We also discuss some of the controversy about the trial as reported in many commentaries in the literature.

I was a very well done and important trial published in NEJM in November 2015 and stands for “Systolic Blood Pressure Intervention Trial”…I guess SBPRINT trial wouldn’t have sounded as good!

The bottom line is that for patients with hypertension, at high risk of cardiovascular disease, but without diabetes or previous stroke, treating them to a systolic blood pressure target of less than 120, compared to less than 140 will decrease their chance of cardiovascular disease by 1.6% over 3.3 years and will decrease their chance of dying by about 1%. But it comes at a cost, most important of which is an increase in acute renal failure by 1.8%, an increase in worsening renal function by 2.7% and an increase in being seriously harmed by episodes of hypotension, syncope or electrolyte abnormalities by about 3%

Here is a more in depth look at the results:

The benefits of treating blood pressure to 120 versus 140 systolic are as follows:
1. A reduction in cardiovascular disease from 6.8% to 5.2% with an absolute reduction of 1.6% or a Number Needed to Treat (NNT) of 63 over 3.3 years.
2. Death from any cause decreased by 1.2% – It went from 4.5% to 3.3% with a NNT of 83 over 3.3 years
3. Cardiovascular death decreased by 0.6% – It went from 1.4% to 0.8% with a NNT of 167
4. Heart failure decreased by 0.8% – It went from 2.1% vs 2.3% with a NNT 125
5. There was no difference in AMI or stroke

The harms of treating blood pressure to 120 versus 140 systolic are as follows:
1. Worsening renal function increased by 2.7% – it went from 1.1% to 3.8% with a Number Needed to Harm (NNH) of 37
2. – Acute renal failure increased by 1.8% – it went from 2.6% in the 140 systolic group to 4.4% in the 120 systolic group. NNH 56
3. Serious adverse events increased (events that were either fatal or life threatening, or required prolonged hospitalisation, or resulting in significant disability). Episodes of hypotension increased from 2% to 3.4% with a NNH 71
– Syncope increased from 2.4% to 3.5%, with a NNH 91
– Electrolyte abnormality also increased from from 2.8% to 3.8% with a NNH 100
– There was no difference in injurious falls, it was about 2.2% in both groups.

Reference: http://www.nejm.org/doi/full/10.1056/NEJMoa1511939
Music by Polyrhythmics, track titled “El Fuego”