Ryan31337
Senior Member (Voting Rights)
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Randomized Trial of Ivabradine in Patients With Hyperadrenergic [POTS], 2021, Taub et al
Ryan31337
Senior Member (Voting Rights)
Pleased to see some higher quality evidence for use of Ivabradine in POTS.
Its been prescribed by the experts for years, I have been taking it since 2016 with good results.
I'm glad to see some acknowledgment of it lowering NE levels too - something that is rarely mentioned in the literature but has been very clear to me as a patient. Most descriptions of Ivabradine go the other way, suggesting its highly selective and only affects heart rate. The only references I ever found to it having an impact on stress hormones were some animal studies and one human study, where it was used in surgical procedures. It has a profound effect reducing the "wired but tired" sensations for me.
The editorial comment from Raj is interesting too:
Higher Quality Evidence to Guide Our Management of Postural Orthostatic Tachycardia Syndrome: A New Era?
https://www.jacc.org/doi/10.1016/j.jacc.2020.12.028
Its been prescribed by the experts for years, I have been taking it since 2016 with good results.
I'm glad to see some acknowledgment of it lowering NE levels too - something that is rarely mentioned in the literature but has been very clear to me as a patient. Most descriptions of Ivabradine go the other way, suggesting its highly selective and only affects heart rate. The only references I ever found to it having an impact on stress hormones were some animal studies and one human study, where it was used in surgical procedures. It has a profound effect reducing the "wired but tired" sensations for me.
The editorial comment from Raj is interesting too:
Higher Quality Evidence to Guide Our Management of Postural Orthostatic Tachycardia Syndrome: A New Era?
https://www.jacc.org/doi/10.1016/j.jacc.2020.12.028
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Thanks for posting this @Ryan31337.
I haven't read the paper itself, but it does look like a nice study, and the editorial is indeed interesting.
It would be great to get some trials done in people with ME/CFS with strong orthostatic intolerance symptoms.
I haven't read the paper itself, but it does look like a nice study, and the editorial is indeed interesting.
the editorial said:
It would be great to get some trials done in people with ME/CFS with strong orthostatic intolerance symptoms.
Ryan31337
Senior Member (Voting Rights)
Utsikt
Senior Member (Voting Rights)
This came up in another thread.
The study is really flawed. Blinding was most definitively broken for many patients, so it’s essentially an unblinded study with subjective outcomes (of course Ivabradine will reduce HR, so that is irrelevant info, and the difference in delta between the groups was 3.9 bpm.)
6/8 of the QoL outcomes did not reach statistical significance, including general health.
The study is really flawed. Blinding was most definitively broken for many patients, so it’s essentially an unblinded study with subjective outcomes (of course Ivabradine will reduce HR, so that is irrelevant info, and the difference in delta between the groups was 3.9 bpm.)
6/8 of the QoL outcomes did not reach statistical significance, including general health.
"Definitions
POTS is a clinical disorder classified by: 1) symptoms upon standing such as lightheadedness, palpitations, tremors, weakness, blurry vision, and fatigue; 2) increase in heart rate ≥30 beats/min upon postural change from recumbent to upright position within 10 min of standing; and 3) absence of orthostatic hypotension (3,5,8,30). Hyperadrenergic POTS, a subtype of POTS, is defined as an elevation in NE >600 pg/ml upon standing and a systolic BP increase of >10 mm Hg when standing upright for 10 min (5). We did not use the systolic BP criteria, as we recognized clinically that many patients had overlapping subtypes (e.g., hyperadrenergic and hypovolemic that resulted in lack of systolic BP increase). A positive head-up tilt table test (HUTT) (heart rate ≥30 beats/min) and NE (≥600 pg/ml) were required for study enrollment.Study design
The study design is presented in Figure 1. Utilizing a randomized, double-blinded, placebo-controlled crossover design, eligible patients with hyperadrenergic POTS were started on either ivabradine or placebo for 1 month, underwent a 1-week washout period and were crossed over to the other treatment for 1 month (Figure 1). Study participation lasted approximately 2.5 months with 7 clinic visits."
On the quality of blinding:
It's not clear to me that the blinding failed. Patients noticing an improvement and assuming that they are on the treatment is unavoidable if the treatment actually works. Why do you say that the blinding failed @Utsikt?
Despite the small sample size there were significant improvements e.g. in physical functioning, and trends to improvement in some other measures. The complete lack of an improvement in general health is interesting though. Perhaps the heart rate increases are a compensation for an underlying issue e.g. not enough blood getting to the heart when standing, so slowing the heart rate 'cures' the POT but doesn't make the patient feel better?
It's not clear to me that the blinding failed. Patients noticing an improvement and assuming that they are on the treatment is unavoidable if the treatment actually works. Why do you say that the blinding failed @Utsikt?
Despite the small sample size there were significant improvements e.g. in physical functioning, and trends to improvement in some other measures. The complete lack of an improvement in general health is interesting though. Perhaps the heart rate increases are a compensation for an underlying issue e.g. not enough blood getting to the heart when standing, so slowing the heart rate 'cures' the POT but doesn't make the patient feel better?
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ChronicallyOverIt
Senior Member (Voting Rights)
This is why I think mestinon is better, since you’re not just masking the symptoms. I don’t think just slowing down the heart to get rid of tachycardia is 100% beneficial.
I remember there was a study on heart preload failure in ME/CFS and another study on mestinon improving cardiac output in POTS or ME/CFS patients. Along with that the hand grip tests showed improved response with mestinon. I feel like these were all discussed here but can’t find them. I think piecing this all together could show that mestinon is far better than propanol than these other treatment for POT or POTS
I did a quick search and found this: https://pubmed.ncbi.nlm.nih.gov/21410722/
Utsikt
Senior Member (Voting Rights)
«Many patients noticed significant differences».
I think it’s pretty clear that the blinding was broken. This is as expected with a drug that affects something very noticeable (HR), so they should probably have designed around it and done a formal check of the blinding.
If the significant differences that the participants noticed was that they were better able to function physically, that isn't a breaking of the blinding. I guess it's possible that participants were measuring their heart rate on standing and so knew that it wasn't increasing as much. BUT, see below
I note that the average increase upon standing at baseline was only 21 bpm, and only 17 bpm when on the placebo. That isn't enough for the average participant to qualify as having POTS (should be more than 30 bpm).
The difference in reduction in increase on standing when on the ivabradine is small when compared to baseline and placebo (8 bpm and 4 bpm). I don't actually think that most of the participants would have been able to work out from those heart rate differences that they were on the treatment.
I'm left feeling quite unsure of what to make of this study. Importantly, the participants don't actually appear to have, on average, had POTS or even POT!
Ivabradine seemed to lower the increase in heart rate on standing a little, but that average reduction is probably not statistically different to the reduction recorded in the placebo group. There were significant improvements in subjective reports of physical functioning and social functioning as compared to the placebo, but, oddly, not in general health.
On balance, I don't think the study constitutes adequate evidence of ivabradine being useful for people with POTS.
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I think that's an odd criteria for POTS, hyperadrenergic or otherwise. POTS stands for Postural Orthostatic Tachycardia Syndrome, and yet they had no requirement for abnormal tachycardia upon standing.
I don't think it is reasonable for them to suggest the group has POTS or for the findings from this study to be extrapolated to people with POTS (or people with ME/CFS and orthostatic intolerance).
Utsikt
Senior Member (Voting Rights)
Why not? Surely the the blinding is broken if the participants can tell when they are on the active drug?
I agree with the rest of the assessment. The entire study is weird and I don’t even know who the results would apply to.
Imagine there is finally a useful treatment for ME/CFS. People receiving the treatment suddenly are able to cope with normal activity levels. In a study with a placebo, people would guess that they were on the treatment, and they probably would be correct. Participants guessing correctly that they are on the effective treatment doesn't mean the blinding is broken - they don't know for sure.
So in this study, if they had a significant improvement in physical function and that was the sole reason they guessed they were on the treatment, that wouldn't mean that the blinding was broken. But yeah, who knows what actually happened here. The admission in the Study Limitations is vague as to what significant differences were noted by the participants.
Yeah.
Utsikt
Senior Member (Voting Rights)
I’m still confused.
Broken blinding literally means that more participants correctly guess the allocation compared to random chance - does it not?
That seems to have happened here.
That isn’t an issue if you have appropriate objective measurements, but it is an issue for the subjective measurements. It’s not as bad in terms of potential bias compared to no blinding, but it’s still a substantial source of bias.
If we assume that the subjective measurements are unreliable due to partially broken blinding, and neither HR nor NE really shows any meaningful difference, the study has a fairly definitive null result.
I don't think it does. If a treatment really works and the placebo doesn't, most participants in the treatment group will guess that they are in the treatment group, while the only some of the participants in the placebo group will guess that they are. I don't think that will mean that the blinding is broken, as the participants are guessing based on an outcome, they don't know for sure. I don't think it's fair to say that blinding is broken in that situation.
But yes, it could mean that the blinding is, while not broken, rather bent. There definitely could be bias. If people think they have improved on one measure (because they have), they might be more inclined to say that things have got better on other measures, even if those outcomes aren't actually really improved by the treatment.
An interesting discussion, thanks Utsikt. It's not as simple as having a blinded study - results for subjective outcomes can still be dodgy. Maybe we are just talking about semantics when it comes to 'broken blinding' - I guess there's actually a continuum from having no idea whether you had the treatment through to knowing for sure.
Utsikt
Senior Member (Voting Rights)
Thanks, it’s been interesting to get into the nuances.
To sum up my view: If the blinding is broken or not is binary. That’s because only a truly non-broken blinding is impervious to the bias that the blinding seeks to eliminate. If the blinding is not perfect, you have to assume bias has affected the outcomes. To which degree would be based on how badly the blinding has been broken - the continuum you mentioned.
I always thought of it as some side effect or other circumstance occurring that makes participants more certain what group they're in, unrelated to the outcome of interest. For example, if a patient gets a characteristic rash that is only known to happen with the active drug, they're no longer blinded.
On the other hand, if "breaking blinding" applies to the outcome you're hoping to change, then you can't have a trial with a subjective outcome and a drug that works well without breaking blinding.
Same with objective trials where the participant can see/feel the objective measure, for example a drug that stops a fever. If the drug actually stops fevers, the cases will feel less feverish than the controls, and so will be more likely to guess they took the drug.
As others have said, every drug that successfully makes people feel better will always break blinding. I do agree that more blinding is broken the more important it is to have a large effect. But just because some patients might guess they have the real drug does not mean the trial is worthless. If that were the case we would have to throw out every trial in which a drug's discernable effects are not identical to placebo.
There are clearly issues with this trial, especially the small sample size. However, I don't think you can hand wave it away as breaking blinding so the results are irrelevant. If significance was a result of the broken blinding for example, it seems strange that the largest improvement in QoL was in physical functioning; the thing you would expect a drug like this to improve. With a larger sample size the results would likely have been more significant.
But all I wanted to point out with this trial is that a label like POTS allows people to run studies to test drugs aimed at improving people's QoL. Clearly a drug that decreases heart rate wouldn't make sense for a person in the broader category of OI that faints immediately upon standing but might make sense for the syndrome of POTS.