Ann: DMC Completes Final Review of Phase 3 Heart Failure Trial, page-44

@Treed
if you read the article in aha journals (https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.314951) they explain that the independent statistical consultant reviewed data without knowledge of the treatment groups to see how the trial was going and that they made modifications to recruitment to add more asa3 (sicker) patients to the trial.
Adding more unwell patients to a trial which includes a sham control (comparison) group is a bit risky because you are subjecting them to a procedure (angiogram) with a risk of stroke (0.2%) and a nice bruise in their groin or arm. So you would rather study more robust patients but then you would need more patients enrolled to get your outcomes. So yes, you are correct.
The censoring is complicated for the researchers. As they explain, one way of looking at the data is to consider all events (heart failure admission, death, transplant, LVAD, resuscitated VF) as equal and just measure the time from the stem cell treatment or sham (pretend) treatment (what I referred to as placebo in the general sense in the last post but is not the best term to use here) - this is the TTFE (time to first event) analysis. The good thing about this is that it will measure lots of different things as outcomes and hopefully then give us an idea about whether the treatment works. But just as they started the trial, general consensus changed and people realised that in heart failure research the fact that a treatment that might reduce someones heart failure admissions from 10 a year to 5 a year might be useful. Unfortunately, with TTFE analysis once you have an event, that patient contributes no further data (there is no time to second or third event recorded). This is what they called censoring, the later events are censored.
Basically they changed the protocol after the study had started to allow consideration of these subsequent (previously censored) events which is a bit of a no-no in general but I think in this case will be accepted by readers. Then as @otherperspective mentions the trial will have to deal with the problem of interpretation of patients who die... let’s say you have two patients who will both die from cardiac failure in 3 months, subject one to stem cell treatment which works and one to the sham treatment. The sham treatment patient dies, but the stem cell treatment patient is saved and lives. But the stem cell patient is admitted to hospital in heart failure 6 times in the next year before returning to running marathons. Does that mean the stem cell treatment improves survival (yes) or does it actually increases hospital admissions with heart failure (yes because it increases survivors). See the dilemma?
None of this is a big deal, all heart failure trials have to deal with this.
@Treed your question about deaths and complications... in this patient population deaths are to be expected, and it is just a question of whether the number of deaths are greater than what we would normally expect, so nothing to worry about.
@otherperspective I enjoyed your post. I agree the phase 2 study was encouraging. I was particularly impressed by the dose-response relationship between stem cell dose and cardiac remodelling efficacy. In my experience dose-response results like that mean that the signal isn’t just noise. I was a little concerned that there wasn’t consistency of effect amongst all outcomes (and when they measure a lot of outcomes like this 1/20 will be ‘positive’ just due to chance ‘noise’ rather than a true effect), but have decided that if stem cells work by improving remodelling (which will likely reduce the incidence of ventricular fibrillation and sudden cardiac death), and don’t really work by improving contractility or heart function (so you don’t get improvement in heart failure admissions or exercise tolerance) then they will still be valuable. Some stem cell studies do show improvement in infarct size and heart function so it might just be the context in which they are used.
Anyway, after initially being put off stem cells by the Dr Piero Anversa’s fraudulent studies and slow progress to demonstrate benefit (some surgeons were injecting stem cells into hearts during open heart surgery in 2007), I’ve purchased a small number of shares. But primarily based on non-msb research into stem cells for cardiac failure. Will be interesting.