To Err Is Human, To Study Errors Is Science

The family of cholesterol lowering drugs known as ‘statins’ are among the most widely prescribed medications for patients with cardiovascular disease. Large-scale clinical studies have repeatedly shown that statins can significantly lower cholesterol levels and the risk of future heart attacks, especially in patients who have already been diagnosed with cardiovascular disease. A more contentious issue is the use of statins in individuals who have no history of heart attacks, strokes or blockages in their blood vessels. Instead of waiting for the first major manifestation of cardiovascular disease, should one start statin therapy early on to prevent cardiovascular disease?

If statins were free of charge and had no side effects whatsoever, the answer would be rather straightforward: Go ahead and use them as soon as possible. However, like all medications, statins come at a price. There is the financial cost to the patient or their insurance to pay for the medications, and there is a health cost to the patients who experience potential side effects. The Guideline Panel of the American College of Cardiology (ACC) and the American Heart Association (AHA) therefore recently recommended that the preventive use of statins in individuals without known cardiovascular disease should be based on personalized risk calculations. If the risk of developing disease within the next 10 years is greater than 7.5%, then the benefits of statin therapy outweigh its risks and the treatment should be initiated. The panel also indicated that if the 10-year risk of cardiovascular disease is greater than 5%, then physicians should consider prescribing statins, but should bear in mind that the scientific evidence for this recommendation was not as strong as that for higher-risk individuals.

 

Oops button - via Shutterstock
Oops button – via Shutterstock

Using statins in low risk patients

The recommendation that individuals with comparatively low risk of developing future cardiovascular disease (10-year risk lower than 10%) would benefit from statins was met skepticism by some medical experts. In October 2013, the British Medical Journal (BMJ) published a paper by John Abramson, a lecturer at Harvard Medical School, and his colleagues which re-evaluated the data from a prior study on statin benefits in patients with less than 10% cardiovascular disease risk over 10 years. Abramson and colleagues concluded that the statin benefits were over-stated and that statin therapy should not be expanded to include this group of individuals. To further bolster their case, Abramson and colleagues also cited a 2013 study by Huabing Zhang and colleagues in the Annals of Internal Medicine which (according to Abramson et al.) had reported that 18 % of patients discontinued statins due to side effects. Abramson even highlighted the finding from the Zhang study by including it as one of four bullet points summarizing the key take-home messages of his article.

The problem with this characterization of the Zhang study is that it ignored all the caveats that Zhang and colleagues had mentioned when discussing their findings. The Zhang study was based on the retrospective review of patient charts and did not establish a true cause-and-effect relationship between the discontinuation of the statins and actual side effects of statins. Patients may stop taking medications for many reasons, but this does not necessarily mean that it is due to side effects from the medication. According to the Zhang paper, 17.4% of patients in their observational retrospective study had reported a “statin related incident” and of those only 59% had stopped the medication. The fraction of patients discontinuing statins due to suspected side effects was at most 9-10% instead of the 18% cited by Abramson. But as Zhang pointed out, their study did not include a placebo control group. Trials with placebo groups document similar rates of “side effects” in patients taking statins and those taking placebos, suggesting that only a small minority of perceived side effects are truly caused by the chemical compounds in statin drugs.

 

Admitting errors is only the first step

Whether 18%, 9% or a far smaller proportion of patients experience significant medication side effects is no small matter because the analysis could affect millions of patients currently being treated with statins. A gross overestimation of statin side effects could prompt physicians to prematurely discontinue medications that have been shown to significantly reduce the risk of heart attacks in a wide range of patients. On the other hand, severely underestimating statin side effects could result in the discounting of important symptoms and the suffering of patients. Abramson’s misinterpretation of statin side effect data was pointed out by readers of the BMJ soon after the article published, and it prompted an inquiry by the journal. After re-evaluating the data and discussing the issue with Abramson and colleagues, the journal issued a correction in which it clarified the misrepresentation of the Zhang paper.

Fiona Godlee, the editor-in-chief of the BMJ also wrote an editorial explaining the decision to issue a correction regarding the question of side effects and that there was not sufficient cause to retract the whole paper since the other points made by Abramson and colleagues – the lack of benefit in low risk patients – might still hold true. Instead, Godlee recognized the inherent bias of a journal’s editor when it comes to deciding on whether or not to retract a paper. Every retraction of a peer reviewed scholarly paper is somewhat of an embarrassment to the authors of the paper as well as the journal because it suggests that the peer review process failed to identify one or more major flaws. In a commendable move, the journal appointed a multidisciplinary review panel which includes leading cardiovascular epidemiologists. This panel will review the Abramson paper as well as another BMJ paper which had also cited the inaccurately high frequency of statin side effects, investigate the peer review process that failed to identify the erroneous claims and provide recommendations regarding the ultimate fate of the papers.

 

Reviewing peer review

Why didn’t the peer reviewers who evaluated Abramson’s article catch the error prior to its publication? We can only speculate as to why such a major error was not identified by the peer reviewers. One has to bear in mind that “peer review” for academic research journals is just that – a review. In most cases, peer reviewers do not have access to the original data and cannot check the veracity or replicability of analyses and experiments. For most journals, peer review is conducted on a voluntary (unpaid) basis by two to four expert reviewers who routinely spend multiple hours analyzing the appropriateness of the experimental design, methods, presentation of results and conclusions of a submitted manuscript. The reviewers operate under the assumption that the authors of the manuscript are professional and honest in terms of how they present the data and describe their scientific methodology.

In the case of Abramson and colleagues, the correction issued by the BMJ refers not to Abramson’s own analysis but to the misreading of another group’s research. Biomedical research papers often cite 30 or 40 studies, and it is unrealistic to expect that peer reviewers read all the cited papers and ensure that they are being properly cited and interpreted. If this were the expectation, few peer reviewers would agree to serve as volunteer reviewers since they would have hardly any time left to conduct their own research. However, in this particular case, most peer reviewers familiar with statins and the controversies surrounding their side effects should have expressed concerns regarding the extraordinarily high figure of 18% cited by Abramson and colleagues. Hopefully, the review panel will identify the reasons for the failure of BMJ’s peer review system and point out ways to improve it.

 

To err is human, to study errors is science

All researchers make mistakes, simply because they are human. It is impossible to eliminate all errors in any endeavor that involves humans, but we can construct safeguards that help us reduce the occurrence and magnitude of our errors. Overt fraud and misconduct are rare causes of errors in research, but their effects on any given research field can be devastating. One of the most notorious occurrences of research fraud is the case of the Dutch psychologist Diederik Stapel who published numerous papers based on blatant fabrication of data – showing ‘results’ of experiments on non-existent study subjects. The field of cell therapy in cardiovascular disease recently experienced a major setback when a university review of studies headed by the German cardiologist Bodo Strauer found evidence of scientific misconduct. The significant discrepancies and irregularities in Strauer’s studies have now lead to wide-ranging skepticism about the efficacy of using bone marrow cell infusions to treat heart disease.

 

It is difficult to obtain precise numbers to quantify the actual extent of severe research misconduct and fraud since it may go undetected. Even when such cases are brought to the attention of the academic leadership, the involved committees and administrators may decide to keep their findings confidential and not disclose them to the public. However, most researchers working in academic research environments would probably agree that these are rare occurrences. A far more likely source of errors in research is the cognitive bias of the researchers. Researchers who believe in certain hypotheses and ideas are prone to interpreting data in a manner most likely to support their preconceived notions. For example, it is likely that a researcher opposed to statin usage will interpret data on side effects of statins differently than a researcher who supports statin usage. While Abramson may have been biased in the interpretation of the data generated by Zhang and colleagues, the field of cardiovascular regeneration is currently grappling in what appears to be a case of biased interpretation of one’s own data. An institutional review by Harvard Medical School and Brigham and Women’s Hospital recently determined that the work of Piero Anversa, one of the world’s most widely cited stem cell researchers, was significantly compromised and warranted a retraction. His group had reported that the adult human heart exhibited an amazing regenerative potential, suggesting that roughly every 8 to 9 years the adult human heart replaces its entire collective of beating heart cells (a 7% – 19% yearly turnover of beating heart cells). These findings were in sharp contrast to a prior study which had found only a minimal turnover of beating heart cells (1% or less per year) in adult humans. Anversa’s finding was also at odds with the observations of clinical cardiologists who rarely observe a near-miraculous recovery of heart function in patients with severe heart disease. One possible explanation for the huge discrepancy between the prior research and Anversa’s studies was that Anversa and his colleagues had not taken into account the possibility of contaminations that could have falsely elevated the cell regeneration counts.

 

Improving the quality of research: peer review and more

Despite the fact that researchers are prone to make errors due to inherent biases does not mean we should simply throw our hands up in the air, say “Mistakes happen!” and let matters rest. High quality science is characterized by its willingness to correct itself, and this includes improving methods to detect and correct scientific errors early on so that we can limit their detrimental impact. The realization that lack of reproducibility of peer-reviewed scientific papers is becoming a major problem for many areas of research such as psychology, stem cell research and cancer biology has prompted calls for better ways to track reproducibility and errors in science.

One important new paradigm that is being discussed to improve the quality of scholar papers is the role of post-publication peer evaluation. Instead of viewing the publication of a peer-reviewed research paper as an endpoint, post publication peer evaluation invites fellow scientists to continue commenting on the quality and accuracy of the published research even after its publication and to engage the authors in this process. Traditional peer review relies on just a handful of reviewers who decide about the fate of a manuscript, but post publication peer evaluation opens up the debate to hundreds or even thousands of readers which may be able to detect errors that could not be identified by the small number of traditional peer reviewers prior to publication. It is also becoming apparent that science journalists and science writers can play an important role in the post-publication evaluation of published research papers by investigating and communicating research flaws identified in research papers. In addition to helping dismantle the Science Mystique, critical science journalism can help ensure that corrections, retractions or other major concerns about the validity of scientific findings are communicated to a broad non-specialist audience.

In addition to these ongoing efforts to reduce errors in science by improving the evaluation of scientific papers, it may also be useful to consider new pro-active initiatives which focus on how researchers perform and design experiments. As the head of a research group at an American university, I have to take mandatory courses (in some cases on an annual basis) informing me about laboratory hazards, ethics of animal experimentation or the ethics of how to conduct human studies. However, there are no mandatory courses helping us identify our own research biases or how to minimize their impact on the interpretation of our data. There is an underlying assumption that if you are no longer a trainee, you probably know how to perform and interpret scientific experiments. I would argue that it does not hurt to remind scientists regularly – no matter how junior or senior- that they can become victims of their biases. We have to learn to continuously re-evaluate how we conduct science and to be humble enough to listen to our colleagues, especially when they disagree with us.

 

Note: A shorter version of this article was first published at The Conversation with excellent editorial input provided by Jo Adetunji.

 

ResearchBlogging.org
Abramson, J., Rosenberg, H., Jewell, N., & Wright, J. (2013). Should people at low risk of cardiovascular disease take a statin? BMJ, 347 (oct22 3) DOI: 10.1136/bmj.f6123

Advertisements

Does Human Fat Contain Stem Cells?

Aeon Magazine recently published my longform essay on our research with human liposuction samples and our attempts to use fat for regenerative and therapeutic purposes. Many research groups, including our own group, have been able to isolate stem cells from human fat. However, when it came to using this cells for treating cardiovascular disease, the cells behaved in a manner that we had not anticipated.

Undifferentiated mesenchymal stem cells (left) and their fat neighbors (right)
Undifferentiated mesenchymal stem cells (left) and their fat neighbors (right) – From our PLOS One paper

We were unable to convert them into heart muscle cells or blood vessel endothelial cells, but we found that they could help build large networks of blood vessels by releasing important growth factors. Within a few years of our initial publication, clinical trials with patients with blocked arteries or legs were already being planned, and are currently underway.

We decided to call the cells “adipose stromal cells” because we wanted to emphasize that they were acting as a “stroma” (i.e. supportive environment for blood vessels) and not necessarily as stem cells (i.e. cells that convert from an undifferentiated state into mature cell types). In other contexts, these same cells were indeed able to act like “stem cells”, because they could be converted into bone-forming or cartilage-forming cells, thus showing the enormous versatility and value of the cells that reside within our fat tissues.

The answer to the question “Does Human Fat Contain Stem Cells?” is Yes, but these cells cannot be converted into all desired tissues. Instead, they have important supportive functions that can be used to engineer new blood vessels, which is a critical step in organ engineering.

In addition to describing our scientific work, the essay also mentions the vagaries of research, the frustrations I had as a postdoctoral fellow when my results were not turning out as I had expected, and how some predatory private clinics are already marketing “fat-derived stem cell therapies” to paying customers, even though the clinical results are still rather preliminary.

 

For the readers who want to dig a bit deeper, here are some references and links:

 

1. The original paper by Patricia Zuk and colleagues which described the presence of stem cells in human liposuction fat:

Zuk, P et al (2001) “Multilineage Cells from Human Adipose Tissue: Implications for Cell-Based Therapies

 

2. Our work on how the cells can help grow blood vessels by releasing proteins:

Rehman, J et al (2004) “Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells

 

3. Preliminary findings from ongoing clinical studies in which heart attack patients receive infusions of fat derived cells into their hearts to improve heart function and blood flow to the heart:

Houtgraf, J et al (2012) “First Experience in Humans Using Adipose Tissue–Derived Regenerative Cells in the Treatment of Patients With ST-Segment Elevation Myocardial Infarction

 

4. Preliminary results from an ongoing trial using the fat-derived cells in patients with severe blockages of leg arteries:

Bura, A et al (2014) “Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia

 

5. Example of how “cell therapies” (in this case bone marrow cells) are sometimes marketed as “stem cells” but hardly contain any stem cells:

The Largest Cell Therapy Trial in Heart Attack Patients Uses Hardly Any Stem Cells

 

6. The major scientific society devoted to studying the science of fat and its cells as novel therapies is called International Federation for Adipose Therapeutics and Science (IFATS).

I am not kidding, it is I-FATS!

Explore their website if you want to learn about all the exciting new research with fat derived cells.

 

7. Some of our newer work on how bone marrow mesenchymal stem cells turn into fat cells and what role their metabolism plays during this process:

Zhang, Y et al (2013) “Mitochondrial Respiration Regulates Adipogenic Differentiation of Human Mesenchymal Stem Cells

 

ResearchBlogging.org

Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, & Hedrick MH (2001). Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue engineering, 7 (2), 211-28 PMID: 11304456

 

 

 

ResearchBlogging.org
Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, & March KL (2004). Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation, 109 (10), 1292-8 PMID: 14993122

The Largest Cell Therapy Trial in Heart Attack Patients Uses Hardly Any Stem Cells

One of the world’s largest clinical cell therapy trials has begun to enroll 3,000 heart attack patients, some of whom will have bone marrow cells extracted with a needle from their hip and fed into their heart using a catheter in their coronary arteries.

pulse-trace-163708_640

The BAMI trial has €5.9m in funding from the European Commission and will be conducted in ten European countries. Enlisted patients will be randomly assigned into two groups: one group will receive the standard care given to heart attack patients while the other will get an added infusion of bone marrow cells.

A number of studies, including one in the New England Journal of Medicine and another in the European Heart Journal, have suggested that bone marrow cells could be beneficial to patients with heart disease. However, because these studies were too small to work out whether cell infusions affected patients’ survival, they instead focused on the extent of scar formation after a heart attack or the ability of the heart muscle to contract after cell infusion.

One commonly used surrogate measure is the cardiac ejection fraction, which measures the fraction of blood squeezed out by the heart during a contraction. A healthy rate ranges from 55% to 65%. Bone marrow cell infusion has been associated with a modest but statistically significant improvement in heart function. In 2012, a comprehensive analysis of 50 major studies with a combined total of 2,625 heart disease patients showed that cardiac ejection fraction in patients receiving these infusions was 4% higher than in control patients.

While the results were encouraging, the study was a retrospective analysis with patients who had varying treatments and endpoints. There also remain questions over 400 patients included in the analysis from trials showing benefits of bone marrow cell infusions that were conducted by controversial German cardiologist Bodo Strauer, who some scientists have accused of errors in research.

The new large-scale BAMI trial will be able to provide a more definitive answer to the efficacy of bone marrow cell infusions and address the even more important question: does this experimental treatment prolong the lives of heart attack patients?

A hard cell

Despite the impressive target of enrolling 3,000 patients, there is a problem with how the trial is being framed. The underlying premise of why bone marrow cells are thought to improve heart function is that the bone marrow contains stem cells which could potentially regenerate the heart. In media reports, the BAMI trial is portrayed as a study which will test whether stem cells can heal broken hearts, and a press release by Barts Health NHS Trust, which is leading on the trial, described the study as “the largest ever adult stem cell heart attack trial”. But the scientific value of the BAMI trial for stem cell research is questionable.

In 2013, a Swiss study reported the results of treating heart attack patients with bone marrow cells. Not only did the study find no significant improvement of heart function with cell therapy, the researchers also reported that only 1% of the infused cells had clearly defined stem cell characteristics. The vast majority of the infused bone marrow cells were a broad mixture of various cell types, including immune cells such as lymphocytes and monocytes.

Scientific studies have even cast doubts about whether any of the scarce stem cells in bone marrow can convert into beating heart muscle cells. A study published in 2001 suggested bone marrow cells injected into mouse hearts could differentiate into heart muscle cells, but the finding could not be replicated in a subsequent study published in 2004.

If there are so few stem cells in the bone marrow and if the stem cells do not become cardiac cells, then how does one explain the improvements observed in the smaller studies? Researchers have proposed a variety of potential explanations, including the release of growth factors or proteins by bone marrow cells that are independent of their stem cell activity.

The disease machine

The success of modern medicine lies in its ability to isolate causal mechanisms of disease and design therapies which specifically target these mechanisms using rigorous scientific methods. Instead of using nebulous “fever tinctures” or willow bark, physicians now prescribe therapies with well-defined active ingredients such as paracetamol (acetaminophen) or aspirin.

Infusing heterogeneous bone marrow cell mixtures into the hearts of patients seems like a throwback to the era of mysterious herbal extracts containing a variety of active and inactive ingredients.

Even if the BAMI trial succeeds in demonstrating that infusion of bone marrow cell mixtures can prolong lives, then the scientific value of the results will still remain doubtful. We will not know whether the tiny fraction of stem cells contained in the bone marrow was responsible for the improvement or whether this effect was due to one of the many other cell types contained in the cell mixtures.

One could argue that it is irrelevant to know the mechanism of action as long as the infusions can prolong patient survival. But for any evidence-based therapy to succeed, it is essential for physicians to know how to dose or modify the therapy according to the needs of an individual patient. This won’t be possible if we don’t even understand how the treatment works.

We should also consider the impact of a negative result. If the BAMI trial fails to show improved survival, will the lack of efficacy be interpreted as a failure of stem cell therapy for heart disease? An alternate explanation would be that a negative result was due to infusing numerous cell types, most of which were not stem cells.

The ultimate test of a treatment’s efficacy is how it fares in controlled, large-scale trials. And these trials need to be grounded in solid scientific data and provide answers that can be interpreted in the context of scientifically sound mechanisms. The BAMI trial might provide an answer to the question of whether or not bone marrow cell infusions are efficacious in heart disease, but it will not teach us much about stem cells.

Jalees Rehman has received research funding from the National Institutes of Health (NIH).

The Conversation

This article was originally published on The Conversation.
Read the original article.

ResearchBlogging.org

 

 

 

 

Rehman, J. (2013). Bone Marrow Tinctures for Cardiovascular Disease: Lost in Translation Circulation, 127 (19), 1935-1937 DOI: 10.1161/CIRCULATIONAHA.113.002775

 

 
Surder, D., Manka, R., Lo Cicero, V., Moccetti, T., Rufibach, K., Soncin, S., Turchetto, L., Radrizzani, M., Astori, G., Schwitter, J., Erne, P., Zuber, M., Auf der Maur, C., Jamshidi, P., Gaemperli, O., Windecker, S., Moschovitis, A., Wahl, A., Buhler, I., Wyss, C., Kozerke, S., Landmesser, U., Luscher, T., & Corti, R. (2013). Intracoronary Injection of Bone Marrow-Derived Mononuclear Cells Early or Late After Acute Myocardial Infarction: Effects on Global Left Ventricular Function Circulation, 127 (19), 1968-1979 DOI: 10.1161/CIRCULATIONAHA.112.001035

Is It Possible To Have Excess Weight And Still Be Healthy?

Is it possible to be overweight or obese and still be considered healthy? Most physicians advise their patients who are overweight or obese to lose weight because excess weight is a known risk factor for severe chronic diseases such as diabetes, high blood pressure or cardiovascular disease. However, in recent years, a controversy has arisen regarding the actual impact of increased weight on an individual’s life expectancy or risk of suffering from heart attacks. Some researchers argue that being overweight (body mass index between 25 and 30; calculate your body mass index here) or obese (body mass index greater than 30) primarily affects one’s metabolic health and it is the prolonged exposure to metabolic problems that in turn lead to cardiovascular disease or death.

256px-Obesity-waist_circumference.svg

 

According to this view, merely having excess weight is not dangerous. It only becomes a major problem if it causes metabolic problems such as high cholesterol levels, high blood sugar levels and diabetes or high blood pressure. This suggests that there is a weight/health spectrum which includes overweight or obese individuals with normal metabolic parameters who are not yet significantly impacted by the excess weight (“healthy overweight” and “healthy obesity”). The other end of the spectrum includes overweight and obese individuals who also have significant metabolic abnormalities due to the excess weight and these individuals are at a much higher risk for heart disease and death because of the metabolic problems.

Other researchers disagree with this view and propose that all excess weight is harmful, independent of whether the overweight or obese individuals have normal metabolic parameters. To resolve this controversy, researchers at the Mount Sinai Hospital and University of Toronto recently performed a meta-analysis and evaluated the data from major clinical studies comparing the mortality (risk of death) and heart disease (as defined by events such as heart attacks) in normal weight, overweight and obese individuals and grouping them by their metabolic health.

The study was recently published in the Annals of Internal Medicine (2014) as “Are Metabolically Healthy Overweight and Obesity Benign Conditions?: A Systematic Review and Meta-analysis” and provided data on six groups of individuals: 1) metabolically healthy and normal weight, 2) metabolically healthy and overweight, 3) metabolically healthy and obese, 4) metabolically unhealthy and normal weight, 5) metabolically unhealthy and overweight and 6) metabolically unhealthy and obese. The researchers could only include studies which had measured metabolic health (normal blood sugar, blood pressure, cholesterol, etc.) alongside with weight.

The first important finding was that metabolically healthy overweight individuals did NOT have a significantly higher risk of death and cardiovascular events when compared to metabolically healthy normal weight individuals. The researchers then analyzed the risk profile of the metabolically healthy obese individuals and found that their risk was 1.19-fold higher than the normal weight counterparts, but this slight increase in risk was not statistically significant. The confidence intervals were 0.98 to 1.38 and for this finding to be statistically significant, the lower confidence interval would have needed to be higher than 1.0 instead of 0.98.

The researchers then decided to exclude studies which did not provide at least 10 years of follow up data on the enrolled subjects. This new rule excluded studies which had shown no significant impact of obesity on survival. When the researchers now re-analyzed their data after the exclusions, they found that metabolically healthy obese individuals did have a statistically significant higher risk! Metabolically healthy obese subjects had a 1.24-fold higher risk, with a confidence interval of 1.02 to 1.55. The lower confidence interval was now a tick higher than the 1.0 threshold and thus statistically significant.

Another important finding was that among metabolically unhealthy individuals, all three groups (normal weight, overweight, obese) had a similar risk profile. Metabolically unhealthy normal weight subjects had a three-fold higher than metabolically healthy normal weight individuals. The metabolically unhealthy overweight and obese groups also had a roughly three—fold higher risk when compared to metabolically healthy counterparts. This means that metabolic parameters are far more important as predictors of cardiovascular health than just weight (compare the rather small 1.24-fold higher risk with the 3-fold higher risk).

Unfortunately, the authors of the study did not provide a comprehensive discussion of these findings. Instead, they conclude that there is no “healthy obesity” and suggest that all excess weight is bad, even if one is metabolically healthy. The discussion section of the paper glosses over the important finding that metabolically healthy overweight individuals do not have a higher risk. They also do not emphasize that even the purported effects of obesity in metabolically healthy individuals were only marginally significant. The editorial accompanying the paper is even more biased and carries the definitive title “ The Myth of Healthy Obesity”. “Myth” is a rather strong word considering the rather small impact of the individuals’ weight on their overall risk.

 

Some press reports also went along with the skewed interpretation presented by the study authors and the editorial.

 

A BBC article describing the results stated:

 

It has been argued that being overweight does not necessarily imply health risks if individuals remain healthy in other ways.

The research, published in Annals of Internal Medicine, contradicts this idea.

 

This BBC article conflates the terms overweight and obese, ignoring the fact that the study showed that metabolically healthy overweight individuals actually do not have a higher risk.

 

The New York Times blog cited a study author:

 

“The message here is pretty clear,” said the lead author, Dr. Caroline K. Kramer, a researcher at the University of Toronto. “The results are very consistent. It’s not O.K. to be obese. There is no such thing as healthy obesity.”

 

Suggesting that the message is “pretty clear” is somewhat overreaching. One of the key problems with using this meta-analysis to reach definitive conclusions about “healthy overweight” or “healthy obesity” is that the study authors and editorial equate increased risk with unhealthy. Definitions of what constitutes “health” or “disease” should be based on scientific parameters (biomarkers in the blood, functional assessments of cardiovascular health, etc.) and not just on increased risk. Men have an increased risk of dying from cardiovascular disease than women. Does this mean that being a healthy man is a myth? Another major weakness of the study was that there was no data included on regular exercise. Numerous studies have shown that regular exercise reduces the risk of cardiovascular events. It is quite possible that the mild increase in cardiovascular risk in the metabolically healthy obese group may be due, in part, to lower levels of exercise.

This study does not prove that healthy obesity is a “myth”. Overweight individuals with normal metabolic health do not yet have a significant elevation in their cardiovascular risk. At this stage, one can indeed be “overweight” as defined by one’s body mass index but still be considered “healthy” as long as all the other metabolic parameters are within the normal ranges and one abides by the general health recommendations such as avoiding tobacco, exercising regularly. If an overweight person progresses to becoming obese, he or she may be at slightly higher risk for cardiovascular events even if their metabolic health remains intact. The important take-home message from this study is that while obesity itself can be a risk factor for increased risk of cardiovascular disease, it is far more important to ensure metabolic health by controlling cholesterol levels, blood pressure, preventing diabetes and important additional interventions such as encouraging regular exercise instead of just focusing on an individual’s weight.

 

ResearchBlogging.org

Kramer CK, Zinman B, & Retnakaran R (2013). Are metabolically healthy overweight and obesity benign conditions?: A systematic review and meta-analysis. Annals of internal medicine, 159 (11), 758-69 PMID: 24297192

Prescribing Male Contraceptives: Ethical Considerations

There have been a series of interesting comments on Twitter about the ethical dilemma involved in prescribing male contraceptives, prompted by my recent essay for Aeon Magazine. Here is the relevant excerpt from the Aeon essay:

The discontinuation of the WHO/CONRAD trial was a major setback in bringing male contraceptives to the market. It also raised difficult ethical questions about how to evaluate side effects in male contraceptive trials. Since all medications are bound to exhibit some side effects, what side effects should be sufficient to halt a trial? Female contraceptives have been associated with breakthrough bleeding, mood changes, increased risk of blood-clot formation, as well as other side effects. Why should we set a different bar for male contraceptives?

The twist here is that female contraceptives prevent unintended pregnancies in the person actually taking the contraceptive. Since a pregnancy can cause some women significant health problems, the risk of contraceptive side effects can be offset by the benefit of avoiding an unintended pregnancy. However, men do not directly experience any of the health risks of pregnancy — their female partners do. Thus it becomes more difficult, ethically, to justify the side effects of hormonal contraceptives in men.

The usage of female hormonal contraceptives has been associated with a higher risk of blood clot formation, but pregnancies carry an even higher risk for blood clot formation and other medical complications. Doctors can make the reasonable argument that the benefits of a contraceptive outweighs the risks for their patient – and prescribe it.

The situation is a bit different when it comes to male contraceptives. I will try to illustrate this with a hypothetical scenario, in which there is a male contraceptive on the market.

Mr. Solo has an appointment with his family physician Dr. Crusher, who informs him that he is in perfect health. Mr. Solo then asks if he could receive a prescription for the newly approved male contraceptive. Dr. Crusher explains to him that this new male contraceptive has a 1% risk of causing side effects such as major depression.

Mr. Solo responds that he and his partner Ms. Amidala-Skywalker have decided not to get pregnant – at least not in the near future. Mr. Solo is very concerned about Ms. Amidala-Skywalker’s family history because her mother had a very difficult pregnancy and even died during childbirth. Ms. Amidala-Skywalker is not as worried about her pregnancy as Mr. Solo is and she does not want either of them to be permanently sterilized, but she and Mr. Solo have agreed to at least postpone having children for a few years. Ms. Amidala-Skywalker has been on an oral hormonal contraceptive for the past years.

Just prior to seeing Dr. Crusher, Mr. Solo was browsing some reading material in the waiting room and came across the magazine “Women’s Health” in which he read that women who regularly use hormonal contraceptives are at a higher risk for blood clot formations and maybe even strokes. All these years, his partner has been taking hormonal contraceptives and exposing herself to this higher risk. Since they both agreed not to have children at this point in time, Mr. Solo feels that it would only be fair if he now started using a male contraceptive and gave his partner a break. He does not mind the 1% risk of side effects, after all, she has been taking the “pill” for so many years and he believes that a true partnership is based on an equitable sharing of risks.

Dr. Crusher tries to dampen his enthusiasm. She says that she respects his desire to be fair towards his partner and she also wants to be supportive of their decision not to have a baby. She understands their concerns about the health risks that Ms. Amidala-Skywalker would face if she became pregnant.

However, Dr. Crusher explains to Mr. Solo that she has a doctor-patient relationship only with him – not with his partner. Dr. Crusher feels comfortable prescribing a medication for a patient when the patient derives a net health benefit from it. She agrees that Ms. Amidala-Skywalker’s well-being is important, but the health of Mr. Solo’s partner (or of any other family member) is not her primary concern. She does not see how she can justify subjecting him to a 1% risk of side effects and declines to prescribe it.

 

I am not suggesting that this is the best way or the only way to analyze the ethics of prescribing a male contraceptive pill which has some side effects. Not everyone has to agree with Dr. Crusher’s choice to focus only on the risks and benefits for her patient and to ignore the greater good or the medical benefits for his partner. These are the kinds of ethical dilemmas that physicians have to grapple with when it comes to addressing the issue of side effects associated with male contraceptives. Concerns about such ethical dilemmas and potential legal repercussions can act as deterrents for physicians and pharmaceutical companies.

But this does not mean that we should abandon the quest for male contraceptives. Doctors perform cosmetic surgeries without any medical benefits, despite the fact that some of the procedures can result in major complications. Physicians prescribe Viagra for men without a clearly defined medical indication even though Viagra can cause significant side effects.

If patients, healthcare professionals and the general public can find ways to ethically justify the risks of cosmetic surgery, it should be possible to resolve the dilemmas surrounding the prescription of male contraceptives. Instead of just maintaining the status quo in which women shoulder most of the burden and responsibility of contraception, we have to educate ourselves about alternatives and address the scientific, medical, ethical, political and cultural obstacles that prevent the development of newer male contraceptives.

//storify.com/jalees_rehman/ethics-of-male-contraception.js[View the story “The Ethics of Prescribing Male Contraceptives” on Storify]

Male Contraception

My recent essay for Aeon Magazine discusses the development of newer male contraceptives which may offer a degree of reliability and reversibility similar to that of female contraceptives. Male hormonal contraceptives have been tested in small clinical trials since the 1970s, but none of them have been approved for general use. Research funding agencies and pharmaceutical companies need to make the necessary investments and forge partnerships so that the stalled research in male contraception can be revitalized.

It is a fascinating area of research and I hope you enjoy reading  the Aeon Magazine essay.

 

I also encourage you to also read some of the original references to learn more about the research. Here is a list of key references and a couple of informative websites:

References

CONRAD (2011). “Male Hormonal Contraceptive Trial Ending Early

Gifford, B. (2011). “The Revolutionary New Birth Control Method for Men.” WIRED

Glasier, A. F., R. Anakwe, et al. (2000). “Would women trust their partners to use a male pill?Human Reproduction 15(3): 646-649.

Heinemann, K., F. Saad, et al. (2005). “Attitudes toward male fertility control: results of a multinational survey on four continentsHuman Reproduction 20(2): 549-556.

Lidegaard, O., E. Lokkegaard, et al. (2012). “Thrombotic stroke and myocardial infarction with hormonal contraceptionNew England Journal of Medicine 366(24): 2257-2266.

Matzuk, M. M., M. R. McKeown, et al. (2012). “Small-molecule inhibition of BRDT for male contraceptionCell 150(4): 673-684.

Mruk, D. D., C. H. Wong, et al. (2006). “A male contraceptive targeting germ cell adhesionNature Medicine 12(11): 1323-1328.

Nieschlag, E. (2010). “Clinical trials in male hormonal contraceptionContraception 82(5): 457-470.

Nieschlag, E. (2013). “Hormonal male contraception: end of a dream or start of a new era?Endocrine 43(3): 535-538.

Trussell, J. (2011). “Contraceptive failure in the United StatesContraception 83(5): 397-404.

Youssef, H. (1993). “The history of the condomJournal of the Royal Society of Medicine 86(4): 226-228. (PDF)

 

Websites:

Parsemus Foundation:  http://www.parsemusfoundation.org/vasalgel-home/

Male Contraception Information Project: http://www.newmalecontraception.org/

Recent Study Raises Questions About Using Adult Stem Cells for Chronic Heart Disease

A recent clinical study (POSEIDON Randomized Trial) investigated the effects of transplanting bone marrow derived adult stem cells into patients with known heart disease. The results were presented at the 2012 American Heart Association (AHA) meeting in Los Angeles and also published in the article “Comparison of Allogeneic vs Autologous Bone Marrow–Derived Mesenchymal Stem Cells Delivered by Transendocardial Injection in Patients With Ischemic Cardiomyopathy: The POSEIDON Randomized Trial“. The article by Dr. Joshua Hare and colleagues appeared in the online edition of the Journal of the American Medical Association on November 6, 2012.

The primary goal of the study was to compare whether adult stem cells from other donors (allogeneic cells) are just as safe as the stem cells derived from the patients’ own bone marrow (autologous cells). Thirty patients with a prior heart attack and reduced cardiac function received either allogeneic or autologous cells. The injected cells were mesenchymal stem cells (MSCs), an adult stem cell type that resides within the bone marrow and primarily gives rise to bone, fat or cartilage tissue. MSCs are quite distinct from hematopoietic stem cells (HSCs) which are also present in the bone marrow but give rise to blood cells. In the POSEIDON study, patients underwent a cardiac catheterization and the MSCs were directly injected into the heart muscle. Various measurements of safety and cardiac function were performed before and up to one year after the cell injection.

The good news is that in terms of safety, there was no significant difference when either autologous or allogeneic MSCs were used. Within the first month after the cell injection, only one patient in each group was hospitalized for what may have been a major treatment related side effect. In the long-run, the number of adverse events was very similar in both groups. The implication of this finding is potentially significant. It suggests that one can use off-the-shelf adult stem cells from a healthy donor to treat a patient with heart disease. This is much more practical than having to isolate the bone marrow from a patient and wait for 4-8 weeks to expand his or her own bone marrow stem cells.

The disappointing news from this study is that one year following the stem cell injection, there was minimal improvement in the cardiac function of the patients. The ejection fraction of the heart is an indicator of how well the heart contracts and the normal range for healthy patients is roughly 55-60%. In the current study, patients who received allogeneic cells started out with an average ejection fraction of 27.9% and the value increased to 29.5% one year after the cell injection. The patients who received autologous cells had a mean ejection fraction of 26.2% prior to the cell transplantation and a mean ejection fraction of 28.5% one year after the stem cell therapy. In both groups, the improvement was minimal and not statistically significant. A different measure of the functional capacity of the heart is the assessment of the peak oxygen consumption. This measurement correlates well with the survival of a patient and is also used to help decide if a patient needs a heart transplant. There was no significant change in the peak oxygen consumption in either of the two groups of patients, one year after the treatment. Some other measures did indicate a minor improvement, such as the reduction of the heart attack scar size in both patient groups but this was apparently not enough to improve the ejection fraction or oxygen consumption.

One of the key issues in interpreting the results is the fact that there was no placebo control group. The enrollment in a research study and the cell injection procedure itself could have contributed to minor non-specific or placebo benefits that were unrelated to the stem cell treatments. One odd finding was that the patient sub-group which showed a statistically significant improvement in ejection fraction was the group which received the least stem cells. If the observed minor benefits were indeed the result of the injected cells turning into cardiac cells, one would expect that more cells would lead to greater functional improvement. The efficacy of the lowest number of cells points to non-specific effects from the cell injection or to an unknown mechanism by which the injected cells activate cardiac repair without necessarily becoming cardiac cells themselves.

The results of this study highlight some key problems with current attempts to use adult stem cells in cardiovascular patients. Many studies have shown that adult stem cells have a very limited differentiation potential and that they do not really turn into beating, functional heart cells. Especially in patients with established, long-standing heart disease, the utility of adult stem cells may be very limited. The damage that the heart of these patients has suffered is probably so severe that they need stem cells which can truly regenerate the heart. Examples of such regenerative stem cells are embryonic stem cells or induced pluripotent stem cells which have a very broad differentiation potential. Cardiac stem cells, which exist in very low numbers within the heart itself, are also able to become functional heart cells. Each of these three cell types is challenging to use in patients, which is why many current studies have resorted to using the more convenient adult bone marrow stem cells.

Human embryonic stem cells can develop into functional heart cells, but there have been numerous ethical and regulatory concerns about using them. Induced pluripotent stem cells (iPSCs) appear to have the capacity to become functional heart cells, similar to what has been observed for human embryonic stem cells. However, iPSCs were only discovered six years ago and we still have a lot to learn more about how they work. Lastly, cardiac stem cells are very promising but isolating them from the heart requires an additional biopsy procedure which can also carry some risks for the patients. Hopefully, the fact that adult bone marrow stem cells showed only minimal benefits in the POSEIDON study will encourage researchers to use these alternate stem cells (even if they are challenging to use) instead of adult bone marrow stem cells for future studies in patients with chronic heart disease.

One factor that makes it difficult to interpret the POSEIDON trial is the lack of a placebo control group. This is a major problem for many stem cell studies, because it is not easy to ethically justify a placebo group for invasive procedures such as a stem cell implantation. The placebo patients would also have to receive a cardiac catheterization and injections into the heart tissue, but instead of stem cells, the injections would just contain a cell-free liquid solution. Scientifically, such a placebo control group is necessary to determine whether the stem cells are effective, but this scientific need has to be weighed against the ethics of a “placebo” heart catheterization. Even if one were to ethically justify a “placebo” heart catheterization, it may not be easy to recruit volunteer patients for the study if they knew that they had a significant chance of receiving “empty” injections into their heart muscle.

There is one ongoing study which is very similar in design to the POSEIDON trial and it does contain a placebo group: The TAC-HFT trial. The results of this trial are not yet available, but they may have a major impact on whether or not bone marrow stem cells have a clinical future. If the TAC-HFT trial shows that the bone marrow stem cell treatment for patients with chronic heart disease has no benefits or only minor benefits when compared to the placebo group, it will become increasingly difficult to justify the use of these cells in heart patients.

In summary, the POSEIDON trial has shown that treating chronic heart disease patients with bone marrow derived stem cells is not yet ready for prime time. Bone marrow cells from strangers may be just as safe as one’s own cells, but if bone marrow stem cells are not very effective for treating chronic heart disease, than it may just be a moot point.

 

Image credit: Wikipedia