Will bone marrow stem cells help heart attack patients? Even cowboy trials have a role to play…

Author: David Kent, 05/06/14

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My last post introduced the large-scale publicly funded clinical trial called BAMI (the effect of intracoronary reinfusion of Bone marrow-derived mononuclear cells on all course mortality in Acute Myocardial Infarction). That post focused on the role of the public purse in funding such trials and concluded that public monies have a major role to play in what companies would consider “not fundable”.

Since clinical trials are enormously expensive, however, it makes the choice of trial to run/fund incredibly difficult and important. The BAMI trial proposes to take whole bone marrow cells from patients who have had a heart attack and transplant them into the hearts of the patients with the hope that these cells will prevent people from re-hospitalization and/or death. Interestingly, the BAMI trial is billed as a stem cell therapy, when in reality it is a hodge-podge of un-fractionated cells that are injected into the heart. Cell therapy, yes. Stem cells, maybe not…

Not there to stay

When we hear about stem cell trials, we often think of permanent cures where the stem cell population(s) replaces damaged stem cells and operates as normal (e.g., as in the case of successful bone marrow transplantations where donor cells repopulate the recipient forever). I don’t think it is likely that the cells in the BAMI trial will be setting up shop in the hearts of patients – but one never knows and it would be very interesting to see if cells are still present at the two year endpoint. Present or not, if these cell suspensions achieve the 25% reduction in mortality and 15% reduction in re-hospitalization, then it may be worth it despite the lack of permanence.

No idea how it works

Even for someone who has trained in the stem cells and regenerative medicine field for 10 years now, it is difficult to imagine how this (stem) cell therapy might work and what the underlying mechanism of action would be. If anything, I think the benefit would come from the other bone marrow cells injected (the non-stem cells) as a sort of directed delivery of key regenerative molecules or cells (e.g., cytokines, immune cells). These molecules may support tissue healing, they may prevent further damage, they may inhibit scarring, but realistically, we simply do not know what they will do and it’s a bit of a cowboy experiment when the data from previous trials are not exactly a ringing endorsement of promised success.

The past likely predicts the future

The only trial I could find, that had any indication of modest effects, was the TAC-HFT trial (clinicaltrials.gov identifier NCT00768066) showing that “the 1-year incidence of serious adverse events was 31.6% for mesenchymal stem cells, 31.6% for bone marrow cells, and 38.1% for placebo controls”. This is a marginal decrease in adverse effects, and the trial only enrolled 65 patients.

On the other hand, the majority of completed studies lack strong positive data (as was also highlighted this Nature News article last week) including:

  • TIME study:  No significant effect (120 patients) NCT00684021
  • The late TIME study: No improvement in global/regional heart function at 6 months (87 patients) NCT00684060
  • FOCUS: In chronic heart failure patients, no improvement in heart function or oxygen consumption (92 patients) NCT00824005
  • FOCUS-HF: In chronic heart failure patients, BM cell transplantation is safe and improves symptoms, quality of life, and possibly perfusion. (30 patients) NCT00203203
  • CARDIO-133: Intramyocardial injection of CD133+ BMC has no relevant effect on global LV function and heart failure symptoms (60 patients) NCT00824005

Not all doom and gloom

Despite these suggestions that this therapy will not benefit patients, the really good news is that the BAMI trial is well-designed, has clear and defined endpoints that are easy to assess (mortality and re-hospitalization) and is unlikely to be damaging to patients since they are receiving their own cells. Moreover, the trial at its conclusion will have developed several protocols that will be useful to the wider community considering future cell therapies. These include standardized methods for bone marrow cell collection and preparation for autologous transplantation into the heart.

Most importantly, the trial is very large (3000 patients) and statistically well-powered meaning that it should really put the question as to whether there is any benefit to the test. A few years from now, we should have a good sense of whether there is something interesting happening and maybe then scientists might invest some energy into figuring out how and why it might work.

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David Kent

David Kent

Postdoctoral Fellow at University of Cambridge
Dr. David Kent is a group leader at the University of Cambridge in the Cambridge Stem Cell Institute (http://www.stemcells.cam.ac.uk/researchers/principal-investigators/dr-david-kent). His laboratory's research focuses on fate choice in single blood stem cells and how changes in their regulation lead to cancers. David is currently the Stem Cell Institute’s Public Engagement Champion and has a long history of public engagement and outreach including the creation of The Black Hole in 2009. He has been writing for Signals since 2010.
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4 Responses

  1. Christopher McCabe says:

    Hi David,
    Interesting blog.

    Unfortunately, I have to disagree with your conclusion. Research resources like health care resources are limited. The 5.1 million euro (?) that is being spent on BAMI could have been spent on other research where the evidence is more compelling about the potential for benefit. So, whilst the patients recruited into the trial are unlikely to be personally harmed, the misdirection of limited resources away from more valuable research is likely to delay the translation of other effective therapies and thus is indirectly harming currently unknown future patients.

    In a world of limited resources cowboy trials really don’t have any role.

    Best wishes

    Chris

  2. David Kent says:

    Hi Chris,

    I know exactly where you are coming from and actually share your opinions about limited resources needing to be distributed properly.

    The danger I see with these cardiac trials is for more of the same continuing (i.e., numerous small trials, occasionally tossing a “statistical difference” into the mix)… the good thing about BAMI is it should finally put to bed these types of trials and we can stop wasting money on injecting unknown suspensions of bulk bone marrow cells into hearts.

    The bad thing, as you’ve correctly identified, is that this type of expenditure could be used on a more promising therapy, although the selection process is mired with complicated factors.

    Thanks for reading/sharing.
    Dave

  3. Christopher McCabe says:

    Hi Dave,

    thanks for the response. I completely relate to your frustration with lots of small inconclusive trials dragging out the death of an candidate therapy and encouraging others to pursue low value research.

    I think the solution lies in research funders and research ethics committees requiring the case for new trials and their sample sizes be based upon the well conducted meta-analyses of existing studies, rather than one-off trials. This should enable funders to identify whether the assumed equipoise is well-based and whether the proposed trial design is capable of advancing the state of knowledge. I am pretty sure this is a position the James Lind Library have argued, but I cant remember the reference right now, so I may be misrepresenting them.

    Good research appraisal processes should be a quicker and much cheaper mechanism for hastening the end of low and/or no value translational technologies.

    Thanks again for the blog and the discussion.

    Chris

  4. Sonja B says:

    Hi Dave,

    I really liked your point about the merits of conducting a trial that is designed and powered well enough to give definitive answers, rather than wasting more money in the long run by continuing a series of small, inconclusive trials. I also wanted to voice the opinion that the ~5 mil euro spent on the trial will be a total bargain if the findings are positive and it ends up (eventually) changing patient care. The cost of developing a new drug are estimated by the pharmaceutical industry to be upwards of $800 million (though this figure has been disputed by many), all of which is of course recouped from the public eventually, either through health insurance plans or out-of-pocket spending. So it would be really gratifying to see a publicly funded trial come up with a new therapy for a lot less $$ than what industry claims is required- it could be a very powerful argument for greater public investment in research, including clinical trials.

    Of course, for something as inextricably linked to socioeconomic status as heart disease, I would much rather see attention redirected towards social determinants of health and preventive strategies- but as long as funders are fixated on biomedical questions/solutions, I think it’s important to study those efficiently.

    As a minor point, I was a little surprised by the assertion that the therapy is “unlikely to be damaging to patients since they are receiving their own cells” – I’m sure everyone’s heard this argument used as evidence of safety by private clinics offering unlicensed autologous “stem cell therapies”, when there are clear examples to the contrary (e.g. http://jasn.asnjournals.org/content/21/7/1218). Although, I suppose, if there was a significant risk of adverse effects related to this specific therapy, it probably would have shown up in the smaller trials already conducted.

    Sonja

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